The NAD(+)/Sirtuin Pathway Modulates Longevity Through Activation of Mitochondrial UPR and FOXO Signaling

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 Jul 23

PMID 23870130

Citations 624

Authors

Laurent Mouchiroud

Riekelt H Houtkooper

Norman Moullan

Elena Katsyuba

Dongryeol Ryu

Carles Canto

Adrienne Mottis

Young-Suk Jo

Mohan Viswanathan

Kristina Schoonjans

Leonard Guarente

Johan Auwerx

Affiliations

Soon will be listed here.

Abstract

NAD(+) is an important cofactor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylases. We show that NAD(+) levels are reduced in aged mice and Caenorhabditis 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 (UPR(mt)) 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.

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