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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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Abstract
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.
Date issued
2013-07
URI
http://hdl.handle.net/1721.1/96399
Department
Massachusetts Institute of Technology. Department of Biology; Massachusetts Institute of Technology. Glenn Laboratory for the Science of Aging
Journal
Cell
Publisher
Elsevier
Citation
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.
Version: Final published version
ISSN
00928674
1097-4172

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