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Review
. 2024 Apr 25;25(9):4680.
doi: 10.3390/ijms25094680.

A Molecular Perspective and Role of NAD+ in Ovarian Aging

Mehboob Ahmed  1   2   3 , Umair Riaz  1   2   3 , Haimiao Lv  1   2   3 , Liguo Yang  1   2   3
Affiliations
Review

A Molecular Perspective and Role of NAD+ in Ovarian Aging

Mehboob Ahmed et al. Int J Mol Sci. .

Abstract

The decline in female fecundity is linked to advancing chronological age. The ovarian reserve diminishes in quantity and quality as women age, impacting reproductive efficiency and the aging process in the rest of the body. NAD+ is an essential coenzyme in cellular energy production, metabolism, cell signaling, and survival. It is involved in aging and is linked to various age-related conditions. Hallmarks associated with aging, diseases, and metabolic dysfunctions can significantly affect fertility by disturbing the delicate relationship between energy metabolism and female reproduction. Enzymes such as sirtuins, PARPs, and CD38 play essential roles in NAD+ biology, which actively consume NAD+ in their enzymatic activities. In recent years, NAD+ has gained much attention for its role in aging and age-related diseases like cancer, Alzheimer's, cardiovascular diseases, and neurodegenerative disorders, highlighting its involvement in various pathophysiological processes. However, its impact on female reproduction is not well understood. This review aims to bridge this knowledge gap by comprehensively exploring the complex interplay between NAD+ biology and female reproductive aging and providing valuable information that could help develop plans to improve women's reproductive health and prevent fertility issues.

Keywords: NAD+ metabolism; aging hallmarks; female fertility; ovarian aging.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Interplay of aging hallmarks, ovarian aging, and role of NAD+. (A) Hallmarks of aging. These hallmarks of aging affect the ovarian aging process. (B) Ovarian aging, influenced by various hallmarks of aging, leads to a cascade of detrimental effects on ovarian reserve, follicular growth, and oocyte quality. The figure describes how increased oxidative stress, aneuploidy, and DNA damage contribute to diminished ovarian function. Moreover, disturbed hormonal regulation, decreased mitochondrial biogenesis, and compromised spindle/chromosomal organization further aggravate the decline in fertility. Ultimately, the consequences extend to decreased fertilization rates, impaired embryo development, and increased pregnancy loss. (C) The role of NAD+ in aging is very important as it plays an important role in numerous biological processes essential for cellular homeostasis and functionality. Firstly, it plays an important role in mitochondrial function through sirtuin-regulated mechanisms. Additionally, NAD+ is implicated in pathways associated with longevity regulation, modulating the cellular stress response and promoting longevity. It also exerts regulatory effects on inflammation, influencing immune response and inflammation through enzymes such as CD38. Furthermore, NAD+ serves as a substrate for enzymes such as PARPs which are involved in DNA repair pathways, contributing to cell survival and genomic stability. It participates in various metabolic pathways, including glycolysis and oxidative phosphorylation, facilitating energy production and nutrient metabolism. Moreover, NAD+-dependent enzymes, particularly sirtuins, regulate epigenetic modifications such as histone deacetylation and DNA methylation, thereby influencing gene expression and cellular differentiation.
Figure 2
Figure 2
NAD+ metabolism (biosynthesis and consuming pathways). (A) NAD+ biosynthesis. The de novo biosynthesis pathway initiates with Trp conversion to QA by TDO. QPRT further converts QA to NAMN, ultimately resulting in NAD+ production via NADS. The Preiss–Handler pathway utilizes NA as a precursor, with NAPRT catalyzing NA conversion to NAMN. Subsequent steps involving NMNAT enzymes lead to NAD+ synthesis. The salvage pathway, more efficient in mammals, utilizes precursors like NAM, nicotinamide NR, and NMN, recycled from NAD+ breakdown. NAMPT catalyzes NAM to NMN conversion, while NR is phosphorylated by NRKs before conversion to NMN and then NAD+ via NMNAT enzymes. Notably, the salvage pathway can utilize precursors from within the cell, distinguishing it from de novo and PHP pathways reliant on dietary amino acids and vitamin B3 precursors. These pathways collectively ensure cellular NAD+ homeostasis critical for various physiological processes, including those vital for female reproduction. (B) NAD+-consuming enzymes. Sirtuins regulate various cellular processes including epigenetic regulation, energy metabolism, and mitochondrial biogenesis. PARPs are involved in DNA damage repair and genomic stability. CD38, acting as a NADase, influences cellular NAD+ levels and intracellular calcium signaling. Age-related changes in CD38 activity contribute to NAD+ decline, impacting the process of inflammation in the body. (Abbreviations: Trp, tryptophan; QA, quinolinic acid; TDO, tryptophan 2,3-dioxygenase; QPRT, quinolinate phosphoribosyltransferase; NaMN, nicotinic acid mononucleotide; NADS, nicotinamide adenine dinucleotide synthase; NA, nicotinic acid; NAPRT, nicotinic acid phosphoribosyltransferase; NAMN, nicotinic acid mononucleotide; NAM, nicotinamide; NR, nicotinamide riboside; NAMPT, nicotinamide phosphoribosyltransferase; NRKs, NR kinases).
Figure 3
Figure 3
Therapeutic potential of NAD+ boosting. The figure depicts the age-related decline in NAD+ levels within the ovary. The young ovaries have sufficient NAD+ concentration, while its level decreases with age. This decline in NAD+ parallels the deterioration of ovarian function and fertility associated with aging. To address this NAD+ decline, the figure outlines three potential therapeutic interventions aimed at rejuvenating aging ovaries: NAD+ boosting through supplementation of its precursors, increasing NAD+ biosynthesis, and decreasing NAD+ consumption. These strategies hold promise for restoring NAD+ homeostasis, thereby restoring ovarian health and potentially extending reproductive lifespan.
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