Aging is characterized by a progressive decline in functional capacity, driven by a broad spectrum of cellular, molecular, and structural alterations. These cumulative changes compromise the ability of the organism to maintain homeostasis, heighten vulnerability to various pathologies, and impair numerous physiological processes. Notable consequences include diminished organ functionality, reduced resilience to stress, and the gradual destabilization of the internal environment [1]. In addition, aging represents the predominant risk factor for human mortality, largely due to its association with functional deterioration, increased frailty, and a higher propensity for developing chronic illnesses [2]. In response to these challenges, intervention strategies for healthy aging have emerged to preserve functional capacity throughout life by targeting physical and cognitive domains alongside environmental and social determinants of well-being [3]. Within this context, microbiota-based therapeutic approaches targeting older adults with complex clinical conditions, such as neurodegenerative diseases, have gained attention as innovative tools to address age-related decline [4].

As organisms age, the gut microbiome (GM) experiences pronounced shifts in both its composition and function, resulting in a state of dysbiosis. This process is influenced by intrinsic factors, including genome instability, mitochondrial dysfunction, and epigenetic alterations, as well as by external factors such as environmental exposures, dietary influences, and diseases [1, 2]. The concept of the GM as a “second genome” underscores its integral role in human health, given its involvement in diverse metabolic, immunological, and physiological processes. These include digestion of foods, synthesis of vitamins and hormones, modulation of immune responses, prevention of external microbial pathogens from invading and colonizing the host, and preservation of intestinal barrier integrity [5]. Building on the aforementioned, growing evidence demonstrates that dysbiosis of the GM exerts a clinical impact on the pathogenesis of several age-related diseases, including neurodegenerative conditions [2]. In light of this, personalized medicine based on remodeling the GM appears to be a novel and impactful avenue for addressing age-related chronic disorders.

In order to mitigate the detrimental consequences of aging and promote healthier aging trajectories, several authors have suggested that the modulation of the GM through the implementation of fecal microbiota transplantation (FMT) may constitute a promising strategy to enhance healthspan and delay age-related decline [1, 5, 6, 7]. FMT involves the transfer of fecal microbial communities from healthy individuals to recipients with a disrupted GM, aiming to restore microbial diversity and balance within the GM [7]. FMT has been utilized as a therapeutic tool for (i) a variety of chronic and recurrent microbial infections, including antibiotic-refractory Clostridioides difficile infection (CDI), Helicobacter pylori infection, multidrug-resistant microorganism infections, and fungal and viral infections; (ii) various gastrointestinal disorders, including Crohn’s disease, constipation, ulcerative colitis, celiac disease, irritable bowel syndrome, colon cancer, and chronic pouchitis; (iii) several metabolic and autoimmune diseases, such as refractory melanoma, non-alcoholic fatty liver disease, metabolic syndrome, obesity, diabetes type 2, fibromyalgia, and cardiovascular inflammation; and (iv) neurodegenerative conditions such as Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS) [4, 8]. Nevertheless, FMT currently poses notable challenges, particularly due to the complexity of GM transfer in comparison to oral microbial communities, as well as to the uneven spatial distribution of microorganisms within the gastrointestinal tract of the host [5, 9]. To address these challenges, repeated administrations of microbial formulations are frequently required during prolonged periods to facilitate the colonization of donor microbiota within the recipient’s gut ecosystem using a washed microbiota transplantation through transendoscopic enteral tubing [10]. Given the growing interest in the gut-brain-aging axis and the emerging use of FMT as a feasible intervention, this narrative review examines the role of the GM in aging, with a specific focus on the therapeutic potential of FMT in promoting healthy aging.

As indicated by the existing literature, greater concentrations of circulating LPS and branched-chain amino acids (BCAAs) have been identified in the blood of older adults. Elderly individuals also exhibit GM dysbiosis, compromised intestinal mucosal barrier function, and diminished synthesis of SCFAs and secondary bile acids. These factors contribute to the development of insulin resistance and reduced muscle protein synthesis, resulting in heightened muscle protein breakdown [33].

An expanding body of evidence indicates that alterations in the GM composition take place with age, affecting the abundance and diversity of both beneficial and harmful bacterial species. These microbial shifts have been demonstrated to affect the production of a series of microbial metabolites that directly impact several physiological and immune host functions [6]. Since GM dysbiosis has been associated with a range of age-related conditions [2, 34], interventions designed to restore gut microbial homeostasis hold considerable potential in promoting healthy aging [11]. Although the history of FMT is extensive [8], this approach did not gain substantial attention in contemporary medicine until 2013, following the publication of the first randomized controlled trial demonstrating its efficacy in treating recurrent CDI [35]. In fact, the efficacy of FMT in restoring a healthy GM has been shown in the treatment of numerous conditions, including not only chronic gastrointestinal disorders but also a range of extra-intestinal disorders and symptoms [5, 34, 36].

Aging is characterized by a complex and interconnected set of factors, including chronic inflammation, deficits in macroautophagy or nutrient uptake regulation, epigenetic modifications, genomic instability, GM dysbiosis, impaired intercellular communication, loss of proteostasis, mitochondrial dysfunction, stem cell depletion, and telomere attrition [55]. In addition, emerging evidence highlights the degradation of the extracellular matrix [56] and the compromised integrity of physiological barriers [57]. Proteomic changes associated with aging have been linked to various age-related markers across biological, physical, and cognitive domains, such as telomere length, frailty index scores, and reaction time performance [58].

Cao et al. [59] identified three primary aging metrics. The first is the CI-PF index, which refers to the concurrent presence of both cognitive impairment and physical frailty in non-demented older adults. The second metric is the frailty index, which aggregates deficits across various domains, including cognitive and physical function, producing a score that reflects the risk of multiple outcomes such as hospitalization and mortality. The third is the motoric cognitive risk syndrome, defined by the simultaneous occurrence of subjective cognitive complaints and slowed gait. Despite their conceptual similarities, these metrics differ significantly in their operational definitions and characteristics. However, these differences have yet to be formally assessed, limiting their applicability in both research and clinical settings. Furthermore, numerous studies have shown that comorbidity in cognitively intact older adults is linked to an increased risk of functional decline, marked by the inability to perform daily activities independently. Higher comorbidity burdens, as measured by comorbidity indices, are also associated with a decline in functional autonomy among individuals with cognitive impairment [60].

As humans age, an array of biological changes unfolds, influencing a range of systems within the organism. In this respect, aging constitutes the primary risk factor for mortality in humans, driven by functional decline, increased frailty, and heightened susceptibility to chronic diseases. This process involves physiological changes in the brain, gastrointestinal disruption, and immune response alterations, many of which are influenced by the gut-brain axis [2]. Dysbiosis, marked by a loss of beneficial bacteria and overgrowth of pathogens, along with changes in metabolic activity and bacterial distribution, is a key feature of aging. As a result, the GM plays a crucial role in aging, contributing to the development of metabolic disorders and age-related diseases [61]. Thus, personalized medicine targeting GM dysbiosis offers a promising approach for managing age-related conditions [62].

The use of FMT to modulate the microbiota of the elderly has gained increasing attention, forming the focus of this review. FMT involves transferring the entire microbial community from a donor’s stool into the recipient’s intestines to normalize or alter their GM composition and function. Initially developed for treating recurrent CDI [33], FMT is now being explored in diverse therapeutic fields, including extra-intestinal conditions such as neurological and mental disorders [34]. Despite significant progress in animal models, translating these findings to humans remains challenging due to differences in microbial complexity and composition between species [63]. While preclinical results are promising, Novelle et al. [5] note that most clinical trials focus on cancer, and gaps remain in applying FMT as an anti-aging therapy.

FMT exerts therapeutic benefits through various mechanisms, such as restoring microbial diversity, modulating immune responses, promoting SCFA production, and enhancing intestinal barrier integrity. Recent studies are investigating the gut-brain axis, the role of specific microbial strains, and the potential applications of FMT beyond gastrointestinal disorders [64, 65]. In addition, nanotechnology-based strategies are being explored to improve the precision and effectiveness of FMT, with the aim of targeting specific gut regions or co-delivering therapeutic agents alongside the fecal material [66]. Furthermore, in vitro fermentation systems offer a controlled setting to examine microbial interactions and metabolism, which may expedite the development of novel FMT therapies [67].

Although FMT seems to be a valuable therapeutic approach, several factors limit its widespread clinical use. These include a lack of consensus on its definition, mechanisms of action, treatment costs, application timing and route, efficacy, tolerability, and safety. To successfully implement FMT for various diseases, it is essential to identify the optimal procedures and microbial factors that determine efficacy for each specific condition. Key areas that require further exploration include criteria for donor-recipient compatibility and preconditioning protocols for both donors and recipients. These factors are critical for ensuring the successful engraftment of donor strains and the overall effectiveness of FMT in clinical practice. The application of analytical models and artificial intelligence tools to large-scale datasets offers a promising strategy for identifying the precise factors that influence FMT outcomes [68].

A close review of the existing literature highlights several critical aspects of FMT that need to be thoroughly investigated before its widespread use in clinical practice can be justified. Central to the success of FMT is the careful selection of an appropriate donor. While autologous FMT is often ideal due to superior compatibility, it is not always feasible, making stool donors a necessity in many cases. Prior to FMT, rigorous screening of the donor’s GM for potentially pathogenic organisms is essential to ensure the safety of the procedure [69]. Research has focused on identifying the characteristics of donors whose stool samples are most likely to result in successful microbial engraftment. Donors with high taxonomic diversity and specific bacterial families are proposed to contribute to disease-specific restoration of gut homeostasis in recipients [70]. Recently, the concept of “super-donors” has emerged, referring to individuals whose fecal microbiota leads to notably higher success rates in FMT compared to standard donors [70]. Beyond donor selection, recipient factors such as genetics, diet, and lifestyle are also likely to influence the long-term success and maintenance of FMT [71].

The administration of FMT has been achieved through various methods, including upper endoscopy, nasogastric/nasoduodenal tube insertion, enemas, colonoscopy, or oral capsules. While several meta-analyses have assessed the efficacy of these delivery routes, only a limited number of studies have directly compared them [72]. Among these methods, FMT capsules have shown promising results in treating a range of pathological conditions. The lyophilized formulation of encapsulated FMT has been proven to be stable over the long term, thereby supporting its potential for sustained microbiome modulation [73]. A metagenomic meta-analysis of 24 studies demonstrated that FMT using combined delivery routes was more likely to result in successful microbial engraftment compared to single-route administration [74]. This indirect finding highlights the potential benefits of combination FMT and suggests it may be a valuable area for further investigation in future research.

Borrego-Ruiz and Borrego [8, 34] highlight the lack of standardization in current FMT protocols due to variability in pretreatment, GM analysis, administration route and dose, fecal infusion selection, and donor criteria. To address these issues, they suggest enhancing fecal bank quality and quantity, citing examples like OpenBiome and the Netherlands Donor Feces Bank, and promoting their operation both nationally and internationally. Another significant challenge in human FMT research is the study design, particularly the lack of control groups and standardized procedures. Implementing double-blind interventions with control groups would mitigate potential publication bias, especially in case reports. Regarding FMT efficacy, the variability in disease severity, particularly in brain disorders, poses a challenge. Longitudinal studies may be more suitable for evaluating outcomes in neurodegenerative diseases such as AD or PD. Furthermore, microbiota analysis results are highly heterogeneous due to differences in sample collection, DNA extraction, sequencing methods, and confounding factors such as medications, diet, and age [75]. Lastly, the mechanisms behind FMT’s efficacy remain unclear, as the treatment contains a complex mixture of viable and inactivated bacteria, other microorganisms (e.g., virome, mycobiome), and microbial metabolites (e.g., bile acids, SCFAs, proteins). Thus, it is still unknown which components are essential for its therapeutic effect.

Although FMT holds potential as an intervention for promoting healthy aging, its feasibility, limitations, and ethical implications require thorough evaluation. While FMT shows promise in restoring a healthy GM, which is closely linked to various aspects of aging, several practical and ethical challenges persist, particularly concerning donor selection, safety, and long-term effects. In terms of feasibility, several key points need to be considered [5, 76]: (i) the increasing use of oral capsules for FMT could alleviate safety concerns associated with more invasive procedures; (ii) FMT has the potential to restore a balanced GM, which is essential for overall health and may reduce the risk of age-related diseases; and (iii) research suggests that FMT may have positive impacts on frailty, cognitive function, cardiovascular health, physical performance, and even telomere length, which are factors critical to healthy aging. However, the limitations of FMT include [76, 77, 78]: (i) the need for more rigorous clinical trials to validate the efficacy and long-term outcomes of FMT for healthy aging; (ii) the variability in FMT protocols, such as pre-treatment, administration route, and follow-up procedures, all of which could influence results; (iii) the possibility that FMT effects on the GM may be temporary, necessitating repeat treatments; (iv) the risk of pathogen transmission, stool toxicity, and difficulties in reproducing positive outcomes; and (v) the scalability of FMT for widespread use, particularly for healthy individuals. The most pressing ethical concerns include [77, 79, 80, 81]: (i) the challenge of identifying and selecting suitable healthy donors, raising questions about donor health and informed consent; (ii) despite its general safety, FMT poses risks, and long-term safety data, particularly for healthy aging, remains insufficient; (iii) defining what constitutes a “suitable healthy donor” and ensuring donor safety and well-being; (iv) the importance of ensuring equitable access to FMT for individuals across different socioeconomic and geographical backgrounds; (v) the need to prevent the commercialization of FMT in ways that could exploit patients or donors; and (vi) the potential public health implications, such as the risk of antibiotic resistance or unforeseen consequences, that require careful consideration.

FMT is generally considered a safe procedure, with the majority of short-term risks linked to the method of administration, particularly endoscopic procedures, rather than to the FMT itself [82]. Common adverse effects are typically mild and transient, and may include symptoms such as diarrhea, abdominal discomfort, bloating, flatulence, and constipation [75]. While the transfer of live microorganisms to individuals with underlying health conditions may pose higher risks, increasing evidence suggests that FMT is well tolerated in higher-risk populations, such as immunosuppressed patients, without a significant increase in side effects [83]. Many potential risks can be minimized through rigorous donor selection and screening procedures. However, there have been notable instances where lapses in this process led to patient harm, including drug-resistant E. coli bacteremia [84]. According to Park and Seo [85], adverse events associated with FMT are influenced by factors such as stool bank practices, delivery routes, and the success of donor microbial engraftment. The long-term consequences of donor microbial engraftment may include a range of health issues, such as increased susceptibility to infections, obesity, immune-mediated disorders, and inflammatory bowel disease [86, 87].

To mitigate the risk of sepsis and eliminate potential pathobionts from donor stool, several studies have employed antibiotic treatments on the fecal matter [84]. However, this strategy is not without notable drawbacks [88]: (i) if the donor stool contains a pathogen with intrinsic or acquired antibiotic resistance to the drugs used, this approach could inadvertently increase the risk of transmission and infection by diminishing competition from other bacterial strains; (ii) the use of antibiotics may also raise the likelihood of de novo antibiotic resistance emerging within both commensal and pathogenic bacterial populations; and (iii) antibiotic treatment could lead to a reduction in overall bacterial diversity, potentially disrupting the microbial balance in the donor’s gut and promoting the unpredictable expansion of other bacteria [88].

Regarding the immune consequences of FMT, only a limited number of studies have investigated this aspect. One study examined the effects of FMT on the immune system in mice treated for eight weeks with a combination of five antibiotics, followed by FMT to resolve the dysbiosis induced by the antibiotic exposure. The depletion of microbiota caused by the antibiotic treatment resulted in a reduction of CD4⁺ and CD8⁺ T lymphocytes in both the gut and lymphoid nodes. In addition, there was a decrease in T cells with a memory/effector phenotype (CD44^hi), Tregs, and co-stimulatory molecules in dendritic cells [89]. The study also found that IFN-$\gamma$, IL-17, IL-22, and IL-10-producing T cells were reduced with antibiotic treatment but were restored after FMT. In another study, Moreau et al. [90] identified immune genes, including pro-inflammatory and Type 2 immune pathways, as upregulated following FMT administration. This finding was corroborated by the observation that antibiotic-induced dysbiosis restored microbial alpha diversity to levels similar to those of the donor mice by day 7 post-FMT. Bulk RNA sequencing of cecal tissue on the second day after antibiotic treatment revealed the upregulation of immune genes, including both pro-inflammatory and Type 2 immune pathways, in mice after antibiotic-induced dysbiosis and FMT. However, expression of these immune genes decreased, while genes associated with restoring intestinal homeostasis increased. Immunoprofiling on day 7 showed an increase in colonic CD45⁺ immune cells, which exhibited dampened Type 1 responses and heightened regulatory and Type 2 responses. This included an increased abundance of eosinophils, alternatively activated macrophages, Th2 cells, and T regulatory cell populations.

Currently, healthy aging represents a significant goal for society, and several non-pharmacological strategies appear to be particularly suitable for its promotion. These strategies often emphasize healthy lifestyle habits, including dietary patterns, physical and cognitive stimulation within social contexts [3], as well as therapies based on microbial interventions, such as the administration of probiotics, prebiotics, synbiotics, postbiotics, and FMT [4]. Among these, FMT holds particular promise, as its full viability and effectiveness are still under investigation, requiring further development and optimization to reach a more refined stage of therapeutic application. In this respect, recent advancements in FMT technology have led to innovative approaches for treating recurrent CDI, such as Washed Microbiota Transplantation (WMT) [91] and spore transplantation [92]. For future FMT treatments to succeed, it is crucial to implement rigorous screening of healthy donors, establish standardized and personalized laboratory and clinical protocols, and test whether high-quality fecal microbiota may act as an anti-aging agent.

In order to contextualize the potential role of FMT as a strategy to promote healthy aging, it is useful to consider how it compares to other commonly proposed interventions for modulating the GM, such as probiotics, dietary modification, and physical exercise. Although these approaches differ markedly in their complexity, invasiveness, and mechanism of action, all influence GM composition and function, which is increasingly recognized as relevant to age-associated physiological changes. FMT, by directly transferring a complete and mature microbial ecosystem, is hypothesized to exert broader and more immediate effects than targeted interventions such as probiotics or diet. However, it also presents significant ethical, safety, and logistical challenges that limit its routine clinical application. In contrast, probiotics, diet, and physical exercise are generally accessible, better tolerated, and widely studied in aging populations, although their effects on the GM tend to be more gradual and potentially less pronounced. Notably, clinical evidence supporting the use of these strategies in the context of aging remains variable and methodologically heterogeneous, and comparative trials are lacking. Thus, the selection of one approach over another may ultimately depend on specific clinical goals, risk profiles, and individual patient characteristics. Given the distinct advantages and limitations associated with each method, future research should aim to establish clearer criteria for intervention choice, as well as explore the possibility of combined or sequential applications.

Finally, FMT impacts aging-related phenotypes through modulation of the gut-brain and gut-liver axes. Data from single-cell sequencing and metabolomics highlight specific microbial and metabolic alterations linked to aging, as well as how FMT can reverse these changes, influencing pathways such as lipid and amino acid metabolism, and neurotransmitter production. Single-cell sequencing offers a high-resolution view of the GM, identifying cell-to-cell variability and revealing specific bacterial populations affected by aging and FMT [93]. Metabolomics further uncovers microbial metabolites that change with aging and how FMT restores them, including SCFAs, bile acids, and amino acid-derived metabolites, all of which play pivotal roles in biological processes [94]. These analyses demonstrate that FMT can modulate the levels of microbial metabolites influencing brain function. For example, increased bile acids in non-alcoholic fatty liver disease activate inflammatory pathways in microglia, disrupting neuronal function. FMT has been shown to restore these metabolic balances, alleviating adverse effects on brain health [95]. By understanding the microbial and metabolic shifts associated with aging, researchers can refine FMT protocols or develop other microbiome-based therapies to promote healthy aging [96].

The use of FMT to restructure the recipient’s GM with donor fecal samples has been applied to treat various chronic conditions in older adults, including microbial infections, metabolic disorders, and neurodegenerative diseases. The selection of an appropriate GM donor is pivotal for the efficacy and safety of FMT, with young donors showing the most beneficial outcomes. Recent studies suggest that modulation of the GM has the potential to enhance human health, mitigate the negative effects of aging, and promote longevity. Therefore, evidence supports the role of GM in facilitating healthy aging.

This review highlights recent studies demonstrating the benefits of FMT in extending lifespan and improving physiological and neurological functions. Given these findings, FMT as a personalized medicine approach shows promise as a therapeutic option for addressing aging-related effects. Nevertheless, other therapeutic modalities, such as biotherapeutic products, phagetherapy, SER-109 (purified ethanol-treated feces from the Bacillota phylum), and the CRISPR/Cas system, should also be considered for future applications.

AB-R and JJB conceptualized the research study, wrote the original draft, conducted the investigation, and reviewed and edited the manuscript. Both authors participated sufficiently in the work to take public responsibility for appropriate portions of the content and agreed to be accountable for all aspects of the work. Both authors contributed to editorial changes in the manuscript. Both authors read and approved the final manuscript.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest.

During the preparation of this work, no artificial intelligence tools were used.