Exercise mimetics: Take two and run circles around me in the morning

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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7 comments

  1. Thanks for a interesting blog! What do you think about ketogenic diet as a way to prolong lifespan? Lots of interesting research, benefits include:

    – D-beta-hydroxybutyrate produces ATP energy more efficiently than glucose or fatty acid
    -mitochondrial biogenesis
    -beneficial effect on biomarkers of cardiovascular diseases
    -neuroprotection
    -decreased ROS
    -minimized insulin
    -PPAR, AMPK benefits

    I have not dived really deep to the keto-research, but from what I have read it sounds like a really good deal.

  2. Until now, the only proven means to halt aging is CRAN (caloric restriction with adequate nutrition) (Harrison’s principle of internal medicine). Avoiding tobacco and doing regular exercise, as you mention, are very vital to stay young. Meditation is another important tool too.

  3. Human randomized controlled trials have been completed. One of the 2 mimetics are under the FDA approval process.

    Schering-Plough has obtained the rights to the one mimetic that works in humans without serious side effects, and it is estimated the pill will be available as a formulary in 2010.

    Elite athletes already are using the drug, but the authors of the paper devised a diagnostic test in parallel with drug development to identify it as a banned substance in athletics.

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