Nicotinamide mononucleotide as a novel therapeutic strategy to counteract the adverse effects of chemotherapy and aging on oocyte quality
- Autores: Noelia Ramírez Martín
- Directores de la Tesis: Antonio Pellicer Martínez (codir. tes.), Sonia Herraiz Raya (codir. tes.)
- Lectura: En la Universitat de València ( España ) en 2026
- Idioma: inglés
- Número de páginas: 252
- Tribunal Calificador de la Tesis: Joaquín Llácer (presid.), María José Escribá Pérez (secret.), Maurizio Zuccotti (voc.)
- Programa de doctorado: Programa Oficial de Doctorado en Bioquímica y Biomedicina
- Menciones:
- Internacional
- Calificación: Sobresaliente Cum Laude
- Materias:
- Enlaces
- Resumen
Aging and chemotherapy represent the main factors responsible for the deterioration of ovarian reserve and oocyte quality, significantly limiting female reproductive potential. Currently, there is no clinically applicable strategy to improve oocyte quality in these patients, who often must resort to oocyte donation as the only viable option to achieve motherhood. In this context, nicotinamide mononucleotide (NMN), the immediate precursor of nicotinamide adenine dinucleotide (NAD⁺), has emerged as a promising strategy to enhance oocyte competence. Previous studies in animal models have shown that NMN can improve oocyte quality impaired by aging and protect ovarian potential against moderate gonadotoxic damage induced by chemotherapy.
Based on this evidence, the present doctoral thesis aims to investigate the effects of NMN against severe chemotherapy-induced gonadotoxic damage and aging, using mouse models and human oocytes, respectively. To this end, two experimental approaches were designed. In the first study, two mouse models with different degrees of ovarian damage induced by alkylating agents were employed, together with young healthy females as a reference group. Animals were orally supplemented with NMN either throughout a complete folliculogenesis cycle or restricted to the final stages of follicular development. Following supplementation, ovarian reserve, oocyte quality, and embryonic development parameters were evaluated. Subsequently, a prospective study was conducted to evaluate the effects of in vitro NMN supplementation on immature oocytes from women of advanced maternal age (AMA), compared with those from younger patients. Nuclear maturation and initial cytoplasmic competence were assessed using the germinal vesicle rescue approach.
NMN supplementation over a complete folliculogenesis cycle enhanced oocyte quality by recovering intracellular NAD⁺ levels, reducing oxidative stress, and redistributing mitochondria, thereby promoting proper meiotic spindle formation and improved oocyte competence.
Furthermore, when supplementation was restricted to the later stages of folliculogenesis, NMN also exerted positive effects on oocyte quality, tough to a lesser extent. Finally, in the human oocyte study, in vitro NMN supplementation improved nuclear competence and parthenogenetic activation in the AMA group, achieving outcomes comparable to those of younger women.
These results highlight the regenerative role of NMN in mouse and human oocytes exposed to the deleterious effects of chemotherapy and aging, representing a potential non-invasive therapeutic alternative for patients undergoing fertility preservation and aged women seeking to achieve motherhood with autologous oocytes.
