Reproductive Ageing: Current insights and a potential role of NAD in the reproductive health of aging fathers and their children

Abstract

In brief: In light of the increasing age of first-time fathers, this article summarizes the current scientific knowledge base on reproductive aging in the male, including sperm quality and health impacts for the offspring. The emerging role of NAD decline in reproductive aging is highlighted.

Abstract: Over the past decades, the age of first-time fathers has been steadily increasing due to socio-economic pressures. While general mechanisms of aging are subject to intensive research, male reproductive aging has remained an understudied area, and the effects of increased age on the male reproductive system are still only poorly understood, despite new insights into the potential dire consequences of advanced paternal age for the health of their progeny. There is also growing evidence that reproductive aging is linked to overall health in men, but this review mainly focuses on pathophysiological consequences of old age in men, such as low sperm count and diminished sperm genetic integrity, with an emphasis on mechanisms underlying reproductive aging. The steady decline of NAD levels observed in aging men represents one of the emerging concepts in that regard. Because it offers some mechanistic rationale explaining the effects of old age on the male reproductive system, some of the NAD-dependent functions in male reproduction are briefly outlined in this review. The overview also provides many questions that remain open about the basic science of male reproductive aging.

Figure 1.. Impact of advanced age on hormonal control, testes morphology and function, and sperm production.

In aging men, the hypothalamic-pituitary-testicular (HPT) axis and associated negative-feedback loop is impaired, resulting in an overall hormonal imbalance and diminished testosterone production compared to younger men (1). Altered testicular structure, morphology, and a disruption in spermatogenesis, accompanied by elevated oxidative stress and inflammation, are characteristic of aging testis (2). Aging sperm can also display severe DNA abnormalities and inadequate epigenetic reprogramming (3).

Figure 2.. Hallmarks of aging in the context of male reproductive aging.

a. NAD is central to most metabolic processes, and many physiological changes during aging are intricately connected to NAD-dependent enzymes and adequate NAD levels (for a recent overview see (Lautrup et al., 2024). b. Some examples of research reports and reviews connecting individual hallmarks to male reproductive aging are listed: (1) Declining stem cell proliferation (Ryu et al., 2006; Zhang et al., 2006; Ozawa et al., 2023); (2) Compromised autophagy (Zhao et al., 2019; Ma et al., 2022; Nie et al., 2022; Wang et al., 2022; Raee et al., 2023); (3) mitochondrial defects (Paniagua et al., 1991; Sokanovic et al., 2018; Garza et al., 2022); (4) metabolic dysfunction (Kanatsu-Shinohara et al., 2019; Nie et al., 2022); (5) inflammation (Frungieri et al., 2018; Matzkin et al., 2021; Nie et al., 2022; Aitken, 2023);(6) loss of epigenetic control (Jenkins et al., 2014; Suvorov et al., 2020; Pilsner et al., 2022; Ashapkin et al., 2023; Bernhardt et al., 2023); (7) telomere length variation (Eisenberg and Kuzawa, 2018; Fice and Robaire, 2019; Amir et al., 2020; Aitken, 2023); (8) impaired DNA damage repair (Singh et al., 2003; Albani et al., 2019; Gonzalez et al., 2022); (9) increased reactive oxygen species and impaired ROS defense (Mueller et al., 1998; Nguyen-Powanda and Robaire, 2020); (10) altered intracellular communication and loss of blood-testis-barrier (Paniagua et al., 1991; Levy et al., 1999; Ma et al., 2022). Note that individual hallmarks are frequently interconnected to each other. Some consequences of NAD decline and / or absence of NAD-dependent enzymes for testicular and male reproductive health have been described (Dantzer et al., 2006; Meyer-Ficca et al., 2011a, 2015, 2022; Ihara et al., 2014; Chung et al., 2021), but more studies are needed to establish individual molecular links and their roles during aging.

Figure 2.. Hallmarks of aging in the context of male reproductive aging.

a. NAD is central to most metabolic processes, and many physiological changes during aging are intricately connected to NAD-dependent enzymes and adequate NAD levels (for a recent overview see (Lautrup et al., 2024). b. Some examples of research reports and reviews connecting individual hallmarks to male reproductive aging are listed: (1) Declining stem cell proliferation (Ryu et al., 2006; Zhang et al., 2006; Ozawa et al., 2023); (2) Compromised autophagy (Zhao et al., 2019; Ma et al., 2022; Nie et al., 2022; Wang et al., 2022; Raee et al., 2023); (3) mitochondrial defects (Paniagua et al., 1991; Sokanovic et al., 2018; Garza et al., 2022); (4) metabolic dysfunction (Kanatsu-Shinohara et al., 2019; Nie et al., 2022); (5) inflammation (Frungieri et al., 2018; Matzkin et al., 2021; Nie et al., 2022; Aitken, 2023);(6) loss of epigenetic control (Jenkins et al., 2014; Suvorov et al., 2020; Pilsner et al., 2022; Ashapkin et al., 2023; Bernhardt et al., 2023); (7) telomere length variation (Eisenberg and Kuzawa, 2018; Fice and Robaire, 2019; Amir et al., 2020; Aitken, 2023); (8) impaired DNA damage repair (Singh et al., 2003; Albani et al., 2019; Gonzalez et al., 2022); (9) increased reactive oxygen species and impaired ROS defense (Mueller et al., 1998; Nguyen-Powanda and Robaire, 2020); (10) altered intracellular communication and loss of blood-testis-barrier (Paniagua et al., 1991; Levy et al., 1999; Ma et al., 2022). Note that individual hallmarks are frequently interconnected to each other. Some consequences of NAD decline and / or absence of NAD-dependent enzymes for testicular and male reproductive health have been described (Dantzer et al., 2006; Meyer-Ficca et al., 2011a, 2015, 2022; Ihara et al., 2014; Chung et al., 2021), but more studies are needed to establish individual molecular links and their roles during aging.

Figure 3.. Timeline of the negative consequences associated with advanced paternal age on sperm

(1), fertilization (2), pregnancy (3), infancy (4), and adolescence/adulthood (5).