The Role of the Gut Microbiome in Healthy Ageing — How May It Influence the Hallmarks of Aging?

The gut microbiome changes with age

The gut microbiome changes throughout life.

In older adults, these changes occur alongside changes in intestinal physiology, immune function, diet, medications and overall health.

Importantly, age-related loss of health varies considerably between people. Microbiome changes also differ between healthy and unhealthy ageing.

Unhealthy ageing may involve the loss of beneficial commensal bacteria and an increase in pathobionts — microorganisms that can contribute to disease under certain conditions.

Particular bacterial patterns are associated with healthy ageing

The review describes evidence from large human cohorts.

An analysis involving approximately 25,000 people identified several bacterial species associated with healthy ageing.

These included Faecalibacterium prausnitzii, Eubacterium rectale, Dorea longicatena, Eubacterium ramulus, Coprococcus comes, Coprococcus catus, Roseburia hominis and Barnesiella intestinihominis.

Their combined levels showed a stronger relationship with healthy ageing than broader measures such as alpha diversity or microbiome uniqueness.

This suggests that general measures such as diversity or uniqueness may not capture all microbiome features associated with healthy ageing.

Extreme longevity is not the same as healthy ageing

Centenarians are frequently studied as models of longevity.

The authors caution against treating their microbiome as an ideal model for healthy ageing.

Their microbiome may reflect extreme age, physiological adaptation, environmental exposures and current health.

Characteristics found in centenarians therefore cannot automatically be interpreted as features that promote healthy ageing earlier in life.

How May the Gut Microbiome Influence the Hallmarks of Aging?

A major part of the review examines how gut microorganisms and their products may interact with the Hallmarks of Aging.

The evidence differs between mechanisms. Some relationships are better established. Others remain under investigation.

Cellular senescence

The authors discuss a possible connection between microbial vitamin K production and cellular senescence.

Experimental findings suggest that vitamin K may influence cellular senescence. Direct evidence linking microbiome-derived vitamin K to this process remains limited.

Mitochondrial dysfunction

Microbial metabolites can influence mitochondrial function.

The review describes possible links between microbiome activity, mitochondrial metabolism and dysfunction.

Their importance in human ageing remains under investigation.

Genomic instability

Some microorganisms produce genotoxic metabolites and toxins.

Experimental evidence shows that particular bacterial products can damage DNA, including causing double-strand breaks.

This provides a possible mechanism linking microbial activity with genomic instability.

Epigenetic alterations

Microbial metabolites can influence histone acetylation and deacetylation and may affect pathways involved in DNA methylation.

These mechanisms could connect microbial activity with changes in gene regulation during ageing. Much of the evidence remains experimental.

Loss of proteostasis and compromised autophagy

Microorganisms may influence protease activity. Microbial metabolites and bacterial surface structures may also modulate autophagy.

These mechanisms could connect the microbiome with cellular maintenance during ageing. Their importance in humans remains uncertain.

Deregulated nutrient sensing

The microbiome transforms dietary components into biologically active compounds that interact with host metabolism.

The authors discuss microbial production of branched-chain amino acids and its relationship with metabolic regulation.

The microbiome may also influence appetite and satiety signals, including cholecystokinin, glucagon-like peptide-1 and peptide YY.

Other proposed interactions involve fatty-acid metabolism, liver function and the gut–brain axis.

Inflammation and inflammaging

The microbiome interacts closely with the immune system and may contribute to inflammaging — persistent low-grade inflammation associated with ageing.

Loss of beneficial commensals and an increase in potentially pro-inflammatory pathobionts are observed in unhealthy ageing.

However, inflammation and disease can themselves alter the microbiome. Direct evidence that microbiome changes are a primary driver of inflammaging remains incomplete.

Cause and Effect Remain Difficult to Separate

A microbiome pattern associated with poorer health does not establish that the microbiome caused the condition.

Disease, diet, medications and age-related physiological changes can all alter the microbiome.

The authors note that some changes described as dysbiosis may be consequences rather than causes of disease.

Establishing causality is therefore essential before microbiome features can become therapeutic targets.

This review moves beyond describing which bacteria increase or decrease with age.

It asks whether microbial activity may interact with the biological mechanisms of ageing itself.

This is important for longevity research. The microbiome may provide information about different ageing trajectories and may contain biological pathways that could eventually become clinical targets.

However, many of these mechanisms still require stronger confirmation in humans. The microbiome is not yet a proven target for slowing human ageing.

Two decades of gut microbiome research have expanded its relevance across medicine, including gerontology.

The authors emphasize the need to understand microbes, their effectors and their cellular targets — what microorganisms produce, how these products affect human cells and which pathways they influence.

They predict that this knowledge will expand opportunities for the diagnosis and treatment of noncommunicable diseases.

For longevity medicine, this creates an important research direction. Understanding microbial function may eventually allow more precise identification and targeting of microbiome-related processes associated with loss of health.

Whether modifying these processes can extend human healthspan remains to be established.