Fight Aging!

The gut microbiome is made up of a diverse collection of microbial species. Some are necessary for good health, some are actively harmful, and some just along for the ride. The immune system does its best to try to keep the balance favorable. The balance of hundreds of different populations making up the gut microbiome is resilient to short-term change induced by diet, probiotics, antibiotics, and the like; it will bounce back to where it was before quite quickly. The gut microbiome can and does change to significant degrees over the course of years and decades, however. The gut microbiome ages, the numbers of inflammatory and harmful microbes growing at the expense of microbes that produce beneficial metabolites. This may be driven in part by the growing incapacity of the immune system in older people, but significant changes in the gut microbiome appear too early in adult life for this to be the only mechanism in play.

It has been noted that long-lived individuals appear to have distinct differences in the composition of the gut microbiome. This may be because having a less inflammatory gut microbiome tips the scales in the direction of lower mortality and lower incidence of age related disease. The chronic inflammation of aging is destructive and undesirable, and less of it is a good thing. Unfortunately even a small increase in the odds of survival to centenarian status resulting from a particular configuration of the gut microbiome would lead to that configuration occurring often in centenarians. Better data than correlation is needed, and the way to obtain that data is to build therapies capable of inducing lasting change in the gut microbiome. At present only a few approaches are well demonstrated to work: (a) inducing the immune system into better garden the microbiome, such as via flagellin immunization, and (b) fecal microbiota transplantation. Both of these are blunt tools, incapable of producing specific population changes. Better approaches are needed.

Consistent signatures in the human gut microbiome of longevous populations

Gut microbiota of centenarians has garnered significant attention in recent years, with most studies concentrating on the analysis of microbial composition. However, there is still limited knowledge regarding the consistent signatures of specific species and their biological functions, as well as the potential causal relationship between gut microbiota and longevity. To address this, we performed the fecal metagenomic analysis of eight longevous populations at the species and functional level, and employed the Mendelian randomization (MR) analysis to infer the causal associations between microbial taxa and longevity-related traits.

We observed that several species including Eisenbergiella tayi, Methanobrevibacter smithii, Hungatella hathewayi, and Desulfovibrio fairfieldensis were consistently enriched in the gut microbiota of long-lived individuals compared to younger elderly and young adults across multiple cohorts. Analysis of microbial pathways and enzymes indicated that E. tayi plays a role in the protein N-glycosylation, while M. smithii is involved in the 3-dehydroquinate and chorismate biosynthesis. Furthermore, H. hathewayi makes a distinct contribution to the purine nucleobase degradation I pathway, potentially assisting the elderly in maintaining purine homeostasis. D. fairfieldensis contributes to the menaquinone (vitamin K2) biosynthesis, which may help prevent age-related diseases such as osteoporosis-induced fractures.

According to MR results, Hungatella was significantly positively correlated with parental longevity, and Desulfovibrio also exhibited positive associations with lifespan and multiple traits related to parental longevity. Additionally, Alistipes and Akkermansia muciniphila were consistently enriched in the gut microbiota of the three largest cohorts of long-lived individuals, and MR analysis also suggests their potential causal relationships with longevity. Our findings reveal longevity-associated gut microbial signatures, which are informative for understanding the role of microbiota in regulating longevity and aging.