Overall, then, exercise and its molecular/cellular consequences are consistent with longevity assurance pathways and life extension interventions. However, there are complications emerging.
One of the results of exercise is increased activity of anabolic pathways, especially in muscle. Building up tissues require new protein synthesis, and new protein synthesis requires activity of the TOR pathway. TOR is increasingly thought to be a pro-aging or gerontogenic pathway: rapamycin, a drug that inhibits TOR, blocks senescence and extends lifespan in mice (we already knew that TOR inhibition increased longevity in worms and yeast).
Until recently, we’d believed that exercise modulated TOR in the “right” direction for longevity assurance (i.e., down). For instance, AMPK, a target of exercise mimetics, appears to downregulate TOR signaling.
But it would appear that the above result, obtained using exercise mimetics, may not be generally applicable to all exercise — in particular, it does not extend to a specific regimen of exercise designed to stimulate anabolism and muscle growth. In blood flow restriction (BFR) exercise, resistance training is combined with pressure cuffs that significantly decrease blood flow to the exercising muscle; it increases protein synthesis in muscle cells and activates the TOR pathway. Now, Fry et al. have shown that in older men (who don’t increase muscle mass in response to ordinary resistance training), BFR activates TOR.
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?
It’s also worth mentioning that BFR exercise may be uniquely bad vis-a-vis longevity control. In worms, one of the targets of TOR is HIF-1, the hypoxia inducible factor. HIF-1 is a gerontogene: knocking it down extends longevity, so its wildtype function must shorten lifespan. I wonder whether 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 (e.g., hGH).
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