Abstract

The alarmingly high prevalence of obesity in older adults coupled with the negative health effects of chronic inflammation in both obesity and aging highlight the importance of studies investigating the impacts of obesity on age-related inflammation. Since shifts in peripheral T-cell metabolism and function drive systemic inflammation in both obesity and aging, we hypothesize that obesity impacts the Th17-dominated inflammaging profile we identified in lean subjects and thus modifies the anti-inflammatory effects of geroprotective drugs like metformin. New cytokine profiling data showed that CD4+ T cells from older people with obesity generate a profile that specifically excludes Th17 cytokines. Metformin failed to change the age-associated T-cell profile in obesity, despite lowering both mitochondrial respiration and reactive oxygen species (ROS) production. Metformin did not improve macroautophagy in T cells from older people with obesity, in sharp contrast to the ability of metformin to promote autophagy in T cells from older lean subjects. These data indicate that body mass index modifies the mechanisms supporting inflammaging in T cells from older subjects, and that metformin-mediated restoration of redox balance is insufficient to stem obesity-associated inflammaging. We conclude that obesity fundamentally changes the mechanisms that promote inflammaging, and thus obesity becomes a critical consideration for clinical trials of geroprotective agents such as metformin.

Document Type

Article

Publication Date

2025

Notes/Citation Information

© The Author(s), under exclusive licence to American Aging Association 2024

Digital Object Identifier (DOI)

https://doi.org/10.1007/s11357-024-01441-4

Funding Information

This work was supported by R56AG06985, 1R01AG079525, and P20GM148326 (BSN); The Barnstable Brown Diabetes and Obesity Research Center (BSN and XDZ); 1U01DK135111, UL1TR001998, and P30 DK020579 (XDZ); R15AG068957 (LPB); T32DK007778 and TL1UL1TR001998 (GHK). The project described was supported by the NIH National Center for Advancing Translational Sciences through grant number UL1TR001998 (PAK). This research was supported by the Flow Cytometry and Immune Monitoring shared resource of the University of Kentucky Markey Cancer Center (P30CA177558). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. No permissions are needed. All work is original.

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