Oral Presentation ESA-SRB-ANZBMS 2024 in conjunction with ENSA

Interrogating the impact of SIRT1 modulation on fertility and stress sensitivity in the male germline (#35)

Shannon P Smyth 1 2 3 , Nathan D Burke 1 2 3 , Shenae L Cafe 1 2 , Charlotte Taylor 4 , Rachel Y Ingham 3 , John E Schjenken 1 2 , David A Skerrett-Byrne 1 2 5 6 , Tessa Lord 1 2 , Jessica E.M Dunleavy 3 , Brett Nixon 1 2 , Elizabeth G Bromfield 1 2 3
  1. Infertility and Reproduction Research Program, Hunter Medical Research Institute, Newcastle, NSW, Australia
  2. School of Environmental and Life Sciences, College of Engineering, Science and Environment, University of Newcastle, Callaghan, NSW, Australia
  3. School of BioSciences, Faculty of Science, Bio21 Institute, University of Melbourne, Parkville, VIC, Australia
  4. Melbourne BioResources Platform, Bio21 Institute, University of Melbourne, Melbourne, VIC, Australia
  5. Institute of Experimental Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
  6. German Center for Diabetes Research (DZD), Neuherberg, Germany

Sirtuin (SIRT) proteins are a family of NAD-dependent deacetylases that have previously been linked to the regulation of lifespan and the protection of somatic cells against proteotoxicity. While this protective effect is untested in reproductive cells, pilot data has revealed that SIRT1 activation significantly reduces protein aggregation in spermatocytes and spermatids (p<0.005), suggesting a potential protective role against oxidative protein damage. Here, we have utilised a transgenic mouse SIRT1 overexpression model (Sirt1tg/+) to assess the impact of SIRT1 on male reproduction and germline stress sensitivity. This is particularly pressing as there is increased public interest in the use of SIRT1 activating supplements to increase longevity. To assess whether SIRT1 overexpression results in a reproductive phenotype, we conducted a breeding trial whereby wildtype females were mated with either wildtype or Sirt1tg/+ males. We observed no changes in the rate of progression to pregnancy, gestation length or litter size, suggesting that male fertility is unaffected by increased SIRT1 at either young (12-16wks) or aged (50-54wks) timepoints. Interestingly, we did observe a trend towards altered sexual behaviour in an aged cohort, with a higher percentage of Sirt1tg/+ males mating with females (92.9%) compared to the wildtype controls (64.3%); indicated by the presence of a copulatory plug and/or viable pregnancy (p=0.065). Preliminary data collected from young Sirt1tg/+ mice revealed no changes in sperm viability, motility, nor the ability to complete capacitation compared to wildtype. These parameters are yet to be assessed in the aged population and additional experimentation is underway to investigate the impact of SIRT1 overexpression on germ cell sensitivity to oxidative stress. Ultimately, we anticipate these data will provide critical insights into whether sirtuin modulation is a viable approach for the mitigation of germline proteotoxicity and enhance our understanding of the impacts of SIRT1 supplementation on male fertility across the life course.