Rapamycin extends murine lifespan but has limited effects on aging

Abstract

Aging is a major risk factor for a large number of disorders and functional impairments. Therapeutic targeting of the aging process may therefore represent an innovative strategy in the quest for novel and broadly effective treatments against age-related diseases. The recent report of lifespan extension in mice treated with the FDA-approved mTOR inhibitor rapamycin represented the first demonstration of pharmacological extension of maximal lifespan in mammals. Longevity effects of rapamycin may, however, be due to rapamycin's effects on specific life-limiting pathologies, such as cancers, and it remains unclear if this compound actually slows the rate of aging in mammals. Here, we present results from a comprehensive, large-scale assessment of a wide range of structural and functional aging phenotypes, which we performed to determine whether rapamycin slows the rate of aging in male C57BL/6J mice. While rapamycin did extend lifespan, it ameliorated few studied aging phenotypes. A subset of aging traits appeared to be rescued by rapamycin. Rapamycin, however, had similar effects on many of these traits in young animals, indicating that these effects were not due to a modulation of aging, but rather related to aging-independent drug effects. Therefore, our data largely dissociate rapamycin's longevity effects from effects on aging itself.

Chronic mTOR inhibition in mice with rapamycin alters T, B, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune‐deficient mice

“…Surprisingly, only few limited reports of immune effects of mTOR inhibitors in longevity or healthspan studies have been published (Neff et al ., 2013), prompting our studies. We describe long‐term effects of eRapa in young and aged C57BL/6 mice on gene expression, function, and differentiation of T and B lymphocytes, myeloid cells, and innate lymphoid cells (ILCs), and effects on gut metagenomes.…”

“…We predict these cells contribute to improved eRapa‐mediated cancer and pathogen protection, and lifespan and healthspan extension. Although mTOR suppression could promote Treg generation, eRapa did not increase Treg numbers in various organs consistent with previous studies (Neff et al ., 2013) but did increase their prevalence in Peyer's patches. We further found no evidence supporting increased Treg suppressive function, although altered function in Peyer's patches remains untested.…”

Dietary restriction and the pursuit of effective mimetics

“…However, rapamycin's effect on the various age-related traits was less clear, appearing to induce many ageindependent effects rather than altering ageing per se (100) . In cancer-prone mice, rapamycin treatment has been shown to decrease the average number of mammary adenocarcinomas per mouse and reduced intrinsic tumour size (93) .…”

Spermidine: a physiological autophagy inducer acting as an anti-aging vitamin in humans?

“…Its potency has been recently quantified to be equivalent to that of rapamycin [23], an FDA-approved immunosuppressant with protective and autophagy-stimulatory properties [24,25]. Importantly, the genetic impairment of autophagy abrogates the beneficial effects of spermidine on longevity of yeast, flies and worms [7].…”