Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase.
A major cause of aging is thought to result from the cumulative effects of cell loss over time. In yeast, caloric restriction (CR) delays aging by activating the Sir2 deacetylase. Here we show that expression of mammalian Sir2 (SIRT1) is induced in CR rats as well as in human cells that are treated with serum from these animals. Insulin and insulin-like growth factor 1 (IGF-1) attenuated this response. SIRT1 deacetylates the DNA repair factor Ku70, causing it to sequester the proapoptotic factor Bax away from mitochondria, thereby inhibiting stress-induced apoptotic cell death. Thus, CR could extend life-span by inducing SIRT1 expression and promoting the long-term survival of irreplaceable cells.
Cohen
Haim Y
HY
Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA.
Miller
Christine
C
Bitterman
Kevin J
KJ
Wall
Nathan R
NR
Hekking
Brian
B
Kessler
Benedikt
B
Howitz
Konrad T
KT
Gorospe
Myriam
M
de Cabo
Rafael
R
Sinclair
David A
DA
D000107:Acetylation; D000273:Adipose Tissue / Q000378:metabolism; D000483:Alleles; D000818:Animals; D034961:Antigens, Nuclear / Q000378:metabolism; D017209:Apoptosis; D031204:Caloric Restriction; D002460:Cell Line; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000378:metabolism; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000378:metabolism; D000072200:Ku Autoantigen; D008099:Liver / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051381:Rats; D011916:Rats, Inbred F344; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D051028:bcl-2-Associated X Protein
D034961:Antigens, Nuclear; C494826:BAX protein, human; C494828:Bax protein, rat; D004268:DNA-Binding Proteins; D007328:Insulin; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D051028:bcl-2-Associated X Protein; D007334:Insulin-Like Growth Factor I; C447939:SIRT1 protein, human; C488368:Sirt1 protein, rat; D056564:Sirtuin 1; D037761:Sirtuins; D006655:Histone Deacetylases; C000606509:Xrcc6 protein, human; C000606511:Xrcc6 protein, rat; D000072200:Ku Autoantigen