Researchers reveal mechanism of lysosomal dysfunction regulating testicular aging

ON2024-04-29TAG: ShanghaiTech UniversityCATEGORY: School of Life Science and Technology

The testes are the site of sperm production and secretion of male hormones. Testicular aging not only leads to a decline in fertility but also significantly affects the quality of life for men. Late-onset hypogonadism (LOH) is a typical pathological change of testicular aging, characterized by testosterone deficiency and other related clinical symptoms. Prolonged testosterone deficiency can also cause metabolic syndrome, such as diabetes and hyperlipidemia, and the onset of diseases like Alzheimer’s, leading to a significant increase in mortality rates. The incidence of LOH in men over 40 years old is as high as 5.6-12.8%. With the aging of the global population becoming more severe, exploring the cellular and molecular mechanisms of testicular aging and developing effective means to delay and treat it are urgent needs to address population aging.


Recently, a research conducted by a joint team uncovered a close relationship between testicular metabolism regulation and aging, demonstrating that modulating lysosomal function with small molecules could alleviate symptoms in LOH mice. The joint team was led by Assistant Professor Zhou Zhi in the School of Life Science and Technology, in the collaboration with the team led by Dr. Li Zheng in the Center for Men’s Health, Shanghai General Hospital, and the team led by Dr. Wang Chenchen in the Shanghai Advanced Research Institute, Chinese Academy of Sciences. On April 22, the team’s study was published in Nature Aging in a paper titled Targeting dysregulated phago-/auto-lysosomes in Sertoli cells to ameliorate late-onset hypogonadism.


In the study, researchers conducted single-cell transcriptomic sequencing of testicular tissues from both normal individuals and LOH patients. By integrating the sequencing data with their previous work on testicular tissues from young individuals, the researchers found that the somatic cell microenvironment in LOH testes exhibited more pronounced aging characteristics compared to germ cells. Notably, phagocytic Sertoli cells residing in the testes, which are responsible for inflammation secretion and aging manifestations, showed the most significant changes. Furthermore, LOH patients’ Sertoli cells displayed significant dysregulation in lysosomal and lipid metabolism-related genes, along with an accumulation of lysosomes and lipids.


The team further explored the relationship between lysosomal defects in Sertoli cells and lipid accumulation, revealing that as coordinators of nutrition and metabolism in the testes, Sertoli cells exhibit decreased metabolic efficiency due to lysosomal acidification, leading to a decline in nutrient supply to the microenvironment.


Obesity is the most significant risk factor for LOH, and a high-fat diet significantly inhibits cellular lysosomal acidification. Researchers found that at the cellular level, excessive saturated fatty acids (such as palmitic acid) significantly increase metabolic stress in testicular Sertoli cells, leading to a decrease in lysosomal acidity and accumulation of metabolites. At the animal level, mice on a long-term high-fat diet exhibit cellular characteristics similar to those of LOH patients and symptoms such as testosterone deficiency and decreased libido. By using a lysosomal TRPML agonist, ML-SA1, researchers significantly enhanced phagocytic/autophagic lysosomal function in damaged Sertoli cells, improving phenotypes such as inflammation secretion and metabolite accumulation. Due to the restoration of the nutritional coordination function of supporting cells, ML-SA1 also improved the testicular microenvironment and testosterone secretion in mice on a long-term high-fat diet. This indicates that enhancement of the metabolic capacity of supporting cells can alleviate symptoms related to gonadal function degeneration.


The schematic on the left illustrates how lysosomal acidity abnormalities in Phago-/auto-lysosome dysregulated (PALD) Sertoli cells lead to metabolite accumulation. The schematic on the right depicts the improvement of metabolic and nutritional support functions in Sertoli cells through the enhancement of lysosomal function.


In summary, this study unveiled the cellular and molecular regulations underlying testicular aging, providing a crucial foundation for understanding the metabolic interactions involved in testicular aging. Additionally, this research also offered novel targets and pathways for clinical assessment of LOH and the development of long-term intervention strategies.


Fourth-year PhD candidate Deng Zhiwen, PhD student Zhao Yuliang and postdoc fellow Li Sha from Zhou’s group are among the co-first authors. Prof. Zhou is one of the corresponding authors.