SIRT2 induces the checkpoint kinase BubR1 to increase lifespan.
Mice overexpressing the mitotic checkpoint kinase gene BubR1 live longer, whereas mice hypomorphic for BubR1 (BubR1(H/H)) live shorter and show signs of accelerated aging. As wild-type mice age, BubR1 levels decline in many tissues, a process that is proposed to underlie normal aging and age-related diseases. Understanding why BubR1 declines with age and how to slow this process is therefore of considerable interest. The sirtuins (SIRT1-7) are a family of NAD(+)-dependent deacetylases that can delay age-related diseases. Here, we show that the loss of BubR1 levels with age is due to a decline in NAD(+) and the ability of SIRT2 to maintain lysine-668 of BubR1 in a deacetylated state, which is counteracted by the acetyltransferase CBP. Overexpression of SIRT2 or treatment of mice with the NAD(+) precursor nicotinamide mononucleotide (NMN) increases BubR1 abundance in vivo. Overexpression of SIRT2 in BubR1(H/H) animals increases median lifespan, with a greater effect in male mice. Together, these data indicate that further exploration of the potential of SIRT2 and NAD(+) to delay diseases of aging in mammals is warranted.
Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging Harvard Medical School, Boston, MA, USA.
Brian J
BJ
North
Cardiovascular Division, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA, USA.
Michael A
MA
Rosenberg
Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
Karthik B
KB
Jeganathan
Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging Harvard Medical School, Boston, MA, USA.
Angela V
AV
Hafner
Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging Harvard Medical School, Boston, MA, USA.
Shaday
S
Michan
Cardiovascular Division, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA, USA.
Jing
J
Dai
Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
Darren J
DJ
Baker
Department of Pharmacology, Weill Medical College of Cornell University, New York, NY, USA.
Yana
Y
Cen
Department of Pharmacology, School of Medicine The University of New South Wales, Sydney, NSW, Australia.
Lindsay E
LE
Wu
Department of Pharmacology, Weill Medical College of Cornell University, New York, NY, USA.
Anthony A
AA
Sauve
Department of Pediatric and Adolescent Medicine, Mayo Clinic College of Medicine, Rochester, MN, USA.
Jan M
JM
van Deursen
Cardiovascular Division, Beth Israel Deaconess Medical Center Harvard Medical School, Boston, MA, USA.
Anthony
A
Rosenzweig
Department of Genetics, Paul F. Glenn Laboratories for the Biological Mechanisms of Aging Harvard Medical School, Boston, MA, USA Department of Pharmacology, School of Medicine The University of New South Wales, Sydney, NSW, Australia david_sinclair@hms.harvard.edu.
David A
DA
Sinclair
D000818:Animals; D018797:Cell Cycle Proteins; D004790:Enzyme Induction / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008136:Longevity / Q000502:physiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009243:NAD / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D056565:Sirtuin 2 / Q000235:genetics / Q000378:metabolism*
C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; D009243:NAD; C584277:BUB1 protein, human; D017346:Protein Serine-Threonine Kinases; C474199:SIRT2 protein, human; C418743:Sirt2 protein, mouse; D056565:Sirtuin 2
BubR1; NAD
+; acetylation; aging; sirtuin