Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy

Abstract

Caloric restriction and autophagy-inducing pharmacological agents can prolong lifespan in model organisms including mice, flies, and nematodes. In this study, we show that transgenic expression of Sirtuin-1 induces autophagy in human cells in vitro and in Caenorhabditis elegans in vivo. The knockdown or knockout of Sirtuin-1 prevented the induction of autophagy by resveratrol and by nutrient deprivation in human cells as well as by dietary restriction in C. elegans. Conversely, Sirtuin-1 was not required for the induction of autophagy by rapamycin or p53 inhibition, neither in human cells nor in C. elegans. The knockdown or pharmacological inhibition of Sirtuin-1 enhanced the vulnerability of human cells to metabolic stress, unless they were stimulated to undergo autophagy by treatment with rapamycin or p53 inhibition. Along similar lines, resveratrol and dietary restriction only prolonged the lifespan of autophagy-proficient nematodes, whereas these beneficial effects on longevity were abolished by the knockdown of the essential autophagic modulator Beclin-1. We conclude that autophagy is universally required for the lifespan-prolonging effects of caloric restriction and pharmacological Sirtuin-1 activators.

Resveratrol Improves Motoneuron Function and Extends Survival in SOD1G93A ALS Mice

“…c Evaluation of Sirt1 activity by measuring the acetylation levels of p53 revealed significant deacetylation and thus, an increased activity of Sirt1 in SOD1 G93A mice treated with resveratrol. *p<0.05 vs. wild type, #p<0.05 vs. untreated SOD1 G93A mice plays its protective role through the modulation of autophagy [45,59], we evaluated the expression of two of the most typical markers of autophagy, LC3 and Beclin-1. Our results revealed that both Beclin-1 and the LC3bII/LC3bI ratio were significantly increased in SOD1 G93A mice compared to wild type littermates, evidencing impairment of the autophagic flux.…”

Autophagy and ageing: Insights from invertebrate model organisms

“…In addition, activation of SIR-2.1 by transgenic overexpression of pnc-1, a gene encoding the pyrazinamidase/nicotinamidase PNC-1 that catabolizes nicotinamide, a sirtuin inhibitor, also extends lifespan in C. elegans. The effect of pnc-1 overexpression on lifespan is abolished by concomitant knockdown of sir-2.1 or by that of either bec-1 or atg-5 (Morselli et al, 2010b). Notably, SIRT1 (human orthologue of sir-2.1) has been shown to directly deacetylate Atg5, Atg7 and Atg8 in vitro (Lee et al, 2008), indicating that the transcriptional control of essential autophagy genes is under the control of SIRT1.…”

“…Consistent with these findings, a loss of function mutation in sir-2.1 prevents the induction of autophagy and the increase in longevity by caloric restriction, suggesting that CR induces autophagy in a sir-2.1-dependent manner. By contrast, rapamycin-induced autophagy is independent of sir-2.1, indicating that rapamycin and sir-2.1 stimulate autophagy through distinct mechanisms (Morselli et al, 2010b). Dietary deprivation (removal of food source Escherichia coli) during adulthood increases lifespan and enhances thermotolerance and resistance to oxidative stress in C. elegans.…”

Antioxidants reveal an inverted U‐shaped dose‐response relationship between reactive oxygen species levels and the rate of aging in Caenorhabditis elegans

“…The effect of RSV on lifespan per se has also been widely tested and positive effects documented in both invertebrates and vertebrates (Bhullar & Hubbard, 2015). In C. elegans , a relatively small but reproducible lifespan‐extending effect has been documented by several groups (Wood et al ., 2004; Viswanathan et al ., 2005; Bass et al ., 2007; Agarwal & Baur, 2011; Morselli et al ., 2010; Zarse et al ., 2010). …”