The NAD+/sirtuin pathway modulates longevity through activation of mitochondrial UPR and FOXO signaling
By L. Mouchiroud, R. Houtkooper, N. Moullan, E. Katsyuba, D. Ryu, C. Cantó, Adrienne Mottis, Y. Jo, M. Viswanathan, K. Schoonjans and 2 more. Cell, 2013
1,146 citations recorded by the source corpus.
Summary NAD+ is an important co-factor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylase. We show that NAD+ levels are reduced in aged mice and C. elegans and that decreasing NAD+ levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD+ prevents age-associated metabolic decline and promotes longevity in worms. These effects are dependent upon the protein deacetylase sir-2.1 and involve the induction of mitonuclear protein imbalance as well as activation of stress signaling via the mitochondrial unfolded protein response (UPRmt) and the nuclear translocation and activation of FOXO transcription factor DAF-16. Our data suggest that augmenting mitochondrial stress signaling through the modulation of NAD+ levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.
Subfields: Aging, Geriatrics and Gerontology, Physiology
View Paper: https://www.semanticscholar.org/paper/f7a008405dc64007d7753575927f965422da83ec
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Citations in the corpus
- The Mitochondrial Basis of Aging (2016, background): “Levels of NAD appears to decline in tissues as they age (Mouchiroud et al., 2013; Yoshino et al., 2011).”
- Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice (2016, positive): “…a number of studies have reported that NAD+ content declines with age in multiple organs, such as pancreas, adipose tissue, skeletal muscle, liver, skin, and brain (Gomes et al., 2013; Massudi et al., 2012; Mouchiroud et al., 2013; Stein and Imai, 2014; Yoshino et al., 2011; Zhu et al., 2015).”
- Therapeutic potential of NAD-boosting molecules: the in vivo evidence (2018, positive): “…however, it has become clear that a steady decline in total NAD+ levels over time is a natural part of life for all species, from yeast to humans (Balan et al., 2008; Belenky et al., 2007; Lin et al., 2004; Massudi et al., 2012; Mouchiroud et al., 2013; Zhang et al., 2016; Zhu et al., 2015).”
- Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging (2013, background): “The mitochondrial unfolded protein response (mtUPR) has been recently linked to longevity (Durieux et al., 2011; Houtkooper et al., 2013; Mouchiroud et al., 2013); however, C under these conditions there was no evidence of a mtUPR at 22 months of age (Figure S1A available online).”
- NAD+ metabolism: pathophysiologic mechanisms and therapeutic potential (2020, background): “Combining the evidence that mitochondrial dysfunction is a hallmark of aging and NAD plays a crucial role in the maintenance of mitochondrial function.(341,345), we can hypothesize that aging-related NAD decline might be the cause of mitochondria dysfunction.”
- Metabolic Control of Longevity. (2016, background): “Similarly, the exogenous supply of nicotinamide riboside or nicotinamide mononucleotide can increase lifespan in C. elegans through activation of the nematode ortholog of SIRT1, induction of the UPRmt, or activation of DAF-16 (Mouchiroud et al., 2013).”
- Kynurenines: Tryptophan’s metabolites in exercise, inflammation, and mental health (2017, background): “Nevertheless, NAD boosting strategies seem to be successful in restoringmitochondrial and stem cell function (121) and in ameliorating diseases such as muscular dystrophy and diabetes (122, 123) or even prolonging life span (124).”
- Defective Mitophagy in XPA via PARP1 Hyperactivation and NAD+/SIRT1 Reduction (2014, background): “SIRT1 usesNAD+ as a substrate and is regulated by NAD+ levels (Mouchiroud et al., 2013).”