Biology subjects

Bertoldo, M. J.

Publications and source records attributed to Bertoldo, M. J..

3 recordsLinked to original sources

bioRxiv2026

Aging disrupts cumulus-oocyte NAD homeostasis

The age-related decline in oocyte nicotinamide adenine dinucleotide (NAD) is associated with reduced developmental potential and female infertility. Despite the extraordinary longevity of the female germline, the mechanism for maintaining oocyte NAD remains unresolved. Here, we used stable isotope tracing to identify a new mechanism for shared, intercellular NAD biosynthesis, whereby somatic-germline metabolic coupling between the oocyte and its surrounding cumulus cells is critical to maintain oocyte NAD homeostasis. We show that this coupling deteriorates with reproductive aging, identifying altered NAD metabolism in cumulus cells from mice and women of advancing reproductive age. This cumulus-oocyte metabolic coupling of NAD biosynthesis contributes to protection against the age-related increases in oocyte reactive oxygen species (ROS). In intact complexes, restoring NAD through supplementation with the precursor nicotinamide mononucleotide (NMN) increased glutathione, reduced ROS and improved mitochondrial membrane potential in oocytes from aged mice and in oocytes exposed to oxidative insult. Importantly, the ability of NMN to resolve elevated ROS depends on the presence of cumulus cells. Together, this new model of somatic-germline metabolic coupling of NAD biosynthesis places an age-related deterioration in cumulus cell-mediated metabolic support as a key driver of impaired oocyte NAD levels and redox dysregulation with aging.

cell biology↗

bioRxiv2025

Chemotherapy accelerated bone ageing is reversed by NMN

Cancer patients face an array of long-term chronic diseases and accelerated biological ageing, due largely to the off-target effects of broadly cytotoxic chemotherapy drugs. This is especially a problem in children, where cancer survivors experience a subsequent high risk of bone mineral deficits and fractures, normally seen in the older population. Here, we model this to show that early-life treatment with a single dose of the commonly used chemotherapy cisplatin profoundly impairs late-life bone health, and that these bone deficits are completely resolved through treatment with the nicotinamide adenine dinucleotide (NAD+) precursor nicotinamide mononucleotide (NMN). While we had previously shown that this same strategy protects against chemotherapy induced female infertility, this maintenance of aged bone health appears to be unrelated to endocrine changes due to protection of the ovarian reserve. Rather, this is driven by altered phosphorus homeostasis and protection against renal damage, which otherwise increases parathyroid hormone secretion to mobilise calcium stores from bone. Overall, this work highlights a new approach for maintaining healthy bone ageing in cancer survivors.

physiology↗

bioRxiv2019

NAD+ repletion rescues female fertility during reproductive ageing

Female infertility is a common and devastating condition with life-long health, emotional and social consequences. There is currently no pharmacological therapy for preserving oocyte quality during aging, which is the strongest risk factor for infertility. This leads to an age dependent decline in natural conception and IVF success rates (1). Here, we show that this is due in part to declining levels of the metabolic cofactor nicotinamide adenine dinucleotide (NAD+), and that restoring NAD+ levels with its metabolic precursor nicotinamide mononucleotide (NMN) rejuvenates oocyte quality and quantity in aged animals, leading to improved fertility. These benefits extend to the developing embryo, where NMN supplementation in embryo culture media following IVF enhances blastocyst formation in older mice. The NAD+ dependent deacylase SIRT2 is sufficient, but not essential, to recapitulate the benefits of in vivo NMN treatment, and transgenic overexpression of SIRT2 maintains oocyte spindle assembly, accurate chromosome segregation, decreased oxidative stress and overall fertility with ageing. Pharmacological elevation of NAD+ may be an effective, non-invasive strategy for restoring and maintaining female fertility during ageing, and for improving the success of IVF.

developmental biology↗