Age-Related Disruption of Endoplasmic Reticulum Homeostasis in Leydig Cells: Mechanisms of Declining Testosterone Biosynthesis and Potential Therapeutic Strategies.

Abstract

A progressive decline in testosterone levels is a hallmark of male reproductive aging and is closely associated with impaired Leydig cell function. Leydig cell function relies on intracellular homeostasis, with endoplasmic reticulum (ER) homeostasis playing a particularly important role in steroidogenesis. The ER supports steroidogenesis by regulating protein quality control, lipid and cholesterol metabolism, calcium homeostasis, and interactions between organelles. With advancing age, the capacity to maintain ER homeostasis and adapt to cellular stress diminishes. These changes interact with other age-associated alterations, contributing to impaired steroidogenesis in Leydig cells. This review synthesizes current evidence on how disrupted ER homeostasis may compromise testosterone biosynthesis in Leydig cells through alterations in the unfolded protein response (UPR) and integrated stress response (ISR), impaired autophagy and cholesterol utilization, mitochondrial dysfunction and altered interorganelle interactions, oxidative stress, inflammation, and apoptosis. We also discuss the influence of metabolic factors and exogenous exposures, along with potential therapeutic strategies aimed at restoring ER homeostasis and improving testosterone biosynthesis in aging Leydig cells. Collectively, this review establishes a mechanistic framework linking disrupted ER homeostasis to Leydig cell aging and declining testosterone biosynthesis, providing insights into the pathophysiology and potential treatment approaches for late-onset hypogonadism and related disorders.

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