NMN Supplementation Rescues Fertility and Bone Strength in Chemotherapy-Treated Mice

Abstract

Background: Cancer survivors often face infertility as a result of ovarian toxicity from cytotoxic chemotherapy drugs, which trigger a cascade of events ultimately causing follicular reserve exhaustion and endocrine disruption. Apart from infertility, this can have severe consequences on women’s health with early-onset menopause and a decline in bone health. For girls with cancer, ovarian tissue cryopreservation (OTC) is the only option for fertility preservation. OTC + transplantation may provide future fertility potential, but it provides minimal/no protection from endocrine failure and osteoporosis. Aim: To assess the effects of the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN) on ovarian function, fertility, and late-life bone health. Method: 7-day old female mice were treated +/- cisplatin (2mg/kg). Two weeks later, +/- NMN was delivered in drinking water (2g/L) and sustained throughout life. A breeding trial was conducted at 6 weeks, and to assess late-life effects on bone structure, mice were maintained until euthanasia at 24 months of age. Results: Cisplatin caused a dramatic decline in all fertility endpoints. NMN supplementation rescued breeding performance in cisplatin treated animals by 5-fold (p=0.015), as measured by the cumulative number of pups/female. Given the importance of ovarian function to estrogen release and the risk of osteoporosis, we sought to determine the impacts of these interventions on late-life bone health. Bones were subject to mechanical and structural analysis to assess differences in the onset of osteoporosis. In cisplatin treated animals, NMN rescued cortical bone thickness (femur diaphysis p[Formula: see text]0.0001, femur metaphysis p=0.0081, tibia p=0.0072), bone volume (femur p=0.0015, tibia p=0.0102), and bone density (femur p=0.0463) to control levels, and increased mechanical strength (tibia, p=0.0024). Conclusion: Long-term NMN treatment delivered following chemotherapy protected against subsequent ovarian failure and infertility, and notably improved late-life bone health, possibly due to the prevention of premature ovarian failure.