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This is the most important column I’ve ever written.  The message is quite complex–dozens of new health parameters to test for and to optimize, all of them interacting in ways that will require new training for MDs.  The message is also as simple as it can be: There is a cure for Alzheimer’s disease. You can stop reading right here, and buy two copies of Dale Bredesen’s book, one for you and one for your doctor:  The End of Alzheimer’s.

Dr Bredesen’s spectacular success is easily lost in a flood of overly-optimistic, early hype about any number of diseases.  This is an excuse for the New York Times, the Nobel Prize committee, and the mainstream of medical research, but it’s no excuse for me.  I’ve known Bredesen for 14 years, and I’ve written about his work in the past.  His book has been out for a year, and I should have written this column earlier.

I suspect you’re waiting for the punch line: what is Bredesen’s cure?  That’s exactly what I felt when I read about his work three years ago. But there isn’t a short answer.  That’s part of the frustration, but it’s also a reason that Bredesen’s paradigm may be a template for novel research approaches cancer, heart disease, and aging itself.

The Bredesen protocol consists of a battery of dozens of lab tests, combined with interviews, consideration of life style, home environment, social factors, dentistry, leaky gut, mineral imbalances, hormone imbalances, sleep and more.  This leads to an individual diagnosis: Which of 36 factors known to affect APP cleavage are most important in this particular case? How can they be addressed for this individual patient?

Brain cells have on their surface a protein called APP, which is a dependence receptor.  It is like a self-destruct switch whose default is in the ON position.  The protein that binds to the receptor is a neurotrophin ligand, and in the absence of the neurotrophin ligand,  the receptor signals the cell to die.

APP cleavage is the core process that led Bredesen down a path to his understanding of the etiology of AD 16 years ago.  APP is Amyloid Precursor Protein, and it is sensitive to dozens of kinds of signals, adding up the pros and the cons to make a decision, to go down one of two paths.  It can be cleaved in two, creating signal molecules that cause formation of new synapses and formation of new brain cells; or it can be cleaved in four, creating signal molecules that lead to trimming back of existing synapses, and eventually, to apoptosis, cell suicide of neurons.

In a healthy brain, these two processes are balanced so we can learn new things and we can forget what is unimportant.  But in the Alzheimer’s brain, destruction (synaptoclastic) dominates creation (synaptoblastic), and the brain withers away.

On the right, one of the fragments is beta amyloid.  Beta amyloid blocks the dependence receptor, so the receptor cannot receive the neurotrophin ligand that gives it permission to go on living.  Beta amyloid is one of the 4 pieces, when the APP molecule goes down the branch where it is split in 4.

One of the signals that determines whether APP splits in 2 or in 4 is beta amyloid itself.  This implies a positive feedback loop; beta amyloid leads to even more beta amyloid, and in the Alzhyeimer’s patient, this is a runaway process.  But positive feedback loops work in both directions–a boon to Bredesen’s clinical approach. If the balance in signaling can be tipped from the right to the left pathway in the diagram above, this can lead to self-reinforcing progress in the healing direction.  In the cases where Bredesen’s approach has led to stunning reversals of cognitive loss, this is the underlying mechanism that explains the success.

Amyloid has been identified with AD for decades, and for most of that time the mainstream hypothesis was that beta-amyloid plaques cause the disease.  (Adherents to this view have been referred to jokingly as BAPtists.) But success in dissolving the plaques has not led to restored cognitive function.  In Bredesen’s narrative, generation of large quantities of beta amyloid are a symptom of the body’s attempts to triage a dying brain.

To tip the balance back toward growing new synapses

Having identified the focal point that leads to AD, Bredesen went to work first in the lab, then in the clinic, to identify processes that tend to tip the balance one way or the other.  He has compiled quite a list.

  • Reduce APPβ-cleavage
  • Reduce γ-cleavage
  • Reduce caspase-6 cleavage
  • Reduce caspase-3 cleavage
    (All the above are cleavage in 4)
  • Increase α-cleavage (cleavage in 2)
  • Prevent amyloid-beta oligomeiization
  • Increase neprilysin
  • Increase IDE (insulin-degrading enzyme)
  • Increase microglial clearance of Aβ
  • Increase autophagy
  • Increase BDNF (brain-derived neurotropliic factor)
  • Increase NGF (nerve growth factor)
  • Increase netrin-1
  • Increase ADNP (activity-dependent neuroprotective protein)
  • Increase VIP (vasoactive intestinal peptide)
  • Reduce homocysteine
  • Increase PPZA (protein phosphatase 2A) activity
  • Reduce phospho-tau
  • Increase phagocytosis index
  • Increase insulin sensitivity
  • Enhance leptin sensitixity
  • improve axoplasmic transport
  • Enhance mitochondnal function and biogenesis
  • Reduce oxidative damage and optimize ROS (reactive oxygen species) production
  • Enhance cholinergic neurotransmission
  • Increase synaptoblastic signaling
  • Reduce synaptoclastic signaling
  • Improve LTP (long-term potentiation)
  • Optimize estradiol
  • Optimize progesterone
  • Optimize E2:P (estradiol to progesterone) ratio
  • Optimize free T3
  • Optimize free T4
  • Optimize TSH (thyroid-stimulating llormone)
  • Optimize piegnenolone
  • Optimize testosterone
  • Optimize cortisol
  • Optimize DHEA (deliydroepiandrosterone)
  • Optimize insulin secretion and signaling
  • Activate PPAR-γ (peroxisome proliferator-activated receptor gamma)
  • Reduce inflammation
  • Increase resolvins
  • Enhance detoxification
  • Improve vascularization
  • Increase cAMP (cyclic adenosine monophosphate)
  • Increase glutathione
  • Provide synaptic components
  • Optimize all metals
  • Increase GABA (gamma-aminobutyric acid)
  • Increase vitamin D signaling
  • Increase SirT1 (silent information regulator T1)
  • Reduce NF-κB (nuclear factor kappa-ligllt-chain-enhancer of activated B cells)
  • Increase telomere length
  • Reduce glial scarring
  • Enhance stein-cell-mediated brain repair

This explains why no single drug can have much effect on AD; it’s because the primary decision point depends on a balance among so many pro-AD (synaptoclastic) and anti-AD (synaptoblastic) signals.  Addressing them all may be impractical in any given patient, so the Bredesen protocol is built around a detailed diagnostic process that identifies the factors that are most important in each individual case.

Three primary types of AD

Bredesen’s diagnosis begins with classifying each case of AD into one of three broad constellations of symptoms, with associated causes.

Type I is inflammatory. It is found more often in people with carry one or two ApoE4 alleles (a gene long associated with Alzheimer’s) and runs in families. Laboratory testing will often demonstrate an increase in C- reactive protein, in interleukin-2, tumor necrosis factor, insulin resistance and a decrease in the albumin:globulin ratio.

Type II is atrophic. It also occurs more often those who carry one or two copies of Apoε4, but occurs about a decade later. Here we do not see evidence of inflammatory markers (they may be decreased), but rather deficiencies of support for our brain synapses. These include decreased hormonal levels of thyroid, adrenal, testosterone, progesterone and/or estrogen, low levels of vitamin D and elevated homocysteine.

Type III is toxic.  This occurs more often in those who carry the Apoε3 allele rather than Apoε4 so it does not tend to run in families. This type tends to affect more brain areas, which may show neuroinflammation and vascular leaks on a type of MRI called FLAIR, and associated with low zinc levels, high copper, low cortisol, high Reverse T3, elevated levels of mercury or mycotoxins or infections such as Lyme disease with  its associated coinfections.  

(This box quoted from Dr Neil Nathan’s book review)

There’s also a Type 1.5, associated with diabetes and sugar toxicity, a Type IV, which is vascular dementia, and a Type V which is traumatic damage to the brain.
These categories are just a start.  The patient will work closely with an expert physician to determine, first, where are the most important imbalances to address, and, second, which of the changes that cna address them are most accessible for the life style of this particular patient.

Success

Bredesen wrote a paper in 2014 about successes in reversing cognitive decline with his first ten patients.  As of this writing, he has treated over 3,000 patients with the protocol called RECODE (for REversal of COgnitive DEcline), and he claims success with all of them, in the sense of measurable improvement in cognitive performance.  This contrasts with the utter failure of all previous methods, which claim, at best, to slow cognitive decline.

Translation to the millions of Alzheimer’s patients will require training of local practitioners all across the country.  A few doctors have already learned parts of the Bredesen protocol, and Bredesen’s website can help you find someone to guide your program, but you will probably have to travel.  The first training for doctors is being organized now through the Institute for Functional Medicine.

Implications

This is a new paradigm for how to study chronic, debilitating diseases.  Type 2 diabetes comes to mind as the next obvious candidate for reversal through an individualized, comprehensive program.  Terry Wahls has pioneered a similar approach with MS.  Cancer and heart disease may be in the future.

I’ll go out on a limb and say I think Bredesen’s protocol is the most credible generalized anti-aging program we have.  (Blame me for the hyperbole, not Dr Bredesen — he has never made any such claim.) Could we adopt Bredesen’s research method to accelerate research in anti-aging medicine?  Perhaps biomarkers for aging (especially methylation age) are approaching a point where they could be used as feedback for an individualized program, but Horvath’s PhenoAge clock will probably have to be 10 times more accurate to be used for individuals.  Averaging over ~100 individuals can give this factor of 10 in a clinical trial.  Still, we don’t have the kind of mechanistic understanding of aging that Bredesen himself developed for AD before bringing his findings to the clinic; and this is probably because causes of aging are more complex and varied than AD.

Disclaimers:  I’m pre-disposed to think highly of Dale Bredesen and his ideas for 3 reasons.  He was a friend to me, and gave me a platform when I was new to the field of aging.  He believes that aging is programmed. And his multi-factorial approach parallels the research I have advocated for researching other aspects of aging.

Rhonda Patrick interviews Dale Bredesen on FoundMyFitness

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Josh Mitteldorf - Aging Matters by Josh Mitteldorf - 2M ago

I’ve been in the field of aging research from the late 1990s, just the time when Aubrey de Grey was getting his start.  Before others, Aubrey had the vision to realize that cancer, heart disease, and Alzheimer’s would never be conquered without addressing their biggest risk factor: aging.

From the beginning, I admired Aubrey’s successes in communicating with scholars and the public, and I reached out to him.  He has always been gracious and supportive of me personally, appreciating the large common ground that we share. There is, however, one foundational issue on which we disagreed from the start.

Aubrey regards aging as an accumulation of damage.  Evolution has permitted the damage to accumulate at late ages because (as Medawar theorized in 1952) there is little or no selection against it, since almost no animals live long enough in the wild to die of old age.  Aubrey’s program is called SENS, where the E stands for “engineering.”   The idea is to engineer fixes to the 7 major areas where things fall apart with age.

I regard aging as a programmed process, rooted in gene expression.  Just as we express growth genes when we are in the womb and ramp up the sex hormones when we reach puberty, so the process continues to a phase of self-destruction.  In later life, we over-express genes for inflammation and cell suicide; we under-express genes for antioxidants, autophagy (recycling), and repair of biomolecules.  I believe in an approach to anti-aging that works through the body’s signaling environment.  If we can shift the molecular signals in an old person to look like the profile of a young person, then the person will become young.  The body is perfectly capable of doing its own repair, and needs no engineering from us.

Over the years, research findings have accumulated, and both Aubrey and I have learned a thing or two.  I’m happy to say that our favored strategies are converging, even as our philosophical underpinnings continue to differ.

A unifying idea in my research has been that aging is an evolved adaptation.  This is a statement about evolutionary biology, but I came to it before I studied evolution, by looking at the phenomenology and genetics of aging.

  • The body does not appear to be doing its best to stay young.  We can see this because when the body is under stress, it has less available resources, but manages to a better job of protecting us from aging damage.  This phenomenon is called hormesis.
  • There are single genes that can be disabled, greatly extending lifespan in worms. Some of these have no known detrimental side-effects (pleiotropy).  These could only have persisted in the genome if natural selection is favoring aging for its own sake.  Similar genes exist in higher organisms, though their effects on lifespan are not as dramatic as the 10-fold increase in worms’ life expectancy in worms that comes from eliminating both copies of AGE-1.
  • Most genes that affect the rate of aging have been around for a long time, and do the same job.  This means they are evolutionarily conserved. For example, insulin is the most effective modulator of aging in mammals (including humans).  In higher animals, insulin is secreted by the pancreas, from whence it regulates blood sugar and fat storage. But yeast cells existed half a billion years before the first mammals, and have no pancreas; and yet insulin was already a primary modulator of aging in yeast.

Programmed aging and optimism

There was a time when I spoke of “aging genes” and looked for drugs that could jam their targets and turn the genes off.  Meanwhile, the science of epigenetics, or gene expression, was coming of age, so to speak. We learned that genes are turned on and off, not just in different tissues, but at different times of life.  I came to think less in terms of “aging genes”, more about multipurpose genes that are deployed in appropriate combinations when we are young, keeping us strong and healthy. But as we get older, the proportions change.  Aging is not accomplished via new mechanisms of self-destruction, which evolution invented for that purpose. Rather, the proportions are re-shuffled and change gradually, with effects that are more and more detrimental over time.

  • For example, the immune system is vital for protecting the body, but it becomes indiscriminate with age. In older people, the immune system fails to protect us from microbial infections, and simultaneously, immunity turns against the self.  Autoimmunity contributes to arthritis and to Type 2 Diabetes (metabolic syndrome), as well as playing a role in AD.
  • For example, p53 is a gene that promotes apoptosis, or cell suicide.  We need for cells to be smart enough to destroy themselves when they are infected with a virus or if they are cancerous.  But later in life, apoptosis is on a hair trigger, and we lose muscle and nerve cells that are still healthy and functional.
  • For example, inflammation is used as a primary defense against microbes, and a way to eliminate tissue around a wound so that it can be replaced; but as we get older, signals that promote inflammation are dialed up higher and higher.  Chronic inflammation contributes importantly to all the diseases of old age.

Twenty years ago, I imagined one or a few medications that would block the effects of aging genes.  I wrote that the thesis of programmed aging implied great optimism about the ease with which aging might be combatted.  I thought that merely lengthening telomeres might add many years to our lifespan.

Ten years ago, I saw that what was needed was re-balancing of signaling molecules to create a more youthful environment.  My hope was that a few transcription factors (master regulator genes) might control a large number of signal molecules and we might set the clock by controlling just a handful of master signals.

More recently, I have come to realize that shortening telomeres are only a small part of the aging program.  Worse, there is no clear line between transcription factors and hormones. Most hormones affect transcription, and most transcription factors have direct metabolic effects.  There are thousands of transcription factors in the human genome.  As a result, my robust optimism has been tempered, and I have come to think that we need to look for ways to re-balance a great number of genes to effect rejuvenation.  I still believe in a signaling approach, but I see signals as a tangled web of cause and effect, in which every cause is also an effect, and every effect has a side-effect.  Modulation of the signaling system toward a more youthful state is possible, but not easy.

Aubrey’s program, too, has changed over time

Aubrey has never believed that aging evolved as a program, but rather that aging is a manifestation of damage that is permitted to accumulate because of evolutionary neglect.  Recently, he has argued explicitly against the idea of programmed aging, not for the reasons that traditional evolutionists offer, but by an argument that is uniquely his own.  In his words, “it is impossible for a species to maintain two sets of genetic pathways whose selected actions diametrically oppose each other. Specifically, since we clearly have a great deal of anti-aging machinery…we cannot also have pro-aging machinery.”  (My response is that we have pro-aging and anti-aging machinery that are activated at different times of life.)

Over two decades, Aubrey, too has paid attention to research results, and his thinking about what is necessary to achieve rejuvenation is changing.  I see changes in the combinations of signal molecules and call it an evolved program. Aubrey sees the same thing and calls it “dysregulation”, which is a kind of damage.  Aubrey and I agree that re-balancing of hormones and other signal molecules is going to be essential.

Aubrey now finds optimism in the existence of what he calls “cross-talk”.  If we engineer a fix for one kind of damage, the body may sometimes regain the ability to repair other, seemingly unrelated kinds of damage.  Hence, we may not have to engineer solutions to everything—some will come for free. A dramatic example is in the benefit of senolytics. Cells become senescent over time.  I see this as a programmed consequence of short telomeres; Aubrey sees it as a response to damage in the cells. But both of us were surprised and delighted to learn, a few years ago, that elimination of senescent cells in mice had 20-30% benefits for lifespan.  Even though only a tiny fraction of all cells become senescent, they are a major source of cytokines (signal molecules) that promote inflammation and can cause nearby cells to become senescent in a vicious circle; this apparently accounts for the great benefit that comes from eliminating them.  If we find appropriately selective senolytic agents that can eliminate senescent cells without collateral damage, then the signals that up-regulate inflammation will be cut way back, and a great deal of the work needed to repair inflammatory damage is obviated.

The SENS 7

The SENS web site still lists the same 7 categories of damage that Aubrey has used for many years.  But the program to address these 7 has shifted a bit from bioengineering of exogenous solutions to signaling approaches that support the body’s innate mechanisms (which we know are sufficient to keep the body in good repair through several decades of early life).  For eliminating the plaques associated with AD, SENS at one time favored the engineering of artificial antibodies that would attack them, but more recently they see promise in the discovery of Dr. Sudhir Paul that our bodies already have catalytic antibodies, each capable of destroying many antibodies and re-cycling itself for the next one.  Where once Aubrey saw the need for tissue engineering to replace worn-out body parts, he now sees promise in reprogramming somatic cells to become stem cells, so that our bodies can regenerate damaged tissues endogenously.  Aubrey’s 1999 dissertation in biochemistry was about the theory that aging was caused by the damage inflicted by free radicals generated in our mitochondria, but he has long since embraced the fact that free radicals have an important role as signal molecules, so that anti-oxidants are not helpful for anti-aging.

Aging is not the only threat to human life

One respect in which my thinking has always departed from Aubrey’s is that I see humans as part of a continuous web of life on earth, integrated into a global ecosystem.  Aubrey doesn’t worry about the Sixth Extinction that human activity has initiated because he anticipates that future humans will invent ways to support future human life as necessary.  I value nature for its own sake, and I also believe that human life depends on ecoystem support in ways for which we have seen hints, but that we have not yet begun to study. Aubrey draws a sharp line between the value of human life and the value of other life, and he is highly optimistic about the ability of our species to find new ways to sustain ourselves in a post-ecologic world.

The Bottom Line

In my youthful enthusiasm, I was entirely too optimistic about the prospects for near-term anti-aging fixes.  Aubrey was probably too conservative about the scope of what needed to be done to generate man-made solutions for problems the body can’t solve itself.  I have come to understand the complexity of the body’s signaling network, and the fact that it is inseparable from cellular metabolism. Aubrey has come to realize that the body has endogenous solutions that can be activated more easily than we can engineer substitutes for them.  I’ve been moving the timeline out, as he has been moving the timeline in, and there is much that we agree about.

I’m grateful to Aubrey — we all are — for the energy, the expertise, and the humor that he has brought to his chosen role, as a public advocate for bringing anti-aging strategies into the mainstream of medical research.

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This week, a headline-making study in the New England Journal of Medicine sought to cast doubts on long-established science that says daily aspirin can be a broadly-effective anti-aging tonic.  I’m writing this response because I think that this new, small study has to be viewed in the context of many larger studies over many decades that together make a solid case for aspirin’s benefits.  

Aspirin has two kinds of effects: First, aspirin thins the blood, reduce clotting, which lowers the risk of most kinds of heart attacks and stroke (ischemic) while raising the risk of bleeding ulcers and  hemorrhagic stroke.  Second, aspirin lowers the level of systemic inflammation, which reduces risk of heart disease, stroke, most cancers, and Alzheimer’s disease.

Historically, daily low-dose aspirin began to be prescribed broadly to middle-aged and older adults in the 1960s as the medical establishment theorized about the first effect.  This led to a grand natural experiment—tens of millions of older people taking low-dose aspirin. Studies comparing these people with matched populations who didn’t take aspirin have shown lower rates of all-cause mortality, Alzheimer’s dementia, and of cancer and probably of heart disease as well.  These studies are based on millions of tabulated deaths. The current study is based on 1052 total deaths in the aspirin group and the placebo group, and the difference between the two was barely statistically significant in the direction against aspirin.

Summary of past studies

Eidelman, JAMA, 2003: Summarizing 5 trials, they found aspirin was associated with a 32% reduction in the incidence of first heart attacks.  Statistical significance was 2 chances in 100,000 (p<0.00002).

Methods  A computerized search of the English literature from 1988 to the present revealed 5 published trials: the Physicians’ Health Study (22,071 participants), the British Doctors’ Trial (5,139), the Thrombosis Prevention Trial (5,085), the Hypertension Optimal Treatment Study (18,790), and the Primary Prevention Project (4,495).

Results  Among the 55,580 randomized participants (11,466 women), aspirin was associated with a statistically significant 32% reduction in the risk of a first MI and a significant 15% reduction in the risk of all important vascular events, but had no significant effects on nonfatal stroke or vascular death.

Conclusions  The current totality of evidence provides strong support for the initial finding from the Physicians’ Health Study that aspirin reduces the risk of a first MI. For apparently healthy individuals whose 10-year risk of a first coronary event is 10% or greater, according to the US Preventive Services Task Force and the American Heart Association, the benefits of long-term aspirin therapy are likely to outweigh any risks.

Rothwell, The Lancet 2011: >Summarizing 8 trials, they found aspirin was associated with a 21% reduction in the incidence of all cancers.  Statistical significance was 1 chances in 10,000 (p<0.0001).

Results
In eight eligible trials (25,570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68–0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23,535 patients, 657 cancer deaths), benefit was apparent only after 5 years’ follow-up (all cancers, hazard ratio [HR] 0·66, 0·50–0·87; gastrointestinal cancers, 0·46, 0·27–0·77; both p=0·003). The 20-year risk of cancer death (1634 deaths in 12 659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72–0·88, p<0·0001; gastrointestinal cancers, 0·65, 0·54–0·78, p<0·0001), and benefit increased (interaction p=0·01) with scheduled duration of trial treatment (≥7·5 years: all solid cancers, 0·69, 0·54–0·88, p=0·003; gastrointestinal cancers, 0·41, 0·26–0·66, p=0·0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0·66, 0·56–0·77, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age—the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42–11·74) at age 65 years and older.

Wang, Journal of Alzheimer’s 2015: Summarizing 11 trials, they found aspirin was associated with a 49% reduction in the incidence of dementia.  Statistical significance was less than 1 chances in a billion (p<0.0000000005).

Abstract
Objective: Alzheimer’s disease, the most prevalent dementia, is a prominent source of chronic illness in the elderly. Laboratory evidence suggests that nonsteroidal anti-inflammatory drugs (NSAIDs) might prevent the onset of Alzheimer’s disease. Since the early 1990s, numerous observational epidemiological studies have also investigated this possibility. The purpose of this meta-analysis is to summarize and evaluate available evidence regarding exposure to nonaspirin NSAIDs and risk of Alzheimer’s disease using meta-analyses of published studies. Methods: A systematic search was conducted using Medline, Biological Abstracts, and the Cochrane Library for publications from 1960 onwards. All cross-sectional, retrospective, or prospective observational studies of Alzheimer’s disease in relation to NSAID exposure were included in the analysis. At least 2 of 4 independent reviewers characterized each study by source of data and design, including method of classifying exposure and outcome, and evaluated the studies for eligibility. Discrepancies were resolved by consensus of all 4 reviewers. Results: Of 38 publications, 11 met the qualitative criteria for inclusion in the meta-analysis. For the 3 case-control and 4 cross-sectional studies, the combined risk estimate for development of Alzheimer’s disease was 0.51 (95% CI = 0.40–0.66) for NSAID exposure. In the prospective studies, the estimate was 0.74 (95% CI = 0.62–0.89) for the 4 studies reporting lifetime NSAID exposure and it was 0.42 (95% CI = 0.26–0.66) for the 3 studies reporting a duration of use of 2 or more years. Conclusions: Based on analysis of prospective and nonprospective studies, NSAID exposure was associated with decreased risk of Alzheimer’s disease. An issue that requires further exploration in future trials or observational studies is the temporal relationship between NSAID exposure and protection against Alzheimer’s disease.

Problems with the present study

Because of small numbers and short duration, the result of the study was only marginally significant (p<0.05).  The aspirin group had higher cancer rates and lower heart attack rates than placebo.

Typically, doctors advise patients to start low-dose aspirin around age 50, but this study was with patients more than 70 years old who had no cardiovascular symptoms by age 70.  Most people by age 70 have had some cardiovascular diagnosis before age 70, so this is an unrepresentative sample. The study fails to address the question, how many deaths and how many diseases could be avoided between the ages of 50 and 70?  This is the period in life when inflammation is most active, and a great deal of destruction of the body’s veins, joints, and nervous system happens during these years. Excluding those with a history of heart disease during those ages is excluding just the people most likely to be helped by aspirin.  Of course, when you’re 50 and considering whether to start on aspirin, you may not know whether you’re lucky enough (or have the right genes) to be in the group that will do fine for the next 20 years without it.

Click to enlarge

This table breaks the composite test group into sub-groups according to various criteria.  Dots to the right of the line mean “aspirin was worse”, and to the left mean “aspirin was better”.  Among the subgroup in the US, aspirin was better. Among people who had never taken aspirin before, aspirin was better.  Among people within fairly wide limits of a “normal” weight range, aspirin was better.

Why are we seeing this?

Scientists are only human, and their environment, their preconceptions, and their incentives shape the way that statistics are handled.  In my experience, it is not difficult to make a small effect look like a (p<0.05) effect by making consistent choices in the way the data are treated, none of which are suspect or dishonest.  If the group had come up with the conventional and accepted conclusion based on such a small study, there would have been no prominent publication, no headlines, probably no follow-on grant. So they had every incentive to perform the analysis in a way that makes the results appear more interesting than they are.

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Heat Shock Protein

[My sources for much of this article are a 2018 review from University of Campinas, Brazil and a 2016 review on hormesis by Joan Smith Sonneborn, as well as the ever-inspiring and accessible summaries by Rhonda Patrick.]

Most animals have the latent ability to live longer when stressed.  It’s called hormesis, and it’s a major clue concerning the nature and evolutionary provenance of aging.  The body compensates when stressed—that’s no surprise—but the remarkable thing is that it overcompensates so that, paradoxically, stress ends up by lengthening lifespan. Sometimes.

One of the prime responses to stress at the cellular level is Heat Shock Proteins, discovered in 1962 in fruit flies.  Heat was the stressor that led to the original discovery of HSP, and the word “heat” remained with the name, though it soon became clear that HSP are secreted in response to many kinds of stress, including cold.  HSP are not a single protein, but a family of molecules, all of which are highly conserved; the human versions are remarkably similar to HSP in flies and even yeast cells.

HSP protects delicate biomolecules from damage.  HSP act as chaperones, helping newly-created proteins to fold properly, and helping misfolded proteins to find their correct shape.  HSP protect against sarcopenia (muscle-wasting) which is responsible for so much frailty. Lab worms with an extra copy of an HSP gene live longer.   Here is a closely-related finding for fruitflies, but there are contradictory findings for mice [pro, con].

Heat Shock Factor (HSF) is a signal molecule that turns on the full set of HSP genes.  It turns on a great many other protective proteins at the same time, a whole library, in fact, of protections.   Calorie restriction and exercise both activate HSP, but protein restriction may attenuate HSP.  HSP induction in response to HSF declines with age in rodents, but not if they are calorically restricted. Pro-biotics and high-fiber diets encourage microbiome signaling that increase HSP expression, at least in mice.  Insulin resistance, characteristic of type 2 diabetes, suppresses HSP in response to HSF.  High fat diets reduce HSP. Garlic in the diet increases HSP.

HSP is neuroprotective when there is potential damage from a stroke or head injury.  Does HSP protect nerves from the slow damage of aging as well?

Saunas

In my reading this week, I’ve come to think that saunas may be the second most powerful form of human hormesis after calorie restriction.  Statistics for saunas suppressing cardiovascular disease and especially dementia make you stand up and take notice. Here’s a clear and straightforward article by Rhonda Patrick (FoundMyFitness) about the benefits of saunas.

If you’ve ever run long distances or exercised for endurance, it’s intuitive that increased body temperature will eventually induce strain, attenuate your endurance performance, and accelerating exhaustion. What might not be as intuitive is this: acclimating yourself to heat independent of aerobic physical activity through sauna use induces adaptations that reduce the later strain of your primary aerobic activity. Hyperthermic conditioning improves your performance during endurance training activities by causing adaptations, such as improved cardiovascular and thermoregulatory mechanisms.

I don’t enjoy getting overheated any more than you do, but hey—stress is stressful.  How surprised can we be that heat is a powerful inducer of Heat Shock Protein? Perhaps more interesting is that saunas are associated with increased growth hormone, a far safer and cheaper way to achieve higher HGH levels than injections.  The combination of HGH and HSP help to maintain muscle mass against the erosion that almost always comes with age. Patrick documents that saunas contribute to maintaining (or restoring) insulin sensitivity, and to growth of new brain cells.  Another pathway by which saunas work their magic is norepinephrine=noradrenaline, which is both a neurotransmitter and a hormone, and higher levels are associated with good attention and cognitive performance.

“The greater the discomfort experienced during your workout or sauna, the better the endorphin high will be afterward.”

Jari Laukkanen, a Finnish cardiologist, followed middle-aged sauna-bathers (men) and matched controls for 20 years.  His study found dramatic decreases in cardiovascular deaths, and a 40% drop in all-cause mortality for those reporting sauna use at least 4 times per week for 20 minutes.  A prospective study–planned in advance to follow 2,300 men over 20 years–is the gold standard for epideiology. A 40% drop in mortality is worth about 3 years of extended life.  An even more impressive number: the Alzheimer’s risk of men taking at least 4 saunas a week was only ⅓ as great as those who took 1 sauna a week.  The benefit compared to no saunas at all is likely to be substantially greater yet.

Just this week, there is a new review by Laukkanen, author of the above study, who also did much of the the original research in his review.

The review doesn’t mention cancer, and there have been mixed reports whether saunas and HSP in particular protect against cancer or add to cancer risk.  On the one hand, localized applicatation of heat and even whole body heat are a well-established cancer treatment over 40 years. On the other hand, HSP increases the ability of cells to survive stress, and that includes cancer cells.  There is some evidence that saunas enhance the immune system and that would likely contribute to cancer resistance.  In my judgment, the balance of the evidence is that saunas lower cancer risk.

Choose your poison.

The body responds to alcohol as a poison, and raises levels of HSP.  This may be the mechanism by which alcohol consumption (~1 drink per day) lowers heart attack risk, though cancer risk is increased even at low doses.

I’ve made my choice, and I’ve been a teatotaler my whole life.  It’s been for personal reasons that I never have written about the established epidemiology of alcohol.  Moderate alcohol consumption has conventionally been associated with a modest increase in life expectancy, (~1 year or less), but conventional wisdom could be wrong.  It’s always difficult to separate variables in large population studies, and alcohol consumption is linked to so many different factors, all of them more powerful influences than alcohol itself.

Cold

HSP is a stress adaptation, not specialized to heat, and in fact cold temperature can also trigger release of HSP.  That said, cold and heat are not symmetric. Saunas work by raising the core temperature of the body several degrees, as in a fever.  Cold is applied on the skin, and the core of the body works harder to keep its temperature close to normal. The benefit is mediated by the cold-sensing nerves in the skin, which trigger release of norepinephrine, similar to heat exposure.  A specific response to cold is a protein called RMB3, which promotes neurogenesis.

It’s tempting to take your cold shower or plunge into an icy stream after you’ve been working out and your core temperature is elevated.  But this may actually cause delayed cramping and lessen the benefit of your workout.  I hate to say it, but after resistance training is the most beneficial time to take your sauna (if the least comfortable).  If you can’t bear the thought of jumping into a cold shower when your body is already cold, you might try a hot shower first.  Here’s a study that demonstrates a drop in infectious disease rates from hot showers followed by cold.  Hof recommends that you take your cold plunge after a course of deep breathing.

One of the most consistent and profound physiological responses to cold exposure is a robust release of norepinephrine into the bloodstream, as well as in the locus coeruleus region of the brain. — Rhonda Patrick

Does the Wim Hof method increase life expectancy

In the last several years, Dutch extreme athlete Wim Hof has popularized a training discipline that combines breathing exercises, cold immersion, yoga and meditation.

Wim Hof is able to suppress immune response to a standard challenge, suggesting he is also able to consciously suppress the auto-immune response that contributes to arthritis, and probably diabetes and AD as well.  When Hof was studied with metabolic and neurologic sensors, the result indicated that he has acquired conscious control over physiological adaptations which, in the rest of us, are entirely automatic.  Is it possible to learn to dial down inflammation by an act of will, or to control our epigenetic age directly from the mind?  This is an approach to health and perhaps to anti-aging that has always fascinated me, though there is little in the mainstream literature on the subject because it is presumed impossible.  There have long been stories about yogis and ascetic devotees of Eastern religions who culture extraordinary control over their bodies and live to extraordinary ages. Of course, we would like to see these claims subjected to controlled conditions and standardized lab tests, but there are probably good reasons why most ascetic hermits have no interest in taking leave from their mountain caves to serve as lab rats.

There is no direct evidence that Wim Hof training affects aging.  Indirect evidence is that it lowers inflammation, which makes a large contribution to all the diseases of old age, and that it releases norepinephrine and RMB3, both of which are neuroprotective  I’m eager to see if Wim Hof method has an effect on methylation age, and will include it in the Data BETA study that is ramping up this fall (DataBETA is the name I’ve chosen for the Mother of All Clinical Trials.  It stands for Database for Epigenetic Evaluation of Treatments for Aging.)

The Bottom Line

If the Finnish review is to be believed, then hyperthermia—overheating—is one of the most powerful modes of hormesis we know of, ranking second only to calorie restriction.  Just as interesting is the fact that hyperthermia works by a path independent of insulin, so we might hope that there is synergy between saunas (or Bikram yoga) and from calorie restriction (or fasting).  In other words, combining low calorie with high heat might, if we’re lucky, yield life extension equivalent to the sum of the two measures separately.  Cold exposure and the full Wim Hof program, including meditation techniques, show promise, but are further from validation as a life-extending practice.

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