Intersections of gastrointestinal dysbiosis of the gut microbiome and aging

Abstract

Geriatric syndromes such as frailty and sarcopenia are multidomain indicators of functional status in relation to the chronic disease burden of an aging adult. The human microbiota has gained increasing spotlight in regulating key aspects inherent of aging. In this review, we survey the current literature exploring the pathophysiological intersections of the gut microbiome and the aging process and associated geriatric syndromes that ultimately influence health span and lifespan. We discuss how intrinsic and extrinsic factors can influence age-related gut dysbiosis and propose areas of future directions for further research for identifying therapeutic targets to promote healthy aging.

Key Words: Gut microbiome; Aging; Frailty; Geriatrics; Sarcopenia

Core Tip: The gut microbiota changes with age and is influenced by a number of intrinsic and extrinsic factors whose mechanisms continue to be studied and elucidated. We discuss how dysbiosis of the gut microbiome can affect geriatric syndromes, and explore current and future applications of how promotion of a diverse and healthy gut microbiome can influence the health span of our aging population.

INTRODUCTION

The microbiome of the human gastrointestinal system continues to develop and diversify through early adulthood, stabilize, starts to decline around 65 years old, and more significantly after age 80[1]. It is comprised of up to 100 trillion microorganisms, more than 100 times the number of genes in the human genome[2].

Microbiota composition profiling has revealed a shift of species in older adults compared to that of younger adults. Centenarians in particular have been found to have a unique microbial profile. These age-related differences in composition of the gut microbiota had been compared among young adults, older adults, and centenarians, revealing a characteristic and signature rearrangement of microbiota in centenarians, specifically, an enrichment in facultative anaerobes[3,4].

Genome-wide studies in cohorts of centenarians across the world have identified a complex remodeling of the gut including that of lipid and amino acid metabolism that promote cellular detoxification mechanisms and in turn support an overall anti-oxidative response that can promote longevity[5,6].

Interestingly, these studies have also identified distinct microbiota compositions associated with older adults living in the community vs long-term residential care communities and older adults in rehabilitation hospitals vs community-dwelling[7,8].

The contribution of the gut microbiome to the aging process has been a topic of wide interest and study. Yet the exact mechanism is long from being comprehensively understood. Here we explore the current literature that shape our current understanding of the gut microbiome’s influence on aging.

METHODS

This minireview was based on a literature search performed on PubMed and Google Scholar database published in the English language through April 2026. This was supplemented by hand-searching key articles and relevant scientific literature. Keywords included “gut microbiome” and “gut dysbiosis” in association with outcomes such as “aging”, “frailty”, “sarcopenia”, “cognition”. The most relevant and up to date articles were selected for review. References were also used to identify other relevant studies in the scope of this review. Preference were made for large prospective cohorts, systematic reviews and meta-analyses. Non-peer reviewed articles, letters, editorials, conference abstracts were excluded.

Gut microbiome and aging-what we know

The adage ‘you are what you eat’ holds significant truth when considering the importance and influence of the gut microbiome on aging. Through various signaling pathways, nutrient-specific and epigenetic, overall symbiosis of the gut microbiome and host are important in understanding the complex interplay between the gut on all the human axes involved with aging.

The process of change of the gut microbiome is one that occurs gradually over time; there is no chronological threshold by which this composition suddenly changes. Gut dysbiosis can trigger the innate immune response and low-grade chronic inflammation through a process coined ‘inflammaging’. This is facilitated by the increased intestinal membrane barrier permeability with aging and resulting translocation of inflammatory cytokines, leading to a number of age-related pathologies such as frailty[9,10].

Similarly, age-related immune changes known as immunosenscence can be accelerated by changes in microbial diversity. For example, reduction in short-chain fatty acid producers, changes in bile-acid and tryptophan-metabolizing bacteria can influence neurotransmitter production and also promote release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin (IL)-6[11,12]. The ability of the gut microbiota to adapt its composition to preserve homeostasis of its human host remains an important function in adjusting the immune and metabolic pathways by which so many of the axes depend upon. Studies have even shown gut microbiota dysbiosis related to impaired vaccine responses[13].

Gut dysbiosis has been implicated in a number of organ systems, across multiple axes, for which we will highlight the gut-brain, and gut-muscle axes in particular and have illustrated in a visual framework for the scope of this paper (Figure 1).

Figure 1  Gut microbiome interaction model with gut-brain and gut-muscle axes, and additional external influences.

Gut microbiome, frailty, and sarcopenia

Frailty is a geriatric syndrome characterized by a decline in physical and mental vigor, and associated with an increased need for assistance with activities of daily living, and increased vulnerability to adverse health outcomes. Although there are many existing criteria for frailty, the most commonly used are that proposed by Fried and Rockwood. In the Fried criteria, an individual is considered frail if three or more criteria are met including: (1) Weight loss of 5% or more per year; (2) Self-reported exhaustion 3-4+ days per week; (3) Decreased gait speed; (4) Decreased grip strength; and (5) Decreased physical activity[14]. Similarly, Rockwood’s Clinical Frailty Scale version 2.0 that was updated in 2020, stratifies an individual’s degree of frailty scored on a 9-point scale based on ease of mobility with or without need for use of gait aids, and abilities to eat, dress, shop, cook and bank[15]. Frailty assessments have been utilitized as additional information to guide medical decision making, provide a more informed prognosis, and guide care conversations. Several studies have shown association between gut dysbiosis, or an altered gut microbiome, and loss of muscle mass and function and thereby, increase in frailty[16]. Cui et al[17] identified particular gut microbes suggested to correlate to frailty.

Similarly, sarcopenia is characterized by the progressive loss of skeletal muscle mass and associated strength and function with aging. As defined by the European Working Group on Sarcopenia in Older People, sarcopenia is associated with an increased risk of adverse outcomes such as falls, fractures, disability and mortality[18]. As the gut-muscle axis continues to be studied, an altered gut microbiota has been demonstrated in persons with sarcopenia across various backgrounds and underlying disease. Lapauw et al[19] at all reviewed thirty-two studies and found consistently that persons with sarcopenia were associated with a less diverse composition of gut microbiota.

We know that higher doses of protein are required in older adults to achieve the same muscle protein synthesis response as younger adults[20]. Mechanisms proposed largely include alteration in muscle protein breakdown and amino acid synthesis. Wang et al[21] identify short-chain fatty acid metabolism, urolithin A and bile acid production as potential factors in the gut-muscle axis. For example, dysbiosis of the gut microbiota leading to compromised function of the intestinal barrier through excess production of pro-inflammatory cytokines such as IL-1 and TNF-α, increases levels of serum lipopolysaccharide and decreases levels of serum short-chain fatty-acids, leading to loss of muscle protein synthesis. Zhang et al[22] identified yet another species Bifidobacterium adolescentis through shotgun metagenomics and metabolomics analyses as yet another species thought to improve muscle mass and function through production of nicotinic acid. At the intracellular level, this dysbiosis-mediated inflammatory response accelerates skeletal muscle degradation by upregulating key ubiquitin-proteasome pathways (e.g., Atrogin-1 and MuRF1) while suppressing mTOR signaling required for muscle protein synthesis[21,22]. These are only few of many mechanistic pathways that are being studied of the gut-muscle axis on a molecular level that will continue to provide new understanding and potentially new targets for microbiome-based therapies.

Gut microbiome on cognitive function

The brain-gut-microbiome axis is described as the bidirectional communication channel between the brain and gastrointestinal tract via the vagus nerve. Communication by a variety of immune and inflammatory pathways, neurotransmitters, and microbial by-products, can work to influence mood, behavior, and ultimately has been linked to cognitive function[23].

Chronic stress, for example, has been shown to disrupt the intestinal barrier, increasing permeability and facilitating “leakage” of proinflammatory molecules. Leaky gut is defined as the impairment of the gut epithelial and vascular barriers and has been associated with not only development of inflammatory intestinal diseases, but also of progression of metabolic and neurodegenerative diseases. There have been associations found between altered stress responses, such as anxiety and depression on gastrointestinal disorders such as irritable bowel syndrome[24-26].

Furthermore, gut dysbiosis has been thought to play a role on pathogenesis of Alzheimer’s and Parkinson’s disease in the increase in neuroinflammation via increased intestinal permeability. Studies have revealed that decreased abundance of certain microbiota (Firmicutes and Bifidobacterium) and increases in Bacteroidetes are found in persons with mild cognitive impairment and Alzheimer’s[27,28]. Similarly, characteristic bacterial profiles have been found in persons with Parkinson’s: Reduced populations of Bacteroidetes and Prevotellacae[29,30].

Studies have also demonstrated association of constipated individuals with increased cardiovascular disease risk, chronic kidney disease, and even neurodegenerative disorders such as Parkinson’s[31-33].

External factors, social and mental health affecting gut microbiome

External factors influence the gut microbiome. Diet, environmental exposures, can all affect the composition and diversity of the gut microbiome. These have been well studied following the changes of microbiome profiles of Asian immigrants to the United States over time, in which native microbiome strains have been found to be replaced by those associated with the United States[34].

One can surmise that socioeconomic factors in turn, may indirectly influence these changes. Interventions can help to drive health policies aimed at reducing socio-economic inequalities that affect healthy eating and in-turn premature aging[35]. Focus on efforts to increase opportunities for persons to be able to access and prepare a healthy diet and increase dietary diversity may be one in which the diversity of the microbiota is preserved.

The intersection on gut microbiome dysbiosis with mental mealth such as depression, leading to social isolation and withdrawal and ultimately poor disease and health span trajectory continues to be studied. While a direct link is not yet established, neuropsychological aspects of social isolation and mental health has been associated with an altered gut microbiome. Similarly, persistent socioeconomic stressors that cause social isolation can influence the composition of the gut-microbiome. Kim et al[36] found microbiome composition of those with social exclusion were enriched with Prevotella, decreased Firmicute/Bacteroidetes ratio and decreased Faecalibacterium. Interestingly, these information provide yet another target and approach for addressing social isolation/exclusion and related mental health disorders. Gut dysbiosis across syndromes is summarized in Table 1.

Table 1 Summary of key gut microbial taxa shifts and functional implications across geriatric syndromes and longevity states.

Condition/state	Microbial taxa alterations	Proposed pathophysiological mechanism/biomarker significance
Extreme longevity/centenarians	Enrichment in facultative anaerobes[3,4]; distinct lipid/amino acid metabolic signatures[5,6]	Enhanced cellular detoxification, anti-oxidative response, and metabolic adaptability[5,6]
Frailty	Overall reduced microbial diversity[16]; loss of SCFA-producing species[11,17]	Intestinal barrier hyperpermeability leading to systemic translocation of inflammatory cytokines (inflammaging)[9,10]
Sarcopenia	Global reduction in microbiota diversity[19]; depletion of Bifidobacterium adolescentis[22]	Reduced nicotinic acid-mediated mitochondrial support[22], lower serum SCFA levels, and elevated IL-1/TNF-α impairing muscle protein synthesis[21]
Alzheimer’s disease and mild cognitive impairment	Decreased Firmicutes and Bifidobacterium; increased Bacteroidetes[27,28]	Barrier breakdown facilitating systemic release of pro-inflammatory bacterial products and neuroinflammation[27]
Parkinson’s disease	Reduced populations of Bacteroidetes and Prevotellaceae[29,30]	Altered microbial metabolite profiles (e.g., reduced SCFAs) correlated with gut dysmotility and neurodegeneration[29]
Social isolation and stress	Enriched Prevotella; decreased Faecalibacterium; decreased Firmicutes/Bacteroidetes ratio[36]	Stressor-induced epithelial barrier disruption (leaky gut) and neuroendocrine axis modulation[24,36]

SCFA: Short-chain fatty acid; IL: Interleukin; TNF-α: Tumor necrosis factor-alpha.

As does the gut microbiome, changes in the oral microbiome also occur with age. And through the close connection and interrelatedness, periodontitis and dental caries have been associated with exacerbation of cognitive impairment via the gut-brain axis[37-40]. This also has become an axis of therapeutic target where studies have revealed the use of probiotics, fecal microbiota transplantation and supplement of short-chain fatty acid to have protective effects on the gut microbiota and in turn, expression of genes associated with learning[41,42]. Already, these unique microbiota patterns and composition are being studied for use as non-invasive biomarkers of biological age[43].

Many herbs, foods and commercial products, specifically supplements and probiotics, advertise promise to promote healthy aging. It is important to review the scientific literature that supports each of these in order to make the most informed decision about use and its benefits. While this review is not focused on the pharmacologic interventions coined ‘senolytics’, we acknowledge the tremendous work conducted to identify drug candidates aimed at optimizing the health span. Herein we survey some of the comestibles that have been studied for healthy impact on aging.

Rosemary (salvia rosmarinus) is an herb native to the Mediterranean that long has been culturally symbolized as “remembrance”. Active ingredients of which have known antioxidant and anti-inflammatory properties which are though to indirectly influence dopamine signaling. More recently, it has been studied for its influence on cholinergic mechanisms, more specifically its effects on cognition and mood. Riby et al[44], albeit a small study, measured eye blink rate and blink rate variability as proxies of dopaminergic activity in individuals after drinking rosemary-containing water.

Turmeric (curcumin) has been associated with a number of anti-inflammatory and anti-oxidant properties. It is perhaps one of the most studied compounds for role in various signaling pathways, for example, blocking NF-κB, AMPK, mTOR, oxidative stress, and telomerase activity, that make it a promising compound for healthy aging, and as a potential therapeutic target[45]. Studies have demonstrated neuroprotective effects, while clinical trials have yet to confirm its benefits in humans[46]. More studies need to be done to investigate its bioavailability and long-term therapeutic effects.

Diets containing red or processed meats, high fats, saturated fat, salt, refined sugars have been associated with worsened symptom severity of neurodenerative disorders such as Alzheimer’s and Parkinson’s, and depression, the mechanism of which includes a disruption of the gut-brain axis and increased systemic inflammation. To no surprise, ultra processed foods remain associated with accelerated aging, in some studies revealing a 28% high risk of mortality in the arms consuming over 2 servings of ultra processed foods daily[47].

Systematic review of randomized control trials in older adults have found that diets rich in fiber, polyphenols, plant-based proteins, and fermented foods promote short-chain-fatty acid production and in turn a healthy microbiota. These diets have been associated with improved cognitive function, frailty, glucose homeostasis. Ultimately, there remains highest evidence towards dietary habits rich in plant-based foods including fruits, vegetables, whole grains, nuts, unsaturated fats, and low-fat dairy products associated with healthy aging[48].

The application of fecal microbiota transplantation to promote healthy aging has gained increasing attention. While currently most health-associated benefits have been studied in mice model, there are several ongoing clinical trials studying the effect of fecal microbiota transplantation on age-related conditions. Beyond broad microbiota restoration, strain-specific probiotics offer targeted clinical utility. For example, clinical trials demonstrate that Lactobacillus plantarum TWK10 improves muscle mass, grip strength, and physical endurance in older adults via SCFA-mediated metabolic pathways.

Research gaps and future directions

We admit that while ideally a PRISMA would be preferred for a systematic review, this was not pursued in context of this minireview. We acknowledge that this work provides a framework for future structured systematic review according to PRISMA-reporting guideline and pre-registered on PROSPERO in order to continue to highlight and review relevant up to date studies in the literature that contribute to our knowledge of the gut microbiome and interplay with aging processes.

Continued understanding of such interaction of the various different gut-system axes involved in aging is important, however also inherently multidimensional and complex. It is important to be able to establish causal inferences and framework, rather than mere associations and conceptual frameworks, the former of which are crucial to supporting underlying mechanical pathways from otherwise proposed. Therefore, there is such a need to conduct randomized controlled trials, multi-omics analyses, and control for otherwise confounding variables. We acknowledge challenges and limitations in recruitment and study in selection of older adults, especially in the oldest old for prospective study.

Identification and validation of non-invasive biomarkers has been a focus of study in aging and applications for preventive medicine. Identification of unique oral/gut microbial profiles can serve as biomarkers to facilitate quantification of biological age, and help to risk stratify those at increased likelihood for developing age-related diseases or at increased risk for mortality. These can further be facilitated by incorporation of agentic workflows to assist with microbiome and data processing into building reliable tools for use in the clinical setting. This, in such a way can in turn pave the way for personalized medicine in a variety of applications including but not limited to guiding care conversations and future planning, healthy aging, provide insight into how we approach age-related diseases, and also promotion of vaccine efficacy.

There may never be a one-diet-fits-all due to various baseline microbiota profile across culture and socioeconomic factors, however knowledge of individual profiles can aid in personalizing diets with respect to individual microbiota profile[49]. Whether through dietary intervention, selective probiotics, fecal microbiota transplantation, the clinical applications to ultimately restore gut microbiota homeostasis remains vast and promising.

Such potential also welcomes applications of machine learning technologies to aid in such a quest to promote healthy aging. Whether integration into digital technologies, wearables or smart sensors, consideration of the gut microbiome can be integrated in how we approach aging.

CONCLUSION

As we summarize the role of the gut microbiome on various aspects of aging, it is without question that it extends to many axes (gut-brain, gut-muscle, gut-bone, etc.) that continue to be studied and whose mechanisms still to be uncovered. Continued understanding of the correlation of these axes and microbiota composition, and biomarker validation will help to inform and guide design of treatment interventions in the future that can be applied to the way we approach age-related disease. We look forward with great interest the endless translational applications that future studies will contribute to how we promote healthy aging.

ACKNOWLEDGEMENTS

We would like to acknowledge Jamie Chung, Naomi Woo, and Nathan Woo who facilitated the smooth operation of our research activities.