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 tissuespecific 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.