Microbiome-based therapeutics towards healthier aging and longevity

Abstract

The gut microbiome is our lifetime companion, regulating our health from birth throughout the lifespan. The gut microbiome composition changes continually with age, influencing both physiological and immunological development. Emerging evidence highlights the close association, and thus implication, of the microbiome with healthy disease-free aging and longevity. Accordingly, targeting the gut microbiome is emerging as a promising avenue to prevent, alleviate, and ameliorate aging-related disorders. Herein, we provide a prospective and inclusive framework of the close connection of the gut microbiome with human aging, while contemplating how this association is intertwined with age-related diseases. We delve into recently emerging and potential microbiome-based therapeutics that are projected to aid in alleviating myriad aging-related diseases, thereby enhancing the health and well-being of the aging population. Finally, we present a foundation and perspective underlining the prospects of microbiome-based therapeutics developed and tailored precisely for the elderly, with the overarching goal of promoting health and longevity.

Keywords: Dysbiosis; Geriatrics; Gut; Inflammaging; Metagenomics; Microbiota; Postbiotics; Prebiotics; Probiotics; Senescence.

Fig. 1

Conceptual overview of biome-aging and microbiome-based therapeutics. As individuals age, significant changes in factors such as diet, lifestyle, and physiology contribute to a process termed “biome-aging”—an aging-associated gut dysbiosis characterized by the loss of beneficial commensals, proliferation of pathogenic microbes, and increased intestinal permeability (“leaky gut”). This dysregulated gut environment facilitates the translocation of microbial toxins into the systemic circulation, promoting chronic inflammation. Concurrently, the decline in functional microbes impairs nutrient metabolism and biosynthesis, leading to nutrient malabsorption and deficiencies in microbially derived essential nutrients. Together, these changes accelerate biological aging and increase the risk of age-related diseases. Microbiome-based therapeutic strategies—including fiber- and polyunsaturated fatty acid-rich diets, polyphenol-rich diets, probiotics, prebiotics, postbiotics, and fecal microbiota transplantation—show potential to mitigate biome-aging by restoring gut microbial balance. These interventions promote the proliferation of beneficial, functional microbes and the production of key microbially derived metabolites such as short-chain fatty acids and neurotransmitters. In turn, they support nutrient biosynthesis, enhance epithelial barrier integrity, and improve mucus production, thereby contributing to healthy aging and disease prevention. Created in BioRender. Nagpal, R. (2025) (https://BioRender.com/5137mjt)

Fig. 2

Dynamic shifts in the gut microbiome composition across the lifespan. Changes in the intestinal bacterial, fungal, and viral communities from infancy to adulthood, old age, and centenarians. Created in BioRender. Nagpal, R. (2025) (https://BioRender.com/dyakwuj)

Fig. 3

An outline of mechanistic insights between gut dysbiosis and aging-associated disorders. Aging-associated gut dysbiosis is manifested by a gradual increase in the abundance of pathobionts and decrease in commensal/beneficial microbial taxa, leading to corresponding shifts in the metabolic pool (e.g., decreased SCFAs and increased harmful metabolites like TMA), with a concomitant increase in intestinal permeability, decrease in mucous production, and elevated blood translocation of microbes, their metabolites, and PAMPs: (1) These perturbations, via a compromised blood–brain barrier (BBB), increase the risk of cognitive disorders (Alzheimer’s and Parkinson’s disease) in the elderly by activating astrocytes and microglia, leading to neuroinflammation and formation of protein aggregates (ß-amyloid/α-synuclein) and tau atrophy. (2) Decreased production of SCFAs also adversely affects mucin production and disturbs modulation of blood vascular tone, posing a risk to cardiovascular health. Moreover, gut dysbiosis metabolism promotes harmful metabolites (e.g., TMA, secondary BAs), further aggravating the situation, leading to atherosclerosis, and finally heart failure. Heart failure induces intestinal ischemia and edema, which further fuels gut leakiness and indirectly heightens the pro-inflammatory response. (3) Inflammaging and immunosenescence is promoted by gut dysbiosis via bacterial PAMPs, OMVs, etc., triggering the NF-κB pathway and secreting proinflammatory cytokines, which in turn promote cellular senescence by delayed DNA damage repair mechanisms. (4) Promotion of certain bacterial species (e.g., Fusobacterium nucleatum) via their PAMPs (e.g., FadA, Fap2, LPS) interacts with receptors (TLR4, E-cadherin), thereby augmenting tumor signaling and suppressing autophagy, leading to the development of intestinal disorders like colorectal cancer. SCFAs, short-chain fatty acids; FadA/Fap2, Fusobacterium adhesins; TLR4, Toll-like receptor 4; NF-κ, nuclear factor kappa; Wnt, wingless/integrated pathway; LPS, lipopolysaccharide; OMVs, outer membrane vesicles; APCs, antigen-presenting cells; MUC2, mucin 2; OR51E2, olfactory receptor 51E2; FFAR3, free fatty acid receptor 3; TMA, trimethylamine; TMAO, trimethylamine N-oxide; FMOs, flavin monooxygenases; BAs, bile acids; PAMPs, pathogen-associated molecular patterns; IL, interleukin; INF, interferon; TNFα, tumor necrosis factor alpha. Created in BioRender. Nagpal, R. (2025) (https://BioRender.com/5xglc1b)

Fig. 4

Potential microbiome-based therapeutics to prevent unhealthy aging and nurture healthier disease-free aging and longevity. With the recognition of the crucial role of the gut microbiome in aging-associated disorders, microbiome-based therapeutics for ameliorating or preventing aging-associated disorders are being actively studied. These therapeutics are designed to restore or promote the beneficial microbiota and its function or reduce pathobionts, thereby rebalancing the gut microbial community and breaking the cycle of disorders. A range of therapeutics have been demonstrated, including consumption of specific diets or food, supplementation with probiotics, prebiotics, synbiotics, postbiotics, drugs, and supplements, and transfer of the gut microbiota. BCFA, branched-chain fatty acid; FMT, fecal microbiota transplant; FOS, fructooligosaccharide; GOS, galactooligosaccharide; ICA, indole-3-carboxaldehyde; LTA, lipoteichoic acid; Med-diet, Mediterranean diet; NF-κB, nuclear factor kappa B; SCFA, short-chain fatty acid; TLR2, Toll-like receptor 2; MAPK, mitogen-activated protein kinase; TMA, trimethylamine; TMAO, trimethylamine N-oxide; Uro B, urolithin B. Created in BioRender. Nagpal, R. (2025) (https://BioRender.com/heaxrmr)