Research Background

This study focuses on late-onset hypogonadism (LOH), aiming to uncover the mechanisms associated with age-related testicular function deviations, such as LOH, which are not yet fully understood. Utilizing single-cell RNA sequencing technology, the study analyzed the testicles of humans with LOH to identify supporting cells (SCs) as key metabolic coordinators within the testicular microenvironment. The research found reduced lysosomal acidity in aging SCs, leading to impaired autophagy and phagocytosis pathways, resulting in the accumulation of metabolites, including cholesterol, and an increase in the expression of inflammatory genes. These cells were thus termed pathologically transformed SCs. The characteristics of LOH could be replicated in mice through diet-induced high-fat stress. Notably, the study found that drug intervention involving efferent ductular injections in SCs and systemic TRPML1 agonist administration restored lysosomal function, thereby correcting testosterone deficiencies and related abnormalities in high-fat diet-induced LOH mice. These findings highlight the central role of SCs in testicular aging and propose promising therapeutic avenues for LOH.

Paper Source

This research was collaboratively conducted by researchers Zhiwen Deng, Liangyu Zhao, and Sha Li, among others, in the field of biomedicine. The institutions involved include the School of Life Science and Technology at ShanghaiTech University and the Shanghai Branch of the Chinese Academy of Sciences. The research results were published in the May 2024 issue of the journal Nature Aging.

Research Methods

The procedures included in the study encompass single-cell RNA sequencing of human testicles with LOH to identify the crucial metabolic coordination role of SCs; investigating the lysosomal acidity and autophagy, phagocytosis functions of SCs through pharmacological means. The study subjects ranged from young individuals to healthy elderly individuals and those with LOH, with a sample size of three young individuals, two healthy elderly individuals, and two individuals with LOH.

Research Results

Data collected from each procedure indicated that the lysosomal acidity in aging SCs was impaired, leading to changes in the metabolic capacity and inflammatory gene expression of SCs in LOH. The experiments showed that a high-fat diet could also induce similar pathological transformations in SCs indicative of LOH.

Conclusion and Research Significance

The study concluded that SCs play a central role in testicular aging and the development of LOH, highlighting how pathological transformations in SC function contribute to testicular dysfunction. It also suggested that strategies aimed at improving the degradative capacity of SCs for treating LOH are viable and have shown efficacy in animal models.

Research Highlights

The most important findings of the study include emphasizing the central role of SCs in testicular aging, identifying potential methods to enhance SC degradative functions as a therapeutic treatment for LOH, and providing a solid scientific basis for further development of new treatment methods.

Additional Information

The study also explored the effects of TRPML1 agonists on the restoration of testicular function and discovered the critical impacts of ML-SA1 on the metabolic extension of pathologically transformed SCs and the release of cholesterol in SCs and overall testosterone production in the testicles.