Restoring NAD⁺-Sirtuins Signaling: A Novel Approach to Combat Male Reproductive Aging

Area of Science:

• Reproductive Biology
• Aging Research
• Molecular Endocrinology

Background:

• Male reproductive aging involves declining testosterone, sperm production, and fertility.
• This decline is linked to multi-system dysfunction and dysregulation of the nicotinamide adenine dinucleotide (NAD⁺)-Sirtuins axis in the testes.

Purpose of the Study:

• To review the role of the NAD⁺-Sirtuins axis in male reproductive aging.
• To explore the mechanisms of age-related dysregulation and potential therapeutic interventions.

Main Methods:

• Literature review synthesizing evidence on NAD⁺-Sirtuins signaling in testicular homeostasis.
• Analysis of pathological features of male reproductive aging.
• Evaluation of preclinical and clinical data on interventions targeting the NAD⁺-Sirtuins axis.

Main Results:

• NAD⁺ depletion and reduced Sirtuins activity impair testicular energy metabolism, antioxidant defenses, steroidogenesis, stem cell maintenance, and barrier integrity.
• Key pathological features include structural compromise, metabolic-oxidative stress, inflammation, epigenetic dysregulation, and hormonal imbalance.
• Interventions like NMN, resveratrol, and lifestyle changes show efficacy in preclinical models, with some clinical support for NMN.

Conclusions:

• The NAD⁺-Sirtuins axis is crucial for male reproductive function and its age-related decline contributes to infertility.
• Targeting this axis offers a promising therapeutic strategy for age-related male reproductive dysfunction.
• Further research is needed on tissue-specific functions, long-term safety, and personalized interventions.