Fight Aging!

In recent years, it has become clear that the gut microbiome contributes meaningfully to long-term health, perhaps to much the same degree as exercise, diet, and other common lifestyle choices. Unlike those choices, the composition of the gut microbiome is more inscrutable, however. While commercial services employing 16S rRNA sequencing can cost-effectively list the microbial species present in the intestines, and their relative proportions, it remains a work in progress to (a) reliably connect differences in the list to pathologies of aging, and (b) reliably alter the gut microbiome in deterministic and lasting ways.

Which is not to say that we know nothing! It is clear that the relative proportions of the microbial species making up the gut microbiome change with age, and some of those changes provoke chronic inflammation. Pro-inflammatory microbes grow in number at the expense of microbial species responsible for producing beneficial metabolites such as butyrate. It is also clear that fecal microbiota transplantation from a young individual produces a lasting reset of the gut microbiome, and consequent improvements in health, even if the full details of what matter in that reset have yet to be determined.

Aging amplifies a gut microbiota immunogenic signature linked to heightened inflammation

Aging is associated with low-grade inflammation that increases the risk of infection and disease, yet the underlying mechanisms remain unclear. Gut microbiota composition shifts with age, harboring microbes with varied immunogenic capacities. We hypothesized the gut microbiota acts as an active driver of low-grade inflammation during aging. Microbiome patterns in aged mice strongly associated with signs of bacterial-induced barrier disruption and immune infiltration, including marked increased levels of circulating lipopolysaccharide (LPS)-binding protein (LBP) and colonic calprotectin.

Ex vivo immunogenicity assays revealed that both colonic contents and mucosa of aged mice harbored increased capacity to activate toll-like receptor 4 (TLR4) whereas TLR5 signaling was unchanged. We found patterns of elevated innate inflammatory signaling (colonic Il6, Tnf, and Tlr4) and endotoxemia (circulating LBP) in young germ-free mice after 4 weeks of colonization with intestinal contents from aged mice compared with young counterparts, thus providing a direct link between aging-induced shifts in microbiota immunogenicity and host inflammation. Additionally, we discovered that the gut microbiota of aged mice exhibited unique responses to a broad-spectrum antibiotic challenge, with sustained elevation in Escherichia (Proteobacteria) and altered TLR5 immunogenicity 7 days post-antibiotic cessation.

Together, these data indicate that old age results in a gut microbiota that differentially acts on TLR signaling pathways of the innate immune system. We found that these age-associated microbiota immunogenic signatures are less resilient to challenge and strongly linked to host inflammatory status. Gut microbiota immunogenic signatures should be thus considered as critical factors in mediating chronic inflammatory diseases disproportionally impacting older populations.