<p>Although most research on testicular aging has traditionally centered on germ cells, recent transcriptomic evidence shows that Sertoli cells are actually the most sensitive cell type to aging, displaying the highest number of aging-related differentially expressed genes and the greatest increase in transcriptional noise. As age advances, Sertoli cells undergo progressive quantitative loss, aberrant morphology, and disorganization of cytoskeletal and junctional structures, changes that collectively impair their ability to maintain the seminiferous epithelium and support germ cell development. This review therefore focuses on the key molecular processes underlying Sertoli cell aging, particularly the accumulation of cellular damage—including oxidative, mitochondrial, metabolic, and DNA lesions—and epigenetic alterations, such as dysregulated histone methylation and chromatin remodeling. Through addressing whether Sertoli cells predominantly undergo apoptosis, necrotic-like degeneration, or persist in a dysfunctional, senescence-associated state, this review highlights how their altered fate contributes to age-related male reproductive decline.</p>