# When Testosterone Fades: Leydig Cell Aging Shaped by Environmental Toxicants, Metabolic Dysfunction, and Testicular Niche Crosstalk

## TL;DR

This paper reviews how aging and environmental factors impair Leydig cells, which are crucial for male hormone production and fertility.

## Contribution

The paper integrates recent findings on environmental toxins, metabolic issues, and cellular aging to explain Leydig cell dysfunction.

## Key findings

- Environmental toxicants and metabolic dysfunction impair Leydig cell steroidogenesis through oxidative and mitochondrial stress.
- Aging alters the testicular niche, reducing regenerative potential and affecting Leydig cell homeostasis.
- Single-cell transcriptomics reveal vulnerable Leydig cell subsets and age-related changes in cell communication.

## Abstract

Declining Leydig cell steroidogenesis contributes to late-onset hypogonadism and to age-associated impairment of male reproductive health. Determinants of dysfunction extend beyond chronological aging. This review synthesizes recent experimental and translational evidence on cellular and molecular processes that compromise Leydig cell endocrine output and the interstitial niche that supports spermatogenesis. Evidence spanning environmental endocrine-disrupting chemicals (EDCs), obesity and metabolic dysfunction, and testicular aging is integrated with emphasis on oxidative stress, endoplasmic reticulum stress, mitochondrial dysregulation, apoptosis, disrupted autophagy and mitophagy, and senescence-associated remodeling. Across model systems, toxicant exposure and metabolic stress converge on impaired organelle quality control and altered redox signaling, with downstream loss of steroidogenic capacity and, in some settings, premature senescence within the Leydig compartment. Aging further reshapes the testicular microenvironment through inflammatory shifts and biomechanical remodeling and may erode stem and progenitor Leydig cell homeostasis, thereby constraining regenerative potential. Single-cell transcriptomic atlases advance the field by resolving Leydig cell heterogeneity, nominating subsets that appear more vulnerable to stress and aging, and mapping age-dependent rewiring of interstitial cell-to-cell communication with Sertoli cells, peritubular myoid cells, vascular cells, and immune cells. Many mechanistic insights derive from rodent in vivo studies and in vitro platforms that include immortalized Leydig cell lines, and validation in human tissue and human clinical cohorts remains uneven. Together, these findings frame mechanistically informed opportunities to preserve endogenous androgen production and fertility through exposure mitigation, metabolic optimization, fertility-preserving endocrine stimulation, and strategies that target inflammation, senescence, and regenerative capacity.