Aging-Associated Microbiota Drives Treg Dysfunction via TNF Signaling
Year: 2025
Type: preprint
Abstract: Aging is associated with a chronic, low-grade inflammatory state referred to as inflammaging, which contributes to impaired immune regulation and increased susceptibility to disease. While regulatory T (Treg) cells are key mediators of immune homeostasis, their role in the context of age-related inflammation remains poorly understood. Here we demonstrate that age-related changes in the microbiota promote impaired Treg cell function, resulting in the differentiation of inflammatory T cells. In agreement, we find that aged germ-free (GF) mice exhibited a more balanced immune profile, where the Treg cells are functional and pro-inflammatory mediators are reduced, suggesting that microbial exposure is essential for the establishment of inflammaging. Furthermore, we show that the use of old microbiota in young animals was sufficient to induce pro-inflammatory T cell responses and impaired mucosal Treg cell proliferation, while young microbiota restored Treg cell function in old animals. Mechanistically, we show that exposure to aged microbiota was associated with sustained TNF signaling, elevated oxidative stress, DNA damage, and increased expression of senescence markers such as γH2AX and p16 in Treg cells. These findings uncover a microbiota-TNF-dependent mechanism by which age-associated microbial dysbiosis drives Treg cell dysfunction and promotes immune aging, highlighting the therapeutic potential of microbiota-targeted strategies to restore immune homeostasis in the elderly.
Authors: Jefferson Antônio Leite, Zeynep Ergün, Emmanouil Stylianakis, Rebecca Jasser, Florian Ingelfinger, Natalia Notarberardino Bos, Aysan Poursadegh Zonouzi, Michal Mark, Katlynn Carter, Xinyuan Liu, Nadine Hövelmeyer, Tommy Regen, Manolis Pasparakis, Christian Neumann, Ido Amit, Nir Yosef, Christoph Reinhardt, Ari Waisman
Institutions: Johannes Gutenberg University Mainz, University Medical Center of the Johannes Gutenberg University Mainz, University of Freiburg, University Medical Center Freiburg, Weizmann Institute of Science, University of Cologne, Cologne Excellence Cluster on Cellular Stress Responses in Aging Associated Diseases, Charité - Universitätsmedizin Berlin, German Centre for Cardiovascular Research
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W4413128221