We know that exercise is good for us, and increasingly we understand how it works at the molecular and cellular level: Physical activity boosts levels of heat shock proteins, which help cells resist stress, and also improves mitochondrial function in a manner reminiscent of calorie restriction (CR). Our current knowledge is sophisticated enough that we can identify and develop small-molecule exercise mimetics and drugs that improve exercise tolerance.
Overall, then, exercise and its molecular/cellular consequences work in concert with longevity assurance pathways and life extension interventions. Recently, however, complications have emerged.
Exercise increases the activity of anabolic pathways, especially in muscle. Building up tissues require new protein synthesis, and new protein synthesis requires the activity of the TOR pathway. However, TOR is a pro-aging (or “gerontogenic”) pathway: rapamycin, a drug that inhibits TOR, blocks senescence and extends lifespan in mice; conversely, TOR inhibition increases longevity in worms and yeast.
Until recently, we’d believed that exercise modulated TOR in the “right” direction for longevity assurance (i.e., downward). For instance, the kinase AMPK, a target of exercise mimetics, appears to downregulate TOR signaling.
However, new findings indicate that results obtained using exercise mimetics, may not be generally applicable to all exercise — in particular, it does not extend to a specific regimen blood flow restriction (BFR), designed to stimulate anabolism and muscle growth. In BFR, resistance training is combined with pressure cuffs that significantly decrease blood flow to the exercising muscle. In a recent paper, Fry et al. showed that in older men (who don’t increase muscle mass in response to ordinary resistance training), BFR increases protein synthesis in muscle cells and activates the TOR pathway.
Superficially, this would seem to represent a contradiction: a lifespan-extending intervention (exercise) activates a lifespan-shortening biochemical signaling pathway (TOR). How might this seeming paradox be resolved?
- TOR activity in the muscle might be irrelevant to lifespan control. We have yet to identify the key tissues responsible for the lifespan extension by rapamycin. Answering this question will probably require the construction of tissue-specific conditional knockdowns of either TOR or downstream pathways (e.g., S6K). This will take a while.
- Not all exercise is lifespan-extending. Perhaps exercise regimens specifically optimized to stimulate anabolism might be gerontogenic, whereas those that create acute stress and activate hormetic pathways might extend lifespan.
It’s also worth mentioning that BFR exercise may be uniquely bad in terms of longevity control. In worms, one of the targets of TOR is HIF-1, the hypoxia-inducible factor, which is a gerontogene: knocking it down extends longevity, implying that its wildtype function must shorten lifespan. It is tempting to speculate that the blood flow restriction in BFR exercise might create low-grade hypoxia in the muscle tissue, inducing HIF-1 activity and incurring some gerontogenic effect.
It certainly wouldn’t be the first time that an intervention that helped older men increase muscle mass ended up being bad for them in the long run. My favorite example of this is human growth hormone (hGH) supplementation, which—like BFR—boosts vigor and muscle tone over the short term, but by driving anabolic pathways is likely to increase the risk of cancer and other age-associated diseases.
Fry, C., Glynn, E., Drummond, M., Timmerman, K., Fujita, S., Abe, T., Dhanani, S., Volpi, E., & Rasmussen, B. (2010). Blood flow restriction exercise stimulates mTORC1 signaling and muscle protein synthesis in older men Journal of Applied Physiology DOI: 10.1152/japplphysiol.01266.2009