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.

What are the most effective things you can do to slow the aging process and extend your life expectancy?  This is the question being asked by a clinical trial that I am organizing, and which seems to be rapidly taking shape.  But before the study begins, we have to have candidates to evaluate. We should begin with hypotheses about what we are evaluating.  My idea is to consult some experienced experts, and also to crowd-source this choice, and to ask for your help in selecting the supplements and life habits to be evaluated.

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Details of the trial were described in two blog posts last spring [One, Two] and a more technical manuscript submitted in May.  Outcome will be evaluated based on a variant of DNA PhenoAge, taken from a blood test before, amid, and after the two-year trial.  We use methylation pattern differences rather than mortality or health outcomes because the latter take a long time to reveal themselves, and make anti-aging trials prohibitively expensive.  Using methylation clocks as an endpoint is a new idea, and we don’t know if it will work, but if it does, it will be 100 times cheaper and 10 times faster than previous methods. We will have enough bandwidth to test a dozen different measures at once, which itself is a revolutionary step.  

Many measures are known that are thought to increase life expectancy by a year or a few years each.  Of course, we want to know which ones offer their greatest benefits. But even more important, we want to know how they interact, synergize, and interfere with one another.  If any one of these measures offered major benefits—say 20 years of life—its effects would be so apparent that we would probably know it already. Likewise, if these measures added up to 20 years of extra life, we would all know some people who are obviously younger than their chronological age.  Realistically, we must assume that most of the things we do are redundant. Combining metformin with berberine and gynostemma may offer little additional life expectancy compared to any one separately.  A panoply of different anti-inflammatory strategies may be little improvement over an aspirin a day.

But we hope there are exceptions.  If two different measures act via completely different metabolic pathways, we have reason to hope that their effects should compound.  For example, perhaps life extension interventions based on mitochondrial health synergize with interventions based on rebooting the immune system.  Then we might hope that the life extension available from these two measures together is greater than the sum of what we get from the two separately.

 

Study design

We will not tell the people who sign up for this study what to eat, what pills to take, or how much to exercise.  We will ask people what they are doing, what they are eating, and what supplements they are taking in a detailed questionnaire.  We will select subjects so as to represent a broad array of different strategies and different combinations among these strategies.

Broad, but not too broad.  We will have enough statistical power to estimate the interactions among every pair of measures out of 12 that we take as our independent variables.  These 12 should be chosen in advance, so the study has a clear focus. If there are more than 12, the number of interactions increases rapidly beyond what we can hope to distinguish (with multivariate statistics).  I’ve decided to start with 15, and winnow the list as people sign up for the study and we see what

Here are the criteria I propose:

• Each measure, separately, should have either human mortality data or longevity data to back it up.
• The measures should be easily available to all (excluding intravenous drugs or transfusions)
• The measures should be well-enough known that they are already in common use (and we will have no trouble identifying a diverse group of subjects who use them)

I find that it’s hard to limit the list to 15.  It may make sense to include a few measures that are so well established that every participant will be required to comply in order to be included in the study.  In this category, we might put

• Non-smoking
• Limited alcohol consumption (or none)
• Vitamin D at least 5,000 IU daily
• Multi-mineral supplement with magnesium, zinc, chromium, and selenium
• Exercise equivalent to minimum 5 hours a week of walking or yoga

Body weight (BMI) is an important longevity factor, but difficult to account.  Studies show that maximum lifespan is associated with BMI between 21 and 25, but in my interpretation, lower BMI is always beneficial for any given individual.  

The reason for the apparent paradox is that individuals have genetic disposition to be overweight or underweight.  Those who are genetically underweight tend to overeat, because they can do so with no social stigma. Those who are genetically overweight feel compelled to diet all the time (women more than men), and they may be restricting calories just to keep their BMI at 25.  These dieters get the most benefit from Caloric Restriction, despite the fact that they don’t look thin.

List of things that lengthen your life

1. Love.  Men who are married or in close relationships have 7% lower mortality than singles.  The number is 4% for women [ref].  These numbers correspond to less than a year of life expectancy.  A different study finds loneliness increases mortality by 50%, corresponding to almost 5 years of life.
2. Empowerment: Staying employed is worth up to 14 years, and I like to think this is more about being needed than making money.  This study claims that the big difference is wealth.
3. Anti-inflammatories: Aspirin, ibuprofen, curcumin, or fish oil.  This study attributes about a year of life expectancy to daily aspirin.
4. High fiber, a proxy for healthy gut flora.  We know that they are important, but don’t yet know how to manage the biota for maximal life expectancy.
5. Vegetable-based diet This review concluded that vegetarians live 3 years longer, but methodologies and results vary considerably.
6. Meditation This is difficult to evaluate, and data is unreliable but encouraging [ref].  The only careful study linked meditation not to mortality but to telomerase activity.  I confess I am including meditation in the list from my own intuition and experience.  
7. Intermittent fasting Extends lifespan in mice and lowers mortality in nursing home studies [ref].
8. Interval training Reputed to be the most efficient path toward cardiovascular fitness [ref], and there is limited documentation of benefit for all-cause mortality [ref].
9. Donating blood This is another quirky inclusion on my part, but there is data to support it, which I reviewed a few years ago.  
10. NAC just one study — 30% increase in lifespan of mice
11. DHEA Lower blood levels of DHEA are clearly associated with greater age and higher mortality at the same age, but the direction of causality is in dispute.
12. Metformin Prescribed for diabetes for decades, this drug also lowers mortality from cancer and heart disease [planned clinical trial].
13. Rapamycin The most convincing data available for any supplement for life extension in mice.  Early adopters are beginning to experiment on their own.
14. Quercetin + Dasatinib (or other senolytics).  Senolytics are the best near-term hope we have for a breakthrough in anti-aging medicine; but the combination of quercetin +dasatinib is not yet discriminating enough to be safe for humans, meaning it kills too many regular cells.
15. Epithalamin  Very promising data from Russia [ref], both in rodents and in people, but there is no one trying to reproduce them in the West.
16. Ashwagandha [many benefits, but no mortality or rodent lifespan data]
17. Selegiline (deprenyl).  In classic studies from the 1980s, lifespan of rats was extended.  Data in humans is contradictory [ref].

Perhaps we should begin with a guess about which combinations are likely to be highly redundant.  In this way, we could cluster together different strategies and condense more strategies into a manageable list.  It might look like this:

1. Anti-inflammatories (aspirin, ibuprofen, statins, omega 3, curcumin, boswellia)
2. Blood sugar control (metformin, berberine, gynostemma, chromium)
3. Social factors (family, employment, wealth, community support, marriage, sex, communing with nature, empowerment)
4. Mitochondrial supplements (NAC, CoQ10, PQQ, NR, melatonin, glutathione, carnosine, ALA)
5. Immune support (reishi mushrooms, cistanche, andrographis, goldenseal, echinacea)
6. Adaptogens (rhodiola, ashwagandha, bacopa, silymarin, pycnogenol)
7. Telomerase activators (silymarin, astragalus, ashwagandha, horny goat weed)
8. Senolytics (quercetin, dasatinib, fasting)
9. Diet (everything from high-protein to high fiber to vegan to paleo in one cluster?)
10. Limiting and intermittency of diet (long- and short-term fasting, CR, BMI)
11. Exercise (aerobic, strength, interval, walking, competitive sports, yoga)
12. Mental focus (meditation, prayer, yoga, tai chi, spiritual practice, cafeine)
13. Neuroprotective (ashwagandha, rhodiola, ginkgo, melatonin, bacopa, selegiline, gotu kola, coffee, tea, blueberries, chocolate)
14. Multivitamin supplements (including mega D, mega-C, B12, carotenoids and tocopherols)
15. Sex and steroid hormones (DHEA, prostaglandin, progesterone, SAMe, testosterone)
16. Angiotensin inhibitors (Lotensin, captopril, enelapril)

Or—the best of both worlds—we might structure the study in such a way that it can be analyzed after the fact either with individual strategies or clusters of strategies.

The best way to design a study is to start at the end.  I imagine I am two years down the road, taking my first look at results from 5,000 life-extenders.  The first thing I will want to do is to look for outliers. Are there a few people who stand out from the bell curve, aging much more slowly?  If so, what do they have in common? The advantage of this approach is that it gives maximal flexibility in telling us exactly what we most want to know.  The disadvantage is that it is easy to fool ourselves and imagine patterns in a small set of random errors. When there is no initial hypothesis, there is no objective way to calculate a probability that what we find is the result of chance.

Our null hypothesis is that there are no systematic outliers, but only a smooth tail to the probability curve.  If there are a few scattered individuals in 5,000 who are aging much more slowly than the rest, we will not find any common thread in what they are doing, and so we must explain their data as anomalies or mistakes.  If this is our result, it will be disappointing, sobering, but liberating as well. Those of us who are compulsive about one or another life extension strategy can ease our discipline.

But there is a chance we will find something more interesting.  We may find that there are dozens of outliers, that their life extension strategies all overlap in some clear and unambiguous way.  We will then have, for the first time, a solid foundation for our personal life-extension habits, and a clear hypothesis for further experiments.

What are your thoughts?  Please comment.