Exploring the impact of metformin on testicular aging in Syrian hamsters.

Biochemical and molecular mechanisms associated with testicular aging are still poorly understood. Here, using the Syrian hamster as a natural model of aging, we observed a disturbed spermatogenesis with reduction of the testicular weight and the gonadosomatic index, altered histology including tubular wall fibrosis, increased collagen deposition, and diminished steroidogenesis in testes of aged animals. These changes took place in parallel with an increase in the levels of inflammatory and oxidative stress markers and a reduction in the cell proliferative, survival, DNA repair, and autophagic capacities. Metformin, beyond its current clinical applications, has been proposed as an anti-aging drug. In vitro incubations of testicular fragments from old hamsters with metformin revealed beneficial effects of this drug on the testicular inflammatory-oxidative state together with stimulation of autophagy and cell ability to fix DNA damage. However, in vivo daily oral administration of metformin to aged hamsters for 2 months in a dose equivalent to that usually received by patients with type 2 diabetes mellitus, reduced body and testicular weights, gonadosomatic index and blood glucose, concomitantly with increased levels of indicators of testicular inflammation, oxidation and fibrosis, decreased signs of autophagy, steroidogenesis and DNA repair capacity, and impaired spermatogenesis. Overall, while in vitro studies suggested beneficial effects of metformin in the aging testis evidenced through anti-inflammatory, anti-oxidant, and pro-autophagic actions, in vivo experiments in aged hamsters supplemented with metformin exhibited completely opposite effects. Therefore, the future of metformin as a testicular anti-aging agent should be further investigated, thoroughly reconsidered and, should the need arise, disregarded.