SIRT1 is involved in cellular senescence, or limitation of cells’ reproductive lifespan, a process thought to ensure that aging cells don’t pass on harmful mutations.
Frederick W. Alt, a Howard Hughes Medical Institute investigator at Children’s Hospital and Harvard Medical School, and colleagues suppressed SIRT1 activity in cultures of mouse embryonic fibroblasts, or primitive cells that give rise to connective tissue, exploring how SIRT1 deficiency affected the cells’ ability to divide.
When Alt, also scientific director of the CBR Institute for Biomedical Research in Boston, and his team switched SIRT1 off in the mouse cells, the cells became ”immortalized,” undergoing continued division. But when the researchers switched SIRT1 back on, the cells again became subject to senescence. The researchers also found that SIRT1 might regulate senescence by down-regulating expression of p19ARF, known to be an important mediator of senescence. Indeed, p19-deficiency in cells similarly eliminates senescence in cell cultures. The researchers also found that SIRT1 affects a particular response pathway to DNA-damaging oxidation: SIRT1-deficient cells, in contrast to normal cells, continued to divide when treated with chronic, low-level doses of hydrogen peroxide (which induces oxidation). However, the SIRT1-deficient cells had a normal senescence response when exposed to high-level oxidation or the activated cancer gene, Ras. These results indicate that SIRT1 has a specific role in the response to chronic oxidative damage.