“Elderly Man Soaks Up the Sun along the Danube – Pest Side – Budapest – Hungary” by Adam Jones, Ph.D. – Global Photo Archive is licensed under CC BY-SA 2.0.
As the global population ages, understanding the biological underpinnings of healthy aging has never been more important. At the ISAPP annual scientific meeting in Banff this July, we learned about some of the fascinating and complex mechanisms behind healthy aging (as uncovered by systems biology approaches) with two insightful talks by Prof Elaine Holmes PhD (Murdoch University, Australia) and Associate Prof Sean Gibbons PhD (Institute for Systems Biology, USA), who were invited to the member pre-meeting program to speak on this subject.
Metabolites, including those derived from the gut microbiome, offer a window into the complex biology of aging. They reflect not just how we live, but how well our bodies are adapting to the passage of time. What makes metabolites particularly valuable is their dynamic nature. Unlike genes, which are static, metabolites can change rapidly in response to diet, exercise, medication, and other lifestyle interventions. This means they not only serve as indicators of health status, but could also serve as potential targets for intervention and guide personalized strategies to promote healthy aging (1).
Gut and host metabolites, and longevity signatures
Centenarians often harbor distinct gut microbiomes that echo youthful patterns, and studies have found that older individuals with microbial and metabolite profiles more similar to younger individuals tend to have better health outcomes. Studies have shown that in some healthy older adults, microbial genes linked to short chain fatty acid (SCFA) production, glycolysis, menaquinone (vitamin K₂), and riboflavin (vitamin B₂) (all of which contribute to reduced inflammation, improved barrier integrity, and enhanced redox metabolism) are notably elevated. Their microbiomes also skew toward secondary bile acids (e.g., iso- and allo‑lithocholic acids), which support immune regulation by suppressing pro-inflammatory T helper cells and promoting regulatory T cells (2).
Beyond the gut, metabolites from other organs such as the liver, muscles, and adipose tissue, also contribute to the aging process. For instance, systemic levels of certain amino acids (e.g., branched-chain amino acids) and lipid metabolites change with age, and may signal shifts in energy metabolism or the onset of metabolic diseases.
Protective SCFAs: Anti-inflammatory mediators
SCFAs, such as acetate, propionate, and butyrate (which are produced by gut microbes) fortify gut epithelial integrity, modulate immune responses, and act as histone deacetylase inhibitors, thereby exerting anti-inflammatory effects (3). Animal models reinforce these findings: aged mice supplemented with SCFAs show reduced “inflamm-aging” (harmful inflammation associated with increased age), less oxidative stress, and improved immune activation in the lungs (4), while others demonstrate improved arterial function and metabolic health. Natural age-related declines in SCFA production have been documented in both humans and mice, highlighting a potential target for dietary or microbial intervention.
Indoles and tryptophan derivatives: Healthspan enhancers
Microbial processing of tryptophan into indoles—such as indole‑3‑propionic acid (IPA)—has recently gained increased attention in the scientific field. These metabolites improve insulin sensitivity and glycemic control, and are depleted in unhealthy aging but enriched in healthier, long-lived individuals (5). Animal and human studies show that indoles can enhance intestinal barrier function and prolong healthspan.
Diet, microbiome, and metabolites: A combined strategy
Diet profoundly shapes the gut microbiome and its metabolite profile, leading to possibilities for healthier ageing through modifying food choices and dietary patterns (6). Epidemiological and clinical studies—like those exploring Mediterranean-style diets—have linked higher abundance of SCFA-producing bacteria (e.g., Faecalibacterium prausnitzii, Roseburia) with reduced frailty and improved metabolic and cognitive markers. In a recent study, specific dietary interventions such as a modified Mediterranean‑ketogenic diet in older adults with mild cognitive impairment, increased fecal propionate and butyrate, and correlated with reductions in biomarkers of Alzheimer’s disease. This study also showed that supplementing polyphenol-rich foods and probiotics further boosts SCFA production, decreases inflammation, and supports gut health in aging individuals.
What’s next?
Research into metabolites and aging is still evolving, but holds immense promise. Gut-derived and other systemic metabolites are increasingly shown to offer a nuanced lens into the aging process. By mapping how specific metabolites correlate with and contribute to age-related health metrics, scientists could develop interventions that can modify the microbiome or target key metabolic pathways. Biotics-based interventions, precision nutrition, and even metabolite-based supplements could become tools for extending healthspan in the future, and could pave the way for personalized, microbial-metabolite informed approaches to healthy aging.
REFERENCES:
(1) Wilmanski T, Diener C, Rappaport N, Patwardhan S, Wiedrick J, Lapidus J, Earls JC, Zimmer A, Glusman G, Robinson M, Yurkovich JT, Kado DM, Cauley JA, Zmuda J, Lane NE, Magis AT, Lovejoy JC, Hood L, Gibbons SM, Orwoll ES, Price ND. Gut microbiome pattern reflects healthy ageing and predicts survival in humans. Nat Metab. 2021;3(2):274-286. doi: 10.1038/s42255-021-00348-0.
(2) Gyriki D, Nikolaidis CG, Bezirtzoglou E, Voidarou C, Stavropoulou E, Tsigalou C. The gut microbiota and aging: interactions, implications, and interventions. Front Aging. 2025;6:1452917. doi: 10.3389/fragi.2025.1452917.
(3) Ragonnaud E, Biragyn A. Gut microbiota as the key controllers of “healthy” aging of elderly people. Immun Ageing. 2021;18(1):2. doi: 10.1186/s12979-020-00213-w.
(4) Hildebrand CB, Lichatz R, Pich A, Mühlfeld C, Woltemate S, Vital M, Brandenberger C. Short-chain fatty acids improve inflamm-aging and acute lung injury in old mice. Am J Physiol Lung Cell Mol Physiol. 2023;324(4):L480-L492. doi: 10.1152/ajplung.00296.2022.
(5) Araújo JR, Marques C, Rodrigues C, Calhau C, Faria A. The metabolic and endocrine impact of diet-derived gut microbiota metabolites on ageing and longevity. Ageing Res Rev. 2024;100:102451. doi: 10.1016/j.arr.2024.102451.
(6) Araújo JR, Marques C, Rodrigues C, Calhau C, Faria A. The metabolic and endocrine impact of diet-derived gut microbiota metabolites on ageing and longevity. Ageing Res Rev. 2024;100:102451. doi: 10.1016/j.arr.2024.102451. Epub 2024 Aug 9.
