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?
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.
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.