The NAD+/Sirtuin Pathway Modulates Longevity through Activation of Mitochondrial UPR and FOXO Signaling

被引：921

作者：

Mouchiroud, Laurent ^{[1
]}

Houtkooper, Riekelt H. ^{[1
,2
]}

Moullan, Norman ^{[1
]}

Katsyuba, Elena ^{[1
]}

Ryu, Dongryeol ^{[1
]}

Canto, Carles ^{[1
]}

Mottis, Adrienne ^{[1
]}

Jo, Young-Suk ^{[1
]}

Viswanathan, Mohan ^{[3
]}

Schoonjans, Kristina ^{[1
]}

Guarente, Leonard ^{[3
]}

Auwerx, Johan ^{[1
]}

机构：

[1] Ecole Polytech Fed Lausanne, Sch Life Sci, Lab Integrat & Syst Physiol, CH-1015 Lausanne, Switzerland

[2] Univ Amsterdam, Acad Med Ctr, Lab Genet Metab Dis, NL-1105 AZ Amsterdam, Netherlands

[3] MIT, Dept Biol, Paul F Glenn Lab, Cambridge, MA 02139 USA

来源：

CELL | 2013年 / 154卷 / 02期

基金：

瑞士国家科学基金会;

关键词：

DIET-INDUCED OBESITY; EXTENDS LIFE-SPAN; HIGH-FAT DIET; CAENORHABDITIS-ELEGANS; POLY(ADP-RIBOSE) POLYMERASE-1; TRANSCRIPTION FACTORS; CALORIE RESTRICTION; ENERGY-EXPENDITURE; OXIDATIVE STRESS; C; ELEGANS;

D O I：

10.1016/j.cell.2013.06.016

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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 (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.

引用

页码：430 / 441

页数：12

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