Long-term sildenafil attenuates age-associated functional and reproductive decline in male rats

Aging in males is accompanied by a progressive decline in physical activity, androgen status, and reproductive function. We investigated whether long-term treatment with the phosphodiesterase type 5 inhibitor sildenafil attenuates these changes and is accompanied by remodeling of mitochondrial homeostasis in the testis. Male rats were treated with low-dose sildenafil from 12 to 18 months of age, with age-matched untreated rats serving as controls and young adult rats providing a reference for the age-associated phenotype. Aging markedly reduced voluntary locomotor activity, circulating testosterone, and sperm production, while increasing circulating corticosterone. Long-term sildenafil treatment increased locomotor activity, testosterone, and sperm number, while corticosterone tended to decrease. Sildenafil-associated body weight changes were observed in animals with access to voluntary running. Treatment was also accompanied by pronounced changes in mitochondrial homeostasis-related gene expression in Leydig cells and spermatozoa. These transcriptional responses differed between cell types, particularly for genes regulating mitochondrial dynamics and quality control. Expression of mitochondrial homeostasis-related genes was more closely associated with circulating testosterone than with corticosterone and showed distinct testosterone-associated patterns in Leydig cells and spermatozoa. Recovery toward young levels differed among parameters, being more pronounced for reproductive and endocrine measures than for locomotor activity. These findings indicate that long-term low-dose sildenafil attenuates age-associated functional and reproductive decline and promotes a partial shift toward a younger male phenotype, accompanied by cell-specific mitochondrial transcriptional remodeling.