Meiotic cohesion requires Sirt1 and preserving its activity in aging oocytes reduces missegregation

Chromosome segregation errors in human oocytes increase dramatically as women age and premature loss of meiotic cohesion is one factor that contributes to a higher incidence of segregation errors in older oocytes. Here we show that knockdown of the NAD⁺-dependent deacetylase Sirt1 during meiotic prophase in Drosophila oocytes causes premature loss of arm cohesion and chromosome segregation errors. We demonstrate that acetylation of the Sirt1 substrate H4K16 increases significantly in sirt1 null and Sirt1 knockdown oocytes and use this as a marker for Sirt1 activity in vivo. When oocytes undergo aging, the H4K16ac signal increases significantly, consistent with an aging-dependent decline in Sirt1 deacetylase activity. However, if females are fed the Sirt1 activator SRT1720 as their oocytes age, the H4K16ac signal on oocyte DNA remains low in aged oocytes, consistent with preservation of Sirt1 activity during aging. Strikingly, age-dependent segregation errors are significantly reduced if mothers are fed SRT1720 while their oocytes age. Our data suggest that maintaining Sirt1 activity in aging oocytes may provide a viable therapeutic strategy to decrease age-dependent segregation errors.