Midlife Obesity and Prediabetes: Influence of cGAS/STING on Later Life Cognitive Impairment

Rates of metabolic stress (obesity, prediabetes, metabolic syndrome, and diabetes) continue to grow worldwide. In parallel, the aging population is also growing. Aging itself is the number one risk factor for cognitive impairment, including dementias such as Alzheimer’s Disease and Alzheimer’s Disease Related Dementias. However, metabolic stress, particularly in midlife, also raises the risk of cognitive impairment later in life. While inflammation and immune system dysregulation are common etiologies of both aging and metabolic stress, precise underlying mechanisms remain unclear. Given its clear role in metabolic stress in the periphery, we hypothesized that midlife metabolic stress also triggers central nervous system over-activation of the innate inflammatory cGAS/STING pathway and contributes to cognitive impairment with age. To test our hypothesis, we used a high fat diet (HFD) fed murine model of obesity and prediabetes. Male and female wild-type (WT) C57BL6 and global cGAS knock out (KO) mice were fed either HFD or standard diet (SD) control chow (8 experimental groups, n=12 mice/group) starting at midlife (1-yr of age) until older age (2-yr of age). We performed longitudinal and terminal metabolic (body weights and glucose tolerance testing) and cognitive (puzzle box) phenotyping, with additional terminal transcriptomic (hippocampal singe cell RNAseq) analyses. We found that cGAS KO had minor effects on HFD-induced weight gain and glucose intolerance, specifically preventing age-associated weight loss and moderately reducing glucose intolerance dependent on time point. While overall HFD negatively impacted cognition in both sexes, females (particularly cGAS KO females) had a more pronounced deficit compared to males. In parallel, single cell transcriptomic analyses showed that HFD impacted gene expression profiles in both sexes and both genotypes (WT and KO). However, in response to HFD feeding, WT males had a gene expression profile that indicated a neurodegenerative and pro-inflammatory environment that was blunted in the male KO animals in response to diet. In contrast, KO females’ gene expression profiles indicated a pro-inflammatory environment in response to HFD feeding that was absent in the WT females. Together, these data highlight that in midlife obesity and prediabetes, cGAS KO has sexually dimorphic effects of on metabolic, cognitive and transcriptomic outcomes with age, potentially suggesting beneficial effects in males but detrimental effects in females. Funding for this work was provided by the NeuroNetwork for Emerging Therapies and from the NIA (K99/R00; 1K99AG071667-01A1). 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.