Resveratrol improves health and survival of mice on a high-calorie diet.
Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.
Baur
Joseph A
JA
Department of Pathology, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02115, USA.
Pearson
Kevin J
KJ
Price
Nathan L
NL
Jamieson
Hamish A
HA
Lerin
Carles
C
Kalra
Avash
A
Prabhu
Vinayakumar V
VV
Allard
Joanne S
JS
Lopez-Lluch
Guillermo
G
Lewis
Kaitlyn
K
Pistell
Paul J
PJ
Poosala
Suresh
S
Becker
Kevin G
KG
Boss
Olivier
O
Gwinn
Dana
D
Wang
Mingyi
M
Ramaswamy
Sharan
S
Fishbein
Kenneth W
KW
Spencer
Richard G
RG
Lakatta
Edward G
EG
Le Couteur
David
D
Shaw
Reuben J
RJ
Navas
Placido
P
Puigserver
Pere
P
Ingram
Donald K
DK
de Cabo
Rafael
R
Sinclair
David A
DA
D000107:Acetylation / Q000187:drug effects; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D002149:Energy Intake / Q000502:physiology*; D006262:Health; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D009765:Obesity / Q000188:drug therapy; D020411:Oligonucleotide Array Sequence Analysis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D015996:Survival Rate; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
D007328:Insulin; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D013267:Stilbenes; D015534:Trans-Activators; D014157:Transcription Factors; D000263:Adenylate Kinase; D000077185:Resveratrol