MINI REVIEW article
Front. Cell Dev. Biol.
Sec. Cell Death and Survival
Volume 13 - 2025 | doi: 10.3389/fcell.2025.1669826
This article is part of the Research TopicImmunosenescence and Metabolic Reprogramming in Aging: Mechanistic Insights and InterventionsView all articles
Testicular Immunosenescence: A Key Player in Age-Related Spermatogenic Decline
Provisionally accepted
- 1Department of Urology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, China
- 2Department of Urology, Hangzhou Integrative Medicine Hospital Affiliated to Zhejiang Chinese Medical University (Hangzhou Red Cross Hospital), Hangzhou, China
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As global populations age, testicular aging has become a key contributor to the gradual decline in male fertility, characterized by lower sperm count, poorer sperm quality, and reduced reproductive potential. While the testis is traditionally viewed as an immune-privileged site, growing evidence shows that this immune protection weakens over time-a process now known as testicular immunosenescence. This review provides a comprehensive overview of age-related changes in the testicular immune landscape. These include the depletion of CD4⁺ and CD8⁺ T cells, dysfunction of regulatory T cells (Tregs), abnormal polarization of macrophages, and the breakdown of the blood-testis barrier (BTB). Together, these changes lead to chronic low-grade inflammation and disrupt the delicate environment required for healthy sperm production. In addition, we explore how immune aging is closely linked to metabolic changes, especially within Sertoli and Leydig cells. These intertwined processes form a feedback loop-an "immune-metabolic axis"-that accelerates germ cell death and impairs spermatogenesis. We also discuss emerging treatment strategies, such as anti-inflammatory therapies, mitochondrial support, and NAD⁺ precursor supplementation, which may help preserve testicular function and male fertility with age. By framing testicular immunosenescence as both a driving mechanism and a potential therapeutic target, this review opens up new directions for tackling age-related male reproductive decline.
Keywords: Testicular immunosenescence, Aging, Spermatogenic dysfunction, Immune-metabolic axis, Blood-testis barrier (BTB)
Received: 20 Jul 2025; Accepted: 29 Jul 2025.
Copyright: © 2025 Zhan, Zhou, Zhao, Bao, Chen and Zhu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Ming-Wei Zhan, Department of Urology, Hangzhou TCM Hospital of Zhejiang Chinese Medical University (Hangzhou Hospital of Traditional Chinese Medicine), Hangzhou, China
Jingyu Zhu, Department of Urology, Hangzhou Integrative Medicine Hospital Affiliated to Zhejiang Chinese Medical University (Hangzhou Red Cross Hospital), Hangzhou, China
Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.