Gut Microbiome and Longevity : What Centenarians Have in Common

In the early 1900s, Élie Metchnikoff — Russian biologist, Nobel Prize in Medicine 1908 — formulated an audacious hypothesis for his time: the exceptional longevity of Bulgarian peasants was linked to their daily consumption of fermented yogurt. This intuition anticipated by a century a scientific revolution we are living through today.

Research on the gut microbiome is one of the most active and most funded biological disciplines of the decade. And among its most promising fields of investigation: the link between microbiota composition and human longevity.

The microbiome: an invisible organ with essential functions

The gut microbiome designates the set of microorganisms — bacteria, archaea, fungi, viruses and protists — that colonize the human digestive tract. Their number is estimated between 38,000 and 100,000 billion, for a total mass of approximately 1 to 2 kilograms. Their collective genome — the metagenome — contains approximately 150 times more genes than the human genome.

This extraordinary genomic density confers on the microbiome metabolic capabilities that the host organism does not possess autonomously: fermentation of dietary fiber into short-chain fatty acids, synthesis of certain vitamins (K2, B12, folates), regulation of the intestinal immune system, and maintenance of epithelial barrier integrity.

The microbiome is not a passenger of the organism. It is a co-evolutionary partner whose functions have been integrated into human physiology for millions of years.

How the microbiome changes with age

In young healthy adults, the microbiome is dominated by two major bacterial phyla: Firmicutes and Bacteroidetes. Diversity is high and composition relatively stable.

With age, several characteristic changes have been documented across multiple cohorts:

Bacterial diversity decreases — one of the most robust markers of microbiome aging. A study by Claesson et al. (Nature, 2012) on 178 elderly Irish individuals showed that microbiome composition was strongly correlated with overall health status.

The proportion of pro-inflammatory bacteria increases at the expense of short-chain fatty acid-producing bacteria such as Faecalibacterium prausnitzii and Roseburia intestinalis.

Intestinal permeability increases — the so-called "leaky gut" phenomenon — allowing systemic passage of bacterial fragments (LPS) that chronically activate innate immunity and contribute to inflammaging.

Centenarians: what does their microbiome say?

Biagi et al. (Current Biology, 2016) compared the microbiome of Italian centenarians, supercentenarians (105 years and older), elderly individuals and young adults. Centenarians present a distinct microbiome composition — characterized by greater abundance of beneficial bacteria and maintenance of a certain diversity despite advanced age.

Studies on centenarians in Sardinia, China and Japan found convergent signatures, suggesting that certain characteristics of the "longevity-associated" microbiome transcend geographical differences.

Akkermansia muciniphila: the longevity bacterium

Among bacteria whose relationship with longevity is best documented, Akkermansia muciniphila occupies a prime position. It colonizes the mucosal layer of the intestinal epithelium, contributing to the maintenance of intestinal barrier integrity.

Several studies have shown an inverse correlation between Akkermansia muciniphila abundance and metabolic syndrome, obesity, type 2 diabetes and chronic systemic inflammation.

Wilmanski et al. (Nature Metabolism, 2021), studying 9,000 individuals, identified that people over 80 in good functional health presented a statistically distinct microbiome — with preserved diversity and specific metabolic profiles.

Gut-brain axis: the microbiome and cognitive aging

The gut-brain axis is the set of bidirectional communication pathways between the gut microbiome and the central nervous system — via the vagus nerve, circulating metabolites and the immune system.

Studies in mice showed that transfer of an aged mouse microbiome to young mice accelerates certain markers of brain aging, and conversely, that transfer of a young mouse microbiome to aged mice improves certain cognitive performances.

Short-chain fatty acids (SCFAs) — butyrate, propionate, acetate — produced by bacterial fermentation of fiber, cross the blood-brain barrier and exert documented neuroprotective effects.

Dysbiosis, intestinal permeability and inflammaging

The proposed causal sequence is: aging reduces microbiome diversity → butyrate-producing bacteria decrease → intestinal permeability increases → bacterial fragments enter systemic circulation → they activate TLR4 receptors of innate immunity → inflammaging is fueled.

This mechanism places the microbiome at the crossroads of several Hallmarks of Aging: dysbiosis (Hallmark #12), chronic inflammation (Hallmark #11) and altered intercellular communication (Hallmark #10).

Urolithin A: when the microbiome produces longevity actives

Urolithin A is a metabolite produced by the intestinal biotransformation of ellagitannins — polyphenols found in pomegranates, walnuts and certain berries. This biotransformation is carried out by specific microbiome bacteria.

Clinical studies published in Nature Metabolism and Cell Reports Medicine have shown that urolithin A activates mitophagy and improves muscle function in older adults.

What urolithin A illustrates is fundamental: the capacity to produce certain bioactive metabolites is not universal. It depends on the presence of specific bacteria — and approximately 30 to 40% of the population may not produce urolithin A significantly despite adequate consumption of precursors.

In conclusion

The gut microbiome is a functional organ whose composition conditions mechanisms directly involved in longevity: intestinal barrier integrity, production of bioactive metabolites, immunity regulation, protection against inflammaging and communication with the central nervous system.

Its inclusion as a Hallmark of Aging in its own right in López-Otín's 2023 revision is the scientific recognition of a decade of transformative research.

Metchnikoff had an intuition. Contemporary geroscience has made it a science.

References: Claesson et al., Nature, 2012 · Wilmanski et al., Nature Metabolism, 2021 · Biagi et al., Current Biology, 2016 · López-Otín et al., Cell, 2023 · Cryan et al., Nature Reviews Neuroscience, 2019

This article is published for informational and educational purposes only. It does not constitute medical advice and does not replace professional medical consultation.