Investigating the role of the intestinal microbiota in unhealthy aging

Abstract

Chronic systemic inflammation increases with age and is associated with late life diseases (e.g. sarcopenia, and frailty) but the mechanisms causing systemic inflammation are largely unknown. Our laboratory has shown that the aged microbiome increases intestinal permeability which allows bacterial products into the circulation, thus causing systemic inflammation. We do not, however, know which microbes drive this phenomenon and ultimately impact healthy or unhealthy aging. To determine the degree to which frailty, sarcopenia, and systemic inflammation can be accelerated or exacerbated via the microbiome, we colonized germfree (recipient) mice with ‘young’ (≤6 months) or ‘old’ (≥ 18 months) microbiota from specific pathogen free mice. Initially, we investigated the impact of recipient age by colonizing young and old germfree mice. Differences in sarcopenia and cellular inflammation were driven by recipient age, not microbiota age, after 6 weeks of colonization, while frailty decreased in old mice colonized with young microbiota. To further investigate the impact of the microbiota in aging, we colonized middle-aged (10-14 month) germfree mice and assessed them 6 weeks and 6 months post colonization. The aged microbiota drove an increase in frailty after 6 months of colonization. To understand the differences between young and old microbial compositions we quantified short-chain fatty acids and sequenced 16S rRNA from fecal pellets of young and old mice. We used frailty, sarcopenia, and cellular inflammation data to identify relationships with short-chain fatty acids and the microbial community. We have identified specific microbes that correlate with age, frailty, sarcopenia, and cellular inflammation from Lachnospiraceae, Akkermansiaceae and Rikenellaceae families. By understanding the role of the microbiome in healthy and unhealthy aging we can develop therapeutics to combat chronic systemic inflammation and prevent and/or reverse poor health outcomes.