The Interplay of Diet, Microbiome and Longevity: Insights

The gut microbiome changes as a person ages, with significant influences coming from factors such as the mode of birth (whether natural or Cesarean), nutrition, environment and life experiences [1-3]. Among these factors, nutrition plays a crucial and variable role, although dietary choices can have profound effects on the variety and function of gut microbes [4-6]. A well-functioning microbiome generates bioactive metabolites, such as Short- Chain Fatty Acids (SCFAs), which attenuate inflammation and contribute to healthy aging [7,8]. On the other hand, dysbiosis or the imbalance in microbial populations, is linked to a variety of illnesses, including those related to metabolism, cardiovascular health, the nervous system and the immune system [9,10]. This leads to a fascinating question: do gut microorganisms have the ability to actively impact the aging process and longevity?

Diet-microbiome links across the lifespan

Emerging research connects dietary habits and the microbiome to both healthspanthe duration of good health-and lifespan [11,12]. Nutrient-rich foods, such as those high in fiber, polyphenols and fermented products, can enhance microbial diversity and resilience, as well as metabolic and immune functions [13,14]. Conversely, diets that are high in sugar and unhealthy fats disrupt metabolism, promote inflammation and accelerate the aging process [15,16]. The microbiome influences digestion, immune response and brain function through its metabolites and communication between the gut and brain [17,18]. While we observe clearer correlations among these relationships, the precise molecular mechanisms underlying these associations remain unexplored. The cross-sectional study conducted in Japan, which spans the entire lifespan from infancy to extreme old age (1-100+ years), is crucial for understanding microbiome dynamics throughout life [3]. This research revealed that the diversity of gut microbes increases from infancy into early adulthood, remains stable during middle age and then declines after the age of 65, with more significant reductions observed after the age of 80. Beneficial microorganisms such as Christensenellaceae and Akkermansia flourish in the gut microbiome of those who live to be 100 or older, possibly playing a role in longevity [19,20]. At the same time, aging is characterized by higher ratios of potentially pathogenic or pro-inflammatory groups, i.e., Proteobacteria, Actinobacteria, Verrucomicrobia and Synergistetes-with Enterobacteriaceae, Alistipes and Ruminococcus gnavus becoming more abundant in frail individuals [21,22]. The results emphasize the significance of different dietary elements throughout various life stages and stress the necessity for agespecific dietary plans aimed at promoting gut microbiota health for enhanced longevity.

Diet-microbiome-epigenetics nexus in aging

One of the emerging areas of research regarding the relationship between the microbiome and dietary factors involves epigenetic mechanisms that influence an individual’s aging process [23,24]. Epigenetic alterations, including DNA methylation, modifications to histones and the role of non-coding RNA, modulate gene expression without changing the underlying DNA sequence [25,26]. Certain environmental factors, especially dietary components, can mediate these molecular changes, which are essential for longevity and overall health in aging individuals [27,28]. Nutrients like polyphenols, vitamins and fiber contribute to DNA repair and inflammation reduction, fostering beneficial epigenetic modifications that aid cellular recovery [29,30]. In contrast, unhealthy dietary patterns, particularly those high in fat and sugar, can lead to deleterious epigenetic alterations that hasten the aging process and increase the likelihood of age-associated diseases [31,32]. Investigating the connections among diet, epigenetics and the microbiome reveals their collective impact on the aging process. This highlights the importance of promoting diets that nurture a healthy microbiome and encourage epigenetic changes associated with longevity [33,34].

Personalized nutrition for microbiome health and healthy aging

Dietary intervention is an increasingly recognized concept that has proven effective in promoting a healthy gut microbiome, though its acceptance varies based on cultural, personal and economic factors [5,35]. Various approaches, including probiotics, prebiotics, synbiotics and Fecal Microbiota Transplantation (FMT), have been researched for their potential to restore microbial equilibrium in adults, particularly among older individuals. Nonetheless, their significance continues to be debated to this day [36,37]. Thus, the ongoing challenge lies in understanding how nutrition impacts microbiome composition to create personalized dietary strategies that may be more beneficial than microbial supplements from a public health perspective. While significant progress has been made in microbiome research, there remain many unanswered questions, especially in identifying causal relationships between microbiome changes and age-related illnesses. Most of the new research is correlational, which limits its therapeutic application and highlights the pressing need for more studies on the relationship between diet, microbiome and longevity, as illustrated in this brief communication. Connecting microbiome research with dietary studies and aging science aids in formulating effective approaches to enhance health and well-being. Shifting our attention from merely addressing age-related diseases to tackling their biological causes will mark a crucial advancement in alleviating healthcare challenges for aging populations.

Against this backdrop, the article first outlines the fundamental mechanisms that link diet, the microbiome and longevity, providing the basis for understanding their interconnected roles. It then examines how dietary restriction shapes microbiota-epigenome interactions that influence aging trajectories. Building on this, the discussion turns to the potential of probiotics in modulating systemic processes associated with age-related decline. The article concludes by considering the connections between dietary patterns, microbial composition and cognitive health, emphasizing their broader implications for brain aging.

Recent studies indicate that diet has an impact on the gut microbiome, which subsequently affects aging by enhancing gut diversity, strengthening immunity, regulating genes and facilitating communication between the gut and brain [3-5,17,18,23-25]. One significant finding is the importance of microbial diversity in influencing lifespan [19,20]. A varied gut microbiota boosts metabolic health and immune functionality, both of which are crucial for healthy aging. The diversity of gut microbes is a key element in sustaining beneficial bacteria that aid in food digestion, maintain gut barrier integrity and modulate immune responses [8- 10]. Additionally, a balanced microbiota helps hinder the growth of pathogens within the intestines as individuals age, thereby improving the symbiotic relationships among microorganisms [38- 40].

Nutrition significantly contributes to the preservation of gut microbial diversity. Components such as fiber, polyphenols and fermented foods are recognized for their role in supporting healthy populations of gut microbes [41]. The generation of SCFAs like butyrate and acetate, which are beneficial for overall health and longevity, plays a crucial role in promoting microbiome health. Gut bacteria break down fiber to create metabolites that enhance immune function by boosting regulatory T-cells (Tregs) and decreasing inflammation [42,43]. SCFAs, particularly butyrate, may help mitigate age-related cognitive decline and Neurodegenerative Diseases (NDs) by alleviating neuroinflammation [44,45]. Furthermore, SCFAs are vital for preserving the integrity of the gut barrier, keeping harmful substances from entering the bloodstream and triggering systemic inflammation, which is a significant concern linked to aging [46,47]. Elevated levels of tight junction proteins or fungal metabolites in the bloodstream may suggest gut permeability, inflammation, dementia and frailty in older individuals [48,49]. A reduction in bacteria that produce SCFAs is often linked to heightened intestinal permeability [46,47]. SCFAs, particularly butyrate, provide energy to colon cells, enhance the gut barrier and may help alleviate inflammation as well as age-related illnesses [50,51].

A study showed that an eight-week Mediterranean diet boosts helpful gut bacteria such as Faecalibacterium prausnitzii, which generates SCFAs and promotes improved health [52,53]. This eating pattern also leads to a decrease in Ruminococcus gnavus, which is linked to gut inflammation [54]. Conversely, diets high in fat and sugar promote the growth of harmful bacteria like Ruminococcus gnavus and Proteobacteria, resulting in increased gut permeability and inflammation [55,56]. Chronic low-grade inflammation, often referred to as “inflammaging,” is associated with aging and various health issues, including Cardio Vascular Disease (CVD), diabetes and NDs [57,58]. Making dietary modifications is essential for resolving inflammation. Consuming foods abundant in fiber, polyphenols and omega-3 fatty acids supports the growth of beneficial bacteria that combat inflammation [59,60]. Certain probiotics and prebiotics found in items like yogurt, kefir and fiber-rich vegetables have been demonstrated to lower the levels of pro-inflammatory cytokines [61,62]. A reduction in bacteria that produce SCFAs can contribute to inflammation among older individuals, whereas Akkermansia and Christensenellaceae are beneficial for SCFA production and immune support [63,64]. Therefore, the microbiome can potentially postpone the emergence of age-related illnesses by managing the immune system and decreasing overall inflammation, which in turn leads to healthier aging.

Microbiota-epigenome crosstalk in caloric restriction: implications for longevity

Research into aging’s molecular pathways emphasizes the importance of Caloric Restriction (CR) in metabolic functioning and inflammation reduction [65,66]. CR mimetics or medicines that can extend lifespan while also improving health, continue to be an exciting topic of research in the realm of aging [67,68]. One of the emerging mechanisms by which CR exerts its beneficial effects is through modulation of the gut microbiome [69,70]. Aging is commonly associated with reduced microbial diversity, an expansion of pro-inflammatory taxa and a decline in beneficial commensals [71]. CR has been shown to reverse these agerelated alterations by promoting a more diverse and balanced gut microbial community. In rodent models, CR increases the relative abundance of health-associated bacteria such as Lactobacillus, Bifidobacterium and Akkermansia muciniphila-the latter being linked to improved intestinal barrier function and attenuation of metabolic inflammation [72,73]. Simultaneously, CR reduces the prevalence of pathobionts and microbial signatures associated with systemic low-grade inflammation (termed “inflammaging”) [74,75].

CR also enhances the microbial production of SCFAs, particularly butyrate and propionate [76]. These SCFAs are key microbial metabolites that influence host gene expression, modulate immune responses and support mitochondrial function [77]. Their beneficial effects are partly mediated through the inhibition of Histone Deacetylases (HDACs) and activation of G-Protein-Coupled Receptors (GPRs), such as GPR41 and GPR43 [78,79]. These combined actions contribute to maintaining gut barrier integrity and reducing systemic inflammation. Moreover, studies on CR mimetics-including resveratrol, metformin and rapamycin-demonstrate their capacity to recapitulate many of the microbiome-modulating effects of CR [80,81]. Collectively, these findings underscore the central role of the diet-microbiome axis in regulating host metabolism, inflammation and longevity.

Importantly, these microbiota-driven effects of CR extend beyond immune and metabolic regulation to include modulation of the epigenome, a critical layer of gene expression control during aging [82,83]. Epigenetic mechanisms greatly influence the aging process, with microbiome metabolites influencing the epigenome via mediating SCFA-induced DNA methylation or histone modification, hence modulating gene expression [84,85]. Butyrate inhibits HDACs, activating genes linked to longevity like FOXO3 (Forkhead box O3) and SIRT1 (Sirtuin 1) [86,87]. The Mediterranean diet raises SCFAs and lowers inflammation-related DNA methylation. CR helps beneficial bacteria, increasing histone acetylation and reducing SIRT6 methylation [88,89].

The role of probiotics in systemic aging processes

Significantly, probiotics can also change gene methylation linked to immunity and oxidative stress, improving cognition and reducing cellular aging [90,91]. Emerging evidence suggests that probiotics can have beneficial actions not only by modulating intestinal microbial community but also through epigenetic remodeling of host gene expression, especially in pathways linked to immune function, oxidative stress and neurocognitive health [92-94]. Certain probiotic species, such as Lactobacillus and Bifidobacterium, modulate the action of epigenetic enzymes like DNA Methyltransferases (DNMTs) and HDACs, thus modifying patterns of DNA methylation and histone modification [95,96]. For example, supplementation with Lactobacillus plantarum has been found to restore normal methylation levels at the promoter region of IL-6, a primary pro-inflammatory cytokine, to promote decreased systemic inflammation in aging models [97,98]. Concurrently, probiotics augment SCFAs availability, notably butyrate, a well-known HDAC inhibitor. Microbial metabolites improve the expression of antioxidant defense genes like SOD2 (Superoxide Dismutase 2) and GPX1 (Glutathione Peroxidase 1), effectively preventing oxidative stress, a key promoter of cellular senescence and neurodegeneration [99,100]. Redox homeostasis, immune tolerance and metabolic control are also maintained by SCFA-mediated epigenetic regulation. In addition, the Gut-Brain Axis (GBA) is a conduit through which probiotics exert their effects on brain health by epigenetically remolding [101,102]. Probiotic treatments have been associated with alterations in neuroprotective gene expression and methylation, such as BDNF (Brain-Derived Neurotrophic Factor), which is crucial for synaptic plasticity and cognition [103,104]. Studies in animals have shown that Bifidobacterium longum or Lactobacillus rhamnosus supplementation elevates hippocampal levels of BDNF, enhances memory performance and decreases anxiety-like behavior-effects that are very likely to be mediated at least in part through epigenetic mechanisms [105,106].

Together, these findings suggest that probiotics possess the capacity to modulate host epigenetic landscapes, thereby influencing key biological processes such as immune regulation, oxidative stress response and neuroplasticity. This positions probiotics and other microbiome-targeted interventions as promising strategies for enhancing cognitive resilience and promoting healthy aging through the epigenetic modulation of aging-related molecular pathways. The evidence further supports the notion that gutdirected dietary interventions may exert systemic effects on aging and longevity by reshaping the epigenome in a manner that favors cellular homeostasis and functional preservation.

Interlinking diet, microbiota and cognitive health in the aging brain

The GBA communication between the microbiota and the aging process is critical [107,108]. Gut microorganisms produce neurotransmitters like serotonin and Gamma-Amino Butyric Acid (GABA), which are essential for mood, cognitive function and neuroplasticity [109,110]. Dysbiosis, an imbalance of gut bacteria, has been linked to neurological diseases such as depression, anxiety and cognitive loss [111,112]. Research suggests that food choices have a direct impact on the microbiome’s ability to generate these neurotransmitters. A fiber-rich diet increases SCFA production, which benefits neuroinflammation and cognitive health [5-7].

The study found that a ketogenic diet boosts the amounts of Akkermansia muciniphila and Lactobacillus, which aid in mitochondrial function and neuroprotection [113,114]. The Mediterranean diet has been proven to promote the growth of Bifidobacterium and Lactobacillus, which therefore improves serotonin metabolism and memory [115,116]. Polyphenolrich foods, such as berries and green tea, also help to boost Bifidobacterium and prevent oxidative damage, which impairs cognitive performance [117,118]. Probiotics may assist in repairing neurotransmitter synthesis pathways, lessen stress levels and reverse cognitive decline [119,120]. Nonetheless, these findings have identified diet-microbiome-longevity integration as a key area for promoting healthy aging. Nutrition, the microbiome and longevity interact in complex ways, affecting microbial diversity, SCFAs, immunity, epigenetics and the GBA. A diet rich in microbial diversity and beneficial metabolites is essential for graceful aging. As shown in Figure 1, the flowchart maps the mechanistic pathway linking diet, microbial diversity and lifespan regulation Although more research is needed, current evidence shows that dietary choices play a major role in promoting longevity and well-being.

Figure 1:The Interplay Between Diet, Gut Microbiome and Longevity. This flowchart represents the mechanistic connection between diet, gut microbiome diversity and longevity. Dietary factors, such as fiber, polyphenols, fermented foods and omega-3 fatty acids, may affect both gut microbiome composition and functions. A well-balanced microbiome boosts Short-Chain Fatty Acid (SCFA) production, mainly butyrate and acetate, which support gut homeostasis. They also help maintain the integrity of the gut mucosal barrier, reduce chronic, low-grade inflammatory responses (“inflammaging”), strengthen immunity responses and balance metabolism. SCFAs support immunity, reduce disease risk and influence gene activity by activating FOXO3 (Forkhead Box O3) and SIRT1 (Sirtuin 1), which boost stress resistance and lower inflammation. Ultimately, the integration of these mechanisms enhances immune resilience, reduces disease susceptibility and extends healthspan, highlighting the critical role of gut microbiome modulation in aging.

Taken together, while the concept of a singular “longevity diet” may be overly reductive, the evidence supporting a microbiometargeted, cognition-preserving dietary approach is increasingly robust. Promoting such dietary patterns across the lifespan may not only enhance systemic metabolic resilience but also protect the structural and functional integrity of the aging brain-positioning the gut microbiome as a central modifiable determinant in mitigating age-related cognitive decline.

Dietary interventions aimed at the microbiome are difficult to implement since the microbiota composition changes during life. Indeed, diet, environment, medication and lifestyle appear to be constantly affecting the generally orderly pattern of microbiome development from infancy to old age. The microbiome during early life is critical for immune system development and maternal nutrition and breastfeeding are especially important [121,122]. Dietary patterns in general have a more particular effect on the microbiomes of adolescents and adults. In aged individuals, where increased inflammation and NDs are associated with dysbiosis, intervention efforts should be tailored to age-related changes in the microbiome to improve health at various phases of life.

Dietary interventions should vary in accordance with timing and microbiological needs throughout a person’s life. Pre-and probiotics, for example, may assist in increasing colonization by “good” bacteria in infants, while fiber-and polyphenol-rich diets may benefit adults by increasing gut microbiota diversity and thereby aiding in metabolic health. Restoring beneficial bacteria to the gut of older adults through fermented foods, resistant starches and synbiotics may reduce age-related gut imbalances and inflammation. A tailored strategy will thus necessitate the use of additional specific biomarkers to track changes in the microbiome as a result of dietary changes. Dietary approaches should be tailored to each life stage. For example, prebiotics and probiotics may help build beneficial bacteria in early life, while fiber-and polyphenol-rich foods support microbial diversity and metabolic health in adults. In older adults, fermented foods, resistant starches and specific synbiotics can help restore healthy microbes and reduce age-related gut imbalances and inflammation. For optimal outcomes, tailored nutrition programs require reliable biomarkers to accurately assess microbiota responses to dietary interventions.

A recent study examined how diet and microbiome interact by analyzing stool, focusing on dietary components and microbial metabolites [123,124]. Metabolomic analysis of stool and other samples helps us understand how the gut processes food and how diet affects microbial changes [125,126]. They most likely find a microbial profile that is important for longevity, metabolic health and/or disease resistance. Feeding analysis, microbiome sequencing and metabolomics appear to have the potential to lead to the development of tailored diets. To improve longevity, we need to combine microbiome research, nutrition and bioinformatics. Long-term studies on diet changes and their effects on gut microbiomes can help identify links to health outcomes. AI-based methods could create personalized dietary recommendations from stool microbiome analysis, aiming to enhance lifespan and health.

Additionally, studying how climate change affects food quality and availability is important, as it may impact global microbiomes and health [127,128]. At the same time, it is important to recognize that a healthy and diverse gut microbiome typically promotes healthy aging; however, Gram-negative bacteria that may be present in probiotics or fecal microbiota may release Lipopolysaccharide (LPS), which is an endotoxin that activates TLR4-NF-κB signaling and inhibits expression and/or activity of sirtuin 1 (SIRT1) [129- 132]. LPS does not directly inhibit SIRT1 enzymatically, but rather LPS downregulates SIRT1 via pro-inflammatory pathways, thereby affecting epigenetic regulation and enhancing “inflammaging.” [133] Given SIRT1’s central role in promoting chromatin remodeling and gene expression associated with longevity, increased LPS levels when presented with dysbiotic or aged microbiota can downregulate important pathways for healthy aging [134,135]. This suggests that we need to reach a balance between microbial diversity and endotoxin burden when devising therapeutics with probiotics or fecal microbiota.

Building on this, correlating specific diets to healthy gut bacteria or isolating specific dietary components to build pharmacological compounds that can potentially expand longevity is a promising field of research. Globally, individuals adhere to specific diets due to diverse factors, including health conditions, economic constraints and cultural practices. That being said, a pharmacological approach dealing with specific dietary components may function as an option to improve gut health in the face of indifference in dietary food choices. This option will provide easier access to critical bioactive components that are not available through certain diets. These approaches, if developed, will be critical to making the microbiome’s benefits more widely available to the general public. Dietary changes that target the microbiome, combined with noninvasive tests on stool sample material and modern pharmaceutical methodologies, could lead to new approaches for promoting gut health and mitigating age-related diseases, thereby improving quality of life in various age groups.

The gut microbiota influences nutrition, metabolism, immune function and epigenetic regulation, all of which contribute to longevity and aging. A healthy and diverse microbiota can enhance the nutritional benefits of fiber-and polyphenol-rich diets by generating bioactive metabolites such as SCFAs. These metabolites play a critical role in strengthening the intestinal barrier and reducing inflammation-both key determinants of aging. Conversely, dysbiosis resulting from diets high in processed foods may accelerate aging and increase susceptibility to age-related diseases. While probiotics and fecal microbiota transplantation hold therapeutic potential, dietary intervention remains the most practical and sustainable strategy to support healthy aging. Future research should prioritize elucidating causative mechanisms and advancing personalized dietary approaches to optimize the microbiome’s impact on healthspan and quality of life.

The authors do not have anything to declare.

This research is supported by Bandhan, Kolkata, India.

Conceptualization and supervision: S. K. C.; Formal analysis: S. K. C.; Original draft preparation: S. K. C.; Writing-review and editing: S. K. C. and D. C.; Project administration: S. K. C.; Funding acquisition: S. K. C.

1. Thursby E, Juge N (2017) Introduction to the human gut microbiota. Biochem J 474(11): 1823-1836.
2. Catassi G, Mateo SG, Occhionero AS, Esposito C, Giorgio V, et al. (2024) The importance of gut microbiome in the perinatal period. Eur J Pediatr 183(12): 5085-5101.
3. Bradley E, Haran J (2024) The human gut microbiome and aging. Gut Microbes 16(1): 2359677.
4. Zhang P (2022) Influence of foods and nutrition on the gut microbiome and implications for intestinal health. Int J Mol Sci 23(17): 9588.
5. Aziz T, Hussain N, Hameed Z, Lin L (2024) Elucidating the role of diet in maintaining gut health to reduce the risk of obesity, cardiovascular and other age-related inflammatory diseases: Recent challenges and future recommendations. Gut Microbes 16(1): 2297864.
6. Soldán M, Argalášová Ľ, Hadvinová L, Galileo B, Babjaková J (2024) The effect of dietary types on gut microbiota composition and development of non-communicable diseases: A narrative review. Nutrients 16(18): 3134.
7. Beaver LM, Jamieson PE, Wong CP, Hosseinikia M, Stevens JF, et al. (2025) Promotion of healthy aging through the nexus of gut microbiota and dietary phytochemicals. Adv Nutr 16(3): 100376.
8. Van Hul M, Cani PD, Petitfils C, De Vos WM, Tilg H, et al. (2024) What defines a healthy gut microbiome? Gut 73(11): 1893-1908.
9. Hrncir T (2022) Gut microbiota dysbiosis: Triggers, consequences, diagnostic and therapeutic options. Microorganisms 10(3): 578.
10. Zhang R, Ding N, Feng X, Liao W (2025) The gut microbiome, immune modulation and cognitive decline: Insights on the gut-brain axis. Front Immunol 16: 1529958.
11. Low DY, Hejndorf S, Tharmabalan RT, Poppema S, Pettersson S (2021) Regional diets targeting gut microbial dynamics to support prolonged healthspan. Front Microbiol 12: 659465.
12. Zhang P (2022) Influence of foods and nutrition on the gut microbiome and implications for intestinal health. Int J Mol Sci 23(17): 9588.
13. Ji J, Jin W, Liu SJ, Jiao Z, Li X (2023) Probiotics, prebiotics and postbiotics in health and disease. Med Comm 4(6): e420.
14. Valentino V, Magliulo R, Farsi D, Cotter PD, Sullivan O, et al. (2024) Fermented foods, their microbiome and its potential in boosting human health. Microb Biotechnol 17(2): e14428.
15. Capra BT, Hudson S, Helder M, Laskaridou E, Johnson AL, et al. (2024) Ultra-processed food intake, gut microbiome and glucose homeostasis in mid-life adults: Background, design and methods of a controlled feeding trial. Contemp Clin Trials 137: 107427.
16. Mostafavi AH, Zhou JR (2024) Gut microbiota dysbiosis, oxidative stress, inflammation and epigenetic alterations in metabolic diseases. Antioxidants 13(8): 985.
17. Chaudhry TS, Senapati SG, Gadam S, Mannam HP, Voruganti HV, et al. (2023) The impact of microbiota on the gut-brain axis: Examining the complex interplay and implications. J Clin Med 12(16): 5231.
18. Carabotti M, Scirocco A, Maselli MA, Severi C (2015) The gut-brain axis: Interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 28(2): 203-209.
19. Wang J, Qie J, Zhu D, Zhang X, Zhang Q, et al. (2022) The landscape in the gut microbiome of long-lived families reveals new insights on longevity and aging-relevant neural and immune function. Gut Microbes 14(1): 2107288.
20. Sepp E, Smidt I, Rööp T, Štšepetova J, Kõljalg S, et al. (2022) Comparative analysis of gut microbiota in centenarians and young people: Impact of eating habits and childhood living environment. Front Cell Infect Microbiol 12: 851404.
21. Wen NN, Sun LW, Geng Q, Zheng GH (2024) Gut microbiota changes associated with frailty in older adults: A systematic review of observational studies. World J Clin Cases 12(35): 6815-6825.
22. Kadyan S, Park G, Singh TP, Patoine C, Singar S, et al. (2025) Microbiome-based therapeutics towards healthier aging and longevity. Genome Med 17(1): 75.
23. Kim B, Song A, Son A, Shin Y (2024) Gut microbiota and epigenetic choreography: Implications for human health: A review. Medicine 103(29): e39051.
24. Shock T, Badang L, Ferguson B, Martinez-Guryn K (2021) The interplay between diet, gut microbes and host epigenetics in health and disease. J Nutr Biochem 95: 108631.
25. Bure IV, Nemtsova MV, Kuznetsova EB (2022) Histone modifications and non-coding RNAs: Mutual epigenetic regulation and role in pathogenesis. Int J Mol Sci 23(10): 5801.
26. Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403(6765): 41-45.
27. Castruita PA, Piña-Escudero SD, Rentería ME, Yokoyama JS (2022) Genetic, social and lifestyle drivers of healthy aging and longevity. Curr Genet Med Rep 10(3): 25-34.
28. Tiffon C (2018) The impact of nutrition and environmental epigenetics on human health and disease. Int J Mol Sci 19(11): 3425.
29. Ramos-Lopez O, Milagro FI, Riezu-Boj JI, Martinez JA (2021) Epigenetic signatures underlying inflammation: An interplay of nutrition, physical activity, metabolic diseases and environmental factors for personalized nutrition. Inflamm Res 70(1): 29-49.
30. Číž M, Dvořáková A, Skočková V, Kubala L (2020) The role of dietary phenolic compounds in epigenetic modulation involved in inflammatory processes. Antioxidants 9(8): 691.
31. Chiu DT, Hamlat EJ, Zhang J, Epel ES, Laraia BA (2024) Essential nutrients, added sugar intake and epigenetic age in midlife black and white women: NIMHD social epigenomics program. JAMA Netw Open 7(7): e2422749.
32. Koemel NA, Skilton MR (2022) Epigenetic aging in early life: Role of maternal and early childhood nutrition. Curr Nutr Rep 11(2): 318-328.
33. Shock T, Badang L, Ferguson B, Martinez-Guryn K (2021) The interplay between diet, gut microbes and host epigenetics in health and disease. J Nutr Biochem 95: 108631.
34. Tian S, Chen M (2024) Global research progress of gut microbiota and epigenetics: Bibliometrics and visualized analysis. Front Immunol 15: 1412640.
35. Conlon MA, Bird AR (2014) The impact of diet and lifestyle on gut microbiota and human health. Nutrients 7(1): 17-44.
36. Hemachandra S, Rathnayake SN, Jayamaha AA, Francis BS, Welmillage D, et al. (2025) Fecal microbiota transplantation as an alternative method in the treatment of obesity. Cureus 17(1): e76858.
37. Ghosh TS, Shanahan F, O'Toole PW (2022) The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol 19(9): 565-584.
38. Ecklu-Mensah G, Gilbert J, Devkota S (2022) Dietary selection pressures and their impact on the gut microbiome. Cell Mol Gastroenterol Hepatol 13(1): 7-18.
39. Moles L, Otaegui D (2020) The impact of diet on microbiota evolution and human health. Is diet an adequate tool for microbiota modulation? Nutrients 12(6): 1654.
40. Quaranta G, Guarnaccia A, Fancello G, Agrillo C, Iannarelli F, et al. (2022) Fecal microbiota transplantation and other gut microbiota manipulation strategies. Microorganisms 10(12): 2424.
41. Nemzer BV, Al-Taher F, Kalita D, Yashin AY, Yashin YI (2025) Health-improving effects of polyphenols on the human intestinal microbiota: A review. Int J Mol Sci 26(3): 1335.
42. Xu X, Zhou J, Xie H, Zhang R, Gu B, et al. (2025) Immunomodulatory mechanisms of the gut microbiota and metabolites on regulatory T cells in rheumatoid arthritis. Front Immunol 16: 1610254.
43. O'Riordan KJ, Moloney GM, Keane L, Clarke G, Cryan JF (2025) The gut microbiota-immune-brain axis: Therapeutic implications. Cell Rep Med 6(3): 101982.
44. Tu J, Zhang J, Chen G (2025) Higher dietary butyrate intake is associated with better cognitive function in older adults: Evidence from a cross-sectional study. Front Aging Neurosci 17: 1522498.
45. Qian XH, Xie RY, Liu XL, Chen SD, Tang HD (2022) Mechanisms of short-chain fatty acids derived from gut microbiota in alzheimer's disease. Aging Dis 13(4): 1252-1266.
46. Vincenzo FD, Gaudio AD, Petito V, Lopetuso LR, Scaldaferri F (2024) Gut microbiota, intestinal permeability and systemic inflammation: A narrative review. Intern Emerg Med 19(2): 275-293.
47. Verma A, Bhagchandani T, Rai A, Nikita, Sardarni UK, et al. (2024) Short-Chain Fatty Acid (SCFA) as a connecting link between microbiota and gut-lung axis-a potential therapeutic intervention to improve lung health. ACS Omega 9(13): 14648-14671.
48. Escalante J, Artaiz O, Diwakarla S, McQuade RM (2025) Leaky gut in systemic inflammation: Exploring the link between gastrointestinal disorders and age-related diseases. Geroscience 47(1): 1-22.
49. Olejnik P, Golenia A, Małyszko J (2025) The potential role of microbiota in age-related cognitive decline: A narrative review of the underlying molecular mechanisms. Int J Mol Sci 26(4): 1590.
50. Du Y, He C, An Y, Huang Y, Zhang H, et al. (2024) The role of short chain fatty acids in inflammation and body health. Int J Mol Sci 25(13): 7379.
51. Kalkan AE, BinMowyna MN, Raposo A, Ahmad MF, Ahmed F, et al. (2025) Beyond the gut: Unveiling butyrate's global health impact through gut health and dysbiosis-related conditions: A narrative review. Nutrients 17(8): 1305.
52. Perrone P, D'Angelo S (2025) Gut microbiota modulation through mediterranean diet foods: Implications for human health. Nutrients 17(6): 948.
53. Abrignani V, Salvo A, Pacinella G, Tuttolomondo A (2024) The mediterranean diet, its microbiome connections and cardiovascular health: A narrative review. Int J Mol Sci 25(9): 4942.
54. Meadows V, Antonio JM, Ferraris RP, Gao N (2025) Ruminococcus gnavus in the gut: Driver, contributor or innocent bystander in steatotic liver disease? FEBS J 292(6): 1252-1264.
55. Randeni N, Bordiga M, Xu B (2024) A comprehensive review of the triangular relationship among diet-gut microbiota-inflammation. Int J Mol Sci 25(17): 9366.
56. Rondinella D, Raoul PC, Valeriani E, Venturini I, Cintoni M, et al. (2025) The detrimental impact of ultra-processed foods on the human gut microbiome and gut barrier. Nutrients 17(5): 859.
57. Müller L, Benedetto SD (2024) Inflammaging, immunosenescence and cardiovascular aging: Insights into long COVID implications. Front Cardiovasc Med 11: 1384996.
58. Andonian BJ, Hippensteel JA, Abuabara K, Boyle EM, Colbert JF, et al. (2025) Inflammation and aging-related disease: A transdisciplinary inflammaging framework. Geroscience 47(1): 515-542.
59. Yu X, Pu H, Voss M (2024) Overview of anti-inflammatory diets and their promising effects on non-communicable diseases. Br J Nutr 132(7): 898-918.
60. Cory H, Passarelli S, Szeto J, Tamez M, Mattei J (2018) The role of polyphenols in human health and food systems: A mini-review. Front Nutr 5: 87.
61. Smolinska S, Popescu FD, Zemelka-Wiacek M (2025) A review of the influence of prebiotics, probiotics, synbiotics and postbiotics on the human gut microbiome and intestinal integrity. J Clin Med 14(11): 3673.
62. Zhou P, Chen C, Patil S, Dong S (2024) Unveiling the therapeutic symphony of probiotics, prebiotics and postbiotics in gut-immune harmony. Front Nutr 11: 1355542.
63. Kumar S, Mukherjee R, Gaur P, Leal É, Lyu X, et al. (2025) Unveiling roles of beneficial gut bacteria and optimal diets for health. Front Microbiol 16: 1527755.
64. Bradley E, Haran J (2024) The human gut microbiome and aging. Gut Microbes 16(1): 2359677.
65. Surugiu R, Iancu MA, Vintilescu ȘB, Stepan MD, Burdusel D, et al. (2024) Molecular mechanisms of healthy aging: The role of caloric restriction, intermittent fasting, mediterranean diet and ketogenic diet-a scoping review. Nutrients 16(17): 2878.
66. Russo L, Babboni S, Andreassi MG, Daher J, Canale P, et al. (2025) Treating metabolic dysregulation and senescence by caloric restriction: Killing two birds with one stone? Antioxidants 14(1): 99.
67. Kim DH, Bang E, Jung HJ, Noh SG, Yu BP, et al. (2020) Anti-aging effects of Calorie Restriction (CR) and CR mimetics based on the senoinflammation concept. Nutrients 12(2): 422.
68. Shintani T, Shintani H, Sato M, Ashida H (2023) Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension. Geroscience 45(6): 3475-3490.
69. Sbierski-Kind J, Grenkowitz S, Schlickeiser S, Sandforth A, Friedrich M, et al. (2022) Effects of caloric restriction on the gut microbiome are linked with immune senescence. Microbiome 10(1): 57.
70. Singh I, Anand S, Gowda DJ, Kamath A, Singh AK (2024) Caloric restriction mimetics improve gut microbiota: A promising neurotherapeutics approach for managing age-related neurodegenerative disorders. Biogerontology 25(6): 899-922.
71. Beaver LM, Jamieson PE, Wong CP, Hosseinikia M, Stevens JF, et al. (2025) Promotion of healthy aging through the nexus of gut microbiota and dietary phytochemicals. Adv Nutr 16(3): 100376.
72. Palomba A, Tanca A, Abbondio M, Sau R, Serra M, et al. (2021) Time-restricted feeding induces Lactobacillus-and Akkermansia-specific functional changes in the rat fecal microbiota. NPJ Biofilms Microbiomes 7(1): 85.
73. Woelfel S, Silva MS, Stecher B (2024) Intestinal colonization resistance in the context of environmental, host and microbial determinants. Cell Host Microbe 32(6): 820-836.
74. Strasser B, Wolters M, Weyh C, Krüger K, Ticinesi A (2021) The effects of lifestyle and diet on gut microbiota composition, inflammation and muscle performance in our aging society. Nutrients 13(6): 2045.
75. Ghosh TS, Shanahan F, O'Toole PW (2022) The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol 19(9): 565-584.
76. Tanca A, Abbondio M, Palomba A, Fraumene C, Marongiu F, et al. (2018) Caloric restriction promotes functional changes involving short-chain fatty acid biosynthesis in the rat gut microbiota. Sci Rep 8(1): 14778.
77. Cheng J, Hu H, Ju Y, Liu J, Wang M, et al. (2024) Gut microbiota-derived short-chain fatty acids and depression: Deep insight into biological mechanisms and potential applications. Gen Psychiatr 37(1): e101374.
78. Li M, van Esch BC, Henricks PA, Folkerts G, Garssen J (2018) The anti-inflammatory effects of short chain fatty acids on lipopolysaccharide-or tumor necrosis factor α-stimulated endothelial cells via activation of GPR41/43 and inhibition of HDACs. Front Pharmacol 9: 533.
79. Tang R, Li L (2021) Modulation of short-chain fatty acids as potential therapy method for type 2 diabetes mellitus. Can J Infect Dis Med Microbiol 2021: 6632266.
80. Shintani T, Shintani H, Sato M, Ashida H (2023) Calorie restriction mimetic drugs could favorably influence gut microbiota leading to lifespan extension. Geroscience 45(6): 3475-3490.
81. Hofer SJ, Davinelli S, Bergmann M, Scapagnini G, Madeo F (2021) Caloric restriction mimetics in nutrition and clinical trials. Front Nutr 8: 717343.
82. Ideraabdullah FY, Zeisel SH (2018) Dietary modulation of the epigenome. Physiol Rev 98(2): 667-695.
83. Zhai J, Kongsberg WH, Pan Y, Hao C, Wang X, et al. (2023) Caloric restriction induced epigenetic effects on aging. Front Cell Dev Biol 10: 1079920.
84. Borrego-Ruiz A, Borrego JJ (2024) Epigenetic mechanisms in aging: Extrinsic factors and gut microbiome. Genes 15(12): 1599.
85. Zhang Q, Liu Y, Li Y, Bai G, Pang J, et al. (2025) Implications of gut microbiota-mediated epigenetic modifications in intestinal diseases. Gut Microbes 17(1): 2508426.
86. Wei X, Xiong X, Wang P, Zhang S, Peng D (2024) SIRT1-mediated deacetylation of FOXO3 enhances mitophagy and drives hormone resistance in endometrial cancer. Mol Med 30(1): 147.
87. Omorou M, Huang Y, Gao M, Mu C, Xu W, et al. (2023) The forkhead box O3 (FOXO3): A key player in the regulation of ischemia and reperfusion injury. Cell Mol Life Sci 80(4): 102.
88. Tsigalou C, Konstantinidis T, Paraschaki A, Stavropoulou E, Voidarou C, et al. (2020) Mediterranean diet as a tool to combat inflammation and chronic diseases an overview. Biomedicines 8(7): 201.
89. Kenanoglu S, Gokce N, Akalin H, Ergoren MC, Beccari T, et al. (2022) Implication of the mediterranean diet on the human epigenome. J Prev Med Hyg 63(2 Suppl 3): E44-E55.
90. Abouelela ME, Helmy YA (2024) Next-generation probiotics as novel therapeutics for improving human health: Current trends and future perspectives. Microorganisms 12(3): 430.
91. Ong JS, Lew LC, Hor YY, Liong MT (2022) Probiotics: The next dietary strategy against brain aging. Prev Nutr Food Sci 27(1): 1-13.
92. Vitetta L, Bambling M, Strodl E (2023) Probiotics and commensal bacteria metabolites trigger epigenetic changes in the gut and influence beneficial mood dispositions. Microorganisms 11(5): 1334.
93. Liu Y, Hu Y, Ma B, Wang Z, Wei B (2025) Gut microbiota and exercise: Probiotics to modify the composition and roles of the gut microbiota in the context of 3p medicine. Microb Ecol 88(1): 38.
94. Latif A, Shehzad A, Niazi S, Zahid A, Ashraf W, et al. (2023) Probiotics: Mechanism of action, health benefits and their application in food industries. Front Microbiol 14: 1216674.
95. Zhang Q, Liu Y, Li Y, Bai G, Pang J, et al. (2025) Implications of gut microbiota-mediated epigenetic modifications in intestinal diseases. Gut Microbes 17(1): 2508426.
96. Lin X, Han H, Wang N, Wang C, Qi M, et al. (2024) The gut microbial regulation of epigenetic modification from a metabolic perspective. Int J Mol Sci 25(13): 7175.
97. Zhao W, Peng C, Sakandar HA, Kwok LY, Zhang W (2021) Meta-analysis: Randomized trials of lactobacillus plantarum on immune regulation over the last decades. Front Immunol 12: 643420.
98. Xiao X, Cui T, Qin S, Wang T, Liu J, et al. (2024) Beneficial effects of Lactobacillus plantarum on growth performance, immune status, antioxidant function and intestinal microbiota in broilers. Poult Sci 103(12): 104280.
99. Tsao SP, Nurrahma BA, Kumar R, Wu CH, Yeh TH, et al. (2021) Probiotic enhancement of antioxidant capacity and alterations of gut microbiota composition in 6-hydroxydopamin-induced parkinson's disease rats. Antioxidants 10(11): 1823.
100. Lee JY, Kang CH (2022) Probiotics alleviate oxidative stress in H₂O₂-exposed hepatocytes and t-BHP-induced C57BL/6 mice. Microorganisms 10(2): 234.
101. Munteanu C, Galaction AI, Turnea M, Blendea CD, Rotariu M, et al. (2024) Redox homeostasis, gut microbiota and epigenetics in neurodegenerative diseases: A systematic review. Antioxidants 13(9): 1062.
102. O'Riordan KJ, Moloney GM, Keane L, Clarke G, Cryan JF (2025) The gut microbiota-immune-brain axis: Therapeutic implications. Cell Rep Med 6(3): 101982.
103. Kumar A, Sivamaruthi BS, Dey S, Kumar Y, Malviya R, et al. (2024) Probiotics as modulators of gut-brain axis for cognitive development. Front Pharmacol 15: 1348297.
104. Molska M, Mruczyk K, Cisek-Woźniak A, Prokopowicz W, Szydełko P, et al. (2024) The influence of intestinal microbiota on BDNF levels. Nutrients 16(17): 2891.
105. Salami M (2021) Interplay of good bacteria and central nervous system: Cognitive aspects and mechanistic considerations. Front Neurosci 15: 613120.
106. Skalny AV, Aschner M, Gritsenko VA, Martins AC, Tizabi Y, et al. (2024) Modulation of gut microbiota with probiotics as a strategy to counteract endogenous and exogenous neurotoxicity. Adv Neurotoxicol 11: 133-176.
107. Chaudhry TS, Senapati SG, Gadam S, Mannam HP, Voruganti HV, et al. (2023) The impact of microbiota on the gut-brain axis: Examining the complex interplay and implications. J Clin Med 12(16): 5231.
108. Jamerlan AM, An SSA, Hulme JP (2025) Microbial diversity and fitness in the gut-brain axis: Influences on developmental risk for alzheimer's disease. Gut Microbes 17(1): 2486518.
109. Mhanna A, Martini N, Hmaydoosh G, Hamwi G, Jarjanazi M, et al. (2024) The correlation between gut microbiota and both neurotransmitters and mental disorders: A narrative review. Medicine 103(5): e37114.
110. Rathore K, Shukla N, Naik S, Sambhav K, Dange K, et al. (2025) The bidirectional relationship between the gut microbiome and mental health: A comprehensive review. Cureus 17(3): e80810.
111. Xiong RG, Li J, Cheng J, Zhou DD, Wu SX, et al. (2023) The role of gut microbiota in anxiety, depression and other mental disorders as well as the protective effects of dietary components. Nutrients 15(14): 3258.
112. Kandpal M, Indari O, Baral B, Jakhmola S, Tiwari D, et al. (2022) Dysbiosis of gut microbiota from the perspective of the gut-brain axis: Role in the provocation of neurological disorders. Metabolites 12(11): 1064.
113. Pietrzak D, Kasperek K, Rękawek P, Piątkowska-Chmiel I (2022) The therapeutic role of ketogenic diet in neurological disorders. Nutrients 14(9): 1952.
114. Zhu H, Bi D, Zhang Y, Kong C, Du J, et al. (2022) Ketogenic diet for human diseases: The underlying mechanisms and potential for clinical implementations. Signal Transduct Target Ther 7(1): 11.
115. Cardelo MP, Corina A, Leon-Acuña A, Quintana-Navarro GM, Alcala-Diaz JF, et al. (2022) Effect of the mediterranean diet and probiotic supplementation in the management of mild cognitive impairment: Rationale, methods and baseline characteristics. Front Nutr 9: 1037842.
116. Barber TM, Kabisch S, Pfeiffer AF, Weickert MO (2023) The effects of the mediterranean diet on health and gut microbiota. Nutrients 15(9): 2150.
117. Jawhara S (2024) How do polyphenol-rich foods prevent oxidative stress and maintain gut health? Microorganisms 12(8): 1570.
118. Plamada D, Vodnar DC (2021) Polyphenols-gut microbiota interrelationship: A transition to a new generation of prebiotics. Nutrients 14(1): 137.
119. Kim CS, Cha L, Sim M, Jung S, Chun WY, et al. (2021) 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. J Gerontol A Biol Sci Med Sci 76(1): 32-40.
120. Kumar A, Sivamaruthi BS, Dey S, Kumar Y, Malviya R, et al. (2024) Probiotics as modulators of gut-brain axis for cognitive development. Front Pharmacol 15: 1348297.
121. DuPont HL, Salge MM (2023) The importance of a healthy microbiome in pregnancy and infancy and microbiota treatment to reverse dysbiosis for improved health. Antibiotics 12(11): 1617.
122. Davis EC, Castagna VP, Sela DA, Hillard MA, Lindberg S, et al. (2022) Gut microbiome and breast-feeding: Implications for early immune development. J Allergy Clin Immunol 150(3): 523-534.
123. Dinsmoor AM, Aguilar-Lopez M, Khan NA, Donovan SM (2021) A systematic review of dietary influences on fecal microbiota composition and function among healthy humans 1-20 years of age. Adv Nutr 12(5): 1734-1750.
124. Shinn LM, Mansharamani A, Baer DJ, Novotny JA, Charron CS, et al. (2023) Fecal metabolites as biomarkers for predicting food intake by healthy adults. J Nutr 152(12): 2956-2965.
125. Vernocchi P, Chierico FD, Putignani L (2016) Gut microbiota profiling: Metabolomics based approach to unravel compounds affecting human health. Front Microbiol 7: 1144.
126. Nandy D, Craig SJ, Cai J, Tian Y, Paul IM, et al. (2022) Metabolomic profiling of stool of two-year old children from the INSIGHT study reveals links between butyrate and child weight outcomes. Pediatr Obes 17(1): e12833.
127. Sosa-Holwerda A, Park OH, Albracht-Schulte K, Niraula S, Thompson L, et al. (2024) The role of artificial intelligence in nutrition research: A scoping review. Nutrients 16(13): 2066.
128. Arslan NÇ, Gündoğdu A, Tunali V, Topgül OH, Beyazgül D, et al. (2022) Efficacy of AI-assisted personalized microbiome modulation by diet in functional constipation: A randomized controlled trial. J Clin Med 11(22): 6612.
129. Xiao Y, Feng Y, Zhao J, Chen W, Lu W (2025) Achieving healthy aging through gut microbiota-directed dietary intervention: Focusing on microbial biomarkers and host mechanisms. J Adv Res 68: 179-200.
130. Sharma A, Martins IJ (2023) The role of microbiota in the pathogenesis of alzheimer’s disease. Acta Scientific Nutritional Health 7(7): 108-118.
131. Martins IJ (2018) Bacterial lipopolysaccharides and neuron toxicity in neurodegenerative diseases. Neurology Research and Surgery 1(1): 1-3.
132. Martins IJ (2017) The future of genomic medicine involves the maintenance of sirtuin 1 in global populations. Int J Mol Biol 2(1): 00013.
133. Tan SY, Zhang J, Tee WW (2022) Epigenetic regulation of inflammatory signaling and inflammation-induced cancer. Front Cell Dev Biol 10: 931493.
134. Zhao L, Cao J, Hu K, He X, Yun D, et al. (2020) Sirtuins and their biological relevance in aging and age-related diseases. Aging Dis 11(4): 927-945.
135. Samoilova EM, Romanov SE, Chudakova DA, Laktionov PP (2024) Role of sirtuins in epigenetic regulation and aging control. Vavilovskii Zhurnal Genet Selektsii 28(2): 215-227.