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SIRT 2 induces the checkpoint kinase BubR1 to increase lifespan
Author(s) -
North Brian J,
Rosenberg Michael A,
Jeganathan Karthik B,
Hafner Angela V,
Michan Shaday,
Dai Jing,
Baker Darren J,
Cen Yana,
Wu Lindsay E,
Sauve Anthony A,
Deursen Jan M,
Rosenzweig Anthony,
Sinclair David A
Publication year - 2014
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201386907
Subject(s) - sirt2 , nad+ kinase , biology , nicotinamide phosphoribosyltransferase , kinase , endocrinology , senescence , medicine , sirt6 , microbiology and biotechnology , cancer research , sirtuin , biochemistry , enzyme
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 ( SIRT 1‐7) 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 SIRT 2 to maintain lysine‐668 of BubR1 in a deacetylated state, which is counteracted by the acetyltransferase CBP . Overexpression of SIRT 2 or treatment of mice with the NAD + precursor nicotinamide mononucleotide ( NMN ) increases BubR1 abundance in vivo . Overexpression of SIRT 2 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 SIRT 2 and NAD + to delay diseases of aging in mammals is warranted.