The sirtuins, oxidative stress and aging: an emerging link

Abstract

Reactive oxygen species (ROS) are a family of compounds that can oxidatively damage cellular macromolecules and may influence lifespan. Sirtuins are a conserved family of nicotinamide adenine dinucleotide (NAD+)-dependent protein deacetylases that regulate lifespan in many model organisms including yeast and mice. Recent work suggests that sirtuins can modulate ROS levels notably during a dietary regimen known as calorie restriction which enhances lifespan for several organisms. Although both sirtuins and ROS have been implicated in the aging process, their precise roles remain unknown. In this review, we summarize current thinking about the oxidative stress theory of aging, discuss some of the compelling data linking the sirtuins to ROS and aging, and propose a conceptual model placing the sirtuins into an ROS-driven mitochondria-mediated hormetic response.

Nicotinamide mononucleotide supplementation reverses vascular dysfunction and oxidative stress with aging in mice

“…However, because adherence to CR is not practical for most humans, there is growing interest in pharmacological therapies that may induce the benefits of CR. In this context, the mammalian SIRT1, one of seven members in the sirtuin family of protein deacetylases/deacylases, is a nicotinamide adenine dinucleotide (NAD + )‐dependent deacetylase that acts as a metabolic energy sensor implicated in several of the beneficial effects of CR, including reduced oxidative stress (Boily et al ., 2008; Merksamer et al ., 2013). Our previous work shows that reduced SIRT1 expression and activity is a key mechanism mediating impaired EDD in aging arteries (Rippe et al ., 2010; Donato et al ., 2011; Gano et al ., 2014), and our recent findings indicate that pharmacological activation of SIRT1 with the compound SRT1720 improves EDD in old mice in part by reducing oxidative stress (Gano et al ., 2014).…”

Enhanced longevity and metabolism by brown adipose tissue with disruption of the regulator of G protein signaling 14

“…The role of BAT in RGS14 KO and its ability to enhance lifespan and improve metabolism, the focus of the present investigation, have never been explored. Sirtuins, which have been shown to be involved in mediating healthful aging (Merksamer et al., 2013; Sack & Finkel, 2012) were also examined. To confirm the essential role of BAT in mediating the protection in the RGS14 KO, we transplanted BAT from RGS14 KO to WT mice, a technique that is equivalent to a BAT KO, as it disrupts the salutary phenotype in the RGS14 KO and transplants these features to their WT, receiving the BAT.…”

Systems biology approaches to study the molecular effects of caloric restriction and polyphenols on aging processes

“…Age-related dysfunctions thus arise from several molecular systems that share central molecular effectors particularly in the sirtuin family (SIRTs, regulators of cellular energy metabolism and mitochondrial biogenesis) and adenosine monophosphate-activated protein kinase (AMPK, central regulator of energy metabolism) and their downstream targets (Salminen and Kaarniranta 2012;Merksamer et al 2013). Dysfunctions in those systems principally result in decreased capacity to respond to stressors, to regulate mitochondrial function and energy metabolism and, through their interaction with the mammalian target of rapamycin (mTOR), to impaired autophagy mechanisms (Rubinsztein et al 2011;Salminen and Kaarniranta 2012;Merksamer et al 2013).…”

“…Dysfunctions in those systems principally result in decreased capacity to respond to stressors, to regulate mitochondrial function and energy metabolism and, through their interaction with the mammalian target of rapamycin (mTOR), to impaired autophagy mechanisms (Rubinsztein et al 2011;Salminen and Kaarniranta 2012;Merksamer et al 2013).…”