Sertoli cell aging: damage accumulation and epigenetic alterations affecting male fertility.

Sertoli cells display the highest number of aging-related differentially expressed genes among testicular cell types.

• Recent transcriptomic evidence identifies Sertoli cells as the most sensitive cell type to aging in the testis.
• Sertoli cells show the greatest increase in transcriptional noise compared to other testicular cell types with aging.
• This finding contrasts with the traditional research focus on germ cells in testicular aging studies.

Aging Sertoli cells undergo progressive quantitative loss accompanied by aberrant morphology and disorganization of cytoskeletal and junctional structures.

• The structural changes include disorganization of cytoskeletal components and junctional structures.
• These changes collectively impair the ability of Sertoli cells to maintain the seminiferous epithelium.
• The morphological and quantitative changes also impair Sertoli cell capacity to support germ cell development.

Multiple forms of cellular damage accumulate in aging Sertoli cells, including oxidative, mitochondrial, metabolic, and DNA lesions.

• The review identifies four distinct categories of damage accumulation: oxidative damage, mitochondrial damage, metabolic damage, and DNA lesions.
• These damage types are described as key molecular processes underlying Sertoli cell aging.
• The accumulation of these damage types is framed as a central mechanism of age-related Sertoli cell dysfunction.

Epigenetic alterations, particularly dysregulated histone methylation and chromatin remodeling, contribute to Sertoli cell aging.

• Dysregulated histone methylation is identified as a key epigenetic alteration in aging Sertoli cells.
• Aberrant chromatin remodeling is also highlighted as a contributing epigenetic mechanism.
• These epigenetic changes are considered alongside damage accumulation as major drivers of Sertoli cell aging.

The fate of aging Sertoli cells is addressed in terms of whether they predominantly undergo apoptosis, necrotic-like degeneration, or persist in a dysfunctional senescence-associated state.

• The review specifically examines three possible cellular fates for aging Sertoli cells: apoptosis, necrotic-like degeneration, or senescence-associated dysfunction.
• Senescence-associated state is described as a condition in which cells persist in a dysfunctional manner.
• The altered fate of Sertoli cells is linked to age-related male reproductive decline.

Altered Sertoli cell fate with aging contributes to age-related male reproductive decline.

• The review highlights how changes in Sertoli cell fate—whether through cell death or senescence—impair male fertility with age.
• Sertoli cell dysfunction is presented as a central mechanism connecting testicular aging to reproductive decline.
• The paper positions Sertoli cell aging as an underappreciated but critical component of male reproductive aging compared to the traditionally emphasized germ cell changes.