As a biologist of aging, one question I get asked frequently is: “What should I be doing in the meantime?” That is, in the absence of any de facto anti-aging medicine, what’s the best way to extend healthspan, and thereby improve one’s chances of being around when bona fide life extension technology becomes available? Usually, the question takes the form, “What pills should I be popping?”

My answer (after issuing the routine qualifications that I’m not an MD, a dietitian or an exercise physiologist) is as follows: Vitamins are good but megadoses are of questionable value. Ditto for “supplements”: the nutraceutical industry is poorly regulated, so you don’t necessarily know what you’re getting. Beyond that, we don’t necessarily know the efficacy or understand the mechanism of action of many of these products, which means that we can’t begin to rationally predict the adverse reactions that could result from their combination.

Kind of bleak, right? Turns out that I do have some constructive advice, however — and it’s the same advice you’ve been getting all your life: Avoid tobacco, eat a reasonable diet, and get plenty of exercise. After all, I usually jest, they’re never going to turn exercise into a pill.

That is, until they do.

Enter the era of PPARβ/δ and AMPK agonists. From Narkar et al.:

AMPK and PPARδ Agonists Are Exercise Mimetics

The benefits of endurance exercise on general health make it desirable to identify orally active agents that would mimic or potentiate the effects of exercise to treat metabolic diseases. Although certain natural compounds, such as reseveratrol, have endurance-enhancing activities, their exact metabolic targets remain elusive. We therefore tested the effect of pathway-specific drugs on endurance capacities of mice in a treadmill running test. We found that PPARβ/δ agonist and exercise training synergistically increase oxidative myofibers and running endurance in adult mice. Because training activates AMPK and PGC1α, we then tested whether the orally active AMPK agonist AICAR might be sufficient to overcome the exercise requirement. Unexpectedly, even in sedentary mice, 4 weeks of AICAR treatment alone induced metabolic genes and enhanced running endurance by 44%. These results demonstrate that AMPK-PPARδ pathway can be targeted by orally active drugs to enhance training adaptation or even to increase endurance without exercise.

Get that? Mice that performed no workout more taxing than taking their medicine were almost 50% better than controls at running — and the effects were even more dramatic when combined with actual exercise.

Assuming — standard caveat — that AMPK agonists like AICAR are efficacious in humans, the potential applications are tremendous, with potential benefits for everyone from bedridden hospital patients to astronauts at the ISS.

An interesting open question: We know that actual exercise extends lifespan, possibly via hormesis (the improvement of chronic stress tolerance in response to regular acute stress). Do the exercise-like effects of PPARβ/δ and AMPK agonists also increase longevity — and if so, does the mechanism involve hormesis? In other words, are these drugs increasing endurance by simulating the acute stress of exercise, or are they activating a response further downstream in the pathway?

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We’ve recently discussed evidence that resveratrol, a compound with some documented longevity-enhancing benefits in model organisms, might act by inducing the heat shock response. Heat shock proteins have been implicated in lifespan determination: Stochastic variations in heat shock protein expression have been invoked to explain variance in longevity between genetically identical organisms, with higher HSP expression associated with longer life.

It is therefore curious to learn that exercise, also thought to have a hormetic effect (i.e., acute stress now increases chronic stress tolerance later) downregulates expression of least one heat shock protein in elderly human subjects. From Simar et al.:

Physical Activity Modulates Heat Shock Protein-72 Expression and Limits Oxidative Damage Accumulation in a Healthy Elderly Population Aged 60–90 Years

Background. Reactive oxygen species production increases during aging, whereas protective mechanisms such as heat shock proteins (HSPs) or antioxidant capacity are depressed. Physical activity has been hypothesized to provide protection against oxidative damage during aging, but results remain controversial. This study aimed to investigate the effect of different levels of physical activity during aging on Hsp72 expression and systemic oxidative stress at rest and in response to maximal exercise.

Methods. Plasma antioxidant capacity (Trolox equivalent antioxidant capacity, TEAC), thiobarbituric acid-reactive species (TBARS), advanced oxidized proteins products (AOPP), and Hsp72 expression in leukocytes were measured before and after maximal exercise testing in 32 elderly persons (aged 73.2 years), who were assigned to two different groups depending on their level of physical activity during the past 12 months (OLow = moderate to low level; OHigh = higher level).

Results. The OHigh group showed higher aerobic fitness and TEAC (both representing 120% of OLow values) as well as lower oxidative damage (50% of OLow values) and Hsp72 expression. Exercise led to a lower increase in oxidative damage in the OHigh group. Aerobic fitness was positively correlated with TEAC and negatively with lipid peroxidation (TBARS). Hsp72 expression was negatively correlated with TEAC but positively correlated with TBARS levels.

Conclusions. The key finding of this study is that, in people aged 60 to 90 years, long-term high level of physical activity preserved antioxidant capacity and limited oxidative damage accumulation. It also downregulated Hsp72 expression, an adaptation potentially resulting from lower levels of oxidative damage.

The authors’ explanation of the lowered Hsp72 levels — that lower overall oxidative damage results in an adaptive decrease in Hsp72 expression — is reasonable; Hsp72 is known to be involved in the cellular response to oxidative stress (e.g., in regulating peroxide-induced apoptosis). But what puzzles me is this: HSPs tend to be coordinately regulated, by elevated temperature or other sources of protein-folding stress. Does this finding suggest that all of the HSPs are lower in elderly patients who exercise? If so, what are the ramifications for the theory that chronically elevated HSPs are a key mechanism of resisting chronic low-level stress?

Following up on our recent discussions of hormesis, in which mild acute stress protects against severe or chronic stress, here’s a review by Suresh Rattan that discusses the phenomenon in light of aging. Stress resistance and longevity, after all, go hand in hand.

Hormesis in aging is represented by mild stress-induced stimulation of protective mechanisms in cells and organisms resulting in biologically beneficial effects. Single or multiple exposure to low doses of otherwise harmful agents, such as irradiation, food limitation, heat stress, hypergravity, reactive oxygen species and other free radicals have a variety of anti-aging and longevity-extending hormetic effects. Detailed molecular mechanisms that bring about the hormetic effects are being increasingly understood, and comprise a cascade of stress response and other pathways of maintenance and repair. Although the extent of immediate hormetic effects after exposure to a particular stress may only be moderate, the chain of events following initial hormesis leads to biologically amplified effects that are much larger, synergistic and pleiotropic. … Healthy aging may be achieved by hormesis through mild and periodic, but not severe or chronic, physical and mental challenges, and by the use of nutritional hormesis incorporating mild stress-inducing molecules called hormetins. The established scientific foundations of hormesis are ready to pave the way for new and effective approaches in aging research and intervention.

The discussion is quite broad, with appropriate emphasis given to classical examples of hormesis (radiation, thermal stress, and the emerging idea that calorie restriction is a form of hormetic stress) as well as forays into unusual stresses such as hypergravity.

At the end of the abstract he mentions “hormetins” — this is a fairly new term that has yet to gain substantial traction in the field, referring to compounds that confer stress resistance and possibly increased longevity by inducing low levels of stress themselves. As we learned recently, resveratrol may be among them.

How might hormesis — the protective effect of low-dose or acute stress against higher-dose or chronic stress — work at the molecular level? One possibility is that the mild “priming” stress tones up the protective actions of stress responses: a hit of peroxide, for example, might accelerate expression of antioxidant enzymes like superoxide dismutase, protecting the cell against a future oxidative wallop. To the extent that chronic stresses can be risk factors for age-related decline in cellular function, hormetic stress might protect the cell against such long-term grinding damage, and ultimately against aging itself.

Compounds that protect against stress and aging might therefore function in a hormetic manner — either by literally stressing cells or by “simulating” stress, i.e., inducing protective stress responses without actually causing even short-term acute damage. Consistent with this idea are some recent findings on resveratrol, a compound found in red wine grapes that has been implicated in extending lifespan, improving exercise tolerance, and as an antioxidant.

Putics et al. have demonstrated that resveratrol induces the heat shock response (HSR), a well-studied and canonical stress response that results in higher expression of protein chaperones. The effect is not due to the compound’s antioxidant activity, and is distinct from endoplasmic reticulum folding stress pathways such as the unfolded protein response. For reasons that escape me, the authors did not attempt to determine whether the known resveratrol target proteins, the sirtuins, play a role in the induction of the HSR.

Furthermore, treatment with resveratrol protect cells against severe heat shock, a hallmark of hormesis. The authors suggest in the final sentence of the abstract that

Our results reveal resveratrol as a chaperone inducer that may contribute to its pleiotropic effects in ameliorating stress and promoting longevity.

This is a long way from having been proven — future work will need to uncover the mechanism by which resveratrol induces the HSR, and manipulate the genetics of both the resveratrol-heat shock connection and the heat shock response itself in a system suitable for the study of longevity — but it’s a promising start.

One wonders whether heating the resveratrol might have a synergistic effect. Glögg, anyone?