Lifespan‐extending caloric restriction or mTOR inhibition impair adaptive immunity of old mice by distinct mechanisms

Abstract

Aging of the world population and a concomitant increase in age-related diseases and disabilities mandates the search for strategies to increase healthspan, the length of time an individual lives healthy and productively. Due to the age-related decline of the immune system, infectious diseases remain among the top 5–10 causes of mortality and morbidity in the elderly, and improving immune function during aging remains an important aspect of healthspan extension. Calorie restriction (CR) and more recently rapamycin (rapa) feeding have both been used to extend lifespan in mice. Preciously few studies have actually investigated the impact of each of these interventions upon in vivo immune defense against relevant microbial challenge in old organisms. We tested how rapa and CR each impacted the immune system in adult and old mice. We report that each intervention differentially altered T-cell development in the thymus, peripheral T-cell maintenance, T-cell function and host survival after West Nile virus infection, inducing distinct but deleterious consequences to the aging immune system. We conclude that neither rapa feeding nor CR, in the current form/administration regimen, may be optimal strategies for extending healthy immune function and, with it, lifespan.

Calorie restriction in rodents: Caveats to consider

“…From the same series of studies, Clinthorne et al (2013) confirmed reduced NK cell maturation in young (6 mo) B6 mice on 40% CR(Clinthorne et al, 2013), and Duriancik and Gardner (2016) observed reduced dentritic cells in mice treated similarly(Duriancik and Gardner, 2016). Goldberg et al (2015) confirmed and extended these findings when they observed increased mortality among 18-mo old B6 mice on 40% CR since 14 weeks of age before being infected with West Nile virus (sc injection)(Goldberg et al, 2015). Appropriate T-cell response to the viral infection in CR had been compromised.…”

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

“…Long‐term eRapa does not increase mouse blood Tregs (Goldberg et al ., 2015). Treg prevalence in spleen and mesenteric lymph nodes of mice started on eRapa at age 6 months for 19 months was unchanged, but the prevalence increased in Peyer's patches (Fig.…”

The Mechanistic Target of Rapamycin: The Grand ConducTOR of Metabolism and Aging

“…The severity of side effects for rapamycin and its analogs is thought to be dose-dependent, and few adverse events were observed in elderly patients who took low doses of everolimus for only six weeks (Mannick et al, 2014). In mice, the effect of rapamycin on the immune system is less clear-cut, with rapamycin treatment resulting in negative effects on immune cell number and function, but with certain immunomodulatory effects of rapamycin possibly being beneficial (Goldberg et al, 2015; Goldberg et al, 2014; Hurez et al, 2015). …”