(ischemia) better than ~85% of the time!

By Mike Darwin

Ischemia: The Problem of “Long Down Time”

 Almost every cryonicist I’ve ever spoken with envisions his cryopreservation will occur under ideal circumstances. He will be diagnosed with  some vague and ill defined terminal illness, bravely decide to end futile treatment and then enter hospice with a team of skilled and caring cryonics personnel at his bedside. He will nap, read, watch TV, and then, near the end, nod off surrounded by loved ones as the cryonics personnel hover nearby. This may not be the most attractive picture in any absolute sense, but it is certainly as reassuring a one as it is possible to find in contemporary cryonics. And while many, or even most cryonicists may find this scenario credible, much of the rest world doesn’t.

 Figure 10:  Approximate U.S. distribution of predictable deaths by cause based on 2004 data. Note that ~57% of all deaths occur sufficiently suddenly, or under circumstances such as accidents, which preclude standby or other cryonics stabilization measures. Chart derived from data: [National Vital Statistics Report, Volume 53, Number 5 (October 2004)]. This data may be compared to the data in Figure 10 to see how closely the US national incidence of sudden and unpredictable death map that of Alcor’s experience (Figure 11).

One likely reason for the scarcity of biomedical people involved in cryonics is that their actual, day-to-day experience is at sharp odds with the scenario I’ve just laid out above.  In countless hours of both focused and casual conversations with such individuals, what emerges is a sense of incredulity about the reversibility of the damage these professional and technical people witness as a part of their duties caring for the very old, and the critically ill dying; not to mention that large fraction of people who die suddenly and without warning, end up as DOAs in the emergency department or coroner’s cases. Regardless of whether their opinions prove the valid ones, we are clearly failing to communicate to them and to the community at large, an experience of cryonics which is not so biomedically adverse.

To do that, it is first necessary to move beyond  anyone’s scenarios or suppositions and evaluate the reality of what is actually happening to the patients we cryopreserve. That turns out to be a hard thing to determine with any degree of precision, because none of the cryonics organizations maintain any kind of statistical database on their members’ cryopreservations. How many cryopatients have dementia? How many were autopsied? What is the mean ischemic time from cardiac arrest to the start of cardiopulmonary support (CPS)? How many patients have ischemic times of 2-5 minutes, 5-10 minutes, 15-30 minutes, 12 hours, 14 hours, 5 days? What is the mean age at cryopreservation? [Absence of data on this last question I find particularly amusing in a group of people supposedly preoccupied with longevity and "life extension": how long are they living, on average?]  There is currently no way to tell.

There is not even any way to determine the age, gender, or any of dozens of other potentially critically important demographic details that are, or could be vital in assuring quality cryopreservations, reducing ischemic times, or reducing known iatrogenenic events. A concern of mine for onto three decades now is that we have no way to spot adverse epidemiological events that might be associated with our unique dietary supplement or other lifestyle practices. Perhaps most incredibly, there are no written criteria, however arbitrary, to assign any degree of quality, or lack thereof, to the cryopreservation a given patient has received (let alone that a given Cryonics Organization (CO) provides, on average). This had lead to what has become known as “the last one is always the best one” to date rating system, wherein each case that is not either an existential or an iatrogenic disaster, is pronounced by the staff who carried it out as, “the best case we’ve done so far!”

We cryonicists may be in some kind of willful, data free fog about what our situation is, however, it’s a safe bet to assume that most of the rest of the world, based on their own professional and personal experiences, are not so ignorant. The first step towards a solution is to understand the scope and severity of the problem by getting reliable numbers. While that is not easy to do, the Alcor Life Extension Foundation does maintain a crude, if incomplete accounting of all the patients they have placed into cryopreservation: http://www.alcor.org/cases.html. A cursory analysis of this yields the following breakdown. Even basic data such as cause and mode of death are missing from ~20 of the cases listed there – these have necessarily been excluded from the analysis below.

Figure 11: A major hurdle to evaluating quality in cryonics operations is the lack of any outcomes (e.g., reanimation followed by evaluation) or of any surrogate markers or scoring systems to serve as evaluation tools to determine not only the quality of cryopreservation care being given, but also the objective neurocognitive status of the patients when they enter cryopreservation. For the purposes of this analysis very crude criteria were used to assess the quality of the patient as a finished product at the end of cryopreservation. These were normothermic ischemic time between cardiac arrest and the start of CPS, catastrophic peri-arrest brain injury such as an intracranial bleed followed by prolonged cerebral no-flow before pronouncement of medico-legal death, very long warm ischemic times (> or = to 12 hours) and autopsy.

Using the criterion of “minimal ischemia” (≤15 minutes)[1], 48% of Alcor’s patients are cryopreserved under these conditions (Figure 10).  Thirty-nine percent of their patients suffer long ischemic periods of 6-12 hours or more (mostly as a result of SCA and UDA); and 13% suffer very long periods of ischemia (> or = to 24 hours) which are not currently preventable, or which conclude in autopsy prior to cryopreservation.  Put more cogently, you have less than a 50% chance of being cryopreserved (with Alcor) under conditions of minimal ischemia. While this number is discouraging, it is spectacular when compared to the Cryonics Institute, where it is somewhere in the low single digits.

Figure 12: The graph above is the same as in Figure 11, with the difference being that the losses have been expanded to include those that would be expected if the population wide incidence of end-stage, GDS-7 dementias were imposed on all the groups. The result is that percentage of patients who might reasonably be expected to have both minimal ischemia and no pre-cryopreservation GDS-7 dementias drops to just 26%.

But once again, these numbers are misleading if the criterion is cryopreservation under minimal ischemia conditions, because they do not take into account the number of patients who enter cryopreservation with dementia, or severe brain injury due to stroke, other neurovascular disease, or massive head trauma. If only dementia, at the current incidence for the general population is factored into the analysis, then the picture becomes considerably more bleak, as can be seen in Figure 10, with only 26% of  Alcor cryonics patients being preserved with relatively intact brains under reasonably good conditions.[2]

Impact of the BDDs on the Likely Survival of Personhood

Figure 13: The effect of advanced Alzheimer’s Disease on the macroscopic appearance of the brain is evident when coronally sectioned brains from an AD (R) patient and a healthy person in their mid-20s (L) are compared side by side.

Deaths from AD are typically deaths from end-stage AD, which usually implies severe global destruction of both cerebral hemispheres (Figures 13 & 14) on both a macro and microscopic level. Death due to AD is a prolonged process (~8 years from diagnosis to death), and the neurological deterioration that occurs as the disease progresses is often scored using the global deterioration scale (GDS) of primary degenerative dementias, which ranges from 1 (least) to 7 (worst) in severity. GDS scores in excess of 5 are associated with major loss of macro- and micro-scale brain structure and will be assumed here to represent serious compromises to, or the destruction of personhood.

Figure 14: The histological appearance of the brain in AD is shown in panels b and c above. In many areas of the brain there is virtually complete loss of the neuropil; the synaptic weave that interconnects neurons which can be seen in its normal state in c, the panel at the far left. The majority of the neurons and many of their supporting glial cells have died and been scavenged by macrophages and histiocyytes.  There are abundant deposits of proteinaceous plaque containing the  neurotoxin protein beta amyloid neurofibrillary tangles which are the remnants of neuronal long processes such as axons and dendrites. The extent and uniformity of the changes seen above varies from patient to patient during the course of the disease, but becomes increasingly uniform throughout both hemispheres of the cortex the longer the patient survives with a GDS score of 7 (end stage dementia).

A Deanimation Warning Device?

Figure 15: The medical imager as a deanimation prediction device?

 In his 1939 science fiction story Life-Line,” Robert Heinlein envisions a device that can predict, with considerable precision, when a person is going to die. While none of us cryonicists wants to die, most of us could certainly profit from knowing when we are going to deanimate. Better still would be also finding out how to postpone our cold dip in liquid nitrogen for a while, if it was possible to do so.

Many cryonicists will be familiar with this graph of Ray Kurzweil’s showing the impending arrival of the singularity (Figure 16).

Figure 16: Ray Kurzweil’s graph showing the exponential increase in neuro-image reconstruction which has occurred largely as a function of the exponential growth in computing capacity since 1970.

Well, if you are a cryonicist, I’m here to tell you that insofar as non/minimally-invasive medical imaging is concerned, the singularity is here.

From the earliest days of medicine physicians have desired one thing almost above all others and that is to possess the power to peer into their patients bodies and observe the goings on there. Since the discovery of x-rays by Wilhelm Conrad Röntgen in 1895 (Crane, 1964) there has been steady progress towards the satisfaction of that desire. The development of contrast media, endoscopy, computerized axial tomography (CAT or CT) scanning and magnetic resonance imaging (MRI) scanning have allowed increasingly exact and impressive images of the interior of the living body to be made.

However, a number of serious limitations have, and to a great extent still do prevent the full realization of the physician’s idealized desire to see inside his patients at will. Those barriers are field, dimensionality and point of view, as well as resolution, color, contrast and the dollar cost of the imaging.

In the case of CT and MRI those barriers have been breached to such a degree that it is now possible for cryonicists to be able to determine with a very high degree of accuracy and precision both of what and when they are going to experience medico-legal death. A corollary of this is that in many cases it will be possible for them to avoid what would have otherwise been an unavoidable very long period of ischemia and quite likely a medico-legal autopsy  as well.

End of Part 2

How to avoid autopsy and long ‘down-time’

(ischemia) better than ~85% of the time!

By Mike Darwin

It’s easy to concentrate on the biggest and most obvious reason that cryonics hasn’t attracted wider acceptance, principally the fact that it doesn’t work “yet” and it will be a long time before we know if does. But there’s a clue to another capital reason for its slow adoption which is to be found in the failure of cryonics to attract much enthusiasm or activism within its own ranks. Why is this?

I believe a central reason for this failure is that cryonics, even as it is currently configured and accepted by those who embrace it, performs dismally. Everyone seriously involved with cryonics is painfully aware, either consciously or subconsciously, that cryonics is at least a two tier lottery. Sure, everyone knows that we’re taking a “chance” on being recovered in the future by being cryopreserved in the first place. But to even get to that round of the lottery, you have to get cryopreserved, and it would seem material whether or not you are cryopreserved well.

For some, perhaps cryonics is a ritual exercise. As long as there are remains, a freezer, someone to take the money and hang picture on the wall, then you have a chance; and all chances are created equal. Their position seems to be same as that of the millions of lottery ticket holders before the winning number is announced: we all have the same chance at the prize. If that’s your attitude, you can stop reading this right now, there’s nothing more here to interest you – not even in terms of idle entertainment value, because this discussion, from here on out is deadly serious, and brass tacks practical.

 Figure 1: The autopsy rate has declined by half in the United State between 1972 and 2007, although it has shown a slight increase since these data were collected. Source: http://www.cdc.gov/nchs/data/databriefs/db67.pdf

As Figure 1 shows, the autopsy rate, which can serve as the ultimate, population wide indicator of a very bad cryopreservation,  constituted 8.5% of all deaths in 2007. That percentage has risen slightly since then and is now at ~ 9%. The situation isn’t quite as grim as it might first appear if you break down the reasons for autopsy and note that 55.4% of autopsies were conducted as a result of deaths due to “external causes,” which means suicide, accident or homicide. If you think you are in a “lower risk” category for these, you may  be right, in which your case your risk may be fractionally smaller. And of course, not all of these autopsies were state mandated: some were requested by the next of kin, or even the decedents themselves. Still, 9% seems a reasonable, overall unavoidable loss number currently confronting cryonicists given the culture we inhabit.

Figure 2: Since the first man was cryopreserved in 1967, the demographics of autopsy have shifted increasingly from the aged to those in younger population cohorts. Source: http://www.cdc.gov/nchs/data/databriefs/db67.pdf

If the age distribution of autopsies in the US is examined, the picture gets even more uplifting if you are, or you expect to live in into old age (which is, incidentally, medically defined as 65 years of age, or older). In this age group, the incidence of autopsy has declined dramatically from 37% of all postmortems since 1972,  near the time cryonics began, to only 17% as of 2007.

However autopsy is only one of a number of factors that can and do interfere with  cryonicists achieving “good,” or even “acceptable,”  (forget  ideal), cryopreservations. The other three factors which loom large are sudden cardiac arrest (SCA), unexpected death (UD, which is different than SCA) and brain destroying diseases ( BDDs, or dementias). While Alzheimer’s Disease is the most common of the BDDs, there are others such as Pick’s, Lewy Body, Parkinson’s and the vascular dementias, which together account for 20-30% of all age-associated BDDs.

Brain Destroying Diseases (Dementias)

Autopsy is only one of a number of factors that can and do interfere with  cryonicists achieving “good,” or even “acceptable,”  (forget  ideal), cryopreservations. The other three factors which loom large are sudden cardiac arrest (SCA), unexpected death (UD, which is different than SCA) and brain destroying diseases (BDDs).

 Figure 3: Incidence of dementias as a percentage of all cause mortality in males, females and the United States population as a whole. Prepared from data in the National Vital Statistics Report Volume 59, Number 10 December 7, 2011Deaths: Final Data for 2008: 2008http://www.cdc.gov/nchs/data/nvsr/nvsr59/nvsr59_10.pdf

 Currently, the BDDs in aggregate (including catastrophic stroke) account for ~3.2% of all deaths in the US (Figure 3). However, insofar as cryonicists are concerned, this number is likely to be misleadingly low, because most cryonicists enter cryopreservation at or after age 65, the point at which the incidence of BDDs begin to climb exponentially. (Evans DA, 1990) This number is expected to, and in fact is exploding as a consequence of both the demographic shift due to an aging population in the West and increasingly longer life spans (Figure 4).

 Figure 4: The large increase in Alzheimer’s Disease as a cause of death in the United States is largely a function of the increasing average age of the population and the survival of many additional individuals into advanced old age. Source: http://www.alz.org/downloads/Facts_Figures_2012.pdf

 Figure 5: A breakdown of dementias by type shows that Alzheimer’s Disease accounts for 47% of the total as the sole cause of the dementia and is a major contributing factor in another 28% making it by far the most common pathological mechanism in play as the cause of dementia in the elderly.  [S. Seshadri, S, Wolf, PA, Beiser, A,  Au, RU, McNulty, K, White,R, et al. Lifetime risk of dementia and Alzheimer's disease: The impact of mortality on risk estimates in the Framingham Study. Neurology, 49:1498-1504,1997.]

 Figure 6: Incidence of Alzheimer’s Disease by age cohort in the US population as of 1988.[ Evans D, et. al. Prevalence of Alzheimer' s Disease in a community population of older persons. JAMA, 262:18;2551-6, 1989.]

In the 74-84 age cohort, 19% of that population has AD (exclusive of other dementias) and in those individuals over the age of 85, the diagnosed incidence is 47%. These numbers are almost certainly low, because many of the elderly are who are institutionalized for falls, or other issues not ostensibly related to primary brain disease, go on to develop brain disease in an institutional setting and ultimately have listed as their causes of death, pneumonia, urosespsis, sepsis  secondary to decubitus ulcers, or other causes that escape epidemiological surveillance for AD. Currently, AD is responsible for 2.8% of deaths in white males men aged 65  or older and 4.7% of white males who are 85 years of age, or older. These numbers are expected to triple by the year 2050.

 Figure 7: The incidence of Alzheimer’s Disease rises roughly exponentially with age such that over 1,100 people out of 100,000 aged 86 or older have the disease.

When cryonics was launched in the mid-1960s the problem of BDDs as a threat to the workability of cryonics was not even considered.  In 1967, the year the first man was cryopreserved, the average life expectancy in the US was ~70 years and the problem of dementias was a fraction of what it currently is.  Additionally, comparatively little was known about the pathophysiology of the BDDs at that time, and there was little or no awareness within the cryonics community of their potential to degrade or altogether destroy personal identity, perhaps even years in advance of the pronouncement of medico-legal death. The problem of BDDs and of age-associated destruction of the brain is arguably the foremost biomedical obstacle confronting cryonics in the long term, and it is for this reason that I will return to this topic again later in this article in the context of discussing its early detection, with a brief discussion of treatment, and ultimately, definitive interventions to halt and reverse it.

Figure 8: The Siemens Biograph mCT PET is a positron emission tomography/computed tomography (PET•CT) scanner that enables precise measurement of metabolic processes and data quantification, including the assessment of neurological disease and malignant tissues (resolution and molecular characterization of neoplasms as small 3 mm in diameter). The device can provide quantitative measurements of brain beta amyloid protein burden.

For now, I will note that because AD is by far the most common of the BDDs and because it has a unique pathophysiological feature, a remarkable advance in early diagnosis via noninvasive  computerized tomography (CT) and positron emission tomography (PET) imaging has recently become clinical available. Beta amyloid is the protein found in the plaques characteristic of AD, and there has been intensive research over the past decade to identify radiolabeled tracer compounds that will safely cross the blood brain barrier (BBB) and bind to both beta amyloid and tau proteins. (Barrio 2008), (Black, 2004)  In February of this year, the US FDA approved the Siemens Biograph mCT, a positron emission tomography-computed tomography (PET-CT) scanner capable of not only detecting, but of quantifying  amyloid in the brain. The Biograph mCT has been very well received, and within the space of a few months the machines have appeared in most major cities in the US. The Biograph mCT in conjunction with the recently developed FDDNP, (2-(1-6-[(2-[F-18] fluoroethyl)(methyl)amino]-2-naphthylethylidene) malonitrile) tracer allows for calculation of total brain amyloid burden (Wang, 2004) and visualization of discrete amyloid containing lesions as small as ~ 3 mm in diameter (tracers for tau protein, the other primary pathological protein in AD are currently in the pipeline for FDA approval).

 Figure 9: Top: PET scan of beta amyloid deposits in the brain of a patient with early moderate Alzheimer’s disease appear in red in the image above. The beta amyloid deposits are concentrated, as expected, in the frontal and prefrontal cortices as well as in the hippocampus. Bottom: Beta amyloid distribution in the brain of a patient with early moderate AD (L) versus normal control (R). One important consequence of this imaging is the growing realization of the global range of AD’s impact on the brain. As recently as a decade ago it was believed that the destruction of brain tissues was confined largely to the hippocampus and the prefrontal cortex, especially early in the disease. It is now understood that the histological destruction of AD is widespread and that during the end-stage of the disease few if any areas can be expected to be spared.

Very early detection of AD may turn out to be critical to achieving effective treatment, or even slowing progression of the disease, since significant beta amyloid and tau deposition seem to promote ongoing inflammation and interfere with putative therapeutic drugs. A good example of this is the recent fate (Vellas, 2010) of the investigational drug  tarenflurbil ((R)-flurbiprofen ) which inhibits gamma-secretase, the enzyme that produces beta amyloid AB-42, the species of beta-amyloid that forms fibrillary plaques. (Black, 2008) Unfortunately, the drug does nothing to remove existing existing AB42 deposits, which presumably continue to exert their neuron killing and pro-inflammatory actions.

(R)-flurbiprofen is highly effective in animal models of very early AD and the drug showed significant promise in Phase I & II clinical trials. However, development of (R)-flurbiprofen was dropped when it became apparent in Phase III trials that the drug would likely only be effective in a clinical setting if it its administration was begun before clinical signs of AD developed; in other words, when beta amyloid levels were very low and would be detectable only by testing cerebrospinal fluid or, now with sensitive CT molecular imaging techniques involving the screening of subpopulations of healthy individuals at risk.

This kind of effort and application of technology and pharmacotherapy may not profitable for pharmaceutical companies, but that does not mean that it would be be worthwhile for us cryonicists. (R)-flurbiprofen  is a close chemical relative of the OTC NSAID ibuprofen and it is a metabolite of the prescription NSAID flubiprofen.  (R)-flurbiprofen  is an enantiomer of flurbiprofen (~ 5%  of (L) flubiprofen is metabolized into (R) flubiprofen by the liver after ingestion) which is completely inactive as  a COX inhibitor, and is thereby free of the anti-COX side effects associated with NSAIDS.  Despite it’s lack of both COX-I and COX-II activity, the drug does have strong anti-inflammatory activity by acting through inhibition of NF-κB and AP-1 activation pathways, and this may provide added benefit in controlling the inflammatory processes associated with AD. (Tegeder, 2001)  As an interesting aside,  (R)-Flurbiprofen has also been shown to suppress prostate tumor cells by inducing p75NTR protein expression. (Quann, 2007)

(R)-Flurbiprofen is an example of a drug with considerable therapeutic potential that will almost certainly not see clinical application due to the high cost associated with regulatory burden and the logistical hurdle of needing to start therapy years before symptoms of AD manifest themselves. (R)-Flurbiprofen might also conceivably be useful as combination therapy with  the already FDA approved skin cancer drug bexarotene (Targretin), an antineoplastic, which has been shown to reverse beta amyloid deposition in a rodent model of AD as well as to improve cognitive function. Targretin rapidly cleared beta amyloid from the brains of animals in a variety of models of AD (<2 months) and while it is not a cytotoxic chemotherapeutic agent, the drug has sufficient adverse effects that it would be problematic to administer over a period of years or decades. A combination of short term therapy with Targretin to remove beta amyloid, followed by long term administration of (R)-Flurbiprofen is a possible treatment strategy that would seem attractive to explore. The ability to dynamically monitor beta amyloid levels in the brains of patients undergoing such novel therapeutic regimens, especially outside the confines of the medical-industrial establishment, is yet another advantage of this evolving singularity in medical imaging.

End of Part 1

Figure 1: Survival of California Adventist men (1980-1988) and other California men (1985) beyond the age of 30 years. The difference between the 2 groups was significant (P,.001). These were non-Hispanic white subjects. Hazards for 1989 are used for non-Adventist Californians older than 94 years (see the “Subjects and Methods” section of the text). AHS indicates Adventist Health Study; CI, confidence interval.

The Seventh-day Adventist Church (SDA) is a Christian denomination that was founded in 1963 as an offshoot of the Millerite movement in the US during the middle part of the 19th century. Ellen White, the principal founder of SDA, advocated a lifestyle incorporating the following five behaviors: not smoking, eating a plant based diet, eating nuts several times per week, engaging in regular exercise and maintaining normal body weight throughout the individual’s lifetime[1] Adventists also typically eschew alcohol (~8% drink), tobacco (~1.8% smoke), butter, strong seasonings (including pepper), caffeine (coffee, tea, cola) and consider the eating of pork, shellfish, and other foods proscribed as “unclean” in Leviticus as especially unwholesome.[2]

Beginning in 1960, two studies were conducted to determine the effects of the SDA lifestyle on all-cause mortality, as well as on disease-specific mortality and morbidity. The first study was conducted in the interval from 1960 to 1965. The Adventist Mortality Study, also known as the Adventist Health Study-1 (AHS-1) was comprised of 22,940 California Adventists and consisted of an intensive 5-year follow-up, and a more informal 25-year follow-up.[3] The AHS-1 found that the mean lifespan for California Adventist men was 6.2 years longer than for non-Adventist California men. The mean lifespan extension achieved by SDA women was more modest; a 3.7-year advantage over their non-SDA counterparts. These statistics were based on life table analyses.[4]

The reduction in disease specific mortality was impressive, with the overall death rate from neoplasms being 60% lower for SDA men and 76% lower for SDA women.[3, 5] The incidence of breast and colorectal cancer were dramatically lower than in the control population with SDA women experiencing 85% less breast cancer [6-8]and SDA men and women experiencing 62% less colorectal cancer.[3, 9, 10]The incidence of coronary heart disease (CHD) was 66% lower for SDA men and 98% lower for SDA women.[11-13] On average Adventist men live 7.3 years longer and Adventist women live 4.4 years longer than other Californians.

The second Adventist Health Study (AHS-2) took place in the time period between 1974 and 1988 and involved approximately 34,000 Californian Adventists over the age of 25. AHS-2 was designed to try to determine which components of the SDA lifestyle provided protection against specific types of disease. The AHS-2 found that the consumption of red and white meat was associated with an increase of colon cancer and that, independent of meat consumption, eating legumes was protective against the disease.[5, 10, 14] The consumption of nuts was found to be inversely related to the incidence of myocardial infarction, and regular consumption of nuts several times a week reduced the incidence of coronary heard disease CHD by ~50%.[15-17] A strong inverse relationship was found between the risk of CHD and the consumption whole grain wheat bread, as opposed to white bread (~45% reduction in CAD).[16] In men, the frequent consumption of tomatoes and of soy milk was associated with a ~60% reduction in the incidence of prostate cancer.[16, 18, 19]

Figure 2: Survival of California Adventist women (1980-1988) and other California women (1985) beyond the age of 30 years. The difference between the 2 groups was significant (P,.001). These were non-Hispanic white subjects. Hazards for 1989 are used for non-Adventist Californians older than 94 years (see the “Subjects and Methods” section of the text). AHS indicates Adventist Health Study; CI, confidence interval.

Unlike the Cretan diet, the dietary practices of the SDAs are less homogenous and typically incorporate foods commonly consumed by Americans (although with more moderation), including many associated with degenerative disease, such as refined sugar and snack foods. Similarly, the SDA diet typically strives to replace traditional American foods with healthier alternatives, while maintaining the flavor, texture and appearance of the original dishes.[20] One way this is done is by using a range of proprietary textured vegetable protein products (TVP) derived from wheat or soy (with corn or soy oil providing the calories from fat) as meat substitutes. There is also a heavy emphasis on the consumption of vegetables, nuts, whole grains and fruits.[21, 22]

Figure 3: Examples of textured vegetable protein products made to resemble commonly eaten meat dishes in the US.

These products have historically been manufactured by companies owned by or closely associated with the SDA church[23] and this was an added factor in their widespread use. Lentils are also often substituted for meat in traditional American recipes, such as meatloaf and soup. The use of TVP meat substitutes increase compliance by making products that allow for the preparation of foods that fill the cultural niche of beef, chicken and turkey. There are even faux-meat hot dogs available (Figure 3). Nuts are also commonly used as an ingredient in TVP dishes to provide added flavor and a more meat-like mouth feel.[20] Examples of commonly used SDA “meatless meat products” (Figure 3) along with their ingredients and nutritional content are available at http://fatsecret.com/calories-nutrition/worthington-loma-linda#Meatless_Foods.

The primary sources of lipids in the SDA diet have historically been from corn and soy oils, and to a lesser extent oils from nuts (corn oil has partly been replaced by canola oil in the contemporary SDA diet). In examining the commonalities between the SDA and the Cretan diet, the following components seem the most likely candidates to explain the reduction in morbidity and mortality observed in both populations:

• No or very low consumption of red meat
• No or low consumption of meat (excluding fish) in general
• Large consumption of fresh fruits and vegetables
• Use of free range hens’ eggs
• No or low consumption of butter
• No or low consumption of unfermented milk products
• Emphasis on legumes in the diet
• Emphasis on the regular consumption of nuts
• Fat intake primarily in the form of polyunsaturated or monounsaturated fats of vegetable origin
• Regular exercise
• Maintenance of near ideal body weight over the lifespan
• Abstention from smoking

Which Diet for a New Lifestyle?

Figure 4: The Greek Food Column and the three critically important lifestyle elements that accompany it; balance, proportionality and regular exercise.

The Lyon Heart Study clearly showed that the diet of Crete can be adhered to over a period of 5 years. Figure 4 is the Greek Column Food Guide based on the diet of Crete. The visualization of this food guide in the form of a Greek column includes the concepts of genetic variation and nutrition and balanced energy intake and energy expenditure; it is based on foods, not food groups. Although it excludes certain foods made with hydrogenated oils, it does not restrict the intake of naturally occurring foods. It also takes into consideration moderation, variety and proportionality. Dietary guidelines shown in Table 1 provide further information on how to implement the diet of Crete.

Table 1.
The seven dietary guidelines of The Cretan Diet
1. Eat foods rich in (n-3) fatty acids such as fatty fish (salmon, tuna,
trout, herring, mackerel), walnuts, canola oil, flaxseeds and green
leafy vegetables. Or, if you prefer, take (n-3) supplements.
2. Use monounsaturated oils such as olive oil and canola oil as your
primary fat.
3. Eat seven or more servings of fruits and vegetables every day.
4. Eat more vegetable protein, including peas, beans and nuts.
5. Avoid saturated fat by choosing lean meat over fatty meat (if you
eat meat) and low fat over full fat milk products.
6. Avoid oils that are high in (n-6) fatty acids, including corn,
safflower, sunflower, soybean, and cottonseed oils.
7. Reduce your intake of trans fatty acids by cutting back on
margarine; vegetable shortening; commercial pastries; deep-fat
fried food; and most prepared snacks, mixes and convenience
food.

Studies on the diets of hunter-gatherers suggest that (n-3) fatty acids were present in practically all foods that humans ate, and present in equal amounts with (n-6) fatty acids (i.e., 1:1 ratio). The depletion of the (n-3) fatty acids in Western diets is the result of the industrialization of farming, and to a lesser extent, the recent emergence of aquaculture. The high ratio of (n-6) to (n-3) fatty acids (16.74:1 instead of 1:1) is a consequence of the inexpensive mass production of vegetable oils and their substitution in much of the diet for saturated fats as a consequence of economic considerations, government policy (corn and soy subsidies) and erroneous health advice by the “experts.” The latter, led by Ancel Keyes,  recommended the indiscriminate substitution of saturated fat and butter with oils high in (n-6) fatty acids to lower serum cholesterol. This effort was successful in reducing the incidence of CVD, however it has not reduced the incidence of other pro-inflammatory diseases, and the mean lifespan has not increased fully commensurate with the decrease in CVD mortality.

The results of the Seven Countries Studies and the Lyon Heart Study based on a modified Cretan diet that is balanced in (n-6) and (n-3) fatty acids, rich in antioxidant micronutrients, and in chemoprotective trace minerals  from fruits, vegetables, wild growing herbs and greens is associated with decreased rates of heart disease and cancer; more so than any other diet, drug intervention, or technique. Indeed, all attempts to date to administer nutrients believed to be protective against disease as supplements have been unsuccessful. Attempts to reduce the incidence of CVD with vitamin C, vitamin E and with folic acid and vitamin B-6 (the latter to achieve reduction in elevated serum homocyeteine levels) have failed, suggesting that the biochemical protection these molecules provide in vitro, and in laboratory animal settings, requires the presence of other molecular species in order to act in vivo.

What appears to be unique about the Cretan (and to a lesser extent the SDA diet) is the content of bioprotective nutrients with a broad range of action, specifically the following: 1) a more balanced intake of essemtial fatty acids (EFAs) from vegetable, animal and marine sources; a ratio of (n-6) to (n-3) fatty acids of ;2:1 instead of the 15:1 in most Western diets (it is 16.74:1 in the US); and 2) a diet rich in antioxidants, i.e., high in vitamin C, vitamin E, b-carotene, glutathione, resveratrol, selenium, phytoestrogens, folate, and other phytochemicals from green leafy vegetables; phenolic compounds from wine and olive oil; high intakes of tomatoes, onions, garlic and herbs, especially oregano, mint, rosemary, parsley and dill, which contain  lycopene, allyl thiosulfinates, salicylates, carotenoids, indoles, onoterpenes, polyphenols, flavonoids and other phytochemicals used in cooking vegetables, meat and fish.

Some Serious Caveats Regarding the Applicability of Historical Data

In asking people about how long they expect to live, I’m often surprised by the high degree of confidence they exhibit based on the longevity of relatives. If you challenge the assumption that because their aunts, uncles or parents lived into their 80s or 90s that they will too, you will likely be met with the vehement assertion that this fact pretty much guarantees a similar outcome for the respondents. This assertion would be more credible if their long lived 1^st or 3^rd degree kin were reared under identical, or at least under similar conditions. And therein lies the rub, because this is usually not the case.

Figure 5: Average weekly hours spent on home production from 1900 to 2000 for two aggregates of the population; those in their productive prime, and those in their declining years.

It must be remembered in making historical comparisons with contemporary Westerners in terms of both life expectancy, and dietary or other interventional lifespan studies, that 20th century Cretans and Adventists were, of necessity, far less sedentary than is the average 21st century Westerner today. In this cohort of people housework (household production) involved a considerable amount of exercise, and often no small amount of hard physical labor. Until the middle of the 20th century in the US, laundry was done by hand, in whole or in part, and clothing was hung up to dry, taken down and ironed. Even operating automobiles involved clutching, shifting gears and manual operation of windows – small things by themselves, but cumulatively important.

Figure 6: Between 1950 and 2000 there was a ~ 20% reduction in the types of work classified as “high activity.” What is neither shown nor known is the degree to which both high and low activity jobs have become less strenuous. [24]

Meal preparation in 1965 required ~ 16.5 hours per week and the total numbers of hours spent in home production was on the order of 51.8 hours at that time. [25] As can be seen in Figure 5, time spent on home production decreased significantly beginning around 1960. Beyond the decrease in total hours spent on housework, there was a much larger decrease in the amount of physical effort required. Washing machines and clothes dryers, prepared meal components and entire prepared meals, as well as countless other “labor saving” devices, goods and services have markedly decreased fitness. The same has been true of strenuous physical activity in the work place where the overall number of high activity jobs have decreased by ~ 20% from 1970-2000.[26, 27]  There has also been a large shift in the workplace demographic since the mid-2oth century. Life expectancy increased from 47.3[28] years in 1900 to 77.8 years today, a consequence of which (in part) was the exodus of teens from the workforce. In 1920, ~20% of the US labor force was comprised of males aged 15 to 18 years of age.[28] Today, very few teenagers work full time jobs, and the number of teens employed in summer jobs has decreased from ~60% in 1994, to ~40% in 2008.[29] Of those teens who do find summer employment very few are in physically demanding (and consequently usually hazardous) areas of work, such as construction or agriculture. This change, coupled with increased TV viewing and other sedentary activities, translates into reduced fitness in the age 15-30 demographic.

Figure 7: The graph above shows the distribution of the Body Mass Index between the 1971–1975 and 1988–1994 surveys. Over this time, median BMI increased by 0.9; the 75th percentile increased by 1.5; and the 95th percentile increased by 2.7.[238]

In their article, “Why Have Americans Become More Obese?” Cutler, et al., take the contrary position and argue that it is not reduced energy expenditure (or fitness) in the the population, but rather, the reduced investment required in terms of time per calorie consumed, that has been the primary cause of the change in US, and increasingly Western European eating habits (and thus is responsible for the current epidemic of obesity and type II diabetes).[30] Superior food packaging and preservation have cut not just meal preparation time dramatically, but also cleanup time. The mess generated in the preparation of multiple elements of a meal is now confined to the factory and the cleanup is included in the price of the food. It is also no longer necessary to spend as much time cooking, or even heating food, because it can be rapidly prepared and be made ready to eat in a matter of minutes from refrigerator or cupboard by the use of the microwave oven. These technological changes have thus reduced the threshold for eating formerly time consuming and messy to prepare dishes to the point of almost no effort or expenditure of time at all. It is now almost as easy to eat a piece of cake or pie, a brownie, or complex entree as it once was to eat an apple. All the mess and time involved in baking a cake or a pie from scratch is gone.

Regardless of the cause, we are most certainly not our parents or our grandparents, and as the current epidemic of obesity and type II diabetes attests, we are not likely to age or die as they did, either. Any doubts about the difference between “us” and “them” (or even “us then” and “us now”) should be laid to rest by a careful perusal of Figure 7.

The generations who participated in the AHS and Seven Countries Study were also fed differently. In Europe, they were subjected to nearly a decade of reduced calorie consumption, and even in the US, the relatively high cost of calories (in time, if nothing else) combined with less leisure time and fewer options for sedentary work, no doubt acted to limit calorie consumption, compared to today. This reduced calorie consumption may have been protective, and might have served to add years to life even in the presence or the absence of a more optimal diet. These generations of people were also fed on agricultural products derived mostly from small farms where crops and livestock had the opportunity to acquire a broad range of micro-nutrients and phytochemicals that are now less abundant in the food supply.

How Square is Curve Already?

Figure 8: The death rate from cardiovascular disease in the US has plummeted since the turn of century in part due to the replacement of saturated fats with of polyunsaturated fats in the diet.[31]

It should also be pointed out that data from longitudinal studies like the AHS-1&2 and the Seven Countries Study reach us as light does from a distant star. When we point and look at the star in the crook of the handle of the Big Dipper we say, “Look, there’s Alcor!” But of course that isn’t the Alcors we are looking at, but rather the light that shows what they looked like 83 years ago. Similarly, all of the data in AHS-1&2 and Seven Countries Study is a generation or two (or three!) old by the time we have it. The participants in those studies are mostly dead now, as indeed they would have to be in order for us to be able to plot lifespan curves for them. Thus, it is easy to make the mistake of saying, “If I adopt this diet I can expect 7 additional years of life, or 10 additional years of life, because that’s what the study participants experienced.

At least one problem with that assumption is that some of the benefits from both studies have very likely already been realized in the form of the switch from saturated to poly- and monounsaturated fats in the diet, which began in the early 1960s and continues through the present. The most significant benefit from both the Seven Countries Cretan diet and the Adventist Vegetarian diet has been the reduction in mortality (and morbidity) from CVD that has been ongoing since ~1968 in the US. The death rate from CVD has been halved since 1960 when both of these studies were undertaken (Figure 8). To those who vilify Ancel Keys for not getting it just right, I can only say, “Look at (Figure 8) and try to tell me that you could have done better.” So, we’ve undoubtedly used up some of benefit from these dietary interventions in terms of mean lifespan extension.

Figure 9: These curves show the best case extension of mean lifespan that can be anticipated with the Adventist Vegetarian diet or the Cretan Diet.

Finally, it is critically important to understand that both the Cretan and the Adventist Vegetarian diets are really not “diets” at all, but rather lifestyles. Both lifestyles have in common a strong emphasis on low impact exercise and a non-sedentary way of life. Both lifestyles were a product of a time without televisions or computers, and both lifestyles required then, and will require now, considerably greater time for food preparation and cleanup. The upside of that is that we should also eat less, if Cutler et al., are correct. That is important to consider as well, because, leaving aside whether fats, carbohydrates or protein should comprise X- percentage of a given diet’s calories, one thing both these diets have in common is modest to moderate calorie restriction.  Five, or possibly even 10 extra years of healthy, productive life should hopefully make the practical costs worthwhile.

The Caveman Diet, or Just How Credulous Are You?

“There are races of people who are all slim, who are stronger and faster than us. They all have straight teeth and perfect eyesight. Arthritis, diabetes, hypertension, heart disease, stroke, depression, schizophrenia and cancer are absolute rarities for them. These people are the last 84 tribes of hunter-gatherers in the world. They share a secret that is over 2 million years old. Their secret is their diet- a diet that has changed little from that of the first humans 2 million years ago, and their predecessors up to 7 million years ago. Theirs is the diet that man evolved on, the diet that is coded for in our genes. It has some major differences to the diet of “civilization”. You are in for a few big surprises.

The basic principles of the Paleolithic Diet are so simple that most high school students can understand them. Within 15 minutes from now you will grasp the major elements. At the technical level, Paleolithic Diet Theory has a depth and breadth that is unmatched by all other dietary theories.” – Dr. Ben Balzer, M.D.

The ideas underlying the Cretan Diet and the SDA Vegetarian diet are complex and do not admit of easy reduction to a catchphrase. The actual foods permitted and consumed in both diets differ markedly – one proscribing all meat, the other urging fish consumption, one obtaining most of the dietary fat calories from PUFAs, and the other from monounsaturated olive oil… It is these differences in the face of the common outcome of greatly improved health and moderate extension of the mean lifespan that are, in fact, key, because they tell us about the likely underlying common mechanisms and thus possibly of their action. They also offer us the opportunity for more choice, and therefore for more flexibility and the likelihood of greater compliance.

The Paleo Diet: A diet so unscientific, only a caveman would do it.

That is not, however, how people make a quick buck. Neither diet is particularly ‘sexy.’ And both diets require an understanding of the underlying biology that makes them work in order to be credible. It’s not possible, or at least not as easy to offer up a one sentence explanation for the feeble minded, such as, “This is a healthy diet that will extend lifespan because it is the natural human diet that our ancestors were evolved to eat.”[32-34] That sounds great because it is simple, easy to understand and “seems right” to a lot of uninformed, ignorant and fearful people. It also speaks to that deep and abiding suspicion that our health (and our other woes) is an artifact of our having lost our way – either from the primordial Garden of Eden, or from our biologically appropriate evolutionary ground state (i.e., before we embarked on agriculture). In fact, the emphasis on a 1:1 or 2:1 ratio of (n-6) to (n-3) fatty acids was derived from observations of contemporary hunter gatherer populations who have a low incidence of inflammatory and age-associated degenerative disease compared to that seen in post-agricultural populations. That was a useful insight that was subsequently validated in many human studies, the best of which extended over a period of decades. That’s the heart and soul of Level 1, Evidence Based Medicine.

In 1988, S. Boyd Eaton, Marjorie Shostak and Melvin Konner published a book entitled The Paleolithic Prescription: A Program of Diet & Exercise and a Design for Living[32] advocating a diet based on what the authors hypothesized the primordial pre-agricultural human diet was like. Subsequently, well over a dozen books have been published advocating variations on this diet based on arm chair hypothesizing from findings in the scientific and ethnographic literature.  The diet (depending upon the version you come across) is low (10-15% energy) or moderate in fat , low in carbohydrate (20–40% energy), and  high in protein diet (19–35% energy) which provides 55–65% of total calories from meat, 35–45% of calories from non-grain and low glycemic index vegetable sources with a primarily saturated fat intake (10%–58% energy) similar to or higher than that found in Western diets.[35-37]

The first problem with this approach is that the diet is not validated; the AHS and the Seven Counties studies had the considerable advantage of being able to study actual, living human beings under real world conditions, and then apply those insights to other populations, including populations already suffering from CVD. Indeed, that is where so many of the insights, as well as so many of the unresolved questions regarding these diets/lifestyles come from (i.e., the data are complex and robust). Late Paleolithic people are not only long dead and gone, they are really long dead and gone, and contemporary hunter gatherers – the few that remain – cannot be considered equivalent. Ironically, most of the data cited on the relationship between CVD and diet by the originators of the Paleolithic diet are from the Seven Countries Study![32, 37]

Even more to the point, there is present in the hypothesis of Eaton, Konner et al.,[32, 33] the notion that 10,000 years of agriculture is evolutionarily insignificant. In essence, they posit that human evolution with respect to diet stopped 10,000 years ago.[32, 35] At first glance this might seem to be credible, because human evolution has occurred over a period of millions years and it would seem that any changes that would occur in population genetics over a mere 10,000 years must be trivial. However, this is not the case for several reasons. First, the rate of evolution is a function of a complex interplay of multiple factors, including environmental change and selection pressure. It is only necessary to look at the various breeds of dogs, or pigeons created by artificial selection to understand that evolutionary change can be swift.

The introduction of agriculture was a watershed event and it would be astonishing if it was not accompanied by significant evolutionary adaptations to the dietary changes that resulted.  To understand that this is so it is only necessary to examine the strong natural selection for the gene that controls lactase production.[38] Human populations with a long history of cattle herding and milk consumption can metabolize lactose present in cow’s milk throughout adulthood, whereas populations that did not domesticate cattle cannot. Natural selection for the heterozygous carriers of the sickle-cell gene to maintain sickle-cell trait in populations exposed to malaria is another post-advent of agriculture evolutionary adaptation. This adaptation was selected for as a direct result of an agriculture-induced alteration to the environment; the clearance of the tropical forests in central Africa, which in turn led to the explosion in the population of the Anopheles mosquitoes that are the vectors for the Plasmodium parasite that causes malaria.

Recently developed techniques for measuring genetic variability now allow for the determination of selection operating in the human genome.[39] Directional selection has been identified in the glucose-6-phosphate dehydrogenase (G6PD) gene, which confers resistance to malaria.[40] What is more, G6PD resistance has evolved not once, but twice in humans, in both Africa and in the Americas.[41] Similarly, the genes expressing chemokine receptor 5 (CCR5) among Europeans, which confers resistance to the human immunodeficiency virus (HIV) are likely to have been selected for within this population over a period of several hundred years in response to Yersinia pestis (bubonic plague) and tuberculosis, both of which use the CCR5 receptor as an entry portal into the host.[42]  Numerous other studies have also provided evidence for the recent operation of natural selection on the human genome as a result of very recently developed techniques that allow for comparisons over long sections of DNA.[43-46]

In addition to the conservation of lactase production into adulthood, there is substantial evidence of evolutionary adaptation to the high carbohydrate diet that was a product of agriculture. The incidence of obesity that occurs upon exposure to high calorie “affluence diets” is known to vary greatly by ethnicity. The Pima people (or Akimel O’odham) are a racial group of Amerindians living in central and southern Arizona. One-half of adult Pima Indians have diabetes and 95% of those with diabetes are overweight or obese.

Obesity is thought to be 50-90% heritable. Genome scans in obesity studies are highly reproducible and, despite ethnic and environmental differences, the loci at chromosomes 2 and 10 are generally confirmed as the source of the phenotype. Obesity is “oligogenic,” with expression modulated by “polygenic modifier genes” interacting with the environment in food choices, physical activity, and smoking.[38] Prior to their introduction to the “American” diet after WWII the Pima were not obese and diabetes was extremely rare.[39-41] The diet of the Pima was a very low fat, high carbohydrate diet consistent with the subsistence agriculture of the desert southwest.[42, 43]  Some variations in the ectonucleotide pyrophosphatase phosphodiesterase gene-1 (ENPP1) are associated with a 50% increase in the risk of morbid obesity in adults and a 69% increased risk of childhood obesity. An ENPP1 mutation, for example, which is known to protect against obesity and type II diabetes, is present in about 90 percent of non-Africans, but nearly absent in Africans and, not coincidentally, in the Pima. Human evolution in response to environmental change and in response to dietary change is both ongoing and dynamic.[47][44]

Of course, the Paleolithic diet may be the best diet yet conceived. I could give many reasons why I believe this is not so, but absent hard data gleaned from human trials, I can’t prove much. And that is my final and most important point. I did a Pubmed search using the keywords “Paleolithic diet” and I got 67 hits. Of those 67 hits only 9 were papers that involved actual human or animal application of the diet, or even discussion of same. I’ve copied all of the cites for these studies below:

1: Konner M, Eaton SB. Paleolithic nutrition: twenty-five years later. Nutr Clin Pract. 2010 Dec;25(6):594-602. PubMed PMID: 21139123.

2: Jönsson T, Granfeldt Y, Erlanson-Albertsson C, Ahrén B, Lindeberg S. Apaleolithic diet is more satiating per calorie than a Mediterranean-like diet in  individuals with ischemic heart disease. Nutr Metab (Lond). 2010 Nov 30;7:85. PubMed PMID: 21118562; PubMed Central PMCID: PMC3009971.

3: Klonoff DC. The beneficial effects of a Paleolithic diet on type 2 diabetes and other risk factors for cardiovascular disease. J Diabetes Sci Technol. 2009 Nov 1;3(6):1229-32. PubMed PMID: 20144375; PubMed Central PMCID: PMC2787021.

4: Eaton SB, Konner MJ, Cordain L. Diet-dependent acid load, Paleolithic[corrected] nutrition, and evolutionary health promotion. Am J Clin Nutr. 2010 Feb;91(2):295-7. Epub 2009 Dec 30. Erratum in: Am J Clin Nutr. 2010 Apr;91(4):1072. PubMed PMID: 20042522.

5: Jönsson T, Granfeldt Y, Ahrén B, Branell UC, Pålsson G, Hansson A, Söderström  M, Lindeberg S. Beneficial effects of a Paleolithic diet on cardiovascular risk factors in type 2 diabetes: a randomized cross-over pilot study. Cardiovasc Diabetol. 2009 Jul 16;8:35. PubMed PMID: 19604407; PubMed Central PMCID: PMC2724493.

6: Frassetto LA, Schloetter M, Mietus-Synder M, Morris RC Jr, Sebastian A. Metabolic and physiologic improvements from consuming a paleolithic, hunter-gatherer type diet. Eur J Clin Nutr. 2009 Aug;63(8):947-55. Epub 2009 Feb  11. PubMed PMID: 19209185.

7: Osterdahl M, Kocturk T, Koochek A, Wändell PE. Effects of a short-term intervention with a paleolithic diet in healthy volunteers. Eur J Clin Nutr. 2008 May;62(5):682-5. Epub 2007 May 16. PubMed PMID: 17522610.

8: Jönsson T, Ahrén B, Pacini G, Sundler F, Wierup N, Steen S, Sjöberg T, Ugander M, Frostegård J, Göransson L, Lindeberg S. A Paleolithic diet confers higher insulin sensitivity, lower C-reactive protein and lower blood pressure than a cereal-based diet in domestic pigs. Nutr Metab (Lond). 2006 Nov 2;3:39. PubMed PMID: 17081292; PubMed Central PMCID: PMC1635051.

9: Eaton SB, Eaton SB 3rd. Paleolithic vs. modern diets—selected pathophysiological implications. Eur J Nutr. 2000 Apr;39(2):67-70. PubMed PMID: 10918987.

If I enter the keywords “Mediterranean diet” I get 2,269 hits, of which 225 are reports of clinical trials. I will not copy those here!

That’s it. Nine papers of poor quality and not a single clinical trial demonstrating reduced morbidity or mortality – even in CHD or type II diabetes.  Sixty-seven papers of hypothesizing 25 years after this diet was put forth. That is dismal science and it is inexcusable to take a position advocating such an intervention in the complete absence of any evidence that it will actually extend the human (or the laboratory animal) lifespan when there is a large body of high quality data that supports far less extreme, and far more practical dietary and lifestyle interventions that will accomplish those ends.

I have no problem with people coming up with a hypothesis, however kooky or sane, and then proceeding to try it out – even on people – as long as those people have informed consent and the data they are given is accurate. In looking over the various books and the countless media articles on the Paleolithic diet, I was struck by how much the Paleolithic Diet’s hype reminded me of the Pritikin diet hype, and even more so of the Pearson & Shaw Life Extension Revolution circus from 30 years ago. “Live to be 100!” “Feel great! Experience all day energy every day!” “Lose Weight!” Well, at least one of those is very likely true, and that is that most people who undertake any version of the Paleo diets I’ve reviewed will likely lose weight. But as to the other claims? Right now they are preposterous. The sad thing is that for first the time in history we have one diet/lifestyle choice that satisfies EBM-1 criteria, and another that satisfies EBM-2 criteria. Both are “proven” to reduce morbidity from a range of degenerative diseases, and both have been proven to significantly extend mean lifespan…

Max More, CEO Alcor Life Extension Foundation

As I so often say, “You pays your money and you takes your chances.” Still,  it is embarrassing to see cryonicists buy into yet another quick fix cure all, with no appropriate science to back it up. In his article “The Cryo-Paelo Solution”[48] Alcor President Max More advocates the Paleolithic Diet as a life extending add-on to cryonics. This recommendation is supplemented by a web interview.[49] His citations consist these of these popular books on the subject: Loren Cordain, The Paleo Diet; Nora T. Gedgaudas, Primal Body, Primal Mind; Mark Sisson, The Primal Blueprint; Gary Taubes, Why We Get Fat;Gary Taubes, Good Calories, Bad Calories; Arthur de Vany, The New Evolution Diet. The expert More cites as the one to consult for an introduction to Paleo-dieting is Loren Cordain, author of  The Paleo Diet. The quote that open this section on the Paleolithic diet is by Dr. Ben Balzer, M.D., and is from the “Introduction” to Cordrain’s book. Need I say more?

End of Part 3

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39.          Bennett PH, Burch TA, Miller M: Diabetes mellitus in American (Pima) Indians. Lancet 1971, 2(7716):125-128.

40.          Bennett PH, Rushforth NB, Miller M, LeCompte PM: Epidemiologic studies of diabetes in the Pima Indians. Recent Prog Horm Res 1976, 32:333-376.

41.          Zimmet P, Arblaster M, Thoma K: The effect of westernization on native populations. Studies on a Micronesian community with a high diabetes prevalence. Aust N Z J Med 1978, 8(2):141-146.

42.          Ravussin E, Valencia ME, Esparza J, Bennett PH, Schulz LO: Effects of a traditional lifestyle on obesity in Pima Indians. Diabetes Care 1994, 17(9):1067-1074.

43.          Boyce VL, Swinburn BA: The traditional Pima Indian diet. Composition and adaptation for use in a dietary intervention study. Diabetes Care 1993, 16(1):369-371.

44.          Malhotra A, Kobes S, Knowler WC, Baier LJ, Bogardus C, Hanson RL: A Genome-Wide Association Study of BMI in American Indians. Obesity (Silver Spring).

45.          More M: The cryo-paelo solution: http://www.alcor.org/magazine/2011/03/07/the-cryo-paleo-solution/. Cryonics (on line edition) 2011.

46.          Snyder S: Alcor CEO Max More and the paleo diet: http://samsnyder.com/2011/05/22/alcor-ceo-max-more-and-the-paleo-diet/. In: A Blog by Sam Snyder. Sam Snyder; 2011.

Figure 1:

The Seven Countries and Adventist Health Studies

Nathan Pritikin drew his initial conclusions about the effect of dietary change from classified data he was privy to during World War II (WWII) on the patterns of age-associated disease in Europe as a consequence wartime calorie restriction and severe reduction of fat intake due to the severely reduced availability of meat and dairy products.  He also observed that the incidence of age-associated degenerative diseases was  very low in human populations where the diet was very low in fat (~10% of the total caloric intake), contained no refined sugars and consisted mostly of fresh vegetables and fruits  with very little meat being consumed. Similarly, the physiologist Ancel Keys (Figure 1), who was working with the Army Quartermaster Corps in developing K-Rations,[1] became involved in the Army’s program to create scientifically informed re-feeding programs for POWs and civilians suffering from starvation, saw the same kind of data. Unlike Pritikin, Keys had the opportunity to do human experimentation afforded by wartime conditions.[2, 3] Keys working hypothesis was different than Pritkin’s, namely that it was primarily saturated fats in the diet that were responsible for the high incidence of cardiovascular disease (CVD) in the affluent and well-fed West.

This epidemiological approach to identifying patterns of food consumption associated with increased or reduced risk of degenerative disease was also being pursued around this time in the US, by physicians at the Loma Linda Medical Center in Loma Linda, CA. Loma Linda was an almost exclusively Seventh Day Adventist community at that time, and these physicians believed that their patients, who practiced a vegetarian diet in conjunction with abstention from tobacco and alcohol, were considerably healthier than the non-Adventist population in California. They began a study of diet, lifestyle and the incidence of disease and all-cause mortality in 1958; the Adventist Health Study-1 (AHS-1) [4-26]

Keys returned to Europe after the war and began a study of six European countries, which later became the Seven Countries Study. [27-72] The dietary recommendations which emerged from the Seven Countries Study are commonly referred to as the “Mediterranean diet.” However, the use of the words “Mediterranean diet” to describe these recommendations is a misnomer. The countries of the Mediterranean basin have large differences in diet, lifestyle and in their corresponding rates of morbidly and mortality. The country with the lowest death rate  (14.0 – 18.0 per 1000 persons), is Crete, whose death rate has been at this level since at least 1930. [73] The diet of Crete is archetypical of the ‘traditional’ Greek diet before the introduction of continental European and American foods into Greece after ~ 1960.

The Seven Countries Study was the first to generate robust data on the incidence of cardiovascular disease in a range of populations (US, Finland, The Netherlands, Italy, the former Yugoslavia, Japan and Greece) with a fairly broad spectrum of dietary patterns. The study showed differences on the order of 5 to 10-fold in coronary artery disease (CAD) between the populations studied. [36, 50, 74]

Figure 2: The Cretan diet food pyramid.

Both the Seven Countries Study and the AHS-1 demonstrated large reductions in disease-specific morbidly and mortality, as well as in all-cause mortality; primarily as a result of diet and lifestyle differences. In the case of the Seven Countries Study, extensive follow-on research using well designed prospective studies, resulted in the development of a set of dietary guidelines which became known as the “Mediterranean” or more correctly, the “Cretan diet.” The guidelines which constitute the Cretan diet satisfy Level-1 EBM criteria for extension of the mean lifespan by ~10 years, reduction in all cause mortality, high levels of compliance, and very importantly, titratability. In other words, the degree of compliance with the diet is roughly commensurate with the benefit that results. [75-77]

What About Cholesterol?

For thirty years an acrimonious debate has raged in the scientific and medical communities over whether cholesterol, or any molecular species of lipoprotein, “causes heart disease” or other CVD. The causes of the inflammatory events that underlie the start of arterial plaque formations are complex, possibly multifactorial (e.g., genetic, viral, microbial, environmental, etc.) and by no means fully elucidated. Keys, Pritikin and many others mistakenly believed that “elevated” serum cholesterol was the primary cause of CVD. This hypothesis is well supported by the epidemiological data. However, there are many people who have normal or even slightly low levels of total cholesterol, or of the low density lipoprotein (LDL) species whose oxidation is usually cited as the motor of atherogenesis.

However, the observations of Keys and Pritkin extended beyond a cause and effect relationship between cholesterol and CVD. In different ways, both men demonstrated that altering the total serum cholesterol level and/or the ratio between the LDL and high density lipoprotein (HDL) species, they could reduce the incidence of the disease. In Pritkin’s case, he even demonstrated that the disease could be reversed by the expedient of a very low fat diet.[78-80] Pritkin demonstrated his theory on a very small population of people; principally those who read his book, or otherwise followed his dietary advice. Keys, on the other hand, conducted an experiment on a grand scale.

Throughout the 1960s Keys campaigned relentlessly to persuade physicians, public health authorities and the public themselves (directly) to replace the bulk of the calories they consumed in (saturated) fat with polyunsaturated fat. The purpose of this international dietary intervention was to reduce the serum cholesterol of the population, and thus the incidence of CVD. This effort enjoyed unprecedented success and it has resulted a doubling of the proportion of the unsaturated fatty acid, linoleic acid, in the tissues of Americans between 1960 and 1975.[81]  The mortality rate from coronary heart disease (CAD) in the US began to fall, starting in 1968, and it has continued to decline since then. It has been estimated that approximately 50% of the decline in CVD is as a result of dietary and lifestyle changes, exclusive of the reduction in tobacco abuse.[82]

As a scientist, I am acutely interested to understand the details of the pathophysiology of atherosclerosis. As someone who wants to avoid CVD, I am much more concerned with what works, even if the biomechanics are incomplete, or even contradictory. In this case, what works is that on a population basis, blood lipids are highly predictive of the risk of disease. Similarly, for most patients, raising HDL and lowering LDL are protective against both the onset of CVD, and to a lesser extent, its progression. Lipid status is thus a useful screening tool, as well as an instructive guide to the individual patient’s likely response to treatment. It is not necessary to believe that “cholesterol,” or any particular species of lipoprotein “causes” CVD. It is only necessary to understand that they are, at the least, useful biomarkers on a population wide basis and that they are often useful in the intelligent management of individual patients.

 Table 1: Fatty Acids Ratios in Different Diets

From the inception of the AHS-1 in 1958, and the Six Countries Study around the same time,[68, 83] the primary focus of the research, as was the case with Pritikin, was on the possible relationship of the diet to the etiology of CVD, with special emphasis on the fatty acid composition of the diet. The 5-year follow-up in the Seven Countries Study found favorable all-cause death rates in Greece, Italy and Japan, as compared with the other countries, including dramatically lower rates of CVD in Crete, and to a lesser extent in Japan.[84]The diet of Crete has in common with the diet of hunter-gatherers similar quantities of antioxidants, saturated fat, fiber, monounsaturated fat and, very importantly, the ratio of (n-6) to (n-3) fatty acids. [75-77]

One the basis of insights gained from the Seven Countries Study a wide range of epidemiologic investigations,  controlled clinical trials and relevant animal experiments have confirmed the hypotriglyceridemic, anti-inflammatory and antithrombotic aspects of (n-3) fatty acids (28 –35) as well as the criticality of (n-3) fatty acids, particularly Docosahexaenoic (n-3) (DHA) acid in the diet for the normal development of the retina and brain in the human infant. As a consequence of these insights, a study of the (n-3) fatty acid composition of diets that were known to be associated with reduced rates of CVD and cancer was undertaken.[75] The initial conclusion was that the high olive oil intake, which accounts for ~35% of the calories consumed in the Cretan diet, was likely responsible for the low rates of CVD and cancer. However, the Japanese have a similarly low incidence of these diseases and yet only ~11% of their calorie intake is from fat, none of which is from olive oil.

Figure 3: Mortality and morbidity difference between populations of patients with coronary artery disease (CAD) eating the Cretan diet and those on the low fat American Heart Association Step 1 diet[151]

The common factors between the populations of Crete and Japan were that they both consumed large amounts of vegetables (including wild plants), fruits, nuts and legumes, all of which are rich sources of folic acid, glutathione and vitamins E, C and other antioxidants. Wild plants are rich sources of (n-3) fatty acids and antioxidants and their consumption is not confined to humans. Both in Crete and in rural Japan, chickens and other livestock, such as goats and cows, are free ranging and consume wild vegetation in abundance (and in the case of chickens, insects, arachnids and worms) which are rich in (n-3) fatty acids and antioxidants, as well as cytoprotective and vasculoprotective trace minerals which are concentrated in the food chain. The result is poultry, eggs and milk which contain radically different ratios of (n-3) to (n-6) fatty acids and are enriched with selenium. For example, eggs from Crete have a ratio of (n-6) to (n-3) of 1:3, whereas the US ‘battery egg’ has a ratio of 19:4. Of course, the presence of this favorable ratio of lipids in eggs is also reflected in prepared foods which contain eggs (such as noodles, some breads and soups, etc.) and in the flesh of the animals that are slaughtered and eaten.

Analysis of the serum (n-3) fatty acid levels of the populations in Crete and Japan demonstrated that they had had higher concentrations of (n-3) fatty acids than did the other populations in the study, all of whom had a far high incidences of age associated degenerative diseases. The two populations with the lowest CAD in the Seven Countries Study consumed the highest amount of α-linoleic acid (α-LNA) the major sources of which were the wild herb purslane, walnuts and figs. By contrast, the Japanese obtained their α-LNA from canola and soybean oils. Interestingly, the Seventh Day Adventists, who experience an increase in mean lifespan of 7.28 years (95% confidence interval, 6.59-7.97 years) in men and by 4.42 years (95% confidence interval, 3.96-4.88 years) in women over that of their non-Adventist cohorts in the US[10], consume a vegetarian diet that is rich in nuts and oils containing α-LNA. The SDAs, like the people of Crete, have not only higher levels of α-LNA, but also lower levels of linoleic acid[9, 85, 86]

Figure 4: The Lyon Diet Heart Study demonstrated a 50 to 70% reduction of the risk of recurrence of myocardial infarction (MI) after four years of follow-up in coronary heart disease (CHD patients. The Lyon diet employed α-LNA as 0.6 to 1% of total daily energy or about 2 g per day in patients who follow a traditional Mediterranean diet. Supplementation with very long chain omega-3 fatty acids (c.1g per day) in patients following a Mediterranean type of diet was shown to decrease the risk of cardiac death by 30% and of sudden cardiac death by 45% in the GISSI trial. [87]

In 1994 de Lorgeril and Renaud published the results of a prospective study to evaluate a diet which contained the types and ratios of essential fatty acids (EFAs) found to be effective at reducing CVD in the Seven Countries Studies. The Lyon Heart Study (LHS), as it came to be known, was a randomized, single-blind secondary prevention trial that combined a modified Cretan diet enriched with α-LNA with that of the Step I American Heart Association diet.[87] The LHS demonstrated a reduction in all-cause mortality of 70% in the experimental population which consumed a diet low in butter and processed meats, but high in fish, nuts, fruits and vegetables (Figure 5).[87] The LHS followed subjects for 5 years after the start of the intervention and examined the reduction of risk for coronary artery disease (CAD) as well as in mortality from all cancers. The reduction in CAD was 56% (P 5 0.03) over that of control subjects, and in cancer mortality it was 61% (P 5 0.05)!

Figure 5: Cardiac morbidity and mortality in the Lyon Diet Heart Study. Of particular importance to cryonicists is the reduction in mortality from sudden cardiac death (SCD). [87]

Olive Oil, or Something Else?

Figure 6: The author has serious questions about whether experiments conducted using industrially prepared laboratory animal chows (right) are representative of the results obtained when fresh fruits and vegetable as well as foods consumed in their native state are used (left).

An initial and obvious conclusion from The Seven Countries Study was that a significant part of the reduction in morbidity and the extension of lifespan due to the Cretan diet was a consequence of the consumption of a large fraction of the calories in the diet in the form of monounsaturated  fats (MUFAs), principally as a result of olive oil consumption. However, recent animal studies have yielded paradoxical results. For instance, experiments in green monkeys have shown that a diet high in MUFAs (olive oil source) causes atherosclerosis equivalent to that observed in animals fed a diet high in saturated fats (SFAs).[88] This effect appears to result from an increased secretion of cholesteryl oleate enriched lipoproteins, as well as due to an increase in the circulating blood levels of chylomicron remnants, which are highly atherogenic lipoproteins. [89-91]

These paradoxical animal results have raised questions amongst epidemiologists and nutritionists about whether MUFAs really have beneficial effects in humans. Green monkeys are metabolically and genetically different than humans and the human data indicate that dietary MUFAs have favorable effects on CHD risk. There is also a significant amount of mechanistic data that indicate that there are molecular species in olive oil that have potent antioxidant and anti-inflammatory properties. In particular, the polyphenolic compounds hydroxytyrosol and oleuropein have been shown to possess these properties both in vitro and in vivo.[92-96] There is also the issue of the way in which olive oil is incorporated into the chow for experimental animals (Figure 6). Olive oil incorporated into a manufactured chow along with other dietary ingredients is not the way in which humans consume it, and this factor should be taken into consideration in future studies.

Figure 7: The titratability of the beneficial effects of the Cretan diet are nicely illustrated in this series of graphs showing all cause mortality over a ten year period with three variations of the Cretan diet; the world Health Organization recommended diet base on the Seven Countries Study, a broadly similar diet, and a carbohydrate restricted version of the Cretan Diet. Kaplan-Meier survival curves for individuals considered adequate reporters of dietary intake, grouped as low-, medium-, or high-adherent individuals to the dietary patterns investigated. Crude hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards regression analyses with the use of low-adherent individuals as the reference group for each dietary pattern. A: World Health Organization (WHO) dietary guidelines, according to the Healthy Diet Indicator: medium adherent (HR: 0.70; 95% CI: 0.43, 1.15), high adherent (HR: 0.97; 95% CI: 0.45, 2.07). B: Mediterranean-like diet, according to the Mediterranean Diet Score: medium adherent (HR: 0.68; 95% CI: 0.44, 1.04), high adherent (HR: 0.29; 95% CI: 0.12, 0.70. C: Carbohydrate-restricted (CR) diet, according to the CR diet score: medium adherent (HR: 1.92; 95% CI: 1.02, 3.62), high adherent (HR: 2.17; 95% CI: 1.05, 4.45).[148]

Anti-inflammatory and Cytoregulatory Lipids in the Cretan Diet

One proposed resolution to the paradoxical animal findings regarding the atherogenicity of olive oil in the laboratory is the observation that both the high fat MFA diet of the Cretans, and the low fat PFA diet of the Japanese, are rich in (n-3) fatty acids and antioxidants, in particular resveratrol, glutathione, vitamin C, vitamin E, lycopene, b-carotene, polyphenols and polyamines obtained from fruits, vegetables, wild plants, and olive oil. [97] [98-101] Additionally, both diets are enriched in α-LNA and eicosapentaenoic acid [EPA, 20:5 (n-3)] from the consumption of large amounts of fish, relative to the control countries.[159, 171, 174] Because olive oil is high in the monounsaturated fatty acid oleic acid [18:1, (n-9)] and low in saturated (n-6) fatty acids it cannot compete with the endogenous desaturation and elongation of α-LNA, or with the incorporation of α-LNA into the constituent phospholipids of cell membranes. This is particularly important in the case of red blood cell (RBC) and platelet membranes, where they act to increase the deformability of RBCs and decrease the aggreability and adhesions of platelets. [102-108]

The ratio of (n-6) to (n-3) lipids in the Cretan diet is between 2:1 and 1:1, which is very close to the dietary ratio of the Japanese, as that of hunter-gatherer societies. The beneficial effects of such a ratio and their importance in normal growth and development [109, 110] as well as in the reduction of risk for CVD, hypertension, type II diabetes, osteoarthritis and, to a lesser extent cancer, are voluminously documented in the literature.[111] [112-116] The traditional Greek diet is very low in animal fat and thus the saturated fat content is quite low (7–8%). This low intake of SFAs is complemented by the high intake of  (n-6) and (n-3) EFAs which are also rich in phytoestrogens and other phytochemicals  as well α-LNA, vitamin C, vitamin E and glutathione.[117, 118] These molecules have been shown to have hypoglycemic, hypocholesterolemic and antitumor properties in animal experiments.[119-124] Consistent with these findings is the fact that the mortality from breast, prostate, bladder and colorectal cancer is lower in both the Cretan and the AHS populations than is the case for controls. [14, 20, 86, 125-129]

The principal EFA in the US diet is LA, an (n-6) fatty acid which is the precursor to the eicosanoids – molecules which have proinflammatory and cytoproliferative effects. The EFAs are converted to prostaglandins by the cyclooxygenases and to leukotrienes (LT) by the lipoxygenases. Arachidonicacid [(AA); 20:4(n-6)] and EPA, an (n-3) fatty acid, compete for cyclooxygenases and lipoxygenases, resulting in the production of eicosanoids with opposing effects. In general, AA-derived eicosanoids, such as the 2-series prostanoids and 4-series LTs, have pro-inflammatory effects, whereas EPA-derived eicosanoids, such as the 3-series prostanoids and5-series LTs, have anti-inflammatory effects. A focus of recent research has been to understand the importance of the (n-6) to (n-3) ratio, rather than the absolute level of either species of PUFA in cancer prevention.[102, 130]

Figure 8: The major active product of the omega-6 fatty acids is arachadonic acid which is converted to the 2-series prostaglandins and 4-series leukotrienes by the action of cyclooxygenase. The 2-series prostaglandins are pro-inflammatory.  In addition to the AA produced endogenously there are vast supplies available from the diet, most notably in meat, eggs and peanut oil.  In the Western diet there are comparatively few products of omega-3 metabolism to moderate the pro-inflammatory action of excessive dietary omega-6consumption. If the amount of omega-3 fatty acids in the diet is increased, their metabolites (primarily EPA and DHA) compete with arachidonic acid for access to cyclooxygenase resulting increased production of anti-inflammatory mediators as well as a decrease in the pro-inflammatory mediators, thereby significantly reducing the ratio of pro-inflammatory to anti-inflammatory mediators.

In animal studies (rats) LA increases the size and number of tumors, whereas fish oil [containing the (n-3) fatty acids EPA and DHA] decreases the incidence of tumor formation, as well as tumor size.[131] This finding is consistent with other studies in rats that indicate that the potent inhibitors of prostaglandin synthesis, the NSAIDs indomethacin and flurbiprofen are effective at reducing the incidence of spontaneously occurring breast cancer. Epidemiological studies in humans have also indicated a potentially chemoprotective effect as result of long term consumption of NSAID drugs.[132-136] Fish oils have been used to adjust systemic levels of  (n-3) fatty acids in animals models of colon, lung, breast, pancreatic and prostate cancers to reduce prostaglandin synthesis, with resulting chemoprevrention and/or slowed growth and metastases in neoplastic disease in the laboratory setting.[131]

These studies, together with the epidemiologic evidence, appear to confirm the importance of a (n-6) to (n-3) ratio of 2:1 as being chemoprotective in cancer, and raise the possibility that (n-3) fatty acids might be used as adjuvant therapy to reduce the risk of recurrence and metastases of breast cancer in humans following surgery and chemotherapy.[132-136] Epidemiological studies have also consistently shown that fish oil consumption protects against the development of a broad range of cancers, but especially breast and prostate cancer. [137-144] Thus, it is not the absolute level of either (n-3) or (n-6) lipids, but rather their presence in a ratio of 1:1 or 2:1 that chemoprotective against a number of cancers[128, 129, 145, 146] Western diets have a ratio of 10–20:1.[147]

Figure 9: The Cretan diet provides significant protection against Alzheimer’s disease (AD) in patients who have been diagnosed with mild cognitive impairment (MCI). Survival curves based on Cox analysis comparing cumulative AD incidence in subjects with MCI at the first evaluation by Mediterranean diet (MeDi) adherence tertile (P for trend = .02). The figure is derived from a model that is adjusted for cohort, age, sex, ethnicity, education, APOE genotype, caloric intake, body mass index, and time between the first dietary assessment and the first cognitive assessment. Duration of follow-up is truncated at 10 years. Results of log-rank tests for pairwise comparisons are as follows: middle vs low tertile, ² = 4.26, P = .03; low vs high tertile, ² = 1.39, P = .23; and middle vs high tertile, ² = 0.12, P = .72.[148, 149]

Both the Cretan and the Adventist vegetarian diets confer substantial protection against the mild cognitive impairment (MCI) of aging and against Alzheimer’s disease (AD)(Figure 9)[148, 149] Interestingly, the AHS-2 results demonstrate a link between the incidence of dementia and the consumption of all meat products, including fish and poultry. This may account for added benefit of Adventist Vegetarian diet over what would be expected on the basis of its lipid constituents and the presence of some adverse foodstuffs, such as refined sugar. Perhaps meat consumption is associated with adverse effects, per se? The literature is open to interpretation on this point.[150, 151]

The two highest quality studies examining the effect of vegetarian diets on lifespan, as well as morbidity were conducted by Key, et al., and were published in 2009.[152, 153] These studies found no significant difference in lifespan between the control and the vegetarian populations in the study. However, as so often happens in studies of this kind, both the control and the vegetarian group experienced statistically significant lower rates of mortality than the general population (UK). This kind of confounding result may be due to self-selection of on average healthier people within the general population to serve as controls. Another limitation on these studies is that they were barely powered adequately to detect small to moderate differences in mortality. The vegetarian group in this study had a lower body mass index (BMI) and consequently less obesity. The incidence of CVD and cancer were not statistically significant between the groups.

End of Part 2

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45.          Jansen DF, Nedeljkovic S, Feskens EJ, Ostojic MC, Grujic MZ, Bloemberg BP, Kromhout D: Coffee consumption, alcohol use, and cigarette smoking as determinants of serum total and HDL cholesterol in two Serbian cohorts of the Seven Countries Study. Arterioscler Thromb Vasc Biol 1995, 15(11):1793-1797.

46.          Jansen MC, Bueno-de-Mesquita HB, Buzina R, Fidanza F, Menotti A, Blackburn H, Nissinen AM, Kok FJ, Kromhout D: Dietary fiber and plant foods in relation to colorectal cancer mortality: the Seven Countries Study. Int J Cancer 1999, 81(2):174-179.

47.          Jansen MC, Bueno-de-Mesquita HB, Rasanen L, Fidanza F, Menotti A, Nissinen A, Feskens EJ, Kok FJ, Kromhout D: Consumption of plant foods and stomach cancer mortality in the seven countries study. Is grain consumption a risk factor? Seven Countries Study Research Group. Nutr Cancer 1999, 34(1):49-55.

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By Mike Darwin

First, Try to Make it to the Mean

For the past two months I’ve been asking people I encounter in public places[1] the question, “How old do you think you’ll live to be?” The answer I get from non-smokers is usually a number somewhere between 75 and 90, regardless of their age. Occasionally, people will remark that they expect to live to be100, or even 120 because of “medical advances,” but mostly people put their prospects at or above the mean lifespan for people living in the US. This shouldn’t be surprising, because the mean life expectancy in the US for men and women combined is currently 77.8 years. Since nobody (except for smokers) wants to be less than average, the lowest number people volunteer is right around the mean lifespan for the population of the US, at present.

Figure 1: In statistics, a median is described as the numerical value separating the higher half of a sample, a population, or a probability distribution from the lower half. The median of a finite list of numbers can be found by arranging all the observations from lowest value to highest value and picking the middle one. If there are an even number of observations, then there is no single middle value; the median is then usually defined to be the mean of the two middle values. At most, half the population has values less than the median, and, at most, half have values greater than the median. If both groups contain less than half the population, then some of the population is exactly equal to the median. For example, if a < b < c, then the median of the list {a, b, c} is b, and, if a < b < c < d, then the median of the list {a, b, c, d} is the mean of b and c; i.e., it is (b + c)/2.

However, life expectancy is not the same as mean, or average lifespan. Rather, life expectancy constitutes the expected number of years, on average, that a particular cohort of individuals in the population will survive if the rate of mortality remains constant (until the maximum lifespan is reached).[2] Life expectancy is thus the median number of years, at birth, that a population born in a particular year is expected to survive. For instance, based on the most recent data, life expectancy at birth in 2008 was 77.8 years.[1] The good news for people in this cohort is that half of them will live longer than 77.8 years, and the bad news is that half of them will not survive to their 77^th birthday.

Table 1. U.S. Life Expectancy at Birth,

by Sex, in Selected Years

(in years)

 Source: For data through 2002, the Congressional Research Service (CRS) compilation from National Center for Health Statistics (NCHS), United States Life Tables, 2002, National Vital Statistics Reports, vol. 53, no. 6, Nov. 10, 2004. For 2003, NCHS, Deaths: Final Data for 2003, National Vital Statistics Reports, vol. 54, no. 13, Apr. 19, 2006.[3]

It is also the case that the lifespan of all of the individuals in the nation does not necessarily increase along with the reported statistical mean lifespan for the nation’s population as a whole. As an example, I was born in 1955, and if we look at the cohort survival data from that period, the median life expectancy for males from my cohort is ~ 66 years. Of course, this includes all males in my cohort, including those who died at birth, those who died in various wars, those who died as a result of youthful indiscretion (some fraction of deaths by accident, suicide and homicide), and those who died due to “random” accidents. A more precise estimate of my life expectancy (and yours) can be had by consulting the chart in Figure 2, below.

Figure 2: US life expectancy as a function of age (2008 data set).

Most people seem to assume that they are guaranteed survival to whatever the current mean US lifespan is. Unfortunately, that isn’t the case, and in fact half of them will die before reaching the mean lifespan. So, when I hear immortalists talking about living to be 120 (or longer) as a result of one or more dietary and/or pharmacological interventions or another, my first thought is, “Shouldn’t you be sure you can crawl before you try to fly?” I say this because, as the data show, it’s not all that easy to make it to “average;” half of those who try die! And if you think about it, why they died (failed) is likely to be very important; even if it was from seemingly random things like a drunk driver hitting them head on, or because they had the misfortune to have the genetic predisposition to type I diabetes.

Table 2. Age-adjusted Death Rates for Various Causes of Death

(per 100,000 population)

Source: CRS compilation from National Center for Health Statistics (NCHS), Health, United States, 2005 with Chartbook on Trends in the Health of Americans, Table 29.

Of course, most people don’t die from freak accidents; they die from fairly predictable, commonplace and to significant extent avoidable causes, as can be seen in Table 2, above. By far the largest causes of death that prevent people from reaching the statistical mean (or beyond) are cardiovascular disease (CVD) and cancer. To give a better understanding of the percentages, I’ve done a quick and dirty pie chart (Figure 3, below). By far the largest source of theoretically preventable mortality is from cardiovascular disease, and what’s more, interventions that reduce the incidence or severity of CVD also have the potential to reduce the incidence of obesity (in particular, visceral adiposity) and thus the incidence of diabetes. Growing understanding of the biology of atherosclerosis has resulted in dietary interventions, and improved treatment in the form of the statin drugs and coronary revascularization.

Figure 3: Graphic presentation of the leading causes of mortality in the US as a percentage of all deaths.

The first insight into how to prevent, and even reverse atherosclerosis, came in the early 1970s and this insight, and its clinical application have a number of important lessons for today’s ‘do it yourself life extensionists.’

When I arrived in Southern California to work full-time on cryonics in 1974, I stayed for several months with Fred and Linda Chamberlain. I hadn’t been in their home for 24 hours when I was introduced to a book and to a diet that offered the promise of “living to be 100 years old.” The book was titled Live Longer Now and its author, Nathan Pritikin (1915 – 1985), an inventor with no medical background, claimed to have found a diet that would not only prevent atherosclerosis, but also reverse it. I was skeptical at the time, but a decade later I had seen enough firsthand evidence to reconsider Pritkin’s claims. Atherosclerosis most often presents in the form of coronary artery and peripheral artery disease (PAD). While the course is variable in terms of the rate progression, the disease itself is irreversible and by the time it is clinically evident, it has typically been underway for decades.

How not Succeed While Trying: The Pritikin Diet

Figure 4: Nathan Pritikin was the classic outsider to medicine. His background was not even that of an academic, but rather that of a successful inventor who made significant contributions to industrial processes in electronics. He was a consummate scientist: a keen observer with an eye for anomalies in the world around him who generated clever hypotheses, and then hammered them into theory using well designed experiments. He was roundly vilified by the medical and scientific communities of the 1970s thru the late 1980s.  His theory, that reduction of total serum cholesterol to ~120 mg/dl, and in particular LDL cholesterol to ~<80 mg/dl, in combination with a program of weight reduction and modification of the diet to exclude simple carbohydrates, keep fat consumption to ~ 10% of calories and eliminate added salt is now widely accepted in a medicine. [2-15]

I began to see patients with severe coronary artery disease (CAD) and intermittent claudication (PAD) become symptom free and recover excellent levels of exercise tolerance. That prompted me to contact the Pritikin Longevity Center in Santa Barbara, CA in 1982 and to begin closely looking at the data from the clinical study they were doing at the Veterans’ Administration Hospital in Long Beach, CA on patients with well documented CAD and PAD. Their data were unequivocal; the diet was capable of reducing atheromatous plaques in the coronary arteries, as demonstrated by angiography, as well as reversing ST-segment changes associated with myocardial ischemia during exercise (treadmill testing).

Shortly thereafter, I began advocating (as well as personally practicing) the Pritikin diet to Alcor members, and to cryonicists in general, as a way to avoid the catastrophe of Sudden Cardiac Death (SCD), and possibly to live longer, as well.[16, 17] I learned a number of important things from that experience. The first was that very low fat diets were intensely unpleasant for most people, and that even people who were well aware that they were dying from CAD would either not adopt the diet, or became noncompliant after a short while on it.

The first lesson was thus that an intervention that works is of little use (beyond the mechanistic insights it offers) if no one will use it. I also learned that any claims for life span extension, or improved wellbeing and overall health (for any intervention), must be backed up with data demonstrating those claims. In particular, I learned that all-cause mortality was the last and the best word in validating claims of extending lifespan.

The Pritikin diet was, in fact, effective at dramatically reducing morbidity and mortality from CVD and type II diabetes.[2, 13, 14, 18-26] However, because the diet eschewed all fats and restricted the calorie intake in fats to 10-15% of the total calorie intake of the diet, with the emphasis on polyunsaturated fats. As previously noted, it proved almost impossible to persuade Alcor members to adopt the diet,[27] or even to embrace a modified version of it, wherein one day a week was a “diet free day,” during which the individual could eat proscribed foods ad lib, as he chose. Somewhat surprisingly, I am still in contact with all six of the surviving individuals who adopted the Pritikin diet between 1974 and 1985; the maximum period of compliance was 6 years, and none of these individuals is still on the diet. Three of these individuals have been treated for cancer, though I would hasten to add that I do not believe that in any of these cases the Pritikin diet was either causative or contributory.

Near Universal Noncompliance = Failure

The reasons for the noncompliance, and ultimately for abandonment of the Pritikin diet, were not difficult to ascertain. The most pressing and immediate were the near constant cravings for prohibited foods which, contrary to statement from the Pritikin Longevity Center and those present in Pritikin-approved books and publications, did not diminish over time. Hunger, per se, was not a problem, since the bulk amount of food consumed typically increased over baseline, due to the low caloric density of the foods allowed on diet.[28]  Additionally, there were serious problems with mood (irritability and depression), fatigue, reduced ability to concentrate, winter pruritis, binge eating and “constantly feeling cold,” including a much reduced ability to tolerate cool or cold environments when at rest or a low level of activity.[27] There have been no long-term compliance or all-cause mortality studies of the Pritikin diet, however one published study of a nearly identical diet showed very poor compliance at one year.[29]

Since the mid-1980s, a significant amount of evidence has accumulated indicating that the very low serum cholesterol levels required to effect the reversal of atherosclerosis can result in mood disorders leading to increased irritability, and even violence.[30-36] Studies of more modest reductions in dietary fat intake have not shown benefit in reducing morbidity and mortality from CVD or cancer, and there is the suggestion that mortality reductions resulting from decreases in CVD, hypertension, obesity and diabetes may be made up for by increases in the incidence cancer, suicide and homicide.[27, 31, 37] However, the bottom lines is that 30 years later, there is still no evidence indicating that the Pritikin diet reduces all-cause mortality, or that the non-compliance obstacle can be overcome. The absence of effect with moderate (i.e., less extreme) or so called “reduced fat” diets is especially discouraging, because it indicates the likelihood of an “almost all or none” effect with little or benefit obtained from partial compliance.[38-40] This is, in fact, the position that Nathan Pritikin took.[41]

So while the Pritikin diet met Level-1 (Evidence Based Medicine) criteria for reversing atherosclerosis (and in some cases, type II diabetes), it failed to meet the three other claims it made; namely a longer lifespan with the prospect of reaching age 100, greatly reduced incidence of cancer and a healthier happier life as a result of decreased disease burden. Despite its failure as a technique to reduce all-cause mortality,[4] the Pritkin diet was important because it demonstrated for the first time that it was indeed possible not only to prevent or slow atherosclerosis, but to reverse it, as well – and to do so by something as seemingly low technology as dietary intervention. The Pritikin diet was also effective at reversing type II diabetes in many patients, as well as reducing or eliminating the need for antihypertensive medication, especially in patients who were overweight. Despite these formidable advantages, its poor rate of compliance (negligible amongst cryonicists and life extensionists, as well as cardiac patients) and its failure to improve all-cause mortality has made it a practical failure for population-wide application. [5]

Footnotes

Calorie Restriction: First You Starve and Then You Die (Horribly)

Figure 1: Supercentenarians in “extreme old age”:  Jeane Calmette, 121; Ingeborg Mestad, 110; Walter Breuning, 114; Marie-Louise Meilleur, 117.

There’s a proven technique in animals for reaching the maximum lifespan; the longest time that animals of a given species have the inherent capacity to survive. It’s called calorie restriction, and there is a large body of animal data in an impressive range of species that says it works. There is even an ongoing project being conducted by the National Institutes of Aging (NIA) to evaluate calorie restriction in primates and it seems to be working in them, too. The calorie restricted Rhesus macaque monkeys have lower death rates, lower rates of age-associated degenerative diseases, and their overall health and activity level are dramatically better than is the case for the control animals, who are fed a diet that simulates the ad lib calorie intake by humans in the Developed World.

There’s just one catch, and that is that calorie restriction, to the extent necessary to get the individual to the maximum end of the lifespan envelope is, for most humans, a miserable experience. It is also one fraught with the potential for malnutrition and the development of eating disorders, such as anorexia nervosa and bulimia. But there’s another problem with calorie restriction in humans, and that’s that the end results are that you end up a blind, debilitated old crone or codger, and then you die.

Having said that, I don’t want to minimize or dismiss the probable very real advantages of calorie restriction in humans and they are that there is likely to be, on average, a 15-25 year extension of the healthy and reasonably productive lifespan, with a large decrease in most of quality of life eroding (and costly) degenerative diseases, such as diabetes, cardiovascular disease, osteoarthritis, dementia and very likely, tooth decay and gum disease. That’s impressive, even if it isn’t very practical for most people without some kind of pharmacological assistance.

There is also ongoing research to discover drugs that mimic the effects of calorie restriction on gene expression so that the benefits of the technique can be had without the attendant suffering and the very real risks of adverse effects on psychology and nutrition.[1] This is a promising area of research, and it will be covered here in considerable detail on an ongoing basis. However, this is not the time to start any discussion of  specific ‘evidence based’ technologies for extending healthy lifespan. Indeed, before we go any further, it is necessary to become familiar with the concept of evidence based medicine (EBM) (Figure 2).

Evidence Based Medicine

Figure 2:  Detailed Diagrammatic representation of the levels of evidence used in Evidence Based Medicine.

Evidence-based medicine (EBM), also called evidence-based practice (EBP) aims to apply the best available evidence gained from the scientific method to clinical decision making. It seeks to assess the strength of evidence of the risks and benefits of treatments, including the lack of treatment, and diagnostic tests.Evidence quality can range from meta-analyses and systematic reviews of double-blind, placebo-controlled clinical trials at the top of the pyramid (above), to conventional wisdom at the bottom.

The discrete types or levels of evidence I will be using in all my discussions here on Chronosphere are those of the Centre for Evidence Based Medicine (CEBM),  as set out in their “’Levels of Evidence’ Document” which is reproduced, below.

1. A summary of how evidence can be graded.

In simple terms, one way of looking at levels of evidence is as follows (the higher the level, the better the quality; the lower, the greater the bias):

or…

• Category I:  Evidence from at least one properly randomized controlled trial.
• Category II-1: Evidence from well-designed controlled trials without randomization.
• Category II-2: Evidence from well-designed cohort or case-control analytic studies, preferably from more than one center or research group.
• Category II-3: Evidence from multiple times series with or without intervention or dramatic results in uncontrolled experiments such as the results of the introduction of penicillin treatment in the 1940s.
• Category III: Opinions of respected authorities, based on clinical experience, descriptive studies and case reports, or reports of expert committees.

[Source: Harris, R.P. et al. (2001). Current methods of the U.S. Preventive Services Task Force: a review of the process. American Journal of Preventive Medicine. April 20 (3 Supplement): 21-35.]

Not surprisingly, the place to start in looking for any reliable method(s) of life extension is at the top of the evidence pyramid, which consists of Systematic Reviews (including well designed meta-analyses) and Randomized Double Blind Clinical Studies.

Figure 3: The EBM pyramid made simple.

The majority of “amateur interventive gerontologists,” or active “life extensionists” who are pursuing lifespan extending therapies on themselves are usually both surprised and dismayed when looking at this pyramid (Figure 3). The first reason for this is that either all, or almost all, of the interventions they are using are at the very bottom of the pyramid. The second reason for the shock and dismay (and often disbelief) is that animal and in in vitro research rank below the ideas, editorializing and opinions of medical professionals, instead of at the top of the pyramid, where most activist life extensionists typically feel they should belong.

However, the fact is that very little animal, or in vitro research has any direct clinical applicability to humans.[2-4] This is not because government regulations or “greedy” pharmaceutical companies don’t want people to benefit from disease-curing or life extending drugs, but rather, because the vast majority of that research is either bad (junk) science or it fails to translate to humans.[4-10] Even when animal studies are well designed and carried out in relevant animal models of disease and show strongly positive results, mostly these findings fail to translate to humans. There are many reasons for this, but chief amongst them is that animals, despite their high ‘percentage’ of genetic overlap with humans, are really biochemically sufficiently different that the findings aren’t applicable to humans. The public are bombarded with numbers, such as chimpanzees are 96% to 98% genetically homologous with humans; cats: 90%, dogs: 82%, cows: 80%, rats: 69% and mice: 67% (http://www.ncbi.nlm.nih.gov/homologene).  These numbers get even more impressive when it is noted that 75% of mouse genes have equivalents in humans and 90% of the mouse genome can be matched to a comparable region on the human genome. In fact, recent research indicates that ~ 99% of mouse genes turn out to have analogs in humans.

Figure 4: If we were mice, most cancers would be treatable or cured, there would be effective drugs for stroke and cerebral ischemia, and a wide range of other conditions would have effective therapies. However, we are not mice.

So what’s the problem with the applicability of animal research to humans? Well, consider that at in 3 out of ten patients the drug prescribed for them fails to work. It’s not that the patient is non-compliant or just doesn’t get better; it is that the drug failed to have the anticipated therapeutic effect. Thus, in those patients, the drug was a waste of money and time; and to the extent that it may have adverse effects, a real danger. In fact, there are 2.2 million serious cases of adverse drug reactions (ADRs) and over 100,000 deaths each year in the US. That makes (ADRs) one of the leading causes of hospitalization and death in the US! Most people take ADRs and lack of therapeutic effect in the drugs they are prescribed (or purchase over the counter (OTC)) for granted. “Oh, that doesn’t work for me,” or “I can’t take that because…” are commonplace remarks. And they apply to people who use only “natural” or herbal remedies as much or more as they do those who use “synthetic” drugs.

The reason for these phenomena is very instructive about why animal research turns out to have so little applicability to humans. The cause of the huge variation in responsiveness to drugs in humans is genetic variation between individuals; even identical twins are not genetically identical, due to mutations and to variations in gene activation (epigenetic factors).[11] There are two types of genetic variations known to impact drug metabolism; copy number variation, which results from deletions, inversions, insertions and duplications in genes, and nucleotide variations, or single nucleotide polymorphisms (SNPs). It is estimated that approximately 0.4% of the genomes of unrelated people typically differ with respect to gene copy number. The nucleotide diversity (SNPs) between humans is about 0.1%, which is 1 difference per 1,000 DNA base pairs! Combine these two numbers and human genetic variation is estimated to be at least 0.5% or, if you prefer, 99.5% similarity between individuals.[11-13]

That seemingly trivial amount of genetic variation is responsible for the observed and well documented large disparity in response to therapeutic drugs observed within the human species. Even the SNPs (pronounced “snips”) have a profound effect on the response (or lack thereof) to therapeutic drugs and they are the sources of a major research effort to develop a catalog of SNPs that can be used as a diagnostic tool to predict and individual person’s drug response. This rapidly developing area of research is called pharmacogenomics and it has already seen clinical application in cancer chemotherapy, anticoagulant dosing, the treatment of Hepatitis C and psoriasis, and in seizure disorders.[14-20]

New Drug Development: May I Suggest Roulette, Instead?

A few more words need to be said about the drug development research and success. Leaving animal data aside, most human clinical trials to evaluate refinements of existing (and proven) drugs or therapies either fail, or result in active harm.[2, 21-23] The chances of a novel molecule making it from in vitro or animal testing to clinical use in humans are ~ 1,000 to 1. You’d be much, much better off playing straight-up roulette, where the odds against you are only 37 to 1. Even in studies or clinical trials where there are ample existing theory and prior in vitro, animal research and clinical trials data that were positive and point compellingly to a favorable outcome, trials often fail.

A good example of this with direct relevance to life extensionists is the saga of vitamin E in the treatment and prevention of atherosclerosis, and in particular, coronary artery disease.There are many animal experiments showing that vitamin E reduces or inhibits the development of atherosclerosis. Epidemiological studies in humans provided robust support to these data, since consumption of vitamin E in the diet was inversely associated with mortality from cardiovascular disease.[24, 25] And to the theoreticians and mechanists, there was the perhaps even more compelling fact that the free radical biochemistry implicated as being a primary factor underlying atherogenesis (oxidized low density lipoprotein (LDL)) is favorably impacted by the addition of vitamin E and similar chain breaking antioxidants to the diet in supraphysiological amounts.[26] The free radical theory of aging also supports the idea that vitamin E and other antioxidant molecules might reduce the incidence of degenerative disease, and perhaps retard aging. Further, in accordance with both theory and the animal data, administration of vitamin E to human volunteers reduced the level of lipid peroxidation, and in particular reduced the level of oxidized LDL.[27]

Figure 5:*NHS indicates Nurses’ Health Study; HPS, Health Professionals’ Follow-up Study; EPESE, Established Populations for Epidemiologic Studies of the Elderly; IWHS, Iowa Women’s Health Study; MI, myocardial infarction; and ellipses, none.

Several prospective studies in which vitamin E was given as a supplement, including the US Nurses’ Health Study[28] and the US Health Professionals’ Follow-up Study, found a 34% and 39% reduction (respectively), in the incidence of myocardial infarction, [29] More impressively still, the  Iowa Women’s Health Study found a 47% reduction in cardiac mortality.[30] These were not small studies published in obscure journals. They were very large trials (Figure 5) and they were published in the New England Journal of Medicine. So what’s the problem? The problem was that other researchers could not duplicate the results and so subsequent, carefully designed trials were conducted.

The largest and best designed of these was the a randomized, placebo-controlled Medical Research Council/British Heart Foundation (MRC/BHF) Heart Protection Study in which antioxidant vitamin supplementation was examined in 20,536 individuals with coronary disease, other occlusive arterial disease, or diabetes mellitus. The study participants were randomized to receive vitamin E (600 mg), vitamin C (250 mg), and beta carotene (20 mg) daily or matching placebo. Intention-to-treat comparisons of outcome were conducted among all participants. An advantage to this study was that critics of earlier failed trials pointed out that vitamin E can act as a pro-oxidant in the absence of vitamin C and that it has in vitro pro-oxidant activity in cell membrane lipids under some conditions. In vivo, vitamin C is the molecule which disposes of the water soluble radical species that can be generated by vitamin E and beta carotene was added to scavenge lipid soluble radicals.

The MRC/BHF study found no significant differences between the vitamin and placebo groups in all-cause mortality, or in deaths caused by vascular or nonvascular conditions. Nor were there any significant differences between groups in the incidence of nonfatal myocardial infarction or sudden cardiac death, nonfatal or fatal stroke, or coronary or non-coronary re-vascularization. In fact, the study found that the use of antioxidant vitamins did not produce any significant reductions in 5-year mortality from, or incidence of, any type of vascular disease, cancer, or other major outcome, compared with placebo.[31]

Other studies also showed no benefit [32-34] and there was even some suggestion of harm in the form of an apparent increase in mortality and morbidity from gastrointestinal and intracranial bleeding. In 2009, a metanalysis of vitamin E supplementation trials by Dotan, et al., using Markov model analysis showed that the vitamin E supplemented “virtual cohort” had 0.30 decrease in their quality-adjusted life year (QALY) (95%CI 0.21 to 0.39) compared to the non-treated “virtual cohort.”[35] QALY is a statistical measurement tool used to evaluate not just death or discrete injurious events, such as heart attack or hemorrhagic stroke, but rather measure these events, along with all deaths or debilities as a single entity, and report them in terms of how much loss or gain of functional life occurs in a given group. This work supports an earlier metanalysis showing increased all-cause mortality associated with vitamin E doses ~500 mg/day or more. When a metanalysis was done to look specifically for the effects of vitamin E on stroke it was found that vitamin E increased the risk for hemorrhagic stroke by 22% and reduced the risk of ischemic stroke by 10%.[1]

The metanalysis indicating that vitamin E supplementation (≥500 mg q.d.) is associated with an increase in morbidity and mortality is consistent with the known effect of vitamin E in such doses on bleeding time. Supraphysiologic vitamin E antagonizes vitamin K and causes platelet dysfunction resulting in an increased prothrombin time. It is almost axiomatic in medicine that any increase in bleeding time (anticoagulation) is associated with an increased incidence of clinically significant gastrointestinal (GI) and intracranial bleeding. For vitamin E to show benefit, it would be necessary for any increase in adverse effects to be offset by the benefits it conferred. For vitamin E, this was not the case, whereas for aspirin, which also increases bleeding time and causes an increased incidence of GI and intracranial bleeding, shows such strong benefit in the reduction of myocardial infarction that it is worth the associated risk in the appropriate patient population (i.e., those 50 or over and those with known cardiovascular disease).

This kind of “reversal of fortune” happens over and over again in medicine with respect to drugs as as to other treatment interventions and it is one of the well justified reasons why the astute clinician is very skeptical about putative therapies to treat disease that have not been scientifically vetted – preferably repeatedly, internationally and in well designed and executed trials. It is thus an unfortunate reality that no matter how compelling a therapy seems theoretically or in the laboratory, it still must be proven clinically. And it is even truer that the overwhelming majority of putative therapeutic interventions either fail to work, or injure or kill the patient. There is absolutely no reason to think that this will not be the case with putative life extension drugs.

It is also usually the case that taking multiple drugs, or polypharmacy as it is formally known, negatively shifts the risk to benefit ratio (especially in the ill the debilitated or the elderly). This is so because the biochemistry of living systems is not only enormously complex; it is also interdependent and self regulating. The vast majority of drugs, or supraphysiological doses of nutrients, will perturb multiple biochemical pathways and the more molecules administered, the more likely it becomes resulting adverse interactions will occur. It is, as the Taoist maxim cautions, virtually impossible “to do just one thing” when dealing with a complex and dynamic system. Alter one part of the system in a desirable way and there will likely be consequences in other parts of it – and the odds are high that they will not be favorable.[2]

Thus, in making decisions about which putative life extension therapies to use, the most rational course is to start with those where there is Level-1 evidence of benefit. That may not even seem possible, since there are no known lifespan extending drugs or treatments in humans, let alone ones that have undergone extensive, well designed and repeated clinical trials. Or are there? The answer to that question will be the subject of the next article in this series.

Footnotes

 References

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31.          Aizawa K, Shoemaker JK, Overend TJ, Petrella RJ: Metabolic syndrome, endothelial function and lifestyle modification. Diab Vasc Dis Res 2009, 6(3):181-189.

32.          Yusuf S, Dagenais, G, Pogue, J, Bosch, J, Sleight, P.: Vitamin E supplementation and cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators:  http://content.nejm.org/cgi/content/full/342/3/154. N Engl J Med 2000;, 342(3):154-160.

33.          Lonn E, Bosch, J, Yusuf, S, Sheridan, P, Pogue, J, Arnold, JM, et al.: HOPE and HOPE-TOO Trial Investigators. Effects of long-term vitamin E supplementation on cardiovascular events and cancer: a randomized controlled trial. JAMA 2005;, 293(11):1338 -1347.

34.          Vivekananthan D, Penn, MS, Sapp, SK, Hsu, A, Topol, EJ.: Use of antioxidant vitamins for the prevention of cardiovascular disease: meta-analysis of randomized trials. Lancet 2003, 1:2017 -2023.

35.          Dotan YP, I. Lichtenberg, D.  Leshno, M.: Decision analysis Supports the paradigm that Indiscriminate supplementation of vitamin E does more harm than good. Arterioscler Thromb Vasc Biol 2009, 29:1304-1309.

Ray Kurzweil with a portrait of his father.

“It’s as if you took a lot of very good food and some dog excrement and blended it all up so that you can’t possibly figure out what’s good or bad. It’s an intimate mixture of rubbish and good ideas, and it’s very hard to disentangle the two, because these are smart people; they’re not stupid.”

– Douglas Hofstadter, author of Gödel, Escher, Bach, on the books of Ray Kurzweil and Hans Moravec. [See Ross, Greg. "An interview with Douglas R. Hofstadter." American Scientist. Retrieved 2011-08-10.]

It is not very often that I see something that simultaneously evokes sympathy, anger and pity. I am a regular viewer of ABC’s “Nightline” program which airs beginning at 2330 in most of the US. It’s part of my ‘wind-down ritual’ at the end of the day. Often, I’m reading, or otherwise engaged while the bits and bytes comprising the program make their way from geosynchronous orbit and chatter out of the television. The introduction to the 09 August program caught my attention, because it was to feature Ray Kurzweil, talking about practical immortality. Of course, I know who Kurzweil is – both of them. There is the maverick Edisonian inventor who brought us the Kurzweil Reader (and thus the CCD flatbed scanner and the text-to-speech synthesizer) and the Kurzweil who transformed digital musical instrumentation with his Kurzweil K250 music synthesizer. And then, well then there is the Ray Kurzweil who brought us the idea of the Singularity, and three books that expound scientifically bankrupt ideas for ‘do it yourself’ interventive gerontology: The 10% Solution for a Healthy Life Fantastic Voyage: Live Long Enough to Live Forever, TRANSCEND: Nine Steps to Living Well Forever.

And last, but by no means least, there is the Ray Kurzweil who made one of the creepiest movies I’ve ever seen, “The Singularity is Near,” which I viewed as a rough cut in a private screening in Europe. That film was the near perfect combination of suggested transgendered autoerotic pedophilia with narcissism of cosmic proportions. I watched it, immobilized as one is when witnessing a public beheading, or the torture of small animals in an Egyptian souk. I was immobilized in a way that only disbelief and shock immobilize you. An extended trailer of his latest documentary, Transcendent Man is available here: http://transcendentman.com/

The “Nightline” segment on Kurzweil opened as follows:

“Ray Kurzweil, a prominent inventor and “futurist” who has long predicted that mind and machine will one day merge, has been making arrangements to talk to his dead father through the help of a computer.

“I will be able to talk to this re-creation,” he explained. “Ultimately, it will be so realistic it will be like talking to my father.”

Kurzweil’s father, an orchestra conductor, has been gone for more than 40 years.
However, the 63-year-old inventor has been gathering boxes of letters, documents and photos in his Newton, Mass., home with the hopes of one day being able to create an avatar, or a virtual computer replica, of his late father. The avatar will be programmed to know everything about Kurzweil’s father’s past, and will think like his father used to, if all goes according to plan.

“You can certainly argue that, philosophically, that is not your father,” Kurzweil said. “That is a replica, but I can actually make a strong case that it would be more like my father than my father would be, were he to live.”
Said to look and sound like Woody Allen’s nerdier younger brother, Kurzweil has been working on predicting the future for decades. At age 17, he was invited to appear on the CBS show “I’ve Got a Secret” to demonstrate how a computer program he invented could compose music.

Kurzweil went on to invent optical scanners, machines that read for the blind and synthesizers. Still inventing today, Kurzweil has developed a reputation for himself from just making predictions, mostly about how fast our technology is advancing.”
The program continued to document Kurzweil’s plan to recreate his father, and he argues that this can be done by using documents, photographs and his own memory of the man. At one point, he even asserts that such an emulation would be “more like my father than my father, had he lived.”

Sympathy? Yes, I felt a great deal of sympathy because I too have lost those I have loved to death, and also suffered, and suffer still, because I lack the power to bring them back to life.

Anger? Yes, a fair bit of anger because what Kurzweil is proposing insults the intelligence of anyone who has even the sketchiest conception of what it is to be human. The idea that a person can be inferred from boxes of paper documents and photographs with technology, extant or foreseeable, let alone in Kurzweil’s possession now, is ludicrous. That Kurzweil’s insight into the nature of personhood, including his own, is so shallow and uni-dimensional goes a long way towards explaining the cluelessness with which he is pursuing his social engineering campaign to make radical life extension, cryonics and uploading socially acceptable.

The “Nightline” program was surprisingly respectful and matter of fact. Kurzwel has superb public relations people and the “Nightline” editors were amply stocked with photos, film clips and in short, a very impressive visual montage to accompany Kurzweil’s modest proposal for resurrection of the dead from letters, news clippings, old photos and presumably rent receipts and cancelled checks documenting visits to the dentist or the haberdasher.

But as even most of the most unreflective and superficial dullards understand, if only emotionally, a person is not and cannot be reconstructed from the empty wrappers of a life long ended. A few bars of melody, a scent, a fragment of a recorded voice, the taste of something long forgotten, all of these can, and do from time to time evoke in reflective and self aware people, streams of memories, and with those memories countless connections, relationships, thoughts sounds, sensations and yes, and very importantly, feelings. One of the things I found so appalling and so narcissistically selfish about the Kurzweil interview is that he is not really interested in having his father live again, rather he is only interested in having his personal experience of his father available for his self-gratification again. It doesn’t matter what his father thinks or feels, it only matters that the Avatar Father makes Kurzweil think and feel that he has been returned to life. The equation of an avatar of the person with the person himself is an utterly repellant thing, because at its root it is the penultimate in dehumanization; and I think that on some level Kurzweil must know this, since he is trying to persuade the rubes that it really is resurrection.

Consider this justifiably oft quoted sentence from Proust’s Remembrance of Things Past:

“And as soon as I had recognized the taste of the piece of madeleine soaked in her decoction of lime-blossom which my aunt used to give me (although I did not yet know and must long postpone the discovery of why this memory made me so happy) immediately the old grey house upon the street, where her room was, rose up like a stage set to attach itself to the little pavilion opening on to the garden which had been built out behind it for my parents (the isolated segment which until that moment had been all that I could see); and with the house the town, from morning to night and in all weathers, the Square where I used to be sent before lunch, the streets along which I used to run errands, the country roads we took when it was fine.”

That is the merest sampling of what a person is. And as beautiful and evocative of the complex tangle of memory, sensation, reaction and the recursion of all those things as that passage is, even a hundred million, or a billion like it would not describe the mind of the dullest human being who moves amongst us.

Actress Marilu Henner was featured on 60 Minutes because it’s a day she’ll never forget — just like every day in her life; pas, present and future.

If you still have any doubts about the staggering volume of information, not to mention the unique wetware on which it is processed, that comprises the human mind, consider the recent scientific verification that people exist who have “superior autobiographical memory,” or hyperthymesia.[1-3] These individuals have essentially complete audiovisual recall of almost every waking moment of their lives. They can “run the movie” of their life experience forward or backward in their head and extract information from what they “re-experience.” As actress Marilu Hennner, one of those identified with this trait remarked on the CBS documentary program “60 Minutes”:”It’s like putting in a DVD and it queues up to a certain place. I’m there again, so I’m looking out from my eyes and seeing things visually as I would have that day.” These are otherwise normal individuals who have no profound cuts in normal cognitive function which might be used to explain the extraordinary storage of such memory minutiae. The “60 Minutes” segment on hyperthymesia is compelling viewing, and it is available on line: http://www.cbsnews.com/video/watch/?id=7166313n

Given the flashes of such recall most of us experience momentarily and erratically in our lives, this phenomenon begs the question: are all of us recording and storing such a broad bandwidth of information? Is it that we are not storing it, or that we cannot, and for good reason, access it with such fidelity at will? The individuals who possess this capability all describe it as burdensome and at times traumatic – memories come unbidden, constantly triggered by cues in the everyday world around them. And with some of those memories come searing emotions. If we need an evolutionary reason for the stoppering-up of such a prodigious memory in dark, amber bottles, to be dispensed only in needful draughts, these people are living examples.

Kurzweil seems to be suffering from an all too common syndrome in highly successful mavericks who have a history of repeatedly proving the experts (as well as their critics) wrong. This course through life is much the same as fame – especially if it brings fortune with it, and thus the ability to surround oneself with people who either share your worldview, or who will (or actually do) agree with any idea or obsession that takes charge. Removed from the tempering focus that reality affords most people, it becomes easy to slip into a world where the line between your dreams and desires, and what is really possible, becomes blurred and then disappears altogether. Kurzweil appears to be well on his way there, if he hasn’t reach that final destination already, and that, well, that is just pitiful.

Many of Kurzweil’s ideas are crazy – a mixture of wishful thinking, inappropriate application of animal data to humans, and in the case of his resurrection scheme, poisonous and dangerous to cryonics on at least two levels. First, it is wrong – people are not scraps of paper, or even whole heaps of them. That is a demeaning idea at best, and a dangerous one at worst, if it is taken seriously. Second, while Kurzweil still commands respect, at some point the men in the media with the butterfly nets will come calling. Kurzweil’s anti-aging program is much more likely to shorten his lifespan and deplete the pocketbook of the average person, upon whom he urges its use, than it is to provide any medical benefit.

This kind of disconnected, narcissistic spiral carried out privately is a thing that evokes pity, and even shame in seeing it. Those of us who have been involved in life extension for 20, 30, or 40 years have seen it before; increasingly desperate and delusion belief that barely suggestively beneficial molecules in animal studies will confer decades of added life, and finally, the decline into frailty and death. As I watched the “Nightline” program, I realized that there is yet another advantage to cryonics that I had not previously considered, and that is the extraordinary dignity and courage with which most cryonicists confront the end of this life cycle. While many were ridiculed for their lack of realism for a lifetime, most were men and women who did what they reasonably could to live as long as possible now, made no exaggerated or unreasonable claims about cryonics – and in fact, regarded it and represented it as what it currently is – a long shot experimental procedure that may well not work, but for them was infinitely better than the alternative.

The extraordinarily accurate, generally matter of fact, and with few exceptions dignified coverage of Bob Ettinger’s passing into cryopreservation is an example. It’s a worthy example and the way we should strive to be seen. Kurzweil reportedly has cryonics arrangements with Alcor. I’m glad to hear that, because I think he is a fundamentally a very good and very decent man who shares our core values. He has improved and enriched the lives of countless people through his scientific and technological innovations. However, as I can tell you from experience, while many disabilities are now tolerated in our society, crazy and creepy are not amongst them.

References

1.            Cahill L, McGaugh JL: Modulation of memory storage. Curr Opin Neurobiol 1996, 6(2):237-242.

2.            Cahill L, McGaugh JL: A novel demonstration of enhanced memory associated with emotional arousal. Conscious Cogn 1995, 4(4):410-421.

3.            Parker ES, Cahill L, McGaugh JL: A case of unusual autobiographical remembering. Neurocase 2006, 12(1):35-49.

By Mike Darwin

Sex and Aging

It is so common place as to be almost axiomatic. The ‘rake’ or ‘slut’ who, in middle or old age, has become not merely transformed into a moralistic prude, but is completely unable to remember what it was like to be young and horny. For those of you who are young (under 40) and reading this, the full impact of what I’m saying here will be lost. That’s because you have to see this transformation in your cohorts and in your own lovers and spouses to believe it – let alone to really appreciate it.

How is it that people who once reveled in the joys of sex and even pushed or went well beyond the boundaries of permissible so uniformly become transformed into little ladies of either sex? Is it bad experiences? Is it improved social station and the respectability that often accompanies it? Mostly the answer to these questions is, “No, it is none of these things so much as it is the biology of the aging brain.”

Figure 1: How is it that what both men and women once reveled in and found unspeakably beautiful in youth, they regard with indifference or even revulsion in middle and old age?

As Robert Ettinger wisely observed, “a great many people have to be coaxed into admitting that life is better than death, healthy is better than sick, smart is better than stupid, and immortality might be worth the trouble! [1] So far, we cryonicists have not managed to find any particularly successful strategy for achieving those ends. Perhaps we should take a leaf from how successful marketing and propaganda work in most other spheres of human activity, ranging from commerce to religion, principally that sex sells.

The Big Business of Sex: Implications for Cryonics & Immortalism?

It has been estimated that the pornograophy industry in the US was a ~12 billion dollar industry in 2003. (http://www.pbs.org/wgbh/pages/frontline/shows/porn/interviews/mcalpine.html). In 2005 the national sales of the guanyl cyclase inhibitor anti-impotence drugs, such as Viagra® were reported to be $1.6 billion, Cialis® sales were $747 million and Levitra® sales were $327 million.  That’s over $2 billion dollars and it does not include the cost outlay for OTC products such as Extenz, nor for mechanical aids such penile vacuum pumps and surgical interventions. A conservative estimate is that today the sex assistance business is well in excess of $5 billion per year – and that is just in the US. If the aggregate of all sexually based marketing is considered then the figure is possibly in excess of $100 billion per annum. Thus, it is hard to argue that sex doesn’t sell.

Sexual Mortality: the Data Speak

In talking with people, young and old, about their personal sexual futures, a striking common thread emerges: virtually all of the subjects I interviewed anticipated that they would experience fairly constant, or at best mild to moderate reductions in their sexual performance with aging. In fact, nothing could be further from the truth. So called “normal healthy aging” kills sex. The sexual death rate, even amongst healthy individuals in highly developed countries, is astonishingly high. Just how bad is it? Well take a look at the graph in Figure 2, below.

Figure 2: The data above reflect the real, measured life expectancy and sexually active life expectancy inUS men and women based on data from a national survey of midlife development in the United States (MIDUS). Lindau, ST, Gavrilova,N. Sex, health, and years of sexually active life gained due to good health: evidence from two US population based cross sectional surveys of ageing BMJ 2010; 340:c810: http://www.bmj.com/content/340/bmj.c810.full

 As can be seem from the data, on average, you have about as much chance of being sexually functional (let alone functional at the level you were in your teens or 20s) at age 55 or 60, as you would have had of living to age 75 in 1800 (the mean lifespan was ~40 years then).

Figure 3: Decline in sexual function compared with decline in cognitive function in normal, healthy human aging.

 What surprises those to whom I show the data in Figure 3, above, is that sexual mortality occurs much earlier than does the loss of cognitive function. This isn’t really surprising when considered in the context of evolutionary biology. Selection pressure has optimized human reproduction to occur in the early teens to mid-20s. Reproduction in females would typically begin almost immediately after menses commenced, at age 13-14, and it was complete typically before menopause, which occurred in earlier generations at ~ 40-45 years of age. Men can (and do) reproduce longer, and their sexual viability curve reflects this. Why women have a significantly shorter sexual lifespan than men is not known with certainty, but the evolutionary biology of the female reproductive cycle, as well as the increased vulnerability of women to infection and other dysfunction of their reproductive systems, may be part of the explanation.

Sexual Morbidity

It is also important to point out that the MIDUS study data shown above only reflect sexual mortality, not sexual morbidity. If you want to see what happens to the ability of men to perform sexually as a function of age, you have only to loook to the graph in Figure 4, below. If you are male, by the time you are 40 you will a 39% chance of having erectile dysfunction to such an extent that you can no longer perform reliably sexually. As someone who has had the unique, or at least not commonplace opportunity to observe this phenomenon in a cross section of gay men, I can tell you that these numbers are very accurate, and may even be low. Many men in their late 20s and 30s are already using aids such as “erection” or “cock rings” to maintain an erection, or to achieve one hard enough to allow for penetration (see Figure 5).

Figure 4: The incidence of erectile dysfunction in aging men by decade of life. The Epidemiology and Pathophysiology of Erectile Dysfunction. The Journal of Urology 1999 Jan; 161(1):5-11

 Whilst some cock rings are used as jewelery, the primary use for these devices, in all their many variations, is to assist in overcoming ED. Nor have the guanyl cyclase inhibitors, such as Viagra, Levitra and Cialis, eliminated the problem. The usual pattern of effect of this class of anti-impotence drugs is that they work reliably and well for most men in their 30s and 40s, becomes less reliable after age 50, and cease to work adequately for a large cohort of men past age 60. There are, of course, many exceptions, but this is the general pattern. From my own questioning and research, I would estimate that ~60% of men using guanyl cyclase inhibitors who are over 55, also rely on either erection rings or penis vacuum pumps with a penile constriction band.

 Figure 5: Metal cock ring on an erect penis. Image courtesy of the Wikipedia Commons: http://en.wikipedia.org/wiki/File:Erect_Penis_with_C-Ring.jpg

If my focus here seems to be heavily slanted towards men, as opposed to women,  there are several reasons for this (aside from misogny). First and foremost, there is comparatively little data about the incidence of sexual dysfunction in women versus age. One reason for this is that in women this complaint must necessarily present as a symptom , rather than as a sign. A symptom is a “subjective” complaint, such as, “I feel hot,” whereas a sign is “measuring a patient’s temperature with thermometer and noting that it is elevated above normal.” It is possible to measure ED, includingthe degree of ED very easily and effectively in men, using a device such as an erectile dusfunction snap-test gauge. Such objectification is not as easy in women.

Additionally, most recruits and most potential recruits to cryonics are, and are likely to remain men. And men, on average, are disproportionately more concerned with sexual dyasfunction and with the preseervation of sexual vitality into old age than are women. Having made these observations, I would be both interested and gratified to see a similar article to this one written about women, and would gladly publish it here.

Lost Libido and the Transformation of the Person

 I would be doing a gross disservice to the devastating impact of aging on sexuality if I did not return to the theme I opened with, namely the obliteration of not just the libido, but of the very memory of what it was like to be a sexual being. A substantial, but unfortunately unknown percentage of people turn into little old ladies of either sex, as they age. They lose not only their ability to perform sexually, but also their desire to do so, and what’s worse, even the memory of what it was like to feel sexual excitement and passion. Such people often become critical of sexual desire and sexual activity in others, and often take to accusing their partners, or younger people with whom they interact, of being excessively preoccupied with sex, or of being “sex fiends,”or in modern parlance, “sex addicts.” While they may have had quite active and adventurous sex lives when younger, they are now judgmental and incredulous at levels of sexual activity in others that would be modest, even for middle aged people!

This is a special kind of horror, because it represents the loss of part of one’s personhood. Sexual activity and sexual desire are a not just a normal part of life, they are one of the most critical predictors of both healthy aging and of longevity. Their absence is not something to be accepted as healthy, but rather, as a potent indicator of a pathological change.

Figure 6: The loss of libido and the transformation of the person from libertine to prude is primarily as function of the degeneration of the brain associated with “normal healthy” aging.

Mistaking drugs to treat ED for drugs to treat loss of libido and atrophy of even the capacity to remember and identify with healthy sexual desire and functioning would be a tragic mistake. These drugs work to restore the ability to get and maintain an erection by increasing the levels of nitric oxide in the body – and in the erectile tissues of the penis, in particular. They do not restore the brain-derived basis of sexuality – libido and its passionate execution. There are drugs which restore libido and mounting behavior in aged animals, and there is evidence that they work in some humans. I will be covering that topic here in the near future.

In the meantime, a potentially powerful message is that our sexual longevity is much, much shorter than our lifespans, and what’s worse, our healthy and vital sexual longevity is much shorter still – for both men and women.

There are many take home messages from these data. For one, enjoy sex as much and as often as you can when you are young. It won’t be there nearly as long as you think – and practice and varierty do, in fact, improve the quality of the experience. Pay attention to what you may be able to do to extend your years of both peak and total sexual functioning.

Finally, use these data relentlessly to reinforcve the point that life is too short and that vital sexual life is much shorter still. The ultimate answer to those problems is extension of the youthful, healthy lifespan and, when all else fails, cryopreservation until we reach a point in time when these problems are not merely tractable – but possibly a thing of the past – with not just treatment of disease – but enhancement of sexual function being a taken for granted reality. If you doubt the latter and you are under 30, or better still, 20 or 25, just try the particular flavor of guanyl cyclase inhibitor that works for you. You will quickly come to see my point here, because you will, at that moment, realize that you have forgotten what it was like to be 16 years old.

The choices are simple really, do you want to be in this position…

…or in this one:

Selected Bibliography

Lindau ST, Schumm P, Laumann EO, Levinson W, O’Muircheartaigh, C, Waite L. A national study of sexuality and health among older adults in the US. N Engl JMed 2007;357:22-34.

Davey Smith G, Frankel S, Yarnell J. Sex and death: are they related? Findings from the Caerphilly Cohort Study. BMJ 1997;315:1641-4.

Palmore EB. Predictors of the longevity difference: a 25-year followup.Gerontologist 1982;22:513-8.

Laumann EO, Nicolosi A, Glasser DB, Paik A, Gingell C, Moreira E, et al. Sexual problems among women and men aged 40-80 y:prevalence and correlates identified in the Global Study of Sexual Attitudes and Behaviors. Int J Impotence Res 2005;17:39-57.

Schoenfeld DE, Malmrose LC, Blazer DG, Gold DT, Seeman TE. Selfrated health and mortality in the high-functioning elderly—a closer look at healthy individuals: MacArthur Field Study of Successful Aging. J Gerontol (AMedical Sciences) 1994;49:109-15M.

Laumann EO, Michael RT. Sex, love, and health in America: privatechoices and public policies. University of Chicago Press, 2000.

DioknoAC, BrownMB,HerzogAR.Sexual functionintheelderly. Arch Intern Med 1990;150:197-200.

Burke JP, Jacobson DJ, McGree ME, Nehra A, Roberts RO, Girman CJ, et al. Diabetes and sexual dysfunction: results from the Olmsted

County study of urinary symptoms and health status among men. J Urol 2007;177:1438-42.

Solomon H, Man JW, JacksonG. Erectile dysfunction and the cardiovascular patient: endothelial dysfunction is the common denominator. Heart 2003;89:251-3.

Hartmann U, Philippsohn S, Heiser K, Ruffer-Hesse C. Low sexual desire inmidlife and older women: personality factors, psychosocial development, present sexuality. Menopause 2004;11:726-40.

US Food and Drug Administration. Drug details: Viagra. Washington, DC, 2009.

AvisNE, Brockwell S, Randolph JF, Shen SH, Cain VS, OryM, et al. Longitudinal changes in sexual functioning as women transition through menopause: results from the Study of Women’s Health Across the Nation. Menopause 2009;16:442-52.

43 Matthias REL, James E, Atchison KA, Schweitzer SO. Sexual activity and satisfaction among very old adults: results from a community dwelling Medicare population survey. Gerontologist 1997;37:6-14.

By Mike Darwin

A short while ago the comment appeared on a medical list serve where I post in response to the article “Going, Going, Gone…” which appeared here on Chronosphere about brain aging and the need to develop effective strategies to halt and reverse it. (http://chronopause.com/index.php/2011/05/30/going-going-gone/, http://chronopause.com/index.php/2011/05/31/going-going-gone%E2%80%A6-part-2/, http://chronopause.com/index.php/2011/05/31/going-going-gone-part-3/):

“This is really depressing.  I am 58 years old and still trying to “learn” a number of things.  It does explain that I have to really work at what comes easy to my kids (25 – 35yrs old). I can stay on top of computer and tech stuff just by working at it a bit. The real drop has already hit in music.  I started back playing music at 50 and although practice a lot and absolutely love to play, I can see that I need the lyrics, chord progression and such even for old songs that I played 35 – 40 years ago.

 I’m in a new job and out of critical care on a day to day basis.  Again, I see the slippage.  I have to work really hard to keep up with the changing literature, new drugs, and details of mechanisms of action etc.

 So now I read it doesn’t matter, and my brain is already 50% fried – perhaps more.

On a slow decline with increasing speed into the twilight of existence.. Not a pretty thought.

 R.A.”

What follows was my response. I wish I could have been more specific, more positive and more activist in my response. However, past experience has shown it would do no good to suggest that support be given to cryonics, or to interventive gerontology research. It is not possible to reach people in this community in that way. Sadly, all that can be done is to raise awareness in the younger readers of such lists, often at the expense of considerable emotional discomfort to the older ones. This approach isn’t particularly just, but I see no alternative. Thus, I am very much hoping for insights from others who will read this here and perhaps be able to suggest how to take sparking awareness of impending death and decay into something more immediately productive:

Incredible! And I’m not being either snide or cruel here; finally somebody get’s it!

What I’ve been trying to say for a decade and half here on this list serve (and much longer elsewhere) is that medical progress to date has been both relatively and, in an absolute sense, illusory. And history will record it as such, and you will be just another sad, anonymous and forgotten statistic.

Figure 1: Sir Astley Cooper (1768 –1841).

In the past, people died very young and mostly “functionally old” (i.e., in their 60s and 70s). They died en masse of infectious disease, they died as children and young adults. They died horribly. An excellent and very worthwhile read is the new biography of Sir Astley Cooper, Digging Up the Dead:Uncovering the Life and Times of an Extraordinary Surgeon (ISBN-10: 1845950135). I am a hardened SOB, long exposed to animal research and human suffering in the clinic, and I had to put that book down at several points, because it upset me too much to read on. Life for the sick and dying was worse than I had imagined; and I am a serious student of medical history. Life for experimental animals was unspeakable.

Figure 2: Today we have antisepsis, anesthesia, and injectable pain killers. Medical and dying have been made seemingly more palatable. But are they, really?

 Now we have antisepsis, anesthesia, parenteral pain killers, effective anxieolytics…life is better, right (Figure 2)? Well, both relatively and absolutely, I suppose that’s true – but much depends on what you want and expect from life. The fact is that most people were just as content to suffer and die in 1760 as in 1960 or in 2011. They did so in more pain, but they had some advantages we don’t; namely they almost always remained cognitively intact, and they had a more credible and matter fact belief in religion and a well specified afterlife that was both eternal, and included friends and loved ones.

Figure 3: Then and now: At left above, a tuberculosis (TB) ward in the late 19^th or early 20^th century was a place fear, loneliness and often little or no hope. A contemporary nursing home (above, right) is little different, except that the people dying there are, on average 30 or 40 years older and they, unlike the TB patients of the previous centuries, know with certainty that for them there will be no escape.

Today, you stand a very good chance of being demented if you live long enough – sometimes pleasantly so – mostly not. In 1760 people simply denied their basic condition. They didn’t think about it and mostly they didn’t look at it. Just consider the current to-do about Betty Ford making breast cancer a “de-stigmatized” illness. When I was a child, people whispered the word cancer, and all kinds of people died of it without any acknowledgement that that was what was what was happening. There was near complete denial. That is exactly as it was with TB, and other horrors as bad or worse, right into the first half of the 20th century. The situation was too horrible to be “looked at in eyes.”

Consider nursing homes and the cognitive and other functional declines of aging today (Figure 3). We simply refuse to see the magnitude of the horror. We refuse to see it. If we could honestly be objective about it, it we would be not just depressing, it would be terrifying. It turns out we have a deeply embedded psychological defense called “terror management” that kicks in to prevent us from being objective and seeing our situation. This is useful, because we’d be even crazier than we already are, if it were not present. The cultural anthropologist  Ernest Becker came to a similar conclusion in his brilliant book, The Denial of Death (ISBN 0-02-902310-6).

Figure 4: Death is death; the end result is the same; non-existence and oblivion. It is also an illusion that the horror and suffering are really less today than they were yesterday, or will be tomorrow. If anything, extension of the mean lifespan in the absence of regenerative and rejuvenating medicine extends the period of suffering and increases the terror. The average lifespan of a patient with Alzheimer’s disease is 8 years from diagnosis to death. More people are interned in extended care facilities today than were ever imprisoned at Auschwitz, Dachau, or all the Nazi concentration camps combined. And unlike many patients dying from infectious disease in the previous centuries, patients in nursing homes and care facilities (if they are not demented) know that for them there is no hope of escape. That is a condition that even the Nazis never managed to uniformly impose on their victims.

We can look at the early and pre-20th century world and shudder, whilst briefly considering it, because we can see the horrors and appreciate the impossible magnitude of the suffering. We are now distant from that, and our situation is “better.” And, in some ways, it is. We do live longer, and early mortality is largely gone. People get to see their grandchildren and often their great grandchildren. But, they still die horribly, depending upon your definition of horrible. If your brain and abilities and body decaying and falling to ruin is acceptable to you and considered inevitable, then there has been a huge absolute improvement in the human condition. Ideally, You might indeed get to be Jane Fonda or Cher, instead of the hobbling, nearly blind, pain-ridden old people that you may remember from your childhood. That’s good, but it is only a delay; you will get to the bad part and it will be sooner, rather than later (Figure 4). As Cicero said, “Nothing that has end is long.”

Figure 5: The Singularity is I fear, not near.

I don’t believe in any magical technological Singularity where we will all wake up someday soon; both immortal and in utopia.

Bullshit.

The best you can hope for is that medicine reaches the same pace of advance now present  in consumer electronics, where every device you buy (literally) is in the trash 2 years later – I just yesterday brought home an ENVISION 19″ flat screen monitor, thoughtfully returned to its original box before being pitched in the trash. But, that isn’t likely to happen in medicine, because we aren’t fault-tolerant in developing new technologies in that area, and we can’t relentlessly experiment on the marketplace (human beings) with the same abandon the makers of iPads, printers, and MP3 players do. So, it will be a long, hard, slow slog.

And again, for those who have already accepted and comfortably surrendered much of their youthful capability, aging and death aren’t so bad. However, be aware that a lot of that acceptance is because of terror management and the fact that what is really happening is hidden from you until someone like me rubs your nose in it; for which I will no doubt be punished severely.

This is your reality and mine, and no one escapes it:

Figure 6: Loss of cognitive capabilities is universal; no man or woman who lives past their teenage years escapes them. The graph above shows the average rate of cognitive decline in humans. Two cognitive functions, verbal ability and numeric ability, show improvement in the middle decades of life as a result of accumulated life experience.

If we survive as a both a humane and a technologically sophisticated species, there will come a time in the not too distant future, when people will not grow old and die as we do. They will have other problems, most of which we can’t even guess at. And it won’t be utopia; any more than your life with computers and the Internet is utopia today. But rest assured, it will be vastly better than the life you are leading and losing now. And those people will look back on this time and they will shake their heads, and they will turn away when they can, and when they can’t, they will weep.

But they will NOT weep for you. They will weep for the whole sordid situation that was the human condition in the first decades of the 21st century. They won’t weep for you because you will be forgotten – utterly and completely forgotten as the person you were – even if you are Cher, or the best, the richest, and the most famous surgeon of your day, as was Astley Cooper. And who really remembers him?

In London, the inevitable has happened and the cemeteries, too expensive to maintain, are being abandoned to become urban wilderness preserves; the tress are growing up, the tombstones being overturned and buried, and in another 50 years it will all be a dim memory (Figure 7).

Your death will make as much, or more accurately, as little sense as the deaths of all those anonymous souls who coughed their lungs out a bit at a time from TB. Keats and Poe: yes their deaths from TB are remembered, as are their works. But they are not remembered. And here, here is the final and most important insight I can try to communicate: only you can remember yourself. And when you are dead you are, in fact, gone and gone forever. And no one will be able to, no matter how much they would like to (and mostly they wouldn’t), remember you. That is the central and ultimate tragedy in your life and the universe doesn’t give a damn. Blind evolution “made” you and it will just as blindly and uncaringly kill you. It will do so without malice and without “intent.” It doesn’t care because it can’t – anymore than a TB bacillus could care about the death of Keats, or Poe, or Chopin.

Figure 7: No marker or monument endures and no man’s life, let alone his personal identity, can be written down on paper in words.

Either you understand that, or you don’t. If you do understand it, then either you face it and decide to fight, or you decide to turn away and accept oblivion. That is a highly personal decision. But I would caution you that if you choose to join the ranks of the dead, rather than fight to stay amongst the living, sooner, much sooner rather than later, nobody will give a damn, or even remember who you were – beyond a name on a genealogy chart, or perhaps a brief biography Or if you are both extraordinary and lucky (or in reality, both), maybe even a book-length biography. If 250 or 350 or 650 pages of print is who you think you are, and all you think you or are, or even just the most important part of who you are, well then, your fate is sealed, even if it is not just.

We do not now inhabit a just world and it will a long while, if ever, before we do.

WHAT ABOUT THE SINGULARITY AND OUR IMMINENT RESCUE BY ADVANCES IN GERONTOLOGY?

Figure 19: Putative technological timeline for the development of technologies now thought to be required to rescue patients from cryopreservation. This timeline assumes optimistic but reasonable dates for the development of the required technologies. If this timeline is considered realistic, then maturation of the technologies required to extend lifespan indefinitely for most people now living who are aged 30 or older will not be developed with sufficient rapidity to prevent their being cryopreserved. The times for these events were culled from predictions made within the last by experts in the respective areas as obtained from peer-reviewed articles in a wide range of scientific journals. This graphic compilation and the placement on the timeline are by Mike Darwin, October, 2010.

A common response to this problem in the Cryonicist/Immortalist/Transhumanist community is to invoke the ‘coming of the Singularity,’ a near future time when societal, scientific, and economic change is hypothesized to be so fast we cannot even imagine what will happen from our present perspective, and when humanity will become ‘posthumanity.’¹¹⁸ Unfortunately,  predicting with precision when the Singularity will happen (or even if it will happen at all) is likely to be about as accurate and reliable as predicting when the San Andreas fault will rupture, and as a consequence,  when those of us living in Southern California will experience ‘The Big One.’¹¹⁹ Two generations have come and gone since seismologists first began warning Californians that the Big One was imminent: inevitable yes, but imminent – that’s a vague word when it comes to predicting the future – whether in the case of earthquakes – or technological advances. A careful examination of the time course of the various technological developments required for practical biological immortality, or even for dramatic life extension, as illustrated in Figure 19, gives no grounds for optimism about near-term rescue from senescence.

Beyond analyses like those in Figure 19, there are lots of more mundane reasons why technologies do not develop at anywhere near the rapidity we (or even the experts) think they will. Half a century ago, at the dawn of the ‘Atomic Age,’ there were confident predictions that nuclear power plants would be everywhere, and that ultra-rapid transcontinental atomic-powered trains would be a reality. The fact is that both of these developments were eminently practical – no fundamental technological advances were required. They didn’t happen because there were hidden real or perceived costs in nuclear energy – costs that were deemed so great that the development of these technologies has been stalled for half a century.^120,121 The enabling technologies for the definitive treatment of aging, such as genetic engineering, stem cell therapy, and nanotechnology, are vastly more problematic and fraught with hazards than was nuclear power and, as a consequence, it is prudent to anticipate that there will be delays and unexpected costs in their implementation.^122-124

Figure 20: Nuclear energy, known as atomic power in the middle of the last century, has been stalled in technological limbo as a result of difficult and largely unanticipated problems associated with it, such as spent fuel disposal, vulnerability to terrorist attacks, and the potential for accidental, uncontrolled release of radioactive materials into the environment.

In addition to the socially obnoxious or technologically hazardous aspects of life extension-enabling technologies, there is also the issue of paying for the enormous cost of their safe and responsible development. 1/2MT, coupled with irresponsible global fiscal policy, has put an enormous and inescapable strain on the economies of the developed world for the foreseeable future. Without doubt, one of the best arguments for radical life extension is the high cost of caring for senescent individuals.

Figure21: Health care costs over the course of human life span are clustered near the end of life, with 2/3rds of all health care dollars being expended in the last two decades of life.

Figure 21 shows how aging rapidly escalates the cost of healthcare near the end of life. As a result of mean life span extension due to 1/2MT, the cost of caring for an increasingly elderly, nonproductive, and ultimately moribund population will rapidly become astronomical, if not altogether unsupportable. The hard reality of this can be seen in Figure 22, which shows the cost of health care for Americans as function of time and a percentage of the Gross Domestic Product (GDP). Thus, the irony is that people who take good care of their health and ‘stay healthy’ actually incur greater health care costs than do those who fail to do so – extension of life span using 1/2MT carries a high cost, indeed.¹²⁵

Figure 22: US healthcare costs projected to 2015 as a percentage of the GDP.

Currently, health care consumes ~16% of the GDP, and within 5 years healthcare costs will be in the range of 22% of the GDP,¹²⁶ an amount that is not considered sustainable by economists of any ideological or political stripe. Nor is it conceivable that increases in productivity due to technological advance will serve to bail us out of this fix, or otherwise even partially offset these staggering costs. It is already too late to rescue the individuals who will be generating these expenses (and in fact are generating them now) from senescence. A practical consequence of this will be that money to pay for the research and development of the enabling technologies to slow, prevent, or reverse age associated morbidity will also likely be delayed or altogether absent. These truly unprecedented and frightening costs associated with modest life span extension as a result of 1/2MT will undoubtedly have serious societal implications, as well.¹²⁷ While it is impossible to predict the future in this regard, it is quite conceivable that there will be a backlash against biomedicine as a result of the hard decisions that will be required, and the shortages both in medical care, and in basic resources that are likely to result.

100 BILLION NEURONS AND COUNTING – DOWN

Figure 23: Left, decline in accommodation (in diopters) as a result of aging: maximal and minimal accommodative amplitudes as a function of age as measured by the ‘push up’ technique in 150 human subjects (Duane 1912) and loss of close accommodation versus decrease in gray matter with age.

As previously noted, the loss of neurons and raw cognitive capability appears to be linear and closely correlated with the age-associated loss of function in other structures/systems that have little or no provision for maintenance during the course of the individual’s life. Loss of close accommodation, also known as presbyopia, occurs in all people who live to age 50 or beyond. Presbyopia results primarily from stiffening of the crystalline lens of the eye due to cross linkage, denaturation, and other damage to the crystallins, the class of proteins that gives the lens its unique optical properties.[1] Degradation of the crystallins, along with other age-associated changes, is the reason people middle-aged and older require reading glasses; the lenses of their eyes are no longer able to focus, or to accommodate sufficiently, to allow for close-up vision.^128,129

The nucleus of the lens is compromised of fibers that are derived from cells produced during embryogenesis, which become engorged with crystalline proteins and then experience loss of both the cell nuclei, as well as the other intracellular organelles. These fibers are thus acellular and have no internal machinery for maintaining or replacing the crystallins. Some secondary lens fibers are produced during adult life, but the optical ‘core’ of the lens, the nucleus, consists of fibers that are nonviable and experience little or no protein turnover following infancy.

I’ve plotted the loss of close accommodation against the loss of gray matter in Figure 23. This is a useful comparison, because when close accommodation drops below 3 diopters of true accommodation, it can no longer be ignored, and reading glasses or other corrections to vision become necessary. Because the decay in close accommodation leads the loss of cerebral gray matter, and approximates the beginning of the steepest period of decline in white matter integrity, it may be used as a personal (and near impossible to ignore) indicator of deterioration in cognitive function. It is also almost certain that the progressive, lifelong stiffening of the lens, and the similarly progressive lifelong decline in gray matter volume (beginning at ~ 4-8 years of age) reflect absence of ‘maintenance programming’; in other words, there was insufficient evolutionary pressure to provide for ongoing housekeeping to maintain viability, or to replace damaged cells/structures in these organs. Neurons do not typically divide in mature mammals, and the lens crystallins, which comprise the lens optical fibers, are not replaced after they are laid down during fetal development, or at latest, in infancy or early childhood. The anatomical consideration which underlies this fact is that because the lens capsule completely encloses the lens, the lack of vascularization prevents large scale transport of structural nutrients into the body of the lens to allow for replacement or remodeling of degraded lenticular fibers.¹³⁰

The crystallins derive their carbon-14 (¹⁴C) content from atmospheric carbon dioxide (via ingested vegetation[2]) and in this way share a feature in common with plant life.¹³¹ Perhaps one of the few redeeming benefits of the atmospheric testing of atomic weapons during the 1950s and 60s is that it resulted in a large pulse of atmospheric ¹⁴C, which subsequently found its way into developing fetuses in gestation at this time. This allows for carbon dating of lens crystallins by comparing the ¹⁴C concentration of the lens crystallins to the ‘bomb pulse’ of ¹⁴C release that occurred during the era of atmospheric nuclear weapons testing, using tree rings from the same period as a reference.  As it turns out, ¹⁴C concentrations fluctuated distinctively year by year with the number of open air tests, and this has allowed for precision dating of lens crystallin proteins. The results of these studies have proved conclusively that almost all lens crystallins are elaborated during fetal development, with only miniscule (and steadily decreasing) additional synthesis over the course of life.¹³¹

Far more importantly, this technique has also been applied to the nuclear DNA of human brain neurons, with careful control for local variations in ¹⁴C levels, as well as excellent study design to exclude any possible contribution to the ¹⁴C of neuronal DNA via DNA methylation. The result of this study has demonstrated conclusively that there is essentially no neuronal cell division in the cerebral cortex of humans after the perinatal period.¹³² In the case of both neurons and glial cells, the brain cells that we are born with are all that we will have for the remainder of our lives. While neuron components such as cell membranes, organelles, and vesicles undergo dynamic molecular turnover, neuronal and most glial cell DNA, remain atomically unaltered throughout life.  The stunning conclusion to be drawn from this research is that the very atoms that comprise our neuronal DNA at, or shortly after birth, are the same ones that we will die or enter cryopreservation with!¹³³

The implications of this cutting edge research for cryonicists who wish to avoid the neurocognitive devastation inflicted as a consequence of aging are obvious, and need not be belabored here. Unfortunately, mature, clinically available, and FDA-approved therapies to slow or halt brain cell loss are a decade, and likely closer to two decades, away. And when clinical application does come, it will likely be only for the most serious disease states, such as AD, Huntington’s Disease (HD), and Amyotrophic Lateral Sclerosis (ALS). Even in these conditions, access to treatment may be limited by many factors, including high cost and government regulation. Thus, for many of us, even another decade of waiting will be too long.

So what are we to do? There are, encouragingly, many technical approaches to slowing and even to achieving dramatic reversal of cerebral atrophy in aging – none of which call for exotic and invasive procedures such as implantation of stem cells or genetically modified cells into the brain (procedures which also carry great risk of complications, as well as likely unaffordable costs). As hinted at in the previous discussion here of the pleiotropic effects of many of the antidepressants, there has been a very recent explosion of insights that would seem to allow for sophisticated pharmacological manipulations to reduce the loss of brain cell mass and cortical neurons. There is also the less certain prospect of inducing genuine (but limited) CNS regeneration by systemically administered drug treatment. These are topics I will explore in detail in a forthcoming article. The issue at hand here and now is: what are the organizational and strategic approaches that can, and indeed arguably must, be implemented to extend our lives and preserve our cognitive function, NOW.

AN URGENT LESSON FROM THE AIDS EPIDEMIC

Figure 24: The heart of the gay Castro District, much as it looked in 1981 when I was in San Francisco, and AIDS was just beginning.

One of the hardest things for people to understand is that it is possible to do good, without doing good enough; and nowhere is this more the case than in medical research.

In 1981, the carefree and hedonistic place that was the Castro District in San Francisco began to sprout signs in the shop windows along Castro Street showing pictures of peculiar lesions on the skin of young gay men.

Those lesions were Kaposi’s sarcoma (KS) and the puzzle was that this skin cancer, which was almost exclusively a disease of elderly Mediterranean Jewish men, was now appearing on young urban gay men.¹³⁴ It was a slow growing cancer in the elderly Mediterranean Jewish men – but not in the young gay of men of ‘the Castro’ – in these men it was an aggressive and rapidly fatal disease. The new disease had a tentative name: Gay Related Immunodeficiency (GRID), and it soon became apparent that KS, and an unusual and formerly rare type of pneumonia (Pneumocystis carinii pneumonia (PCP)), were just the two most common presentations of what was soon to become a terrifying and lethal epidemic.¹³⁵ Within a short time it would become apparent that GRID was not confined to homosexual men, as cases surfaced in hemophiliacs, and shortly thereafter in Haitian immigrants to the US. The disease got a new name: Acquired Immunodeficiency Syndrome (AIDS).¹³⁶

Figure 25: Photographs of formerly healthy young men began to appear on handmade placards placed in the windows of pharmacies and other businesses on Castro Street, showing the disgusting and terrifying lesions of Kaposi’s sarcoma in mid- to late 1981 and urging immediate medical attention.

Figure 26: The terror sets in: every potential (or actual partner) came to be viewed a potentially lethal encounter.

AIDS was an utterly mysterious disease, and as it would turn out, a surprisingly exotic one. Nothing in the history of infectious disease provided any precedent.  For two years there was not even the barest clue as to what the etiologic agent might be. Speculation raged, with some taking the position it was due to chemically induced damage to the immune system from a combination of recreational drugs, including inhaled nitrates (‘Poppers’).¹³⁷ In the midst of the uncertainty, one thing was certain – AIDS was a uniformly lethal disease, and a lot of gay men were infected with it. Still, it was not until ~2 years after the epidemic began that the terror began to become more or less universal amongst urban gay men. Universal terror required that most of the target population know at least one person who was dead or dying of AIDS. That point was reached by July of 1982, when a total of 452 cases, from 23 states, had been reported to the Centers for Disease Control in Atlanta, GA (CDC) and certainly by November of 1982 when that number had jumped to 716 cases.¹³⁸ What happened next was arguably more amazing than the disease itself.

For the first time history, an utterly lethal (and gruesome) disease was targeting a small, relatively affluent minority that was both young and marginalized. These men also comprised a combination of male and female behavioral characteristics that would prove invaluable in shaping their response. Being male, they had the testosterone fueled aggressiveness of straight men, while being gay conferred on them the ‘feminine’ traits of verbal fluency, expertise in the arts, the service industries, and communications. Dying young men with no wife and children to distract them, and with time on their hands as death stalked them, became angry and radicalized. Indeed, the latter two ingredients were already in place as a consequence of their outsider and often vilified status as homosexuals, in a ghettoized and politicized urban environment. The gay rights movement had already set the stage for what was to come.

Figure 27: Radicalization lead to in-your-face and confrontation demonstrations that commanded the attention of the media, the political infrastructure, and most importantly, other gay men with substantial talents and energy, as well financial resources to bring to bear on the problem.

By 1983 demonstrations, peaceful and otherwise, had begun, and those men who found themselves or loved ones dying of AIDS decided to take both research and treatment into their own hands. Broadly, this effort took two forms: intense lobbying and application of pressure within the system to obtain government money at every level to support research and provide care for the dying, and the creation of the ‘AIDS Underground’: a guerrilla effort to find or to develop treatments that would do anything to improve the situation for those ill with or dying of the disease. Those efforts ranged from finding more effective ways to manage symptoms, to a full blown effort to find a definitive cure.  Importantly, any advance in treating the illness and extending the lives of patients suffering from it, was the subject of underground research efforts.

Almost from the start, this effort exhibited a surprising degree of coherence and organization, probably because it sprung from underground newsletters, published by well- organized and detail-oriented personalities, exploring novel treatments and explaining how to manufacture the molecules – or smuggle them into the US. A fascinating and heart-rending account of the AIDS underground is given in the book One Boy at War: My Life in the AIDS Underground by Paul Sergios (ISBN-10: 0679418393).¹³⁹

Very quickly, gay physicians and scientists began the systematic evaluation of putative compounds to cure, slow the advance of, or even just to treat the various illnesses – from PCP to opportunistic intestinal parasites. From these efforts sprang many useful treatments, including two of the first truly effective antiretrovirals, Dideoxyinosine (DDI) and dideoxycytidine (DDC), inhaled aerosolized pentamadine as a prophylaxis for PCP, and several non-FDA approved antibiotics for the relentless (and lethal) diarrhea caused by cryptosporidium.   Given the small size, marginalized, and minority status of the affected population, truly staggering amounts of money were raised and funneled into precisely targeted research efforts aimed not just at ‘finding a cure’ but at finding effective treatments that would extend the lives of dying men long enough to reach a cure – a completely new idea at the time. In this effort, the gay community was astonishingly effective. They succeeded in redirecting government and private money (completely out of proportion to other healthcare priorities) to mechanistic and empirical drug research. They forced restructuring of Federal (US-FDA) drug approval process for HIV drugs, and they radically altered public perception of and attitude towards the disease by using leverage in the entertainment and  publishing industries, where they had special entre.  As someone who was involved in this AIDS Underground effort, I can attest to its effectiveness, and I personally know of at least two people who were actively dying of AIDS, who are still alive today because they received underground treatments which permitted then to survive until the advent of the protease inhibitor drugs, and the emergence of Highly Active Antiretroviral Therapy (HAART).

AN EXTRAORDINARY AND UNPRECEDENTED RECORD OF ACHIEVEMENT

These men were, by and large, non-scientists, though they had the extraordinary good sense to seek out and find gay men who were scientists, as well as members of the heterosexual scientific establishment who understood their research priorities and who were willing to spend the money raised not as they would have perhaps chosen, but rather how the men who had raised it wanted it to be spent.

While most involved understood the need to undertake complex, long-term mechanistic research in order to understand the pathophysiology and natural history of the etiological agent, that research was in no way to take a back seat to finding effective treatments for the opportunistic infections, AIDS wasting syndrome, and other ancillary diseases that were the proximate cause of the loss of lives for the majority of the men dying from the illness.

Additionally, basic mechanism studies were to be prioritized, and focused not on niche-type research to explore an isolated signaling mechanism, or an observed change, say, in cell morphology, but rather to fund projects that would return insights leading to almost immediate improvement in treatments. A global high priority was to identify and characterize the etiologic agent; and the gay AIDS research community, realizing that the US government was spending tens of millions of dollars on this effort, wisely chose to put their money into the hands of a scientist, Luc Montagnier, with the best track record for this kind of research, who was working at an institution that was sensitive to their priorities and concerns: The Institut Pasteur, in Paris, France. In this approach they were wholly justified, and the Institut quickly isolated the HIV virus as the causative agent of AIDS – leading to the sad spectacle of the US CDC, in the person of Robert Gallo, subsequently trying to usurp credit for this discovery.¹⁴⁰

So, let us pause here and do a recap of what happened in the case of AIDS between 1981 and the time the causative organism was identified and a diagnostic test developed:

1981: The Disease is medically identified with fewer than 50 cases reported. This identification took place because a gay physician, Joel Weisman (a DO with a practice of almost exclusively gay men working Los Angeles), noticed unusual symptoms in his patients and began a collaboration with world-renowned UCLA immunologist Michael Gottlieb, leading to publication of the first article on GRID in the New England Journal of Medicine that same year.¹⁴¹

1982: Radicalization, and ultimately ‘militarization,’ of a small, but vocal and increasingly powerful cadre of men who became organized and who used a variety of directly confrontation attacks on the scientific, regulatory, and government infrastructure of the US – including confrontations with the President of the United States and the Catholic Church. Grass roots efforts were also begun to raise money and create NGOs to further a community-determined and community-based approach to research.^{142,143, 144, 145}

1982-1983: Underground experimentation with a wide range of non-FDA approved treatments began, initially disseminated by clandestine publications such as AIDS Treatment News and Notes From the AIDS Underground which was followed almost immediately by the creation of People With AIDS  (PWA) ‘AIDS Buyers Clubs’ to make unapproved medications available to ill and dying gay men.^{146, 147}

The disease was also identified as almost certainly being due to a transmissible infectious agent.

Figure 28: The HIV virus was identified and characterized, and an antibody test developed in an unprecedentedly short period of time.

1983-1985: The Etiologic agent, an exotic and heretofore completely unknown type of retrovirus, was identified and molecularly characterized^148,149, (and within less than 4 years of the identification of the epidemic, a highly reliable antibody test was tested, validated, licensed and put into universal clinical application.^{150, 151, 152, 153} Most of the basic research to achieve these ends was funded by NGOs, industry, and other non-US government sources, such as the Institut Pasteur.

1987: The first (marginally) effective therapeutic drug approved (AZT): zidovudine (AZT),^{154, 155} was introduced despite very limited effectiveness and  high toxicity over the vociferous objection of the FDA, and other regulatory bodies; as well as a majority of the physicians who comprised the government-funded AIDS research community.^156,157 This unprecedented exception in FDA procedures and protocol resulted almost completely from political and financial pressures brought to bear by gay AIDS activists, such as ACTUP.^158,159

1987-1995: The AIDS Underground continues aggressive and largely rationally self-experimentation to find treatments and a cure.¹⁶⁰ Compound Q is made available through underground Buyer’s’ Clubs¹⁶¹ and subsequently shown to be worthless (and indeed harmful) as are many other putative treatments.¹⁶² Two effective antiretrovirals are identified and put into underground use,^163,164,165 and a plethora of drugs, of varying degrees of effectiveness, are identified and put into clinical use to treat a wide range of AIDS complications, such as AIDS wasting syndrome,¹⁶⁶ Mycoplasm avians intracellularae (MAI), CMV retinopathy, PCP pneumonia, cryptosporidium,¹⁶⁷ and a variety of other bacterial and micro-parasite infections refractory to drugs available in the US (then or now).¹⁶⁸

Figure 29: By 1994 the molecular mechanics of HIV infection were unraveled allowing the development of the protease inhibitors, converting AIDS into a treatable disease with most patients surviving long-term.

By 1993-1994 the molecular pathophysiology of HIV infection was largely elucidated,¹⁶⁹ again due to carefully targeted funding to achieve this end and to not run off on tangents that would have  provided interesting, but not particularly clinically useful insights.

1995: Highly Active Antiretroviral Therapy (HAART) was introduced leading to long-term survival for most patients with HIV/AIDS. This treatment was highly controversial, and was roundly denounced because it employed a ‘cocktail’ of drugs which only worked effectively to control the disease when used in combination.¹⁷⁰ This presented fundamentally new problems for the FDA, since they were (and still largely are) geared only to the approval of ‘mono-drug therapy.’ In other words, each drug in the ‘cocktail’ must be shown to be safe and effective, independent of the others!

Thus, effective control of a complex and heretofore unknown type of highly lethal etiologic agent was achieved 14 years after the start of the epidemic. There is simply no precedent for this medical accomplishment, and it is only necessary to look at the sorry pace of progress, and the veritable ocean of tangential and off the mark research, funded by disease-specific NGOs, such as the American Heart Association, the American Cancer Society,¹⁷¹ the Muscular Dystrophy Association and countless others, to understand this.¹⁷²

These unprecedented advances, in terms of both the absolute progress and the phenomenal rate at which it was achieved, were largely a result of these factors:

• Outcome (results driven) experimentation focused heavily (indeed almost exclusively) on achieving life extending or lifesaving results in real time.
• Immediate translation of bench results to bedside application based on the urgency of the affected patients’ needs.¹⁷³
• Zero outside regulatory constraints and rational, cost-benefit analyzed, internal, non-governmental regulatory controls.¹⁷⁴
• The understanding that most treatments would prove worthless or harmful (i.e., compound Q) and a studied refusal to become emotionally invested in them: results and only results mattered.
• High quality local and, ultimately centralized, record keeping and statistical analysis of underground trial results.
• Rapid feedback and turnaround of results from underground trials: e.g.; ddI, aerosolized pentamidine, ganciclovir were validated.
• Excellent data sharing, no data hoarding or secrecy, and no overt or covert desire to ‘get rich’ from discoveries that would impede the rapid and complex open and honest flow of data.

• Ideal interdisciplinary basic, clinician, and bench scientist interaction. The scientists developing treatments were often the same ones employing them (often on themselves) and this provided intimate and detailed feedback about adverse effects, effectiveness, or lack thereof – as well as more nuanced and effective ways of delivering the treatments being developed.¹⁷⁵

• Collaboration with big Pharma companies when required: DDI and DDC became big Pharma drugs, as did aerosolized pentamadine for PCP, and ganciclovir for CMV retinopathy.

• COURAGE and the ability to understand that human experimentation, preferably by those with the most to lose and the most to gain, is the only path to the development of fast and effective therapies. Animals are not people, just as certainly as people are not animals: and while animal research can provide useful leads, and help to explicate the mechanics of both disease processes and therapies, it is no substitute for human experimentation. The increasing absence of the latter has arguably become one of the most critical elements in slowing medical progress today.

SIMILARITIES BETWEEN THE HIV EPIDEMIC IN GAY MEN AND AGING IN CRYONICISTS

Gerontology is too important to be left to the Gerontologists

-Aschwin de Wolf, February, 2011

Ar first blush, interventive gerontology and AIDS may seem nearly identical in every important way, at least in terms of a subpopulation of the people afflicted: cryonicists. Aging and the cognitive decline associated with it, which includes the progressive and relentless destruction of the very structure, the very fabric of our personal identities, is happening to all of us and it is a 100% fatal disease. What’s more, just as was the case with AIDS, aging facilitates attack of its victims by a veritable deluge of grotesque, debilitating, and dignity-robbing diseases: cancers of almost area of the body, stroke and other cardiovascular diseases, blindness from macular degeneration, and, for everyone, the disfiguring and performance robbing changes that are the core of the aging process itself. It would also be hard to find a group of people in contemporary society more marginalized or vilified than cryonicists are today.

However, the analogy with AIDS cannot be completely sustained, because the median survival rate after diagnosis of AIDS before the advent of HAART typically only ~ 6 months to 2 years. Something which added a sense of urgency most likely not shared by those effected by brain aging, including cryonicists. I suspect that the personal and cultural traits of the male gay community culture are more conducive to pursuing such an aggressive and effective course of action than are the traits of the typical cryonicist, but serious call to arms might still be successful.

Certainly it is disheartening to see projects like this one, Research Project 2010b – Microglia Stem Cells: http://www.imminst.org/Research2010B, being funded by the Immortality Institute. This study is described as aiming to “to replace non-functional microglia with new and young microglia cells derived from adult stem cells. We will inject these young microglia cells into ‘Alzheimer mice’- a model for Alzheimer’s disease.  After giving the cells some time to work, we will sacrifice the mice and measure microglia activity, neurogenesis, proliferation of neuroprogenitors and plaque density in the brain. A reduction in plaque density of Alzheimer mice would be a first proof that the transplanted microglia are performing their expected function.”  It is disheartening not because this isn’t important and worthwhile work, but rather because it is scientific research of the kind that is being well funded by large, well established governmental and NGO research entities, with disease-specific agendas. A quick perusal of Pubmed shows these studies (very similar in design, therapeutic mechanism, and objectives) to have been already undertaken and completed (see Appendix A). These are the very entities who have been trying (unsuccessfully) to cure cancer heart disease, muscular dystrophy and multiple sclerosis, for decades having expended billions of dollars in taxpayers’ and charitable givers’ money with little to show in the way of progress.

THE TAKE-HOME MESSAGE

Figure 30: Survival from age 25 years. Cumulative survival curve for HIV-infected individuals and general-population controls. HIV-infected individuals are divided into three calendar periods of observation. The yellow line indicates the current life expectancy of HIV infected individuals and the red line the life expectancy before HAART was developed.  Lohse N, Hansen A-BE, Pedersen G, et al, Danish HIV Cohort Study. Median survival and age-specific mortality of Danish HIV-infected individuals: a comparison with the general population. In: Program and abstracts of the XVI International AIDS Conference; August 13-18, 2006; Toronto, Canada. Abstract MOPE0310.  View poster: Download PDF

If “Research Project 2010b” were completed successfully in 5 years or even in 3 years, it would still produce no results that will do anything to stop the 1 per second, 85,000 per day, or ~31 million per year brain cells you and I are losing right now – not to mention the concurrent staggering loss in neuronal and glial cell mass and function. What’s more, treatments such as these are invasive, require extraordinarily skilled practitioners to deliver the therapeutic cells to the targeted areas of the brain, carry the risk of serious (surgical) adverse events, and will cost a fortune. They also will require FDA approval and the approval of the medical infrastructure for their application – an infrastructure that does not even recognize aging as a disease and is not going to do so anytime soon. This is wonderful research, but it is research of the kind that was not undertaken by AIDS activists, and that typifies why AIDS was made a controlled and highly manageable condition whilst other, far less complex and equally devastating diseases, remain untreatable.  Project 2010b is Big Medicine, disease-specific research that, at least in my opinion, is one of the last places cryonicists, and others who are trying to stay alive and cognitively healthy now, should put their time, their effort, or their money into (if for no other reason than that others will do that work and do it better).

Rather, we should look to the paradigm that brought HIV/AIDS, a fundamentally new and extraordinarily complex disease, to its knees in a scant 14 years. That paradigm focuses on identifying, funding and executing projects which offer the prospect of immediate intervention that can make material differences in the clinical condition of patients (us!) in the shortest possible time. With the advent of sophisticated brain imaging technology, and indeed even using far simpler, standard clinical MRI, as well as sophisticated psychological neurocognitive testing, such as has been developed by Salthouse and his colleagues,¹⁷⁶ it is possible, right now, to begin evaluating the large and rapidly growing pool of molecules, both singly and in combination, that have been demonstrated to slow, and in some cases reverse, both the structural and functional neurocognitive decline associated with so-called ‘healthy aging.’

Instead of the alarmingly reckless, arbitrary, and feedback-free self experimentation that is seen with great frequency on the Immortality Institute Forums, and other life extension-related list-serves, there should be a well designed and well coordinated program of both animal and human experimentation to identify pharmacological interventions that are actually proven to slow, halt, or reverse neurocognitive decline. The imaging technology and the neurocognitive testing (much of which can be administered at a distance using a PC and the Internet) that are now both available and affordable, should be immediately pressed into service to validate the efficacy, or lack thereof, of these potentially powerful therapeutic molecules. If we had nothing more sophisticated or promising than that old standby for the treatment of bipolar disorder, lithium carbonate,[3] such research would be more than justified.  But there are many promising and (so far) largely adverse effect free molecules, that cry out for further animal evaluation, followed by rapid application to those of us humans willing to take the risks – risks that I believe are wholly acceptable within the context of a well designed program of self-experimentation (with careful monitoring for both efficacy, and for the emergence of adverse effects).

Twenty years ago, gay men dying in droves from a bizarre and unprecedented illness made the decision that AIDS research was too important to be left to the mainstream government and big Pharma scientists. Instead, they took personal responsibility for their plight, organized, mobilized, agitated, and struck out on their own in search not just of a cure, but for any treatment that offered the real prospect of longer life, or a reduced disease burden. They achieved amazing things, because they knew they were dying NOW, and because they also well understood that the society they were embedded in fundamentally didn’t give a damn about them – or their priorities.¹⁷⁷ If you want graphic proof of just how miraculously effective their efforts were, all you need to do is look at Figure 30, or at mortality data from similar studies.¹⁷⁸

We cryonicists are in exactly the same position today. The question is, are we smart enough to realize it, and courageous enough to take the necessary action?

The End

Footnotes