The microbiome and age-related disease

These GEITP pages have discussed numerous publications on the importance of the microbiome — which we believe is (in every animal) an excellent example of gene-environment interactions. It is now well accepted that the microbiota has essential metabolic and immunological functions that are evolutionarily conserved from worms to humans. In mammals (e.g. mouse, human), the gut microbiota is involved in food processing, activation of satiety (i.e. relief from hunger) pathways, protection against pathogens, and production of metabolites — including vitamins, short-chain fatty acids, and secondary bile acids.

The gut microbiota also signals to distant organs (including liver but especially the brain), contributing to maintenance of host physiology. Alterations in the intestinal microbiota are associated with major disorders (e.g. obesity, type-2 diabetes, cardiovascular disease, nonalcoholic fatty acid liver disease, cancer, response to anti-cancer drugs). Although some research studies have explored the microbiome profile (metabolome) of long-lived humans, no studies have been described in accelerated-aging syndromes. Authors [see attached article] studied the gut microbiome of two mouse models — Hutchinson–Gilford progeria syndrome (HGPS), human HGPS patients, and Nestor–Guillermo progeria syndrome (NGPS) — as well as human centenarians and their controls (the mouse and human progeria syndromes show rapid aging with shortened longevity, whereas 100(+)-year-old humans exhibit long lives).

Authors found these two different mouse models of progeria are characterized by intestinal dysbiosis (i.e. microbial imbalance or maladaptation in the gut) — with changes that include an increased abundance of Proteobacteria and Cyanobacteria, and a decrease in abundance of Verrucomicrobia. Consistent with these findings, authors discovered that human progeria patients also display intestinal dysbiosis and that long-lived human centenarians exhibit a substantial increase in Verrucomicrobia and decreases in Proteobacteria. Fecal microbiota transplantation from wild-type mice improved healthspan and lifespan in both progeria mouse models; transplantation with verrucomicrobia (Akkermansia muciniphila) was also sufficient to exert beneficial effects.

Even more exciting, metabolomic analysis of ileal (distal small intestine) contents suggested that restoration of secondary bile acids is a possible mechanism for the beneficial effects of reestablishing a healthy microbiome. These data demonstrate that correction of accelerated aging-associated intestinal dysbiosis is beneficial — suggesting the existence of a link between aging and the gut microbiota. These findings provide a rationale for microbiome-based interventions against age-related diseases (i.e. should everyone eat more of the ‘right kind’ of fecal material, in order to live longer?). 😉



· Nat Med Aug 2019; 25: 1234-1242

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