The [NAD[superscript +] over Sirtuin] Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling
Author(s)Mouchiroud, Laurent; Houtkooper, Riekelt H.; Moullan, Norman; Katsyuba, Elena; Ryu, Dongryeol; Canto, Carles; Mottis, Adrienne; Jo, Young-Suk; Viswanathan, Mohan; Schoonjans, Kristina; Auwerx, Johan; Guarente, Leonard Pershing; ... Show more Show less
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NAD[superscript +] is an important cofactor regulating metabolic homeostasis and a rate-limiting substrate for sirtuin deacylases. We show that NAD[superscript +] levels are reduced in aged mice and Caenorhabditis elegans and that decreasing NAD[superscript +] levels results in a further reduction in worm lifespan. Conversely, genetic or pharmacological restoration of NAD[superscript +] 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[superscript 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[superscript +] levels may be a target to improve mitochondrial function and prevent or treat age-associated decline.
DepartmentMassachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Glenn Laboratory for the Science of Aging
Mouchiroud, Laurent, Riekelt H. Houtkooper, Norman Moullan, Elena Katsyuba, Dongryeol Ryu, Carles Cantó, Adrienne Mottis, et al. “The [NAD[superscript +] over Sirtuin] Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling.” Cell 154, no. 2 (July 2013): 430–441. © 2013 Elsevier Inc.
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