Researchers have discovered that butyrate, a short-chain fatty acid with well-documented gut benefits, fights senescence in T cells.
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High-Fiber Foods May Fight T Cell Senescence
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Steve H
, Nov 10 2025 05:15 PM
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Posted 10 November 2025 - 05:15 PM
Senescence of the immune system (immunosenescence) is a problem that drives many others. In particular, T cells are known to secrete inflammatory SASP compounds [1] and drive the constant, age-related inflammation known as inflammaging [2]; in essence, the aged immune system overactivates itself. However, instead of being more effective against pathogens, this overactivated system has a degraded ability to effectively respond to threats [3], which is part of why older people have suffered from significantly greater COVID-related mortality [4].
An increase in T cell senescence has been found to drive pathologies in other systems in mice, including the muscles, vasculature, and cognition [5]. In people, this immunosenescence has been linked to arthritis [6] and acute heart failure [7]; unsurprisingly, there is an possible Alzheimer’s link as well [8].
The authors of this paper focus on butyrate as a potential method of mitigating T cell senescence, pointing to previous papers that suggest that it has beneficial influences in this area [9] along with benefits for B cells, another immune cell type [10]. However, while the gut microbiome has been heavily investigated in the context of aging and a link between butyrate and decreased T cell senescence has been found [11], these researchers stated that “no studies have systematically investigated how butyrate influences the function of aged immune cells.”
Butyrate is correlated with less senescence in people
This study’s first experiment used blood and stool samples from 40 healthy people over the age of 60 and 40 more between the ages of 18 and 37. Slightly more women than men participated in this study. None of the participants had any known chronic infections or any immunological problems.
The researchers first noted that older people have significantly less butyrate in their feces than younger people do; they also reported an age-related decrease in blood butyrate, which they noted to be never previously reported. Furthermore, they found that blood butyrate was significantly negatively associated with the prevalence of senescent T cells in the older group.
Cells and mice suggest a causal link
Encouraged, the researchers performed an in vitro experiment, introducing butyrate to T cells that had been driven senescent through a chemical regimen particular to these cells. While they found no change in the cells’ viability, there was a significant decrease in the cells’ production of IL-6, a major component of the SASP. This suggests that butyrate is a senomorphic; while it cannot reverse senescence on its own, it affects how senescent cells behave and may reduce the rate at which they drive other cells senescent through the SASP. This effect was stronger on younger cells than older cells.
This diminishment of the senescent phenotype was accompanied by other decreases in senescence-related features. The treated cells had decreased levels of the tumor suppressor p53, and they had fewer DNA strand breaks as measured by the marker γH2AX. While p38 was unaffected, there was a significant decrease in the key inflammatory factor NFκB. CD8-expressing T cells had fewer reactive oxygen species (ROS) after butyrate administration, but CD4-expressing T cells did not. These findings were buttressed by a gene expression analysis, which found that the butyrate-exposed senescent cells express less of a compound that prevents death by apoptosis, and they had reductions in the expressions of other inflammatory compounds.
These findings were accompanied by a mouse study. After treatment with antibiotics to purge their gut microbiomes, older mice were given fecal filtrations rich in butyrate derived from younger mice. The treatment group had significantly fewer p53-expressing T cells and significantly less IL-6.
The researchers note that butyrate cannot be the sole arbiter of the senescence-related behavior of T cells, and they also note that the concentrations used in cellular experiments may not always reflect those in people, particularly because there is a large difference between gut and serum levels. However, the problems with accurate dosing are less relevant in this case, as this is one of the few interventions that could be entirely conducted through diet alone; butyrate is a naturally occurring short-chain fatty acid, and fibrous fruits and vegetables are well-known to be rich in it. These researchers suggest a clinical trial using butyrate supplements or precursors to confirm their findings.
Literature
[1] Callender, L. A., Carroll, E. C., Beal, R. W., Chambers, E. S., Nourshargh, S., Akbar, A. N., & Henson, S. M. (2018). Human CD 8+ EMRA T cells display a senescence‐associated secretory phenotype regulated by p38 MAPK. Aging cell, 17(1), e12675.
[2] Dugan, B., Conway, J., & Duggal, N. A. (2023). Inflammaging as a target for healthy ageing. Age and ageing, 52(2), afac328.
[3] Duggal, N. A. (2018). Reversing the immune ageing clock: lifestyle modifications and pharmacological interventions. Biogerontology, 19(6), 481-496.
[4] Covre, L. P., De Maeyer, R. P., Gomes, D. C., & Akbar, A. N. (2020). The role of senescent T cells in immunopathology. Aging cell, 19(12), e13272.
[5] Desdín-Micó, G., Soto-Heredero, G., Aranda, J. F., Oller, J., Carrasco, E., Gabandé-Rodríguez, E., … & Mittelbrunn, M. (2020). T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science, 368(6497), 1371-1376.
[6] Raza, K., Sharma-Oates, A., Padyukov, L., van der Helm-van Mil, A., Pratt, A. G., Jones, S. W., … & A Duggal, N. Specific Features of Immune Ageing are Detected in the Earliest Stages in Rheumatoid Arthritis Development. Arthur G. and Jones, Simon W. and Filer, Andrew and Lord, Janet and A Duggal, Niharika, Specific Features of Immune Ageing are Detected in the Earliest Stages in Rheumatoid Arthritis Development.
[7] Youn, J. C., Jung, M. K., Yu, H. T., Kwon, J. S., Kwak, J. E., Park, S. H., … & Shin, E. C. (2019). Increased frequency of CD4+ CD57+ senescent T cells in patients with newly diagnosed acute heart failure: exploring new pathogenic mechanisms with clinical relevance. Scientific reports, 9(1), 12887.
[8] Gate, D., Saligrama, N., Leventhal, O., Yang, A. C., Unger, M. S., Middeldorp, J., … & Wyss-Coray, T. (2020). Clonally expanded CD8 T cells patrol the cerebrospinal fluid in Alzheimer’s disease. Nature, 577(7790), 399-404.
[9] Bachem, A., Makhlouf, C., Binger, K. J., de Souza, D. P., Tull, D., Hochheiser, K., … & Bedoui, S. (2019). Microbiota-derived short-chain fatty acids promote the memory potential of antigen-activated CD8+ T cells. Immunity, 51(2), 285-297.
[10] Kim, M., Qie, Y., Park, J., & Kim, C. H. (2016). Gut microbial metabolites fuel host antibody responses. Cell host & microbe, 20(2), 202-214.
[11] Monaghan, T. M., Duggal, N. A., Rosati, E., Griffin, R., Hughes, J., Roach, B., … & Kao, D. H. (2021). A multi-factorial observational study on sequential fecal microbiota transplant in patients with medically refractory clostridioides difficile infection. Cells, 10(11), 3234.
View the article at lifespan.io
