Details

Autor(en) / Beteiligte

• Iljas, Juvita D.
• Wei, Zhe
• Homer, Hayden A.

Titel

Sirt1 sustains female fertility by slowing age‐related decline in oocyte quality required for post‐fertilization embryo development

Ist Teil von

• Aging cell, 2020-09, Vol.19 (9), p.e13204-n/a

Ort / Verlag

England: John Wiley & Sons, Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• The NAD+‐dependent sirtuin deacetylase, Sirt1, regulates key transcription factors strongly implicated in ageing and lifespan. Due to potential confounding effects secondary to loss of Sirt1 function from the soma in existing whole‐animal mutants, the in vivo role of Sirt1 in oocytes (oocyte‐Sirt1) for female fertility remains unknown. We deleted Sirt1 specifically in growing oocytes and study how loss of oocyte‐Sirt1 affects a comprehensive range of female reproductive parameters including ovarian follicular reservoir, oocyte maturation, oocyte mitochondrial abundance, oxidative stress, fertilization, embryo development and fertility during ageing. Surprisingly, eliminating this key sirtuin from growing oocytes has no effect in young females. During a 10‐month‐long breeding trial, however, we find that 50% of females lacking oocyte‐Sirt1 become prematurely sterile between 9 and 11 months of age when 100% of wild‐type females remain fertile. This is not due to an accelerated age‐related decline in oocyte numbers in the absence of oocyte‐Sirt1 but to reduced oocyte developmental competence or quality. Compromised oocyte quality does not impact in vivo oocyte maturation or fertilization but leads to increased oxidative stress in preimplantation embryos that inhibits cleavage divisions. Our data suggest that defects emerge in aged females lacking oocyte‐Sirt1 due to concurrent age‐related changes such as reduced NAD+ and sirtuin expression levels, which compromise compensatory mechanisms that can cover for Sirt1 loss in younger oocytes. In contrast to evidence that increasing Sirt1 activity delays ageing, our data provide some of the only in vivo evidence that loss of Sirt1 induces premature ageing. The very first oocyte‐specific Sirt1‐knockout mouse was generated in this study. Mice lacking Sirt1 activity in their oocytes were phenotypically indistinguishable whilst young, but became prematurely sterile between 9 and 11 months of age. The latter was not due to decline in oocyte numbers, but rather due to decline in oocyte quality. Here, we discovered that Sirt1 plays a critical role in slowing age‐related decline in oocyte quality required for post‐fertilization embryogenesis.