Impact of T Cells on Metabolic Dysregulation in Aged Mice

Decreased glucose tolerance ( GT ) and insulin sensitivity ( IS ), and impaired immune function contribute to metabolic diseases and are exhibited with advanced age. Our laboratory has previously demonstrated that GT is improved in old mice depleted of T cells. Here, we sought to elucidate the contributions of intrinsic changes to T cells and increased T cell recruitment to metabolic tissues regarding age-related metabolic dysfunction. We hypothesized that metabolic dysregulation will occur in young immuno-deficient mice in response to older T cells, and young T cells will improve metabolic function in aged mice, driven by lower T cell immune burden. T cells were isolated from young (4-6mo) or old (22-25mo) C57BL/6 (C57) mice spleens and transferred into young or old RAG1 -/- mice, which lack mature T and B cells. After 4 weeks, GT and insulin tolerance tests were performed to assess metabolic function. White adipose tissue (WAT) and liver, both sites of metabolic activity, were removed to assess T cell infiltration. Lifelong T cell absence resulted in higher fasting blood glucose ( FBG ) in young RAG1 -/- compared to C57 mice (p=.001). After T cell transfer to RAG1 -/- mice, there were main effects for mouse (p<.001) and T cell (p=.022) age, with old mice having a lower FBG than young regardless of T cell age received. Glucose intolerance (Area Under Curve, AUC ) observed in old vs young C57 mice (p=.0458) improved in old vs young RAG1 -/- mice lacking T cells (p=062). After adding T cells, speed of glucose recovery improved at some timepoints (group, p=.044), but not GT ( AUC ) in young RAG1 -/- mice (p=.300). There were no differences in GT among old RAG1 -/- mice without or with young or old T cells transferred (p=.219). IS ( AUC ) was similar between young and old RAG1 -/- mice (p=.474). After adding young, but not old T cells, IS was enhanced in young RAG1 -/- mice (p=.038). Young mice given young T cells were the most IS, while old mice given young T cells had the lowest IS (post hoc, p=.028). In WAT, there was a lower percentage of T cell infiltration in old mice that received young T cells, and a higher percentage in young mice that received young T cells (T cell Age, p=.7003; Mouse Age, p=.015; Interaction, p=.069). Among transfer groups, a greater proportion of CD8+ compared to CD4+ T cells infiltrated both WAT (p<.0001) and liver (p<.0001). Still, there were no mouse or T cell age related differences in CD4+ or CD8+ T cell infiltration into the WAT. Unlike in the WAT, neither total nor percentage T cell infiltration into the liver differed between young and old groups, although CD4+ T cells were higher in old mice regardless of T cell age (T cell Age, p=.054; Mouse Age, p<.0001). Overall, young mice demonstrated a higher proportion of CD8+ T cells infiltrating the liver compared to old mice (T cell age, p=.207; Mouse Age, p<.0001). Our findings show that mouse age has a more profound effect on FBG and GT than T cell age, with the absence of T cells improving GT in old, but not young mice. Supplementation of young or old T cells to old RAG1 -/- mice did not improve IS although young T cells improved IS of young mice. Young mice have superior glucose regulation compared to old mice. This may be because T cells are better able to infiltrate young WAT, which we have found in this study, resulting in greater control of immune function. The difference in T cell subpopulation in liver may partly explain isolated effects of T cell age on the IS of young, but not old mice. Overall, these results suggest that GT is more dependent on the age of the mouse and WAT T cell immune activity, with young mice faring better; whereas IS is more reliant on the interplay of T cell age-related properties and the subpopulation of T cells that home to the liver, with young T cells, particularly, improving IS. NIH-NIA, R01 AG060395. NIH-NHLBI T32 CRTP This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.