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

Male reproductive aging manifests as progressive declines in testosterone synthesis, spermatogenic efficiency, and fertility, driven by multi-system dysfunction. This review synthesizes evidence establishing the nicotinamide adenine dinucleotide (NAD⁺)-Sirtuins axis as a central regulator of testicular homeostasis and its age-related dysregulation. Mechanistically, NAD⁺ depletion impairs energy metabolism (glycolysis/TCA cycle), antioxidant defenses, and steroidogenesis, while reduced Sirtuins activity (SIRT1/SIRT3/SIRT6) disrupts spermatogonial stem cell maintenance, blood-testis barrier (BTB) integrity, epigenetic programming, and immune privilege. Key pathological features include: (1) Structural compromise (lysosomal dysfunction in Sertoli cells, BTB disruption); (2) Metabolic-oxidative stress (lipid accumulation, mitochondrial failure, reactive oxygen species overproduction); (3) Chronic inflammation (NLRP3 inflammasome activation, T-cell infiltration); (4) Epigenetic dysregulation (aberrant histone acetylation, ncRNA imbalances); and (5) hormonal synthesis disorder. Interventions targeting this axis-NAD⁺ precursors (NMN/NR), Sirtuin activators (resveratrol/quercetin), and lifestyle strategies (intermittent fasting/exercise)-demonstrate efficacy in preclinical models: NMN restores sperm quality (+40% normality) and testosterone synthesis; resveratrol reduces sperm DNA fragmentation by 45% via SIRT3 activation. Clinical data suggest improved physiological parameters (e.g., muscle function, biological age) with NMN supplementation. Critical knowledge gaps persist regarding tissue-specific Sirtuin functions, long-term safety of NAD⁺ boosters, and individualized intervention protocols. Future research should prioritize testicular-targeted delivery systems, NAD⁺-based biomarkers, and randomized trials. Restoring NAD⁺-Sirtuins signaling represents a promising therapeutic strategy against age-related male infertility.