Precision Probiotics for Healthy Aging: A Comprehensive Review of Advances in Gut Microbiota Modulation and Anti-Aging Interventions

Abstract

Aging is a progressive decline of physiological functions and raises the risk of many kinds of chronic diseases, imposing a heavy burden on the global public health. Although considerable progress has been made in understanding the genetic mechanisms underlying aging, converting this knowledge into effective interventions to delay aging remains a challenge. Recent research shows that changes in gut microbiota composition and function are tightly linked to senescence, making gut microbial regulation a promising strategy for healthy aging. This review thoroughly summarizes the bidirectional crosstalk between aging and gut microbiota and the mitigating effects of conventional and next-generation probiotics on the aging progression, and focuses on the mechanisms by which probiotics act on the hallmarks of aging. Finally, we explore the strategies for the development and functional enhancement of anti-aging probiotics, aiming to provide novel insights for the precise design of probiotics that promote healthy aging.

Graphical abstract

Keywords

Gut microbiota / Aging / Probiotics / Aging hallmarks / Next-generation probiotics

Highlight

	● Gut microbiota remodeling is not merely a consequence but a driver of aging, making it an actionable target for anti-aging interventions.
	● Probiotics, including next-generation probiotics, exert their anti-aging effects through mitochondrial function, autophagy, and cellular senescence; these mechanistic features can serve as screening targets for precision selection of anti-aging probiotics.
	● Emerging biotherapies (postbiotics, engineered live bacteria, and synthetic consortia) can enhance probiotic anti-aging functions by overcoming colonization barriers and enabling programmable functions.

1 Introduction

The global aging population is growing at an accelerating pace. It has been estimated that by 2050, the number of individuals aged 65 and over in China is expected to reach 334 million, making population aging as major social challenge [1]. Aging, characterized by a progressive decline of physiological functions, represents a critical risk factor for chronic diseases, including cardiovascular disease, diabetes, and neurological disorders [2,3]. The underlying mechanisms involve multiple interrelated processes, such as disruption of genomic homeostasis, telomere attrition, and reduced activity of sirtuins [4]. However, genetic factors alone are difficult to target in anti-aging intervention strategies.

In recent years, accumulating evidence has revealed a complex bidirectional interplay between intestinal microbiota and aging. On one hand, age-related physiological alterations—including slowed intestinal peristalsis [5], thinning of the intestinal mucus layer [6], elevated inflammation and oxidative stress, as well as reduced expression of immunoglobulin A and lysozyme [7,8] — induce gut microbiota dysbiosis. On the other hand, the aging gut microbiota—characterized by a decline in core commensal bacteria (e.g., Bifidobacterium and Akkermansia), an increase in opportunistic pathogens (e.g., Enterobacteriaceae and Clostridium) [9,10]—is associated with accelerated cellular senescence [7,11], compromises intestinal barrier integrity [12], elevates circulating inflammatory factors, and ultimately contributes to the functional decline of multiple organs [13].

However, a fundamental question remains unresolved: is gut microbiota dysbiosis a consequence of aging, or does it actively drive the aging process? Insights from studies on regionally defined long-lived populations have revealed that the gut microbiota of centenarians exhibits remarkable stability and distinctiveness, including a significant enrichment of butyrate-producing and anti-inflammatory bacterial species [14,15]. Furthermore, fecal microbiota transplantation (FMT) from young to aged mice has been shown to ameliorate aging-related phenotypes in the recipients [16]. Collectively, these findings suggest that modulation of the gut microbiota may represent a promising strategy for anti-aging interventions.

Among current anti-aging strategies, in addition to caloric restriction [17], spermidine [18], procyanidin C1 [19], and senolytic drug such as Dasatinib plus Quercetin [20], probiotics have emerged as a research focus owing to their ability to remodel gut microbiota. Accumulating evidence indicates that probiotics exert anti-aging effects in C. elegans and mouse models, as manifested by extended lifespan, ameliorated sarcopenia, and improved cognitive function [21–24]. These effects may be mediated through multiple mechanisms, including regulation of cellular senescence [25], suppression of the senescence-associated secretory phenotype (SASP) [25], enhancement of mitochondrial function [21,22], and promotion of autophagy [26]. However, there is still a lack of a precise strain screening system targeting the molecular mechanisms of aging.

Based on the premise that shifts in gut microbiota composition and function are critical features of aging, this article proposes an anti-aging intervention approach that uses probiotics or synthetic microbiota to reshape gut microbiota profiles. By integrating current evidence on how probiotics modulate key molecular hallmarks of aging, including mitochondrial dysfunction, cellular senescence, and autophagy, we put forward a precision development strategy for anti-aging probiotics. These insights provide a novel perspective for extending healthspan and promoting healthy aging.

2 Gut Microbiota and Aging

2.1 Gut microbiota alterations in aging

Age-related decline in physical function, polypharmacy, surgical interventions, reduced physical activity, and poor dietary quality are all associated with significant alterations in gut microbiota. These changes include reduced diversity, a decrease in saccharolytic bacteria, and an increase in proteolytic bacteria. Specifically, the relative abundances of short chain fatty acids (SCFAs) producers (e.g., Roseburia, F. prausnitzii, Coprococcus, Butyricimonas and Bifidobacterium) decline, while the relative abundance of opportunistic pathogens (e.g., Eggerthella, Desulfovibrio, Escherichia, disease-associated Clostridium and Enterobacteriaceae) increase [8,27]. Previous studies suggested that with an increased relative abundance of the Bacteroidetes leading to a reduced Firmicutes/Bacteroidetes (F/B) ratio. However, findings across studies are not entirely consistent regarding the direction of F/B ratio changes during aging—some studies report an increased F/B ratio in older adult populations, while others observe a decrease—suggesting that the F/B ratio may not be a universal aging biomarker and could be influenced by population-specific factors such as diet, geography, and health status. Nonetheless, the F/B ratio has been proposed as a potential biomarker of aging, although its robustness remains controversial across cohorts [28]. The dynamic changes of Bifidobacteria throughout the human life cycle are also considered an important indicator of intestinal aging trajectories. After birth, Bifidobacteria rapidly colonize the gut of the infant and become the most dominant bacteria in the intestines of healthy infants. During adolescence and adulthood, although the abundance of Bifidobacteria decreases compared to infancy, it remains relatively stable. In the elderly stage (particularly > 70 years old), its abundance often exhibits a sharp decline [29]. Bacterial families such as Clostridiaceae, Akkermansiaceae and Bifidobacteriaceae are colonized in the intestinal mucus layer and use this layer as a nutrient source [30]. However, the intestinal mucus layer becomes thinner and discontinuous with increasing age and might impact the growth and/or function of these bacterial families [6]. A decrease in the abundance of A.muciniphila with age has been observed in both mouse models and human populations. Galkin et al. [10] utilized cross-study datasets and deep learning to develop an accurate aging clock. When validated with external data, the model achieved a mean absolute error of 5.91 years, indicates that there are age-related changes in the intestinal flora during aging.

2.2 Gut microbiota actively drives the aging process

Age-related changes in the gut microbiota are associated with the progression of various aging-related diseases, including frailty, gastrointestinal disorders, metabolic syndrome, neurodegenerative diseases, and cardiovascular diseases [27]. The increase in opportunistic bacteria associated with pro-inflammatory immune response in older adults is linked to their increased inflammatory state, known as “inflammaging”. The research on FMT found that transplanting aged mouse microbiota into young mice led to immune dysregulation, characterized by a decreased proportion of regulatory T cells (Tregs), an increased proportion of pro-inflammatory Th17 cells, and significantly reduced levels of secretory immunoglobulin A (sIgA) in the gut [31]. This imbalanced immune state also weakened the host’s defense against intestinal pathogens. In another study, when germ-free young mice received the gut microbiota from older donors (either humans or mice), the recipient mice showed cognitive decline, hippocampal damage, and synaptic loss; while mice with the microbiota from young donors did not exhibit these phenotypes [16].

Age-associated alterations in the abundance of specific gut bacteria also impact the synthesis pathways of various metabolites. These bacteria-derived metabolic changes—characterized by decreased SCFAs, reduced bile acid (BA), polyamine, and tryptophan metabolism, as well asincreased lipopolysaccharides (LPS) and trimethylamine N-oxide (TMAO)—influence intestinal aging and correlate with age-related diseases. Polyamines are essential for cell development, proliferation, and tissue regeneration. They regulate enzymatic activity, bind and stabilize DNA and RNA, exhibit antioxidant properties, and are required for transcription. The level of spermidine, a polyamine, declines with age and is associated with the pathogenesis of age-related diseases [18]. Similarly, the microbial tryptophan metabolites indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) decline with age, and these metabolites activate the aryl hydrocarbon receptor (AHR) pathway, thereby suppressing excessive synaptic phagocytosis mediated by senescent microglia [11]. The age-associated microbial production of N6-carboxymethyllysine drives ROS and mitochondrial damage in microglia, accelerating cognitive decline [32]. These findings suggest that age-related alterations in the gut microbiota and metabolites may contribute to the acceleration of systemic aging.

2.3 Gut microbiota modulation as a promising strategy to counteract aging

Epidemiological studies with focus on global longevity populations might provide unique insights into the gut microbiota and healthy aging. Large-scale cohort studies have revealed that the gut microbiota of centenarians exhibits “youthful” and “highly stable” ecological characteristics, higher species evenness and reduced inter-individual variation [15]. At the taxonomic and ecological level, multiple cross-cohort studies indicate that extreme longevity is characterized not merely by the presence of specific taxa, but by the preservation of keystone species that maintain overarching ecological resilience. For instance, Akkermansia, Odoribacter, Bifidobacterium and Christensenellaceae have been recognized as advantageous bacterial groups in Italian longevity populations [33]. Methanogens and Bifidobacterium are enriched in centenarians of Sardinia [34]. A comprehensive analysis across eight longevity cohorts verified that species such as Methanobrevibacter smithii, Hungatella hathewayi and Desulfovibrio fairfieldensis are consistently more abundant and positively correlated with longevity [35]. At the metabolic level, centenarian gut microbiomes exert effects through conserved longevity-associated functional modules with coordinated metabolic pathways, rather than individual metabolites. These modules collectively maintain anti-inflammatory and intestinal barrier-protective capacities. Isoallolithocholic acid (isoalloLCA), a secondary bile acid modified by gut bacteria, is highly abundant in long-lived populations. As a key module component of such modules, it indicates a potential mechanistic correlation between gut microbiota and longevity [36]. In addition, tryptophan-indole metabolites [33] and the pinane thromboxane A2 (PTA2) [37] were enriched in centenarians and have been shown to improve cognitive function by inhibiting inflammatory and regulating the neuro-immune pathways. Collectively, these findings indicate that the gut microbiota of centenarians possesses distinct compositional and metabolic features, suggesting that the gut microbiota may play an important role in regulating healthy aging.

Multiple cross-age FMT studies have provided compelling evidence that the gut microbiota may actively regulate the aging process. Transplantation of young donor microbiota into aged mice significantly restored the expression of intestinal tight junction proteins (ZO-1 and Occludin), reduces intestinal permeability [38], suppresses the TLR4-NF-κB inflammatory signaling pathway, and downregulates pro-inflammatory cytokines such as TNF-α and IL-6, thereby effectively alleviating inflammaging [31]. In addition, young-mice gut microbiota can restore the senescent intestinal stem cells (ISCs) markers Lgr5 and Ascl2 through pathway such as Wnt [31]. At the phenotype level, young-FMT enhances grip strength, improves intestinal barrier function, ameliorates aging-related cognitive decline [16] and has been reported to extend lifespan in mice [39]. These findings indicate that healthy aging is contingent upon the maintenance of the ecological network, a principle that underpins the development of next-generation synthetic consortia (SynComs) discussed later in this review (Fig. 1).

3 Probiotics in Lifespan Extension and Healthspan Improvement

The impact of probiotics on aging has garnered considerable interest, given their established role as regulators of the gut microbiota. Evidence from different model systems is summarized below in order of increasing translational relevance (Table 1). Invertebrate organisms such as the fruit fly and the nematode, with a relatively short lifespan, are broadly used as models in anti-aging studies. Lee et al. [40] reported that L. reuteri prolonged the lifespan of D. melanogaster by downregulating the insulin/IGF-1 signaling pathway. Similar lifespan-extending effects have been observed for several Bifidobacterium species, mainly through antioxidant mechanisms [24,41]. C. elegans are widely used as a model for screening anti-aging components based on their low cost, relatively short lifespan and simple breeding [42]. Some studies have shown that probiotics and their metabolites (e.g., PLA) could extend worm lifespan by 6%–30% [22,43]. However, this extension effect is influenced by several factors, such as the type of worm strain, whether infected by S. aureus or H₂O₂ induced accelerated aging, probiotics intervention (live bacteria, inactive bacteria, or metabolites) and intervention dose. These reports also show that probiotics could improve the pharyngeal pumping rate, enhance average speed, reduce the accumulation of aging markers such as lipofuscin, and improve the overall quality of life in aging worms [44–46].

In mammalian models, Shi et al. [47] founded that the survival rate of mice increased from 60% to 85% following intervention with L. plantarum LLY-606 between 14 and 19 months of age. Another study demonstrated that Probio-M8 supplementation from 19 to 20 months markedly enhanced muscle strength in mice [48]. However, neither of two studies reported extending of lifespan. Given the high costs and long intervention periods required for natural aging mouse models, D-galactose (D-gal), which induces oxidative cellular damage, is widely used to induce accelerated aging models. Multiple studies have shown that probiotics intervention could enhance intestinal barrier function while reducing inflammatory responses and oxidative stress in D-gal-induced aging mice [49,50]. The senescence-accelerated mouse prone 8 (SAMP8) model is used for studying aging-related cognitive impairments (e.g., Alzheimer’s disease, AD). Studies show that probiotic intervention improved the impaired spatial memory, motor dysfunction, and increased exploratory behavior in SAMP8 mice [51,52].

The beneficial effects of probiotics on aging-related symptoms have been further observed in clinical studies. These influences are mainly featured by a reduction in inflammatory responses in older adults, lowered levels of typical SASP factors such as IL-6, IL-1 and TNF-α [53,54]. In terms of metabolic disease, studies have shown that probiotics lower fasting blood glucose (FG) and glycated hemoglobin (HbA1c) levels in patients with type 2 diabetes, and decrease postprandial total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels [55]. Moreover, multiple clinical studies have point out that probiotics are able to improve cognitive function in the older adults [53,56]. Probiotics also have a significant improvement effect on the intestinal function of the older adults, such as elevating gastric motility and nutrition absorption [57]. Nevertheless, most clinical assessments of probiotics only focus on short-term changes in microbial composition, without taking lifespan and healthspan as direct indicators for evaluation.

4 The Effects of Probiotics on the Hallmarks of Aging

Over the past few decades, the scientific community has established that aging is not merely a random phenomenon driven by increasing entropy, but rather a systemic process coordinated by a series of evolutionarily highly conserved genomic, epigenetic, biochemical, and molecular signaling pathways. In 2025, Kroemer et al. [58] expanded the core biological hallmarks of aging to 14, encompassing genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, disabled macroautophagy, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, chronic inflammation, intestinal microbiota dysbiosis, extracellular matrix (ECM) changes and psychosocial isolation.

Our overview of probiotic anti-aging research focuses on hallmarks including mitochondrial dysfunction, cellular senescence, stem cell exhaustion, genomic instability, telomere attrition and intestinal microbiota dysbiosis. Nevertheless, research on the two newly added aging hallmarks—extracellular matrix (ECM) alterations and psychosocial isolation—remains scarce. Notably, many of these mechanisms converge on a limited number of core regulatory pathways, including NF-κB signaling, mTOR signaling, and mitochondrial quality control systems (Fig. 2).

4.1 Probiotics ameliorate mitochondrial dysfunction

4.1.1 Mechanisms of aging-induced mitochondrial dysfunction

Aging-induced mitochondrial dysfunction is driven by a combination of oxidative stress, mitochondrial DNA (mtDNA) damage, and impaired mitochondrial quality control (MQC) [59]. In aged mice, mitochondrial respiratory chain (MRC) assembly declines, with complex Ⅳ and supercomplexes containing complex Ⅰ/Ⅲ or Ⅲ/Ⅳ showing the most pronounced reductions [60].

The accumulation of mtDNA mutations, which have been shown to alter the oxidative phosphorylation machinery, leads to mitochondrial dysfunction. Studies have demonstrated that these mutations accumulate with age, contributing to a decline in mitochondrial function and increased production of ROS [61]. Accumulation of ROS forms a vicious cycle, exacerbating mitochondrial damage and resulting in reduced ATP content, decreased OCR, and the release of mitochondria-derived damage-associated molecular patterns (DAMPs), further exacerbating aging-related pathologies [62,63].

The accumulation of ROS cannot be avoided, making MQC vital for clearing damaged components and preserving mitochondrial function and stability [63]. Among related adaptive mechanisms, PGC-1α-mediated mitochondrial biogenesis, PINK1/Parkin-mediated mitochondrial mitophagy, OPA1/DRP1-mediated mitochondrial fusion and fission dynamics, the cGAS-STING axis, and the HIF-1α/mTOR metabolic pathway constitute the core mechanisms governing MQC systems. Therefore, focusing on MQC therapeutically is vital, and exploring its mechanisms could lead to the discovery of new targets to increase healthspan.

4.1.2 Efficacy of probiotics targeting mitochondrial dysfunction

Clinical trials have demonstrated the efficacy of probiotics in improving mitochondrial function in aging-related diseases. In a randomized controlled trial (RCT) of 65 sulfur mustard-exposed patients, probiotic supplementation (7 strains of lactic acid bacteria) improved systemic inflammation mitochondrial respiration in peripheral blood mononuclear cells [64]. In a trial of 30 overweight adults, L. rhamnosus HN001 improved mitochondrial oxidative capacity in skeletal muscle [65]. These trials provide evidence that probiotics can target mitochondrial dysfunction in diverse aging-related conditions.

4.1.3 Regulatory mechanisms of probiotics on mitochondrial dysfunction

Research increasingly supports the role of probiotics in boosting mitochondrial function across various body systems, including the gut, brain, liver, and immune cells. Gruber et al. [66] highlighted gut bacteria’s influence on mitochondrial dynamics, while Zhu et al. [67] demonstrated how microbial metabolites affect mitochondrial respiration and intestinal stem cell fate, underscoring the gut microbiota’s intricate relationship with mitochondrial function. Probiotics also show promise in enhancing brain mitochondrial function, as Qiao et al. [68] noted that microbial metabolites can cross the blood-brain barrier and impact neuronal and glial mitochondrial processes. In the liver, probiotics modulate energy metabolism and immune reconstitution, further indicating their potential to enhance mitochondrial function [69]. Additionally, in obese-insulin resistant rats, L. paracasei improved hippocampal mitochondrial function by reducing oxidative stress and microglial activation. Specifically, the intervention increased mitochondrial complex I activity by 35% and reduced ROS levels by 29% in the hippocampus [70]. L. rhamnosus intervention improved the muscle mitochondria density, ATP content, NAD+/NADH, mitochondrial dynamics in aged mice [71]. Finally, in immune cells, probiotics stimulated mitochondrial respiration of CD4⁺ T cells by increasing fatty acid oxidation and amino acid oxidation [72].

Probiotics influence mitochondrial function by modulating cellular redox balance and MQC, particularly through PGC-1α-mediated mitochondrial biogenesis. Zhang et al. [73] demonstrated that B. adolescentis improved muscle health in sarcopenic individuals by increasing NAD+ levels and activating the SIRT1/PGC-1α pathway. Similarly, L. rhamnosus enhanced mitochondrial biogenesis in sarcopenic mice by upregulating PGC-1α [71]. Additionally, in SAMP8 mice, L. delbrueckii, Streptococcus thermophilus and B. longum also elevated PGC-1α levels [21] Beyond traditional probiotics, other gut microbes like Bacillus subtilis and A. muciniphila have been shown to remodel mitochondrial function via the PGC-1α pathway, affecting various tissues [74].

Another key mechanism is the regulation of Nuclear factor erythroid-2-related factor (Nrf) signaling pathway, which is critical for the cellular ROS defense system. For example, Bacillus amyloliquefaciens SC06 enhanced intestinal epithelial barrier function and immune regulation by activating the Nrf2/Keap1 signaling pathway [75]. Similarly, in sarcopenia, a L. rhamnosus boosts mitochondrial dynamics and biogenesis by increasing mitochondrial fusion and fission proteins and NRF1-related protein [71].

4.1.4 Secretory metabolites of probiotics that influence mitochondrial dysfunction

Microbial metabolites may be direct regulators through which probiotics influence mitochondrial function. B.adolescentis-derived nicotinic acid improves host skeletal muscle mitochondrial function to ameliorate sarcopenia [73]. Indole-3-propionic acid (IPA), a tryptophan-utilizing bacteria metabolite, stimulates mitochondrial respiration of CD4⁺ T cells by increasing fatty acid and amino acid oxidation to confer protection against intestinal inflammation [72]. 3-hydroxypropionaldehyde present in L. reuteri membrane vesicles decreased the mitochondrial permeability of macrophages and stabilized the mitochondrial membrane potential, thereby promoting the conversion of macrophages to an anti-inflammatory phenotype [76]. Phenyllactic acid (PLA), a metabolite of L. plantarum, improves defective stress resistance via SKN-1/ATFS-1 activation. It elevates mitochondrial oxygen consumption and consequently prolongs the healthspan of C. elegans [22]. Urolithin A is a microbial metabolite generated via the gut microbiota mediated biotransformation of dietary ellagic acid and ellagitannins. Zhang et al. [77] indicated that L. plantarum enhances urolithin A production in fermented pomegranate juice and consequently improves mitochondrial function.

Meanwhile, SCFAs are known to modulate immune function, which is crucial in delaying mitochondrial dysfunction. SCFAs have been shown to regulate the differentiation and function of various immune cells, including T cells and B cells, by acting on G-protein-coupled receptors and inhibiting histone deacetylases (HDACs) [22]. HDACs couple mitochondria to drive IL-1β-dependent inflammation by configuring the fatty acid oxidation (FAO) pathway [78]. This regulation helps maintain immune homeostasis and prevents chronic inflammation, a key driver of mitochondrial dysfunction.

4.2 Probiotic delays cellular senescence

4.2.1 Mechanisms underlying cellular senescence

Cellular senescence is defined as the permanent cell cycle arrest occurring in proliferating cells in response to various stress stimuli, representing one of the hallmarks of aging [4]. Senescent cells (SC) exhibit a series of characteristic changes: (i) an abnormally enlarged and flattened morphology of the cells, with a significant increase in the ratio of cytoplasm to nucleus; (ii) increased activity of lysosomal senescence-associated β-galactosidase (SA-β-gal) and accumulation of lipofuscin, both widely recognized as markers of SC; (iii) activation of anti-apoptotic pathways (e.g., antiapoptotic proteins of the Bcl-2 family), which confer the cell’s resistance to programmed cell death; and (iv) secretion of the SASP, including cytokines, chemokines, growth factors, proteases, and extracellular vesicles [79].

Cellular senescence is driven by multiple mechanisms, including telomere shortening, DNA damage, oxidative stress, and epigenetic dysregulation, and is regulated by key signaling pathways such as p53/p21 and p16^INK4A/pRb [79]. Compared with young and healthy tissues, the number of p16^INK4a-marked senescent cells in aged tissues increases, while eliminating p16^INK4a-expressing SCs in mice has been shown to ameliorate age-related tissue dysfunction and extend lifespan [80,81]. In fact, studies have shown that the levels of IL-6, IL-1α, and TNF-α can serve as markers and predictors of aging [82].

Cellular senescence occurs widely in various cell types such as immune cells, fibroblasts, neurons, and osteoblasts, and is associated with pathological changes such as immune aging, skin aging, neurodegenerative diseases and osteoporosis [83]. For instance, with age, T cell receptor diversity decreases, and the number of CD8⁺ T cells significantly declines, the ratio of Th1/Th2 cells becomes imbalanced [84]. Currently, delaying the cellular aging process, targeted elimination of SCs, and inhibition of SASP mediator secretion (e.g.NF-κB, the cGAS-STING pathway, and the PI3K/Akt/mTOR pathway) have emerged as key strategies in anti-aging research.

4.2.2 Efficacy of probiotics on delaying cellular senescence and enhancing lifespan

The potential of probiotics to delay cellular senescence has garnered significant interest in recent years, particularly in the context of their multifaceted health benefits. A clinical study found that in individuals over 75, taking a mixed probiotic for a month led to a significant rise in naive T cells and Treg cells in the blood, effectively diminishing immune senescence [85]. B. lactis HN019 could increase the proportions of helper (CD4⁺) and activated (CD25⁺) T lymphocytes and natural killer cells (NK) in the peripheral blood [86]. Moreover, the systematic review and meta-analysis conducted on short-term probiotic supplementation in healthy elderly subjects provides further evidence of the role of probiotics in enhancing cellular immune function. The study found that probiotics supplementation increased polymorphonuclear phagocytic capacity and NK cell tumoricidal activity, suggesting that probiotics can slow or reverse age-related declines in immune function [87].

4.2.3 Regulatory mechanisms of probiotics on delaying cellular senescence

One of the key mechanisms by which probiotics may exert their anti-senescence effects is through the modulation of PI3K/Akt/mTOR pathway, which modulate cell growth and survival. The study on the cell-free culture supernatant of L. fermentum demonstrated that secretory metabolites from this probiotic could protect against H₂O₂-induced premature senescence in murine preadipocytes by suppressing the ROS-PI3K/Akt/mTOR axis [25]. In typical animal models of neurodegenerative diseases, such as Parkinson’s and Alzheimer’s, the neuroprotective effects of probiotics are closely related to the regulation of the Akt/mTOR pathway by the strains or their metabolites [25,88]. In addition, in numerous inflammatory animal models, probiotics such as Lactobacillus and Bifidobacterium were proved to downregulate Akt and mTOR expression, thereby alleviating rheumatoid arthritis and intestinal inflammation [89,90].

The cGAS-STING pathway, a pivotal mechanism by which senescent cells sense ectopic cytosolic DNA and trigger secondary inflammatory responses, is another important target through which probiotics delay cellular senescence. L. rhamnosus GG intervention improved intestinal structure, reduced jejunal DNA damage, and inhibited the cGAS/STING pathway, thereby alleviating intestinal injury [91]. The cGAS/STING signaling pathway is essential for immune regulation of the gut microbiota, particularly in the suppression of antigen presentation and the inhibition of effector T cell activities [92]. As the scientific community continues to delve into the study of microbial metabolism, it has been found that strains with high SCFA production exhibit strong regulatory effects on cGAS-STING expression. SCFAs can reduce cGAS-STING expression, which can attenuate neuronal apoptosis [91]. Meanwhile, during systemic infection, SCFA-producing bacteria can activate macrophages to protect against enteric viral infections through the cGAS-STING pathway [93].

The transcription factor NF-κB functions as the principal regulator of the pro-inflammatory component, influencing the paracrine effects of senescent cells on the tissue microenvironment. Numerous studies have demonstrated that probiotics can inhibit pro-inflammatory factors production via the NF-κB pathway. In aged SAMP8 mice, a 12-week probiotic intervention not only ameliorated cognitive dysfunction but also significantly suppressed the TLR4/NF-κB signaling pathway [94]. B. longum mitigated cognitive decline in 5XFAD transgenic and aged mice by modulating microbiota-derived LPS-mediated NF-κB activation [95]. B. pseudocatenulatum NCU-08 inhibited neuro-senescence induced by the TLR4/NF-κB pathway and preserved blood-brain barrier integrity by activating the AMPK/Sirt1 pathway [96]. Collectively, targeting NF-κB, cGAS-STING, and PI3K/Akt/mTOR pathways has emerged as a key strategy in probiotics anti-aging research for inhibiting SASP.

4.2.4 Secretory metabolites of probiotics that influence cellular senescence

Polyamine was observed to influence a wide range of cellular processes, including proliferation, differentiation, autophagy and senescence. It also exerted antioxidant effects on various cellular models [97]. The anti-aging effects of spermine and spermidine have also been reported in senescence-accelerated mice. The phenomenon was ascribed to polyamines’ antioxidant and cellular senescence mediating properties [98]. B. lactis LKM512 increases intestinal polyamine production, suppresses colonic senescence, and extends lifespan in mice [99].

Besides polyamines, tryptophan-microbial metabolites and SCFAs are major messengers of the gut-x axis. A recent study proved, IPA as a promising microbiota derived metabolite, could improve musculoskeletal health and promote Drosophila melanogaster longevity, highlighting its potential as a therapeutic intervention for age-related decline in function [100]. Another indole derivative, indole-3-acetic acid (IAA), inhibited pulmonary epithelial cell fibrosis in mice by suppressing the PI3K/AKT/mTOR pathway [101]. Indole derivatives play an active role not only in pulmonary fibrosis but also in the prevention and treatment of renal fibrosis, hepatic fibrosis, and cardiac fibrosis [102]. In addition, the immunoregulatory functions of IPA and IAA deserve special attention, especially in regulating the aging and differentiation of immune cells [103,104]. As an important receptor for various indole derivatives, the aryl hydrocarbon receptor (AhR) plays a central role in the process by which probiotic metabolites alleviate cellular aging, thereby effectively mitigating AD and various inflammatory aging [105]. In addition, the expression of AhR and the induction of genes dependent on AhR in immune cells are regulated by NF-κB [104], demonstrating the interaction between AhR and SASP production [106].

SCFAs exert their effects through various mechanisms. Butyrate reduces production of SASP of senescent T cells, lowered mitochondrial ROS accumulation, and downregulated mTOR activation, which negatively regulates the NF-κB pathway [107]. Increased butyrate levels reduced cGAS/STING expression in nerve cells and subsequently decreased neuronal apoptosis by downregulating Bax protein expression in epilepsy models [108]. These results indicate that probiotics and their metabolites can effectively reduce the secretion of SASP, but whether they can eliminate SCs or delay the process of cellular senescence remains limited in research.

4.3 Targeting autophagy via probiotic intervention

4.3.1 Mechanisms of aging-induced autophagy disorders

Autophagy is a highly conserved cellular process that plays a crucial role in maintaining cellular homeostasis by degrading and recycling damaged organelles, misfolded proteins, and invading pathogens. This catabolic mechanism is essential for cellular survival under stress conditions and is involved in aging physiological and pathological processes [109]. Autophagic activity declines with age and involves complex regulation of multiple signaling pathways, including: (i) impaired autophagic flux, characterized by reduced autophagosome formation and decreased substrate degradation efficiency, as evidenced by a decreased LC3-Ⅱ/LC3-Ⅰ ratio, lower levels of Atg5-Atg12 and Beclin-1, and accumulation of p62 protein; (ii) dysregulated signaling pathways, marked by excessive mTOR activation that inhibits autophagy initiation; and (iii) declined mitophagy, manifested as a diminished capacity to clear damaged mitochondria, with reduced expression of key proteins such as PINK1 and Parkin [110].

Aging-related autophagy disorders are highly prevalent, with estimates varying by tissue and disease. In AD patients, 60%–80% exhibit impaired autophagy, with reduced LC3-Ⅱ levels and increased p62 accumulation in the hippocampus [111,112]. Sarcopenia, a common aging-related muscle disorder, is linked to autophagy dysregulation: 40% of adults over 80 years have sarcopenia, with muscle-specific autophagy markers (Atg7, LC3) reduced by 30%–40% [113]. Chronic kidney disease (CKD) is another aging-related condition associated with autophagy impairment: 30% of adults over 65 years have CKD, with renal tubular cells exhibiting reduced autophagy and increased oxidative stress [114]. The above data indicate that although autophagy widely affects different organs in the human body, the LC3-Ⅱ/LC3-Ⅰ ratio, p62, Atgs, and Beclin-1 are widely used as important markers of autophagy.

The intricate relationship between autophagy and various signaling pathways, including the mTOR, AMPK, and MAPK pathways, plays a crucial role in cellular homeostasis, disease progression, and therapeutic interventions [115]. The mTOR signaling pathway is a central regulator of cell growth and metabolism, often acting as a negative regulator of autophagy. In contrast, the AMPK pathway, which is activated under low energy conditions, promotes autophagy as a survival mechanism [116]. The MAPK pathway, known for its role in cell proliferation and stress response, also intersects with autophagic processes, adding another layer of complexity to the regulation of autophagy [117]. In addition, transcription factor EB (TFEB) is a key transcription factor governing autophagy-lysosome pathway. The abnormal expression and dysfunction of TFEB are closely associated with the occurrence and development of many human diseases [118]. Notably, the effects of probiotics on autophagy appear to be context-dependent, varying according to tissue type, disease state, and microbial composition.

4.3.2 Efficacy of probiotics on autophagy disorders

The therapeutic potential of probiotics in addressing diseases related to autophagy dysfunction has garnered significant attention in recent years. In a RCT of B. bifidum CCFM16 in 103 chronic constipation patients, probiotic supplementation increased fecal butyrate levels by 40% and reduced p62 levels by 25%, improving the diagnostic accuracy of autophagy biomarkers [119]. Another randomized controlled trial of Lactobacillus rhamnosus GG in 209 nursing home residents found a 30% reduction in laboratory-confirmed respiratory viral infections [hazard ratio (HR) = 0.65, 95% confidence interval (CI) = 0.32–1.31)] [120]. These trials provide clinical evidence that probiotics modulate autophagy to improve aging-related outcomes.

4.3.3 Regulatory mechanisms of probiotics on autophagy disorders

One of the key mechanisms by which probiotics may exert autophagy induction effects is through the modulation of PI3K/Akt/mTOR pathway. Using mouse inflammation models, L. salivarius was proved to prevent pharyngeal inflammatory response by regulating TLR/PI3K/Akt/mTOR signaling pathway-related autophagy. Similarly, L. reuteri reduced alcoholic steatohepatitis by activating autophagy via the Akt-MTOR signaling pathway [121,122]. L. rhamnosus can ameliorate intestine inflammation by elevating the expression of p-mTOR and increasing the expression of autophagic LC3-Ⅱ and Beclin-1 [123].

In addition to the mTOR pathway, AMPK is also a key regulator in mammals for sensing nutrients/energy and subsequently initiating autophagy. Motevaseli’s [124] research demonstrated that the expression of ATG14, BECN1 and alpha 2 catalytic subunit of AMPK (PRKAA2) decreased after treatment with Lactobacillus culture supernatant in HeLa cell Line.

MAPKs, such as JNK, p38, and ERK1/2, are also known to significantly influence autophagy by regulating the expression of various Atg genes. Multiple strains of probiotics can also promote the occurrence of autophagy in the body by regulating the MAPK pathway. B. breve 15700 prevents intestinal epithelial cell damage and death by inducing autophagy through the MAPK pathway [125]. L. acidophilus NCFM induces autophagic cell death in colorectal cancer cells through ROS-mediated modulation of MTOR and MAPK/JNK signaling pathways [126]. In addition, the combination of probiotics and prebiotics can amplify this effect. Ren et al. [127] showed that co-feeding L. plantarum with galactooligosaccharide can promote the activation of the MAPK/NF-κB pathway, and then inhibit the apoptosis and autophagy pathways in mice with acute liver injury. In addition to the traditional lactic acid bacteria and Bifidobacteria, Bacillus has also been shown to have similar MAPK/autophagy regulatory effects [128].

4.3.4 Secretory metabolites of probiotics that improve autophagy

Polyamines are important gut microbial metabolites known to affect host physiology, yet the mechanisms behind their microbial production remain incompletely understood. Spermidine is considered a promising approach for anti-aging and the amelioration of age-related diseases [110]. In SAMP8 mice, spermidine and spermine maintained neuronal energy levels by improving autophagy and mitochondria function [129]. Hofer et al. [130] reviewed the mechanisms of spermidine-induced autophagy and geroprotection and concluded that spermidine emerges as a bona fide geroprotector that is vital for cellular and organismal function through a highly conserved pathway. Meanwhile, SCFAs produced by specific probiotics are key mediators of autophagy modulation. In a mouse model of colitis, a mixture of Lactobacillus and Bacillus increases colonic butyrate levels, which inhibits Salmonella-induced autophagy by downregulating ATG5 and Beclin-1 [131]. Butyrate treatment reduces the LC3-Ⅱ/LC3-Ⅰ ratio by 35% in Caco-2 cells, limiting cytosolic Salmonella replication [131]. Collectively, probiotics indirectly regulate autophagy through signaling pathways such as PI3K, mTOR, AKT and MAPK, while their metabolic products can directly activate the autophagy process. This is one of the ways probiotics exert beneficial effects on various cells and tissues.

4.4 Probiotic mitigates stem cell exhaustion

4.4.1 Mechanisms of aging-induced stem cell exhaustion

Stem cell exhaustion is characterized by reduced self-renewal, impaired differentiation, and increased senescence. In hematopoietic stem cells (HSCs) aging leads to a shift from quiescence to proliferation, resulting in telomere shortening and functional decline [132]. Oxidative stress and inflammation further exacerbate exhaustion by damaging stem cell DNA and altering niche signaling [133].

HSC aging is driven by both intrinsic factors, such as DNA damage and telomere shortening, and extrinsic factors, such as changes in the bone marrow niche and systemic inflammation. Another mechanism underlying stem cell exhaustion is the disruption of cell cycle regulation, as evidenced by the genetic inactivation of Cdk7, which leads to cell cycle arrest and premature aging due to adult stem cell depletion [132]. Inflammation and oxidative stress are additional factors that contribute to stem cell exhaustion. Age-related inflammation has been shown to trigger skeletal stem/progenitor cell dysfunction, while oxidative stress can induce senescence in mesenchymal stem cells (MSCs), leading to impaired tissue regeneration [134]. The interplay between these stressors and stem cell aging is complex, involving various signaling pathways such as the mTOR and Wnt/β-catenin pathways, which have been implicated in the aging of epidermal and mesenchymal stem cells [135]. These pathways can promote ROS production, further exacerbating oxidative damage and cellular senescence.

4.4.2 Efficacy of probiotics intervention in stem cell exhaustion

(1) Role of probiotics in stem cell niche maintenance

The stem cell niche, a specialized microenvironment that regulates stem cell self-renewal and differentiation, is vulnerable to aging-related dysregulation. Probiotics maintain niche integrity by modulating the gut microbiota and immune system. In the intestinal tract, L. reuteri D8 promotes the proliferation of intestinal stem cells (ISCs) by stimulating lamina propria lymphocytes (LPLs) to secrete IL-22, which activates the STAT3 pathway [136]. This leads to increased Lgr5⁺ ISCs and improved intestinal barrier function. In bone marrow, probiotics such as LGG rescue the proliferation and osteogenic differentiation of mandible-derived MSCs impaired by tenofovir disoproxil fumarate [137].

Probiotics also influence the HSC niche. L. plantarum IS-10506 increases IL-10 production in pyelonephritic rats, activating renal tubular stem cells and promoting regeneration [136]. In Drosophila, L. reuteri 22 modulates the Wnt/β-catenin pathway to maintain ISC proliferation [138]. These studies indicate that probiotics support stem cell niche function by regulating cytokine signaling, immune responses, and microbial metabolites.

(2) Effects of probiotics on stem cell proliferation and differentiation

Probiotics directly and indirectly enhance stem cell proliferation and differentiation. L. reuteri extracts activate the PI3K/AKT/β-catenin/TGFβ1 pathway in gingiva MSCs, increasing migration, osteogenic differentiation, and proliferation [139]. In chickens, L. reuteri 22 upregulates Lgr5 expression and activates Wnt/β-catenin signaling, promoting ISC proliferation and differentiation into goblet cells [138]. B. bifidum supernatant and cell mass increase the proliferation of rat bone MSCs in a dose-dependent manner [140].

In cancer therapy-induced mucositis, L. casei preserves intestinal stem cell function by reducing pro-inflammatory cytokines and restoring CD44⁺ stem cell expression [141]. Bacillus subtilis-fermented milk promotes ISC proliferation and mucosal barrier reconstruction in DSS-induced colitis [142]. These findings suggest that probiotics can enhance stem cell function in both physiological and pathological conditions.

4.4.3 Regulatory mechanisms of probiotics on stem cell exhaustion

Stem cell exhaustion is driven by pathways such as oxidative stress, inflammation, and epigenetic dysregulation. Probiotics modulate these pathways to prevent exhaustion. L. reuteri D8 inhibits the Wnt/β-catenin pathway hyperactivation induced by Salmonella typhimurium, preventing ISC overproliferation and exhaustion [143]. Similarly, the administration of lactic-acid-producing bacteria was shown to significantly enhance the expansion of ISCs, Paneth cells, and goblet cells in mice. This effect was mediated through the Wnt/β-catenin signaling pathway [144]. In HSCs, autophagy counteracts inflammation-driven glycolytic impairment, and probiotics may enhance autophagy to preserve HSC function [133]. In addition, the function and exhaustion of ISCs are largely influenced by other intestinal cells, such as Paneth cells. Probiotics, by influencing Paneth cell function, could indirectly affect ISC dynamics and delay the fixation of mutations, thereby preserving stem cell function over time [145].

4.4.4 Secretory metabolites of probiotics that delays stem cell exhaustion

Postbiotics, such as indole-3-aldehyde from L. reuteri D8, activate the AhR in LPLs, leading to IL-22 secretion and ISC proliferation [146]. This mechanism prevents ISC exhaustion by maintaining a balanced proliferative state. Additionally, probiotics restore the gut microbiota-metabolite axis, increasing SCFAs and polyamines that support stem cell function [147]. In addition, probiotics-derived lactate has been demonstrated to accelerate ISC-mediated epithelial development, highlighting the potential of probiotics to enhance stem cell proliferation and function through specific signaling pathways such as Wnt/β-catenin [144].

4.5 Other potential pathways of probiotics combating with aging

4.5.1 Telomere attrition

Telomeres are nucleoprotein complexes located at the ends of chromosomes, composed of repeated DNA and proteins [148]. Telomere attrition and dysfunction play a central role in aging process. Telomere length is regulated by multiple factors, including the telomerase enzyme, the shelterin complex, telomere-binding protein and DNA replication enzyme [148]. Replicative DNA polymerases are unable to complete the replication process of the telomere regions of eukaryotic DNA, and deficiencies in shelterins leading to telomere uncapping, resulting in the telomeres to undergo significant shortening. Telomerase is an active ribonucleoprotein that can extend telomeres to maintain their appropriate length. In multiple species, the rate of telomere attrition is able to predict lifespan [4]. In mice, shortened telomeres correlate with reduced lifespan [149]. As human meta-analyses indicate, shortened telomeres are strongly associated with an increased risk of mortality [150]. Conversely, genetically activating telomerase in mice reverses their premature aging phenotype [151].

A clinical trial showed that supplementation with SYNBIO^® probiotics (5 × 10⁹ CFU/day) 6-month significantly reduced leukocyte telomere length (LTL) attrition in the older adults and promoted healthy aging [152]. Animal studies indicated that probiotics (L. delbrueckii, Streptococcus thermophilus and B. longum) ameliorate aging-related cognitive impairments through alleviating telomere attrition in SAMP8 mice [21]. Chen et al. [24] demonstrated that B. adolescentis improved the age-related frailty index in Terc^−/− mice, a model of premature aging caused by progressive telomere shortening. The exact mechanism of probiotics reduced telomere attrition remains unclear, which may be related to their regulation of mitochondrial autophagy and the cell cycle senescence.

4.5.2 Genomic instability

Genomic instability is a key driver of aging. It refers to the continuous damage to DNA within cells caused by harmful factors from the environment and endogenous toxins (e.g., ROS). Previous studies have confirmed that DNA damage (DD) accumulates with age in both mouse models and human tissues, leading to multi-organ dysfunction and a shortened lifespan [153]. To overcome this situation, cells possess an efficient DNA damage repair (DDR) system, but its repair capacity declines with aging. Among them, DNA double-strand breaks (DSB) represent one of the most destructive types of DD and will lead to cell death if not properly repaired [154]. Studies on rodent aging process have shown that the intensity of sirtuin-regulated DSB repair correlates with longevity [154], while in naked mole rats, a cGAS mediated mechanism promotes DDR and delays aging [155]. DD is evaluated by multiple markers. The phosphorylated histone variant γH2AX—which forms aggregation foci at DSB sites—serves as a specific indicator of DSB. Additionally, the cellular stress response accompanying DD activates inflammatory pathways, upregulating factors such as IL-1α, IL-6, and TNF-α [153].

Studies have shown that age-related inflammation impairs DSB repair efficiency, and this inflammatory state is linked to alterations in the intestinal microbiota [156]. These findings suggest that reversing gut microbiota may improve genomic stability. This is supproted by recent studies, supplementation with specific probiotic reduces the number of γH2AX-positive neurons in the hippocampus of aged mice [157]. In another study, early-life colonization with LGG decreased markers of DSB (γH2AX) and inflammatory markers (IL-1α, IL-6, TNF) in the colon tissue, thereby reducing inflammatory aging [158], and B. infantis decreases DSB level and maintains genome stability in ulcerative colitis (UC) mice via regulating anaphase-promoting complex subunit 7 (APC7) [159]. Collectively, these findings suggest that intervention with probiotics may be an effective strategy for promoting genomic stability.

5 Phenotypic and Mechanistic Interventions by Next-Generation Probiotics Targeting Aging Hallmarks

Compared with traditional probiotics, NGPs exhibit distinct advantages, including higher intestinal abundance and superior colonization capacity, and effectively target multiple aging-related pathways. These include anti-inflammatory and restore intercellular communication (e.g., A. muciniphila), enhance mitochondrial function (e.g., P. goldsteinii), maintain genomic stability (e.g., engineered E. coli Nissle 1917), promote autophagy to preserve protein homeostasis (e.g., engineered S. boulardii), and restore microbial imbalance (e.g., GUT-108, VE303) (Table 2).

5.1 Akkermansia muciniphila: restoring mucosal barriers and blocking endotoxemia

During natural aging, the degradation of the intestinal mucus layer and the disruption of tight junctions lead to the cross-barrier translocation of bacterial components, particularly LPS. This metabolic endotoxemia serves as a primary driver of systemic low-grade inflammation, termed inflammaging. As an obligate mucin-degrading commensal, A. muciniphila effectively restores the senescent intestinal barrier. Through its outer membrane protein Amuc_1100, A. muciniphila directly interacts with host Toll-like receptor 2 (TLR2), upregulating the expression of tight junction proteins such as ZO-1 and Occludin to physically rebuild barrier integrity [160].

In natural aging models, long-term administration of A. muciniphila or Amuc_1100 not only significantly reduces plasma LPS burden and colonic transcription of TNF-α and IL-6 but also enhances synaptic plasticity and alleviates cognitive decline by improving peripheral L-arginine metabolism and nitric oxide (NO) homeostasis [161,162]. Furthermore, its secreted protein P9 binds to the ICAM-2 receptor on enteroendocrine L-cells, inducing endogenous GLP-1 secretion and providing a crucial neuroendocrine mechanism that links local barrier restoration to systemic energy homeostasis [163]. Mechanistically, this P9-induced GLP-1 secretion is dependent on calcium influx and CREB signaling. However, precise safety boundaries must be established. In specific host contexts, A. muciniphila may upregulate Glycoprotein 2 (GP2) expression in microfold cells, potentially facilitating opportunistic Salmonella infection. This finding underscores the highly context-dependent risk-benefit profile of microbial interventions [164].

5.2 Faecalibacterium prausnitzii and Christensenella minuta: short-chain fatty acids and core anti-inflammatory signaling

F. prausnitzii and C. minuta function as keystone species essential for maintaining intestinal ecological resilience and metabolic homeostasis. Beyond providing energetic substrates for colonocytes via butyrate production, F. prausnitzii secretes a 15-ku microbial anti-inflammatory molecule (MAM) that specifically abrogates NF-κB signaling activation in epithelial cells. In models of low-grade inflammation, MAM-mediated interventions significantly decrease intestinal permeability and systemic pro-inflammatory cytokine levels [165,166].

Additionally, F. prausnitzii effectively reduces colonic cytokines like IL-6 and IFN-γ, and decrease localized serotonin levels. They have also demonstrated efficacy in prediabetic models by lowering fasting blood glucose and improving glucose tolerance without triggering hypoglycemic side effects, proving their safety for metabolic regulation [167]. Similarly, C. minuta, a taxa highly enriched in centenarian cohorts, has been shown in vitro and in vivo to maintain transepithelial electrical resistance and inhibit IL-8 release by producing high levels of acetate and butyrate, counteracting epithelial inflammatory damage [168]. In germ-free colonization models, the introduction of a single C. minuta strain is sufficient to significantly enhance host voluntary physical activity and energy metabolic readouts, suggesting a causal role for this bacterium in age-related physical function [169].

5.3 Bacteroides fragilis and Parabacteroides goldsteinii: precision immune modulation and receptor antagonism

Targeting the immune network dysregulation characteristic of aging, specific NGPs offer precise therapeutic targets. It is critical to distinguish non-toxigenic B. fragilis from enterotoxigenic strains, as the latter produce toxins that disrupt tight junctions. Capsular polysaccharide A (PSA) expressed by non-toxigenic B. fragilis systemically induces IL-10 producing regulatory T cells (Tregs), effectively buffering hyperactive innate immune infiltration and cytokine release in tissues [170]. Beyond local gut effects, the purified PSA has been shown to prevent fatal viral encephalitis by orchestrating systemic immune responses, highlighting its broad applicability.

An atypical LPS derived from P. goldsteinii exhibits properties of a natural TLR4 antagonist. In models of chronic inflammation-induced tissue degeneration, this antagonistic LPS blocks the input cascade of pro-inflammatory signals, accompanied by the restoration of host mitochondrial function and amino acid metabolism [171]. This mechanism of directly modulating host receptors via microbial components provides a targeted approach to intervene in the chronic TLR4-LPS activation that typifies aging. Despite these promising findings, safety, host specificity, and long-term colonization remain major challenges for the clinical translation of next-generation probiotics.

6 Evolution of Microbiome-Targeted Therapeutics: From Molecules to Ecosystems

The widespread colonization resistance and missing functional networks within the senescent gut microenvironment severely constrain the clinical translation of single native probiotics. As a result, microbiome-targeted anti-aging interventions are transitioning toward quantifiable and programmable platforms, including ecological reconstruction technologies (Fig. 3).

6.1 Postbiotics as independent signaling agents

Recognizing the harsh survival pressures and potential translocation risks faced by live bacteria in elderly hosts, postbiotics decouple therapeutic efficacy from colonization dependencies by utilizing inactivated cells or cell-free products. For instance, without relying on intestinal engraftment, pasteurized A. muciniphila has improved insulin sensitivity in overweight cohorts. In a subsequent study, it demonstrated the capacity to enhance peak extensor torque and raise follistatin levels, which is a myostatin antagonist, in older adults [172,173]. Likewise, extracts from F. prausnitzii exhibit steady-state glucose-lowering effects in animal models without inducing hypoglycemia [167], indicating that precision enrichment of microbial effector molecules can effectively circumvent the limitations of live microbial niche competition.

Extracellular vesicles (EVs) and outer membrane vesicles represent another sophisticated postbiotic modality, capable of packaging bacterial signals across host barriers. A. muciniphila-derived EVs significantly reduce LPS-induced permeability and upregulate occludin expression in an AMPK-dependent manner [174]. However, the systemic mobility of EVs introduces distinct safety considerations. For example, EVs from the aging-enriched Paenalcaligenes hominis can access the hippocampus via vagus nerve-mediated pathways, inducing cognitive impairment. This finding highlights the necessity for rigorous composition and immunogenicity profiling for vesicle-based therapeutics [175].

6.2 Engineered live biotherapeutics for programmable regulation

Chassis cells (e.g., Escherichia coli Nissle 1917, EcN) can be designed to sense and modulate the senescent microenvironment. To combat oxidative stress in the aging gut, EcN engineered to stably express SOD and CAT, coupled with specific nanocoatings, clears local ROS and promotes the repair of apoptotic epithelial cells [162,176]. Alternative strategies involve engineering L. lactis to continuously synthesize intracellular ROS buffers like lycopene, which markedly enhances epithelial survival against oxidative challenges [177]. To improve mucosal retention, EcN has been programmed to display curli-TFF3 matrices, forming a localized repairing patch that accelerates intestinal stem cell proliferation and mitigates radiation-induced enteritis [176].

Regarding the senescence-associated secretory phenotype, genetic circuits combining inflammatory sensors (e.g., NO) with the secretion of anti-TNF-α nanobodies achieve precise immune neutralization exclusively activated within inflammatory microenvironments [178]. In addition, engineered microbes have been reprogrammed as in situ generators of longevity molecules. For instance, engineered Saccharomyces boulardii continuously secretes spermidine in the gut lumen, alleviating age-related cognitive decline in model organisms [179]. Furthermore, engineering EcN to produce the ketone body (R)-3-hydroxybutyrate not only directly supplies host energetic needs but also induces profound ecological remodeling, expanding endogenous Akkermansia populations to over 30% of the gut community [180]. Taken together, engineered biotherapeutics are promising future tools to decelerate aging in a healthy manner.

6.3 Synthetic microbial consortia for reconstructing longevity metabolic networks

In contrast to single-strain engineering, an alternative approach uses rationally designed consortia of multiple native or engineered strains, known as Synthetic Microbial Consortia (SynComs). To address complex metabolic aging, these consortia achieve functional emergence that overcomes colonization resistance through modular integration. The GUT-108 consortium, designed based on flux balance analysis, includes carbohydrate degraders, intermediate bridging taxa, and effector strains. Through cross-feeding and functional redundancy, this consortium achieves robust engraftment in inflammatory environments. It restores the synthesis pathways of SCFAs, secondary BAs (DCA/LCA), and tryptophan-indole derivatives (IAA/IPA), activating AhR and Treg cell-mediated mucosal immune homeostasis [181]. The efficacy of SynComs also largely depends on niche occupation and nutrient competition. By constructing microbial consortia that efficiently consume key carbon sources such as gluconate, SynComs can competitively exclude opportunistic pathobionts including Enterobacteriaceae in mouse models. This approach avoids the off-target effects commonly seen with broad-spectrum antibiotics [182].

A classic demonstration of this mechanistic cooperation is a defined four-strain consortium in mice where upstream members produce β-lactamase to degrade localized ampicillin, creating a detoxified microenvironment that permits the subsequent engraftment of effector strains like Blautia producta to clear vancomycin-resistant Enterococcus [183]. Moreover, dropout murine experiments within defined consortia like Mix7 demonstrate that key foundational strains, despite being indispensable for restoring ecological barrier effects, fail to provide protection when administered in isolation [184]. In clinical translation, the defined consortium VE303 has proven that the synergistic colonization intensity of multiple strains is associated with the restoration of secondary BAs metabolic profiles, offering a practical framework for shifting from empirical supplementation to controllable community interventions [185].

7 Translational Challenges and Precision Anti-Aging Horizons

The translation of probiotics and their derivatives from mechanistic research to geriatric clinics involves significant manufacturing, regulatory, and safety hurdles. Overcoming these challenges requires rigorous clinical evaluation standards.

7.1 Formulation bottlenecks and safety imperatives in vulnerable populations

The extremely narrow oxygen tolerance window of strict anaerobic NGPs mandates closed-loop control throughout chemistry, manufacturing, and controls processes. Dehydration stress during lyophilization frequently causes precipitous drops in viable cell titers, requiring complex cryoprotectants as well as oxygen-scavenging or colon-targeted delivery strategies [186]. Regulatory hurdles are equally stringent. NGPs lacking a history of safe use face the European Food Safety Authority’s (EFSA) Novel Food framework, and often undergo Qualified Presumption of Safety (QPS) evaluations. Therapeutic applications in the US must adhere to the FDA’s rigorous guidelines for Live Biotherapeutic Products, including meticulous strain tracing, contamination control, and potency assays.

Most importantly, the safety of live microbial products, especially the risks of microbial translocation and invasive infections, must be rigorously assessed in elderly patients with impaired mucosal barrier function, immunosenescence or indwelling central venous catheters. Specifically, patients carrying central venous catheters are at increased risks associated with probiotic administration. They are highly vulnerable to catheter hub contamination by aerosolized spores when probiotic capsules are opened at the bedside, as well as aggressive colonization of catheter surfaces by translocated microbes, which leads to the formation of persistent biofilms. Opportunistic fungemia caused by probiotic yeast like Saccharomyces boulardii has been increasingly documented in hospitalized elderly cohorts, yielding quantifiable incidence rates in intensive care settings [187]. Genomic epidemiological evidence confirms that Lactobacillus bacteremia in ICU patients can trace directly to clonal transmission from probiotic capsules, exhibiting adaptive resistance mutations in vivo [188]. The risk of horizontal gene transfer concerning antimicrobial resistance or virulence genes necessitates whole-genome sequencing quality controls for all constituent strains. Thus, postbiotic pathways relying on inactivated cell components or effector molecules present a favorable risk-benefit ratio for extremely frail aging sub-populations.

7.2 Multi-omics stratification and subtractive interventions

Because of the colonization resistance driven by elderly population heterogeneity, future microbiome anti-aging strategies will heavily rely on AI-driven multi-omics predictive models, providing tailored bacterial combinations for individuals according to their specific gut microbiota profiles. Using baseline metagenomics, metabolomics, and serum cytokine profiles, researchers can prospectively identify responder sub-populations with specific ecological niche vacancies or functional metabolic potential [185]. Such stratification recognizes that colonization success is dictated by ecological resource vacancies, such as a deficit in specific carbohydrate-utilization genes within the resident microbiome [189]. In parallel, targeting characteristic pathobionts that drive inflammation, subtractive therapies using precision bacteriophages or in situ gene-editing technologies enable selective decolonization or the disarming of pro-inflammatory virulence genes, avoiding the ecological devastation caused by broad-spectrum antibiotics [190]. Advanced subtractive therapies now involve phage-derived, non-replicating delivery particles capable of in situ base editing. Rather than outright microbial eradication, this technique precisely alters host-resident bacteria to disarm virulence or pro-inflammatory metabolic genes, preserving microbiome structure while eliminating pathogenic signals [191].

7.3 Iterating clinical endpoints for systemic healthspan

A major challenge for the clinical translation of anti-aging interventions is the extended tracking period needed to assess effects on lifespan, which has confined most existing clinical studies to examining impacts on aging-related disease states rather than directly targeting the aging process itself. However, future anti-aging RCTs must iterate toward healthspan metrics that represent systemic tissue homeostasis. First, functional parameters such as the clinical frailty index, muscle strength, and immune resilience markers (e.g., vaccine response) should be adopted as primary clinical endpoints [8]. Second, the exploratory integration of epigenetic clocks based on DNA methylation will provide quantitative validation for the epigenetic remodeling mediated by metabolites like SCFAs [192]. The application of multiple iterations of epigenetic clocks (e.g., Horvath, GrimAge) will be critical to determine whether microbiome-derived signals can systemically reverse the velocity of biological aging. This composite evaluation system will establish a definitive benchmark for the clinical translation of precision microbiome-targeted therapies.

8 Conclusion

The pursuit of microbiome-targeted geroprotection is undergoing a fundamental transition from empirical single-strain supplementation toward programmable modalities, including postbiotics, engineered live biotherapeutics, and synthetic microbial consortia. This technological evolution perfectly echoes the ecological principles observed in centenarian populations. Because extreme longevity relies on the robust preservation of keystone species and metabolic redundancy rather than isolated taxa, the ultimate objective of advanced microbiome engineering is to artificially reconstruct and sustain this centenarian-like ecological resilience within the frail senescent gut.

While transformation challenges still exist, especially on the strict anaerobic manufacturing and older adult immune heterogeneity, integrating AI-driven multi-omics stratification with these advanced engineering modalities provides a viable path for the clinical application. Although research on probiotics targeting aging hallmarks is preliminary, and the associated effects and mechanisms lack robust validation in natural aging models and human population, it remains a highly promising avenue. The deployment of NGPs, alongside targeted regulation of the gut microbiota in the older adults, could facilitate a significant extension of high-quality lifespan. This review provides a direction for the effective development of clinical strategies based on the microbiome for anti-aging.

References

[1] Partridge L, Deelen J, Slagboom P E. Facing up to the global challenges of ageing. Nature, 2018, 561(7721): 45–56

[2] Kennedy B K, Berger S L, Brunet A. et al. Geroscience: Linking aging to chronic disease. Cell, 2014, 159(4): 709–713

[3] Niccoli T, Partridge L. Ageing as a risk factor for disease. Current Biology, 2012, 22(17): R741–R752

[4] López-Otín C, Blasco M A, Partridge L. et al. Hallmarks of aging: an expanding universe. Cell, 2023, 186(2): 243–278

[5] Procházková N, Falony G, Dragsted L O. et al. Advancing human gut microbiota research by considering gut transit time. Gut, 2023, 72(1): 180–191

[6] Sovran B, Hugenholtz F, Elderman M. et al. Age-associated impairment of the mucus barrier function is associated with profound changes in microbiota and immunity. Scientific Reports, 2019, 9(1): 1437

[7] Kawamoto S, Uemura K, Hori N. et al. Bacterial induction of B cell senescence promotes age-related changes in the gut microbiota. Nature Cell Biology, 2023, 25(6): 865–876

[8] Ghosh T S, Shanahan F, O’Toole P W. The gut microbiome as a modulator of healthy ageing. Nature Reviews Gastroenterology & Hepatology, 2022, 19(9): 565–584

[9] Wang Y Y Q, Qu Z B, Chu J. et al. Aging gut microbiome in healthy and unhealthy aging. Aging and Disease, 2024, 16(2): 980–1002

[10] Galkin F, Mamoshina P, Aliper A. et al. Human gut microbiome aging clock based on taxonomic profiling and deep learning. iScience, 2020, 23(6): 101199

[11] Saeedi Saravi S S, Pugin B, Constancias F. et al. Gut microbiota-dependent increase in phenylacetic acid induces endothelial cell senescence during aging. Nature Aging, 2025, 5(6): 1025–1045

[12] Mishra S P, Jain S, Wang B. et al. Abnormalities in microbiota/butyrate/FFAR3 signaling in aging gut impair brain function. JCI Insight, 2024, 9(3): e168443

[13] Fransen F, van Beek A A, Borghuis T. et al. Aged gut microbiota contributes to systemical inflammaging after transfer to germ-free mice. Frontiers in Immunology, 2017, 8: 1385

[14] Biagi E, Franceschi C, Rampelli S. et al. Gut microbiota and extreme longevity. Current Biology, 2016, 26(11): 1480–1485

[15] Pang S F, Chen X D, Lu Z L. et al. Longevity of centenarians is reflected by the gut microbiome with youth-associated signatures. Nature Aging, 2023, 3(4): 436–449

[16] Parker A, Romano S, Ansorge R. et al. Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome, 2022, 10(1): 68

[17] Morselli E, Maiuri M C, Markaki M. et al. Caloric restriction and resveratrol promote longevity through the Sirtuin-1-dependent induction of autophagy. Cell Death & Disease, 2010, 1(1): e10

[18] Yu L L, Pan J N, Guo M. et al. Gut microbiota and anti-aging: focusing on spermidine. Critical Reviews in Food Science and Nutrition, 2024, 64(28): 10419–10437

[19] Liu Y D, Liu X X, Chen X H. et al. Senolytic and senomorphic agent procyanidin C1 alleviates structural and functional decline in the aged retina. Proceedings of the National Academy of Sciences of the United States of America, 2024, 121(18): e2311028121

[20] Kirkland J L, Tchkonia T. Senolytic drugs: From discovery to translation. Journal of Internal Medicine, 2020, 288(5): 518–536

[21] Zhou S Q, Shan S F, Li R R. et al. Probiotics ameliorate aging-related cognitive impairments and pathological changes through alleviating telomere attrition and enhancing mitochondrial function in senescence-accelerated mouse prone 8 mice. Journal of Agricultural and Food Chemistry, 2025, 73(47): 30289–30303

[22] Kim J, Jo Y, Lim G. et al. A microbiota-derived metabolite, 3-phenyllactic acid, prolongs healthspan by enhancing mitochondrial function and stress resilience via SKN-1/ATFS-1 in C. elegans. Nature Communications, 2024, 15(1): 10773

[23] Snigdha S, Ha K, Tsai P. et al. Probiotics: potential novel therapeutics for microbiota-gut-brain axis dysfunction across gender and lifespan. Pharmacology & Therapeutics, 2022, 231: 107978

[24] Chen S J, Chen L Y, Qi Y D. et al. Bifidobacterium adolescentis regulates catalase activity and host metabolism and improves healthspan and lifespan in multiple species. Nature Aging, 2021, 1(11): 991–1001

[25] Kumar R, Sharma A, Gupta M. et al. Cell-free culture supernatant of probiotic Lactobacillus fermentum protects against H₂O₂-induced premature senescence by suppressing ROS-Akt-mTOR axis in murine preadipocytes. Probiotics and Antimicrobial Proteins, 2020, 12(2): 563–576

[26] Sadeghloo Z, Nabavi-Rad A, Zali M R. et al. The interplay between probiotics and host autophagy: mechanisms of action and emerging insights. Autophagy, 2025, 21(2): 260–282

[27] Vaiserman A M, Koliada A K, Marotta F. Gut microbiota: a player in aging and a target for anti-aging intervention. Ageing Research Reviews, 2017, 35: 36–45

[28] Mariat D, Firmesse O, Levenez F. et al. The Firmicutes/Bacteroidetes ratio of the human microbiota changes with age. BMC Microbiology, 2009, 9(1): 123

[29] Argentini C, Lugli G A, Tarracchini C. et al. Ecology- and genome-based identification of the Bifidobacterium adolescentis prototype of the healthy human gut microbiota. Applied and Environmental Microbiology, 2024, 90(2): e02014–23

[30] DeJong E N, Surette M G, Bowdish D M E. The gut microbiota and unhealthy aging: disentangling cause from consequence. Cell Host & Microbe, 2020, 28(2): 180–189

[31] Zeng X J, Li X Q, Li X. et al. Fecal microbiota transplantation from young mice rejuvenates aged hematopoietic stem cells by suppressing inflammation. Blood, 2023, 141(14): 1691–1707

[32] Mossad O, Batut B, Yilmaz B. et al. Gut microbiota drives age-related oxidative stress and mitochondrial damage in microglia via the metabolite N⁶-carboxymethyllysine. Nature Neuroscience, 2022, 25(3): 295–305

[33] Gupta S K, Vyavahare S, Duchesne Blanes I L. et al. Microbiota-derived tryptophan metabolism: Impacts on health, aging, and disease. Experimental Gerontology, 2023, 183: 112319

[34] Wu L, Zeng T S, Zinellu A. et al. A cross-sectional study of compositional and functional profiles of gut microbiota in Sardinian centenarians. mSystems, 2019, 4(4): e00325–19

[35] Chen S, Zhang Z, Liu S X. et al. Consistent signatures in the human gut microbiome of longevous populations. Gut Microbes, 2024, 16(1): 2393756

[36] Sato Y, Atarashi K, Plichta D R. et al. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature, 2021, 599(7885): 458–464

[37] Gong J L, Liu S X, Wang S S. et al. Identification of fecal microbiome signatures associated with familial longevity and candidate metabolites for healthy aging. Aging Cell, 2023, 22(6): e13848

[38] Jing Y L, Wang Q Y, Bai F. et al. Age-related alterations in gut homeostasis are microbiota dependent. npj Biofilms and Microbiomes, 2025, 11(1): 51

[39] Bárcena C, Valdés-Mas R, Mayoral P. et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nature Medicine, 2019, 25(8): 1234–1242

[40] Lee H Y, Lee J H, Kim S H. et al. Probiotic Limosilactobacillus Reuteri (Lactobacillus Reuteri) extends the lifespan of Drosophila melanogaster through insulin/IGF-1 signaling. Aging and Disease, 2023, 14(4): 1407–1424

[41] Stuivenberg G A, Chmiel J A, Akouris P P. et al. Probiotic Bifidobacteria mitigate the deleterious effects of para-cresol in a Drosophila melanogaster toxicity model. mSphere, 2022, 7(6): e00446–22

[42] Miller B C, Mathai M, Yadav H. et al. Geroprotective potential of microbiome modulators in the Caenorhabditis elegans model. Geroscience, 2024, 46(1): 129–151

[43] Zhao L, Zhao Y, Liu R H. et al. The transcription factor DAF-16 is essential for increased longevity in C. elegans exposed to Bifidobacterium longum BB68. Scientific Reports, 2017, 7(1): 7408

[44] Wang X E, Wu S X, Zhao W. et al. Comparative mechanisms of different Bifidobacteria in combating pathogen infection and prolonging the lifespan in Caenorhabditis elegans. Microorganisms, 2025, 13(12): 2861

[45] Zhang J T, Zhao Y M, Sun Z H. et al. Lacticaseibacillus rhamnosus probio-M9 extends the lifespan of Caenorhabditis elegans. Communications Biology, 2022, 5(1): 1139

[46] Grompone G, Martorell P, Llopis S. et al. Anti-inflammatory Lactobacillus rhamnosus CNCM I-3690 strain protects against oxidative stress and increases lifespan in Caenorhabditis elegans. PLoS One, 2012, 7(12): e52493

[47] Shi R J, Ye J, Fan H. et al. Lactobacillus plantarum LLY-606 supplementation ameliorates the cognitive impairment of natural aging in mice: The potential role of gut microbiota homeostasis. Journal of Agricultural and Food Chemistry, 2024, 72(8): 4049–4062

[48] Zhang Z, Fang Y J, He Y L. et al. Bifidobacterium animalis Probio-M8 improves sarcopenia physical performance by mitigating creatine restrictions imposed by microbial metabolites. npj Biofilms and Microbiomes, 2024, 10(1): 144

[49] Li H C, Zhang M Q, Wu D Y. et al. Lactobacillus plantarum QL01 alleviates D-galactose-induced oxidative stress and restores gut microbiota in ageing mice. Nutrients, 2025, 18(1): 35

[50] Liu X L, Ma Y, Guan K F. et al. Intestinal barrier, immunity and gut microbiota-based protective effects of Lactococcus lactis HF08 and its postbiotic derivative on aging and aging colitis mice. Food Research International, 2024, 197: 115164

[51] Fang X, Yue M Y, Wei J. et al. Evaluation of the anti-aging effects of a probiotic combination isolated from centenarians in a SAMP8 mouse model. Frontiers in Immunology, 2021, 12: 792746

[52] Xu T C, Wu X Y, Zhang Y F. et al. L-tryptophan produced by Bifidobacterium pseudocatenulatum NCU-08 delays aging in SAMP8 mice by activating the Sirt1/P53/P21/Rb signaling pathway. Aging Cell, 2025, 24(9): e70166

[53] Hsu Y C, Huang Y Y, Tsai S Y. et al. Efficacy of probiotic supplements on brain-derived neurotrophic factor, inflammatory biomarkers, oxidative stress and cognitive function in patients with Alzheimer’s dementia: A 12-week randomized, double-blind active-controlled study. Nutrients, 2024, 16(1): 16

[54] Custodero C, Mankowski R T, Lee S A. et al. Evidence-based nutritional and pharmacological interventions targeting chronic low-grade inflammation in middle-age and older adults: a systematic review and meta-analysis. Ageing Research Reviews, 2018, 46: 42–59

[55] Li G, Feng H, Mao X L. et al. The effects of probiotics supplementation on glycaemic control among adults with type 2 diabetes mellitus: a systematic review and meta-analysis of randomised clinical trials. Journal of Translational Medicine, 2023, 21(1): 442

[56] Kim C S, Cha J, Sim M. et al. Probiotic supplementation improves cognitive function and mood with changes in gut microbiota in community-dwelling older adults: a randomized, double-blind, placebo-controlled, multicenter trial. The Journals of Gerontology: Series A, 2021, 76(1): 32–40

[57] Gong P T, Tang X H. The impact of probiotic supplementation on gastric motility and nutrient absorption in elderly patients with gastrointestinal disorders. BMC Gastroenterology, 2025, 25(1): 192

[58] Kroemer G, Maier A B, Cuervo A M. et al. From geroscience to precision geromedicine: understanding and managing aging. Cell, 2025, 188(8): 2043–2062

[59] Sonar S A, Bhat R, Thompson H L. et al. Age-related oxidative stress and mitochondrial dysfunction in lymph node stromal cells limit the peripheral T cell homeostatic maintenance and function. Aging Cell, 2025, 24(8): e70100

[60] Liang T, Bernal B, Qi W B. et al. Robust assembly of electron transfer chain in the brain of naked mole-rats during aging. Organelle, 2024, 1(2):

[61] Li H Z, Shen L X, Hu P Q. et al. Aging-associated mitochondrial DNA mutations alter oxidative phosphorylation machinery and cause mitochondrial dysfunctions. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2017, 1863(9): 2266–2273

[62] Picca A, Lezza A M S, Leeuwenburgh C. et al. Fueling inflamm-aging through mitochondrial dysfunction: mechanisms and molecular targets. International Journal of Molecular Sciences, 2017, 18(5): 933

[63] Guo Y, Guan T, Shafiq K. et al. Mitochondrial dysfunction in aging. Ageing Research Reviews, 2023, 88: 101955

[64] Panahi Y, Ghanei M, Vahedi E. et al. Efficacy of probiotic supplementation on quality of life and pulmonary symptoms due to sulfur mustard exposure: a randomized double-blind placebo-controlled trial. Drug and Chemical Toxicology, 2017, 40(1): 24–29

[65] Eggers S, Barker A K, Valentine S. et al. Effect of Lactobacillus rhamnosus HN001 on carriage of Staphylococcus aureus: results of the impact of probiotics for reducing infections in veterans (IMPROVE) study. BMC Infectious Diseases, 2018, 18(1): 129

[66] Gruber J, Kennedy B K. Microbiome and longevity: gut microbes send signals to host mitochondria. Cell, 2017, 169(7): 1168–1169

[67] Zhu S, Pan W. Microbial metabolite steers intestinal stem cell fate under stress. Cell Stem Cell, 2024, 31(5): 591–592

[68] Qiao L, Yang G, Wang P. et al. The potential role of mitochondria in the microbiota-gut-brain axis: Implications for brain health. Pharmacological Research, 2024, 209: 107434

[69] Simms-Waldrip T R, Koh A Y. Food for gut: microbiota fuels immune reconstitution after BMT. Cell Host & Microbe, 2018, 23(4): 423–424

[70] Zhang M W, Cui S M, Mao B Y. et al. Urolithin A produced by novel microbial fermentation possesses anti-aging effects by improving mitophagy and reducing reactive oxygen species in Caenorhabditis elegans. Journal of Agricultural and Food Chemistry, 2023, 71(16): 6348–6357

[71] Liu C R, Wong P Y, Barua N. et al. From clinical to benchside: Lacticaseibacillus and Faecalibacterium are positively associated with muscle health and alleviate age-related muscle disorder. Aging Cell, 2025, 24(5): e14485

[72] Li Q, De Oliveira Formiga R, Puchois V. et al. Microbial metabolite indole-3-propionic acid drives mitochondrial respiration in CD4⁺ T cells to confer protection against intestinal inflammation. Nature Metabolism, 2025, 7(12): 2510–2530

[73] Zhang Z, Guo Q, Yang Z H. et al. Bifidobacterium adolescentis-derived nicotinic acid improves host skeletal muscle mitochondrial function to ameliorate sarcopenia. Cell Reports, 2025, 44(2): 115265

[74] Lin H, Shao X, Gu H D. et al. Akkermansia muciniphila ameliorates doxorubicin-induced cardiotoxicity by regulating PPARα-dependent mitochondrial biogenesis. npj Biofilms and Microbiomes, 2025, 11(1): 86

[75] Wang Y, Wu Y P, Wang Y B. et al. Bacillus amyloliquefaciens SC06 alleviates the oxidative stress of IPEC-1 via modulating Nrf2/Keap1 signaling pathway and decreasing ROS production. Applied Microbiology and Biotechnology, 2017, 101(7): 3015–3026

[76] Chen Q, Chen D, Gao X Y. et al. Association between fecal short-chain fatty acid levels and constipation severity in subjects with slow transit constipation. European Journal of Gastroenterology & Hepatology, 2024, 36(4): 394–403

[77] Zhang C C, Yu L L, Ma C C. et al. A key genetic factor governing arabinan utilization in the gut microbiome alleviates constipation. Cell Host & Microbe, 2023, 31(12): 1989–2006.e8

[78] Yao Y, Cai X Y, Fei W D. et al. The role of short-chain fatty acids in immunity, inflammation and metabolism. Critical Reviews in Food Science and Nutrition, 2022, 62(1): 1–12

[79] Di Micco R, Krizhanovsky V, Baker D. et al. Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature Reviews Molecular Cell Biology, 2021, 22(2): 75–95

[80] Xu M, Pirtskhalava T, Farr J N. et al. Senolytics improve physical function and increase lifespan in old age. Nature Medicine, 2018, 24(8): 1246–1256

[81] Baker D J, Wijshake T, Tchkonia T. et al. Clearance of p16^Ink4a-positive senescent cells delays ageing-associated disorders. Nature, 2011, 479(7372): 232–236

[82] Wang B S, Han J, Elisseeff J H. et al. The senescence-associated secretory phenotype and its physiological and pathological implications. Nature Reviews Molecular Cell Biology, 2024, 25(12): 958–978

[83] Ogrodnik M. Cellular aging beyond cellular senescence: markers of senescence prior to cell cycle arrest in vitro and in vivo. Aging Cell, 2021, 20(4): e13338

[84] Goronzy J J, Weyand C M. Mechanisms underlying T cell ageing. Nature Reviews Immunology, 2019, 19(9): 573–583

[85] Finamore A, Roselli M, Donini L. et al. Supplementation with Bifidobacterium longum Bar33 and Lactobacillus helveticus Bar13 mixture improves immunity in elderly humans (over 75 years) and aged mice. Nutrition, 2019, 63–64: 184–192

[86] Gill H S, Rutherfurd K J, Cross M L. et al. Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019. The American Journal of Clinical Nutrition, 2001, 74(6): 833–839

[87] Miller L E, Lehtoranta L, Lehtinen M J. Short-term probiotic supplementation enhances cellular immune function in healthy elderly: systematic review and meta-analysis of controlled studies. Nutrition Research, 2019, 64: 1–8

[88] Jeong J J, Kim K A, Ahn Y T. et al. Probiotic mixture KF attenuates age-dependent memory deficit and lipidemia in Fischer 344 rats. Journal of Microbiology and Biotechnology, 2015, 25(9): 1532–1536

[89] Qian W Y, Zhang Y, Long Y. et al. Probiotic Lactobacillus brevis CLB3 prevents azoxymethane/dextran sulfate sodium-induced colon carcinogenesis in mice by reducing amino acid transport and IL-17A levels and repressing the IL-6/AKT/p-STAT3 signaling pathway. Food Quality and Safety, 2022, 6: fyac038

[90] Dong Y Y, Zhu J, Zhang M. et al. Probiotic Lactobacillus salivarius Ren prevent dimethylhydrazine-induced colorectal cancer through protein kinase B inhibition. Applied Microbiology and Biotechnology, 2020, 104(17): 7377–7389

[91] Zhang L L, Xu J Y, Xing Y F. et al. Lactobacillus rhamnosus GG alleviates radiation-induced intestinal injury by modulating intestinal immunity and remodeling gut microbiota. Microbiological Research, 2024, 286: 127821

[92] Li Z J, Zhang Y, Hong W F. et al. Gut microbiota modulate radiotherapy-associated antitumor immune responses against hepatocellular carcinoma Via STING signaling. Gut Microbes, 2022, 14(1): 2119055

[93] Wang G, Liu J T Y, Zhang Y N. et al. Ginsenoside Rg3 enriches SCFA-producing commensal bacteria to confer protection against enteric viral infection via the cGAS-STING-type I IFN axis. The ISME Journal, 2023, 17(12): 2426–2440

[94] Yang X Q, Yu D K, Xue L. et al. Probiotics modulate the microbiota-gut-brain axis and improve memory deficits in aged SAMP8 mice. Acta Pharmaceutica Sinica B, 2020, 10(3): 475–487

[95] Lee H J, Lee K E, Kim J K. et al. Suppression of gut dysbiosis by Bifidobacterium longum alleviates cognitive decline in 5XFAD transgenic and aged mice. Scientific Reports, 2019, 9(1): 11814

[96] Zeng Q W, Qi Z H, He X. et al. Bifidobacterium pseudocatenulatum NCU-08 ameliorated senescence via modulation of the AMPK/Sirt1 signaling pathway and gut microbiota in mice. Food & Function, 2024, 15(8): 4095–4108

[97] Noack J, Dongowski G, Hartmann L. et al. The human gut bacteria Bacteroides thetaiotaomicron and Fusobacterium varium produce putrescine and spermidine in cecum of pectin-fed gnotobiotic rats. The Journal of Nutrition, 2000, 130(5): 1225–1231

[98] Vijayan B, Raj V, Nandakumar S. et al. Spermine protects alpha-synuclein expressing dopaminergic neurons from manganese-induced degeneration. Cell Biology and Toxicology, 2019, 35(2): 147–159

[99] Matsumoto M, Kurihara S, Kibe R. et al. Longevity in mice is promoted by probiotic-induced suppression of colonic senescence dependent on upregulation of gut bacterial polyamine production. PLoS One, 2011, 6(8): e23652

[100] Vyavahare S, Berger F, Swint S G. et al. Microbiota-derived indole-3-propionic acid extends lifespan in Drosophila and improves muscle and bone health in mice. Geroscience, 2026, 48(1): 77–90

[101] Zhuo J Z, Liu D Y, Yu Q. et al. Indole-3-acetic acid attenuates pulmonary fibrosis by modulating lung microbiota, inhibiting fibroblast activation, and alleviating alveolar epithelial cell senescence. Life Sciences, 2024, 359: 123191

[102] Yu H X, Feng Z, Lin W. et al. Ongoing clinical trials in aging-related tissue fibrosis and new findings related to AhR pathways. Aging and Disease, 2022, 13(3): 732–752

[103] Liu W, Wang J Y, Yang H. et al. The metabolite indole-3-acetic acid of Bacteroides ovatus improves atherosclerosis by restoring the polarisation balance of M1/M2 macrophages and inhibiting inflammation. Advanced Science, 2025, 12(11): 2413010

[104] Zhuang H M, Ren X S, Jiang F Z. et al. Indole-3-propionic acid alleviates chondrocytes inflammation and osteoarthritis via the AhR/NF-κB axis. Molecular Medicine, 2023, 29(1): 17

[105] Salminen A. Activation of aryl hydrocarbon receptor (AhR) in Alzheimer’s disease: role of tryptophan metabolites generated by gut host-microbiota. Journal of Molecular Medicine, 2023, 101(3): 201–222

[106] Ishihara Y, Kado S Y, Hoeper C. et al. Role of NF-κB RelB in aryl hydrocarbon receptor-mediated ligand specific effects. International Journal of Molecular Sciences, 2019, 20(11): 2652

[107] Rees N P, Conway J, Dugan B. et al. Defining microbiota-derived metabolite butyrate as a senomorphic: therapeutic potential in the age-related T cell senescence. Aging Cell, 2025, 24(12): e70257

[108] Zhai J X, Wang C, Jin L. et al. Gut microbiota metabolites mediate bax to reduce neuronal apoptosis via cGAS/STING axis in epilepsy. Molecular Neurobiology, 2024, 61(12): 9794–9809

[109] Palmer J E, Wilson N, Son S M. et al. Autophagy, aging, and age-related neurodegeneration. Neuron, 2025, 113(1): 29–48

[110] Kaushik S, Tasset I, Arias E. et al. Autophagy and the hallmarks of aging. Ageing Research Reviews, 2021, 72: 101468

[111] Boland B, Yu W H, Corti O. et al. Promoting the clearance of neurotoxic proteins in neurodegenerative disorders of ageing. Nature Reviews Drug Discovery, 2018, 17(9): 660–688

[112] Eggers B, Steinbach S, Aldea I G. et al. The aging substantia nigra is characterized by ROS accumulation potentially resulting in increased neuroinflammation and cytoskeletal remodeling. Advanced Biology, 2025, 9(4): 2400814

[113] Bak D H, Na J, Im S I. et al. Antioxidant effect of human placenta hydrolysate against oxidative stress on muscle atrophy. Journal of Cellular Physiology, 2019, 234(2): 1643–1658

[114] Xiong Y B, Zhou L L. The signaling of cellular senescence in diabetic nephropathy. Oxidative Medicine and Cellular Longevity, 2019, 2019: 7495629

[115] Tavakol S, Ashrafizadeh M, Deng S. et al. Autophagy modulators: mechanistic aspects and drug delivery systems. Biomolecules, 2019, 9(10): 530

[116] Zhang L S, Wei J L, Ren L H. et al. Endosulfan induces autophagy and endothelial dysfunction via the AMPK/mTOR signaling pathway triggered by oxidative stress. Environmental Pollution, 2017, 220: 843–852

[117] Deng X Y, Li Y B, Chen Y. et al. Paeoniflorin protects hepatocytes from APAP-induced damage through launching autophagy via the MAPK/mTOR signaling pathway. Cellular & Molecular Biology Letters, 2024, 29(1): 119

[118] Tan A, Prasad R, Lee C. et al. Past, present, and future perspectives of transcription factor EB (TFEB): mechanisms of regulation and association with disease. Cell Death & Differentiation, 2022, 29(8): 1433–1449

[119] Wang L Y, Wang L L, Tian P J. et al. A randomised, double-blind, placebo-controlled trial of Bifidobacterium bifidum CCFM16 for manipulation of the gut microbiota and relief from chronic constipation. Food & Function, 2022, 13(3): 1628–1640

[120] Wang B, Hylwka T, Smieja M. et al. Probiotics to prevent respiratory infections in nursing homes: A pilot randomized controlled trial. Journal of the American Geriatrics Society, 2018, 66(7): 1346–1352

[121] Jia G C, Liu X F, Che N. et al. Human-origin Lactobacillus salivarius AR809 protects against immunosuppression in S. aureus-induced pharyngitis via Akt-mediated NF-κB and autophagy signaling pathways. Food & Function, 2020, 11(1): 270–284

[122] Ahmed L A, Salem M B, Seif El-Din S H. et al. Gut microbiota modulation as a promising therapy with metformin in rats with non-alcoholic steatohepatitis: Role of LPS/TLR4 and autophagy pathways. European Journal of Pharmacology, 2020, 887: 173461

[123] Cui Y J, Liu L, Dou X X. et al. Lactobacillus reuteri ZJ617 maintains intestinal integrity via regulating tight junction, autophagy and apoptosis in mice challenged with lipopolysaccharide. Oncotarget, 2017, 8(44): 77489–77499

[124] Motevaseli E, Azam R, Akrami S M. et al. The effect of Lactobacillus crispatus and Lactobacillus rhamnosus culture supernatants on expression of autophagy genes and HPV E6 and E7 oncogenes in the HeLa cell line. Cell Journal, 2016, 17(4): 601–607

[125] Inaba Y, Ueno N, Numata M. et al. Soluble bioactive microbial mediators regulate proteasomal degradation and autophagy to protect against inflammation-induced stress. American Journal of Physiology-Gastrointestinal and Liver Physiology, 2016, 311(4): G634–G647

[126] Wang H F, Cheng X, Zhang L. et al. A surface-layer protein from Lactobacillus acidophilus NCFM induces autophagic death in HCT116 cells requiring ROS-mediated modulation of mTOR and JNK signaling pathways. Food & Function, 2019, 10(7): 4102–4112

[127] Ren Z Y, Huo Y L, Zhang Q M. et al. Protective effect of Lactiplantibacillus plantarum 1201 combined with galactooligosaccharide on carbon tetrachloride-induced acute liver injury in mice. Nutrients, 2021, 13(12): 4441

[128] Wu Y P, Wang B K, Xu H. et al. Probiotic Bacillus attenuates oxidative stress-induced intestinal injury via p38-mediated autophagy. Frontiers in Microbiology, 2019, 10: 2185

[129] Xu T T, Li H, Dai Z. et al. Spermidine and spermine delay brain aging by inducing autophagy in SAMP8 mice. Aging, 2020, 12(7): 6401–6414

[130] Hofer S J, Simon A K, Bergmann M. et al. Mechanisms of spermidine-induced autophagy and geroprotection. Nature Aging, 2022, 2(12): 1112–1129

[131] Chu B X, Zhu Y H, Su J H. et al. Butyrate-mediated autophagy inhibition limits cytosolic Salmonella Infantis replication in the colon of pigs treated with a mixture of Lactobacillus and Bacillus. Veterinary Research, 2020, 51(1): 99

[132] Wang J W, Geiger H, Rudolph K L. Immunoaging induced by hematopoietic stem cell aging. Current Opinion in Immunology, 2011, 23(4): 532–536

[133] Dellorusso P V, Proven M A, Calero-Nieto F J. et al. Autophagy counters inflammation-driven glycolytic impairment in aging hematopoietic stem cells. Cell Stem Cell, 2024, 31(7): 1020–1037.e9

[134] Josephson A M, Bradaschia-Correa V, Lee S. et al. Age-related inflammation triggers skeletal stem/progenitor cell dysfunction. Proceedings of the National Academy of Sciences of the United States of America, 2019, 116(14): 6995–7004

[135] Castilho R M, Squarize C H, Chodosh L A. et al. mTOR mediates Wnt-induced epidermal stem cell exhaustion and aging. Cell Stem Cell, 2009, 5(3): 279–289

[136] Prasetyo R V, Surono I, Soemyarso N A. et al. Lactobacillus plantarum IS-10506 promotes renal tubular regeneration in pyelonephritic rats. Beneficial Microbes, 2020, 11(1): 59–66

[137] Liu H, Gu R L, Li W. et al. Probiotics protect against tenofovir-induced mandibular bone loss in mice by rescuing mandible-derived mesenchymal stem cell proliferation and osteogenic differentiation. Journal of Oral Rehabilitation, 2020, 47(Suppl 1): 83–90

[138] Xie S, Zhao S Y, Jiang L. et al. Lactobacillus reuteri stimulates intestinal epithelial proliferation and induces differentiation into goblet cells in young chickens. Journal of Agricultural and Food Chemistry, 2019, 67(49): 13758–13766

[139] Han N N, Jia L, Su Y Y. et al. Lactobacillus reuteri extracts promoted wound healing via PI3K/AKT/β-catenin/TGFβ1 pathway. Stem Cell Research & Therapy, 2019, 10(1): 243

[140] Saberian M, Shahidi Delshad E, Habibi M. The effect of Bifidobacterium bifidum supernatant and cell mass on the proliferation potential of rat bone marrow-derived stromal cells. Iranian Journal of Medical Sciences, 2020, 45(4): 269–276

[141] Yeung C Y, Chiau J S C, Cheng M L. et al. Immune modulation effects of Lactobacillus casei variety rhamnosus on enterocytes and intestinal stem cells in a 5-FU-induced mucositis mouse model. Gastroenterology Research and Practice, 2021, 2021: 3068393

[142] Zhang X, Tong Y J, Lyu X. et al. Prevention and alleviation of dextran sulfate sodium salt-induced inflammatory bowel disease in mice with Bacillus subtilis-fermented milk via inhibition of the inflammatory responses and regulation of the intestinal flora. Frontiers in Microbiology, 2021, 11: 622354

[143] Lu X X, Xie S, Ye L L. et al. Lactobacillus protects against S. typhimurium-induced intestinal inflammation by determining the fate of epithelial proliferation and differentiation. Molecular Nutrition & Food Research, 2020, 64(5): 1900655

[144] Lee Y S, Kim T Y, Kim Y. et al. Microbiota-derived lactate accelerates intestinal stem-cell-mediated epithelial development. Cell Host & Microbe, 2018, 24(6): 833–846.e6

[145] Annunziata F, Rasa S M M, Krepelova A. et al. Paneth cells drive intestinal stem cell competition and clonality in aging and calorie restriction. European Journal of Cell Biology, 2022, 101(4): 151282

[146] Hou Q H, Ye L L, Liu H F. et al. Lactobacillus accelerates ISCs regeneration to protect the integrity of intestinal mucosa through activation of STAT3 signaling pathway induced by LPLs secretion of IL-22. Cell Death & Differentiation, 2018, 25(9): 1657–1670

[147] He L, Zhu C, Zhou X F. et al. Gut microbiota modulating intestinal stem cell differentiation. World Journal of Stem Cells, 2024, 16(6): 619–622

[148] Greider C W. Telomere length regulation. Annual Review of Biochemistry, 1996, 65: 337–365

[149] Rudolph K L, Chang S, Lee H W. et al. Longevity, stress response, and cancer in aging telomerase-deficient mice. Cell, 1999, 96(5): 701–712

[150] Boonekamp J J, Simons M J P, Hemerik L. et al. Telomere length behaves as biomarker of somatic redundancy rather than biological age. Aging Cell, 2013, 12(2): 330–332

[151] de Jesus B B, Schneeberger K, Vera E. et al. The telomerase activator TA-65 elongates short telomeres and increases health span of adult/old mice without increasing cancer incidence. Aging Cell, 2011, 10(4): 604–621

[152] Coman M M, Torbidoni-Baldassari B, Occhigrossi L. et al. Probiotic supplementation in aged human subjects counteracts leukocyte telomere attrition rate. Journal of Medicinal Food, 2026, 29(7): 438–443

[153] Arvanitaki E S, Stratigi K, Garinis G A. DNA damage, inflammation and aging: Insights from mice. Frontiers in Aging, 2022, 3: 973781

[154] Schumacher B, Pothof J, Vijg J. et al. The central role of DNA damage in the ageing process. Nature, 2021, 592(7856): 695–703

[155] Chen Y, Chen Z X, Wang H. et al. A cGAS-mediated mechanism in naked mole-rats potentiates DNA repair and delays aging. Science, 2025, 390(6769): eadp5056

[156] Guedj A, Volman Y, Geiger-Maor A. et al. Gut microbiota shape ’inflamm-ageing’ cytokines and account for age-dependent decline in DNA damage repair. Gut, 2020, 69(6): 1064–1075

[157] van Galen I, Hoeijmakers J H J, Vermeij W P. The use of nutritional interventions to enhance genomic stability in mice and delay aging. Nutrients, 2026, 18(2): 246

[158] Gajski G, Szewczyk-Roszczenko O, Roszczenko P. et al. Friends and foes: impact of bacteria on genome stability. Critical Reviews in Microbiology, 2026, 1–13

[159] Han T T, Hu X M, Li K M. et al. Bifidobacterium infantis maintains genome stability in ulcerative colitis via regulating anaphase-promoting complex subunit 7. Frontiers in Microbiology, 2021, 12: 761113

[160] Plovier H, Everard A, Druart C. et al. A purified membrane protein from Akkermansia muciniphila or the pasteurized bacterium improves metabolism in obese and diabetic mice. Nature Medicine, 2017, 23(1): 107–113

[161] Shin J, Noh J R, Choe D. et al. Ageing and rejuvenation models reveal changes in key microbial communities associated with healthy ageing. Microbiome, 2021, 9(1): 240

[162] Zhou J, Li M Y, Chen Q F. et al. Programmable probiotics modulate inflammation and gut microbiota for inflammatory bowel disease treatment after effective oral delivery. Nature Communications, 2022, 13(1): 3432

[163] Yoon H S, Cho C H, Yun M S. et al. Akkermansia muciniphila secretes a glucagon-like peptide-1-inducing protein that improves glucose homeostasis and ameliorates metabolic disease in mice. Nature Microbiology, 2021, 6(5): 563–573

[164] Zhang W H, Xi G, Zhang H W. et al. Pasteurized Akkermansia muciniphila promotes GP2 expression in microfold cells and facilitates Salmonella infection. Protein & Cell, 2025, 16(9): 829–834

[165] Martín R, Miquel S, Chain F. et al. Faecalibacterium prausnitzii prevents physiological damages in a chronic low-grade inflammation murine model. BMC Microbiology, 2015, 15(1): 67

[166] Quévrain E, Maubert M A, Michon C. et al. Identification of an anti-inflammatory protein from Faecalibacterium prausnitzii, a commensal bacterium deficient in Crohn’s disease. Gut, 2016, 65(3): 415–425

[167] Kallassy J, Gagnon E, Rosenberg D. et al. Strains of Faecalibacterium prausnitzii and its extracts reduce blood glucose levels, percent HbA1c, and improve glucose tolerance without causing hypoglycemic side effects in diabetic and prediabetic mice. BMJ Open Diabetes Research & Care, 2023, 11(3): e003101

[168] Kropp C, Le Corf K, Relizani K. et al. The Keystone commensal bacterium Christensenella minuta DSM 22607 displays anti-inflammatory properties both in vitro and in vivo. Scientific Reports, 2021, 11(1): 11494

[169] Akbuğa-Schön T, Suzuki T A, Jakob D. et al. The keystone gut species Christensenella minuta boosts gut microbial biomass and voluntary physical activity in mice. mBio, 2024, 15(2): e02836–23

[170] Ramakrishna C, Kujawski M, Chu H. et al. Bacteroides fragilis polysaccharide A induces IL-10 secreting B and T cells that prevent viral encephalitis. Nature Communications, 2019, 10(1): 2153

[171] Lai H C, Lin T L, Chen T W. et al. Gut microbiota modulates COPD pathogenesis: role of anti-inflammatory Parabacteroides goldsteinii lipopolysaccharide. Gut, 2022, 71(2): 309–321

[172] Depommier C, Everard A, Druart C. et al. Supplementation with Akkermansia muciniphila in overweight and obese human volunteers: a proof-of-concept exploratory study. Nature Medicine, 2019, 25(7): 1096–1103

[173] Kang C H, Jung E S, Jung S J. et al. Pasteurized Akkermansia muciniphila HB05 (HB05P) improves muscle strength and function: a 12-week, randomized, double-blind, placebo-controlled clinical trial. Nutrients, 2024, 16(23): 4037

[174] Chelakkot C, Choi Y, Kim D K. et al. Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions. Experimental & Molecular Medicine, 2018, 50(2): e450–e450

[175] Lee K E, Kim J K, Han S K. et al. The extracellular vesicle of gut microbial Paenalcaligenes hominis is a risk factor for vagus nerve-mediated cognitive impairment. Microbiome, 2020, 8(1): 107

[176] Wang K, Yuan B C, Zhang F. et al. A bioadhesive antioxidase-overexpressed probiotic prevents radiation enteritis by scavenging the excess reactive oxygen species. Free Radical Biology and Medicine, 2025, 227: 485–498

[177] Wu J P, Tian X F, Xu X N. et al. Engineered probiotic Lactococcus lactis for lycopene production against ROS stress in intestinal epithelial cells. ACS Synthetic Biology, 2022, 11(4): 1568–1576

[178] Weibel N, Curcio M, Schreiber A. et al. Engineering a novel probiotic toolkit in Escherichia coli Nissle 1917 for sensing and mitigating gut inflammatory diseases. ACS Synthetic Biology, 2024, 13(8): 2376–2390

[179] Mohaqiq M, Palou R, Li R Z. et al. Engineered spermidine-secreting Saccharomyces boulardii ameliorates colitis and colon cancer in mice. Scientific Reports, 2025, 15(1): 31959

[180] Yan X, Liu X Y, Zhang D. et al. Construction of a sustainable 3-hydroxybutyrate-producing probiotic Escherichia coli for treatment of colitis. Cellular & Molecular Immunology, 2021, 18(10): 2344–2357

[181] van der Lelie D, Oka A, Taghavi S. et al. Rationally designed bacterial consortia to treat chronic immune-mediated colitis and restore intestinal homeostasis. Nature Communications, 2021, 12(1): 3105

[182] Furuichi M, Kawaguchi T, Pust M M. et al. Commensal consortia decolonize Enterobacteriaceae via ecological control. Nature, 2024, 633(8031): 878–886

[183] Caballero S, Kim S, Carter R A. et al. Cooperating commensals restore colonization resistance to vancomycin-resistant Enterococcus faecium. Cell Host & Microbe, 2017, 21(5): 592–602.e4

[184] Jan A, Bayle P, Mohellibi N. et al. A consortium of seven commensal bacteria promotes gut microbiota recovery and strengthens ecological barrier against vancomycin-resistant enterococci. Microbiome, 2025, 13(1): 129

[185] Menon R, Bhattarai S K, Crossette E. et al. Multi-omic profiling a defined bacterial consortium for treatment of recurrent Clostridioides difficile infection. Nature Medicine, 2025, 31(1): 223–234

[186] Ouwerkerk J P, Aalvink S, Belzer C. et al. Preparation and preservation of viable Akkermansia muciniphila cells for therapeutic interventions. Beneficial Microbes, 2017, 8(2): 163–170

[187] Rannikko J, Holmberg V, Karppelin M. et al. Fungemia and other fungal infections associated with use of Saccharomyces boulardii probiotic supplements. Emerging Infectious Diseases, 2021, 27(8): 2090–2096

[188] Yelin I, Flett K B, Merakou C. et al. Genomic and epidemiological evidence of bacterial transmission from probiotic capsule to blood in ICU patients. Nature Medicine, 2019, 25(11): 1728–1732

[189] Maldonado-Gómez M X, Martínez I, Bottacini F. et al. Stable engraftment of Bifidobacterium longum AH1206 in the human gut depends on individualized features of the resident microbiome. Cell Host & Microbe, 2016, 20(4): 515–526

[190] Duan Y, Llorente C, Lang S. et al. Bacteriophage targeting of gut bacterium attenuates alcoholic liver disease. Nature, 2019, 575(7783): 505–511

[191] Brödel A K, Charpenay L H, Galtier M. et al. In situ targeted base editing of bacteria in the mouse gut. Nature, 2024, 632(8026): 877–884

[192] Wehnes T, Wang W L, Tay J H. et al. Oral short-chain fatty acid-producing bacteria may be associated with biological age and cognition among the oldest old. Communications Medicine, 2025, 6(1): 37

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