Abstract
Calorie restriction (CR) without malnutrition is the most robust intervention to slow aging and extend healthy lifespan in experimental model organisms. Several metabolic and molecular adaptations have been hypothesized to play a role in mediating the anti-aging effects of CR, including enhanced stress resistance, reduced oxidative stress and several neuroendocrine modifications. However, little is known about the independent effect of circulating factors in modulating key molecular pathways. In this study, we used sera collected from individuals practicing long-term CR and from age- and sex-matched individuals on a typical US diet to culture human primary fibroblasts and assess the effects on gene expression and stress resistance. We show that treatment of cultured cells with CR sera caused increased expression of stress-response genes and enhanced tolerance to oxidants. Cells cultured in serum from CR individuals showed a 30% increase in resistance to H2O2 damage. Consistently, SOD2 and GPX1 mRNA, two key endogenous antioxidant enzymes, were increased by 2 and 2.5 folds respectively in cells cultured with CR sera. These cellular and molecular adaptations mirror some of the key effects of CR in animals, and further suggest that circulating factors contribute to the CR-mediated protection against oxidative stress and stress-response in humans as well.
Highlights
Calorie restriction (CR) without malnutrition is the most potent and reproducible intervention for slowing aging and protecting against cancer in mammals [1,2]
Our findings show that the incubation of human fibroblasts with CR sera induces a transcriptional activation of several anti-oxidant genes along the NF-E2-related factor 2 (Nrf2) pathway
These molecular and cellular adaptations are consistent with findings in CR rodents and monkeys, and may contribute at least in part to the protective anti-aging effects of CR [1,3]
Summary
Calorie restriction (CR) without malnutrition is the most potent and reproducible intervention for slowing aging and protecting against cancer in mammals [1,2]. It has been hypothesized that changes in circulating factors may contribute, at least in part, to some of these beneficial effects of CR in rodents [4]. Nothing is known on the molecular and cellular adaptations induced by circulating factors in men and women practicing long-term severe CR. The importance of circulating factors in modulating health and longevity is supported by data obtained by heterochronic parabiosis experiments in mice [5]. Exposure of old mice to circulating factors present in young serum increased neurogenesis and regeneration after muscle injury [6,7]. It is well known that senescent stromal cells secrete a number of factors that can promote cancer and aging by increasing proliferation www.impactaging.com
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