How Diet, Gut Bacteria, and Aging Are Connected

The human gut, with its 200–300 m² of surface area, is home to around 30–40 trillion different microbes (symbionts including 50 bacterial groups and 100–1000 species), together called the "gut microbiota". This is roughly comparable in number to human cells, giving an approximate 1:1 ratio. These microbes outnumber the body's own cells by about ten to one. The combined genetic material of these microbes is called the "microbiome", and it is about 150 times larger than the human genome. In each person, around 150–170 main bacterial species thrive in the gut's warm, nutrient-rich environment, where they carry out important protective, metabolic, and structural roles [5].

The human gut microbiota is made up of various microorganisms, including viruses, bacteria, archaea, parasites, and eukaryotic microbes. The microenvironment of the gut mainly supports the growth of bacteria that belong to seven dominant groups: Bacteroidetes, Proteobacteria, Firmicutes, Cyanobacteria, Verrucomicrobia, Actinobacteria, and Fusobacteria (Figure 1). When analyzing these, Firmicutes and Bacteroidetes together account for over 90% of the prevailing bacterial population. Many of the bacterial species that belong to the phylum Bacteroidetes are categorized under the genera Prevotella and Bacteroides. In the Firmicutes group, key species include Clostridium clusters IV and XIVa, which are particularly from the genera Ruminococcus, Clostridium, and Eubacterium, the genera that are predominant in the gut [6].

The human microbiome experiences several crucial changes throughout life. From birth, there is an accelerated growth of different microbial species that help to form the infant's microbiome, leading to an initial development of the infant's microbiome, which varies depending on the mode of delivery and whether the infant is fed formula, milk, or breast milk. Around the age of three, almost all the gut microbiota begin to stay more stable, fully developed, and strong. This stability continues into adulthood, with minor changes caused by daily cycles and lifestyle habits like diet, physical activity, smoking, the use of antibiotics, and place of residence [7].

Children who were only fed breast milk tend to have a higher number of beneficial bacteria, especially Bifidobacteria, than children who received formula milk. When milk is replaced with solid food, the gut microbiome undergoes significant changes. After this shift, Firmicutes and Bacteroidetes become the main types of bacteria and remain dominant throughout childhood [6].

The composition of the gut microbiome gradually grows over time, along with the ability to digest complex carbohydrates and foreign compounds, like xenobiotics, to form vitamins. By the age of three, a child's microbiota is similar to that of an adult, although some groups of microbes only fully develop during adolescence [6].

Gut microbiota has several important functions that contribute to the wellness and health of an individual. The gut microbiome, rather than the human genome, plays a crucial role in the metabolism of dietary carbohydrates [8]. Bacteria in the gut assist in the development of the immune system, protect against pathogenic microbes, and play an important role in xenobiotic metabolism, aiding in the digestion of carbohydrates. During the digestion of carbohydrates, short-chain fatty acids (SCFAs) such as acetate, propionate, and butyrate are produced. The amount of carbohydrate intake, along with the ability of the microbes to inhabit the intestine, determines the type and amount of fatty acid chain synthesized [9].

Through collaboration with species specialized in oligosaccharide fermentation (e.g., Bifidobacteria), Firmicutes and Bacteroidetes produce SCFAs from indigestible carbohydrates that escape digestion in the small intestine. SCFAs constitute approximately two-thirds of the colonic anion concentration (70–130 mmol/L) [8].

Some of the most important roles of these microbes are to help maintain the integrity of the mucosal barrier, to provide nutrients, such as vitamins, or to protect against pathogens. In addition, the interaction between commensal microbiota and the mucosal immune system is crucial for proper immune function [10]. They contribute to epithelial homeostasis, promote wound healing, and regulate mucus production and glycosylation. Through interactions with immune receptors, they stimulate the production of antimicrobial peptides, secretory IgA, and anti-inflammatory mediators while also preventing pathogen colonization. Disruptions in this microbial ecosystem due to antibiotics or poor diet can impair these functions, increasing susceptibility to infections, inflammation, and metabolic disorders [10].

A healthy host–microorganism balance must be respected in order to optimally perform metabolic and immune functions and prevent disease development [11]. Various perinatal determinants, such as cesarean section delivery, type of feeding, antibiotic treatment, gestational age, or environment, can affect the pattern of bacterial colonization and result in dysbiosis. The alteration of the early bacterial gut pattern can persist over several months and may have long-lasting functional effects with an impact on disease risk later in life. In elderly individuals, reduced diversity and loss of beneficial taxa weaken intestinal barrier function and promote low-grade systemic inflammation. This immune dysregulation contributes to conditions such as type 2 diabetes, cardiovascular disease, and frailty. In parallel, microbial metabolites, including short-chain fatty acids and tryptophan derivatives, interact with the neuroendocrine system through the gut–brain axis, influencing cognitive decline and mood disorders. These diseases, by sustaining chronic inflammation and oxidative stress, accelerate biological aging and weaken resilience against further insults. Neurodegenerative changes, vascular damage, and metabolic dysfunction amplify functional decline, thereby linking dysbiosis-driven disorders directly to unhealthy aging. Dysbiosis is, therefore, not only a feature of aging but also a driver of its comorbidities. Hence, the gut microbiota interacts extensively with the host, and there are accumulating data linking many human diseases—such as inflammatory bowel disease, obesity, diabetes, asthma, and allergies—with dysbiosis, that is, an alteration in its composition [12].

The composition of the human gut microbiota varies along the GI tract due to variations in pH, O₂ tension, digesta flow rates, substrate availability, and host secretions. Due to infant transitions and age, changes may occur within the same individual. The small intestine provides a more challenging environment for microbial colonizers, given the fairly short transit times (3–5 h) and the high bile concentrations. In contrast, the large intestine, characterized by slow flow rates and neutral to mildly acidic pH, harbors by far the largest microbial community [11]. A shift in diet composition can have an impact on this ratio as gut microbiota responds quickly (within 24 h) to changes in diet in both people and mice [13].

The Mediterranean diet (MD), acknowledged by UNESCO (United Nations Educational, Scientific, and Cultural Organization) as part of the world's intangible cultural heritage, is widely recognized for its nutritional benefits. It emphasizes high consumption of fruits, vegetables, legumes, nuts, and minimally processed cereals, includes moderate amounts of fish, limits the intake of saturated fats, red meat, and dairy, and allows for regular but moderate alcohol consumption, typically in the form of red wine during meals [22]. The main source of dietary lipid in the MD is olive oil, and the diet requires an adequate amount of water each day [18]. Other than recommending different dietary components, the MD emphasizes physical activity to support both physical and mental well-being. A great advantage of this diet is its dependence on traditional and locally found food products, aligning food choices with seasonal harvests and promoting a diverse intake of food products [18].

Beyond its widely recognized nutritional value, greater adherence to the Mediterranean diet has been associated with a notable decline in both mortality and morbidity indicators [23]. Particularly, the MD has also been linked to an increment in beneficial gut microbiota composition, including a decline in proteobacterial levels and enhanced production of short-chain fatty acids (SCFAs) [32]. The elevated fecal SCFA levels observed normally reflect the increased microbial fermentation of indigestible carbohydrates that reach the colon [22].

The favorable shifts in gut microbiota linked to the MD are mainly due to dietary components such as dietary fiber, extra virgin olive oil, and polyunsaturated fats (PUFAs), particularly omega-3 fatty acids. These components support the growth of SCFA-producing bacteria, like Clostridium leptum and Eubacterium rectale, as well as other beneficial taxa, including Bifidobacteria, Bacteroides, and Faecalibacterium prausnitzii. In contrast, a notable decline in certain Firmicutes, particularly Blautia species, has also been observed [33].

One special observation in MD adherence is its potential to reduce harmful bacteria. Studies prove that high adherence to the MD was associated with lower counts of E. coli, an indicator pathogenic bacterium. Additionally, the MD has improved the Bifidobacteria/E. coli ratio, an indicator of gut microbial balance and overall health of a person. Similarly, sustained intake of polysaccharide-rich diets has been linked to declines in Enterobacteriaceae, such as Shigella and Escherichia, and dietary antioxidants can retard the growth of E. coli strains [22]. In line with this, another study, utilizing the MedDietScore, a validated index measuring adherence to the Mediterranean diet, observed that individuals with higher MedDietScores exhibited lower levels of E. coli, increased total bacterial counts, improved Bifidobacteria/E. coli ratios, and had a greater prevalence of Candida albicans and short-chain fatty acids (SCFAs) [23].

Despite these well-documented advantages, older adults worldwide have limited adaptation to the MD. One of the major challenges in elderly healthcare is the prevalence of restricted diets, particularly in long-term care settings, which is linked to a reduction in gut microbiome diversity. In a 6-month dietary intervention study, elderly participants received a daily supplement of 20 g of five prebiotic compounds. Even though this supplementation showed microbial shifts, no considerable changes in overall diversity or statistically strong reductions in inflammatory markers were observed. This suggests that even though prebiotics, like therapeutic supplements, are given without a broader adoption of the MD, measurable improvements may not be produced [32].

Over the last hundred years, industrial agriculture and modern food processing have significantly changed the way people eat by creating a critical shift toward diets rich in saturated fats, refined sugars, salt, and artificial sweeteners while reducing the intake of fiber-rich, plant-based carbohydrates [34]. The Western diet, often defined by these characteristics, has become a major factor influencing gut microbiota composition and function.

This Western dietary pattern, typically high in saturated fats and simple sugars, has been strongly linked to gut dysbiosis, a disruption in the normal microbial balance. Western diets modify the diversity, structure, and metabolic capabilities of the gut microbiota. They diminish the presence of beneficial saccharolytic bacteria that ferment fiber while fostering the growth of bile-tolerant and potentially harmful microorganisms, such as Bilophila wadsworthia. These alterations may occur within just 1–2 days of adopting a Western diet, and some shifts may persist even after reverting to a healthier dietary pattern [35]. More importantly, high-fat diets, which are one of the main components of a Western diet, can enhance the ratio of Firmicutes to Bacteroidetes, although this outcome is not always consistent across individuals.

While being consistent with previous observations, a study on Syrian hamsters revealed that a Western diet marked by high fat and high fructose could significantly induce rapid shifts in microbial communities just within a week. The Western diet led to an elevated ratio of Firmicutes/Bacteroidetes bacteria and a marked drop in beneficial genera, like Prevotella. Simultaneously, an expansion in microbial taxa, such as Ruminococcaceae and Roseburia, was observed, reflecting the fact that alterations have taken place in microbial metabolic output, including the production of short-chain fatty acids and branched-chain amino acids [28]. Moreover, commonly used emulsifiers in processed foods, such as carboxymethylcellulose (CMC), have been shown to negatively impact the gut microbiota by reducing the populations of beneficial microbes, like Faecalibacterium prausnitzii and Ruminococcus spp., while increasing Roseburia sp. and Lachnospiraceae, which were proven through human trials. Even though Roseburia is usually considered beneficial, its role is not absolute. Abundance can vary depending on diet quality and interactions with other microbes. In low-fiber, high-fat contexts, its increase does not necessarily mean positive outcomes because metabolite balance and microbial interactions are altered. Furthermore, although fecal lipopolysaccharide (LPS) levels were not significantly changed, there is a possibility of compromising the gut barrier integrity and disruption of host–microbiota interactions [36]. Ultra-processed foods, which are a staple of the Western diet, have also been linked to microbiota imbalances favoring pro-inflammatory bacterial species.

These negative alterations in gut microbiota composition are further enhanced by other Western diet components such as refined sugars, acellular nutrients, and food additives. Such components can modify the microbial composition, reduce the gut barrier integrity, and impair immune function. Furthermore, some studies show that these diet-mediated microbial changes may be transmitted across generations through epigenetic mechanisms, implying the negative effect of long-term poor dietary choices and the requirement of food regulation that prioritizes microbial health [37].

Both animal and human studies have demonstrated the fact that the consumption of red and processed meat, a typical dietary component of the Western diet, can significantly influence the gut microbiome composition. Individuals with high intake of these foods have a gut microbial composition predominated by Bacteroides-rich microbiota rather than a Prevotella-rich one. This microbial profile is noteworthy because Bacteroides species are more efficient at converting dietary L-carnitine, prevalent in red meat, into trimethylamine (TMA), a compound subsequently oxidized in the liver to form trimethylamine-N-oxide (TMAO), a metabolite strongly associated with atherosclerosis and adverse cardiovascular outcomes [38]. Additionally, the Western diet, which is high in saturated fatty acids (SFAs), has been shown to promote the proportion of Gram-negative bacteria, potentially contributing to further microbial imbalance and inflammation [39]. In addition to altering microbiota composition, the Western diet disrupts microbial function by modifying the nutrient landscape available to gut microbes. These changes can impair microbial signaling pathways and weaken gut barrier integrity. While a balanced diet supports microbial homeostasis and barrier function, the pro-inflammatory nature of Western dietary patterns contributes to compromised epithelial defenses and dysregulated host–microbe communication, establishing a self-reinforcing cycle of gut dysbiosis [34].

A plant-based diet is generally characterized by its high intake of plant-based foods while limiting the consumption of animal-based products. The diet usually includes whole grains, fruits, vegetables, legumes, and nuts, which have been associated with reduced risk of several chronic conditions [40]. The specific composition of such diets appears to play a pivotal role in shaping the gut microbiota.

Both vegetarian and vegan diets are associated with a distinct gut microbial profile characterized by greater overall diversity and increased abundance of several taxa involved in the metabolism of plant polysaccharides. These vegetarian and vegan diets are often characterized by their potential to increase levels of Ruminococcus, Eubacterium rectale, and Roseburia, while shifting the Bacteroidetes to Firmicutes ratio in a significant manner. These changes appear to stem from high intake of dietary fiber and polyphenols, along with limited consumption of animal-based nutrients. Collectively, these adaptations foster an intestinal environment better equipped to ferment complex plant substrates and support gut health [41].

Microbial diversity has been positively associated with increased variety in plant-based food intake. Consumption of a broad range of plant-based products offers a higher range of substrates that support the proliferation of multiple microbial taxa [17]. As an example, consumption of dietary fiber and resistant starch has been linked to a significant increment in microbial diversity and selectively promotes the growth of species like Lactobacillus, Ruminococcus, and E. rectale, which ferment these substrates in the colon [42].

On the other hand, going beyond the shaping of microbial composition, plant-based diets lead to meaningful functional adaptations within the gut ecosystem. Continuous intake of a vegetarian diet has been linked to a diminished microbial capacity for carnitine metabolism, a compound abundant in red meat that can be converted to pro-atherogenic metabolites, such as trimethylamine-N-oxide. Simultaneously, an enhanced expression of microbial genes related to nitrogen assimilation was observed, reflecting a lower intake of animal-derived amino acids. These findings illustrate a metabolic reprogramming of the gut ecosystem in response to plant-based nutrient inputs [30].

Consistently, individuals adhering to vegetarian diets exhibit relative abundances of Clostridium species and Bilophila wadsworthia compared to omnivores, suggesting a gut microbiota composition that is less dependent on animal-based products [43]. A study reported the same kind of result, indicating that the people who adhere to vegetarian diets show particularly elevated levels of Bacteroidetes-related taxa when compared to omnivores. These observations suggest that sustained plant-based eating supports a more complex and diverse microbial ecosystem [44].

Vegans, in particular, display a distinct gut microbial profile. One study reported that exclusive consumption of plant-based foods was associated with elevated abundance of Bacteroidetes and higher levels of Lachnospira, a genus specialized in fiber fermentation. Concurrently, reduced levels of Enterobacteriaceae and Streptococcus were observed, suggesting a microbial community that is less prone to pro-inflammatory activity [45]. Another study reported an elevated abundance of Akkermansia muciniphila, a mucin-degrading bacterium known for reinforcing gut barrier integrity and exerting anti-inflammatory effects, adding further support to the view that vegan dietary patterns promote intestinal homeostasis [46].

However, plant-based diets do not uniformly elevate all beneficial microbial taxa. In one study, individuals adhering to a vegan diet exhibited significantly lower levels of Bifidobacterium and Bacteroides compared to omnivores, potentially reflecting the reduced intake of dietary fats and proteins. This suggests a distinctive microbial restructuring, where certain populations decline while others, particularly those adept at utilizing complex carbohydrates, proliferate in response to the prevailing nutrient landscape [31]. Additionally, adherence to a vegan diet has been associated with a lower stool pH, a shift that coincided with decreased populations of Escherichia coli and Enterobacteriaceae. This more acidic gut environment may contribute to the suppression of potentially pathogenic microbes, supporting a microbial ecosystem less conducive to inflammation and disease [47].

Collectively, these findings underscore that vegetarian and vegan diets influence not just the composition of the gut microbiota but also its functional and ecological dynamics. By enhancing microbial diversity, shifting nutrient-processing pathways, and altering gut pH and overall richness, plant-based eating patterns appear to cultivate a microbial ecosystem finely tuned for the fermentation of complex carbohydrates and the support of host health.

Shaping gut microbial composition and metabolic activity is one of the major roles played by carbohydrates, especially non-digestible dietary fiber. While digestible carbohydrates provide energy for the host, other fibers, including oligosaccharides and resistant starches, are fermented to short-chain fatty acids (mainly butyrate) by gut microbes. Through this fermentation, microbial diversity is promoted, and the proliferation of taxa adapted to plant-derived substrates is enhanced while establishing a metabolically active and resilient gut ecosystem [13].

The beneficial impacts of dietary fiber on gut microbiota have been discussed in several studies. Such a study reported that supplementation with microbiota-accessible carbohydrates increased microbial richness and promoted the growth of Bacteroides, Prevotella, Bifidobacterium, and Faecalibacterium, species known for fermenting prebiotics into SCFAs, like acetate and butyrate. These shifts were involved in improved gut barrier integrity, thicker mucus layers, and better cognitive performance [63]. Another study observed that greater fiber intake by older adults led to increased abundances of Bifidobacterium, Lactobacillus, and Akkermansia while increasing SCFA levels. This reinforced the idea that fiber sustains fermentative microbes and supports gut health with age [64].

Across diverse populations, microbial responsiveness to fiber is consistent. A study that utilized 21 short-term dietary fiber interventions observed consistent shifts in gut bacterial communities, even though the participants showed high individual variation, mainly in genera such as Bifidobacterium, Lactobacillus, Ruminococcus, and Prevotella [65]. Another study reported that higher plant-derived fiber intake by older adults who are at risk of frailty showed elevated levels of Faecalibacterium prausnitzii and Bifidobacterium. The SCFAs that were produced by these taxa contributed to the improvement of muscle strength and preservation through enhanced mitochondrial function and anabolic muscle signaling [66].

The host's metabolic activities and immune health are linked to the production of SCFAs. In a study, mice were fed fiber-enriched high-fat diets. This diet elevated butyrate and acetate levels, and enrichment of microbial diversity was observed. Further, enhancement of intestinal epithelial barrier function was also observed while fueling colonocytes and suppressing inflammation. As a result, Akkermansia and Bifidobacterium species were also found in elevated levels [67]. Further, another study supplied microbiota-accessible carbohydrates to a Clostridium difficile infection (CDI) model, which resulted in elevated SCFA production while suppressing pathogen growth and reducing microbial burden. Even though animal studies help to understand how carbohydrates affect gut microbiota, they have limits. Mice have different gut microbes and body systems than humans, so the results may not fully apply. The diets used in the study are simpler than real human diets. Also, antibiotics were used to trigger infection, which does not match all human cases [68]. In addition to these, the growth of Akkermansia muciniphila and butyrate-producing taxa, like Faecalibacterium, was promoted through increased intake of complex carbohydrates. The fermented products produced by these microorganisms serve as mitochondrial fuel and epigenetic regulators. Since butyrate can inhibit histone deacetylases, activate gut-expressed G protein-coupled receptors, and help preserve epithelial integrity, aging pathways and a healthy lifespan are promoted. However, while animal and cellular studies suggest that fiber-derived SCFAs influence pathways related to longevity, mechanistic evidence directly linking fiber intake to human lifespan is still limited [69].

Garlic, bananas, and chicory root are rich in microbiota-accessible carbohydrates (MACs). The systemic relevance of MACs, including inulin, oligofructose, raffinose, and cellulose, was demonstrated by a study that indicated that MACs promoted saccharolytic fermentation and enriched Lactobacillus and Faecalibacterium prausnitzii. Further, it emphasized that improvement in gut barrier integrity, reduction in inflammation, and modulation of insulin sensitivity and lipid profiles were observed by the action of MACs through promoting the production of SCFAs. Additionally, an increment in Bifidobacterium species and suppression of Clostridium clusters were observed due to inulin supplementation. Further, the study demonstrated that an irreversible reduction in microbial diversity and mucus layer thickness can occur due to long-term fiber deprivation, even though fiber reintroduction is performed later. This fact highlights that consistent dietary intake is important [70].

Fats are essential macronutrients that supply energy, support cellular membrane structure, and regulate both metabolic and inflammatory pathways. Dietary fats are broadly categorized according to their chemical structure. Mainly, they are categorized as saturated fats and unsaturated fats. The unsaturated fats are then further categorized as monounsaturated (MUFAs) and polyunsaturated fatty acids (PUFAs). The physiological impact of these fats and their effect on gut microbiota is determined by these structural changes [71].

Western diets are typically characterized by high intake of saturated fats. Unfavorable microbial and metabolic outcomes have been consistently linked to this high intake of saturated fats. The promotion of gut dysbiosis, linked to reduced microbial diversity and a decline in beneficial bacteria, like Bifidobacterium, Faecalibacterium, and Lactobacillus, is the main disadvantage of these saturated fat-rich diets. On the other hand, the growth of pro-inflammatory taxa such as Clostridium, Prevotella, and Enterococcus is promoted by these diets while impairing gut barrier function and increasing systemic inflammation [72,73]. In a study related to maternal nutrition, the subjects were fed a high-fat lard-based diet during pregnancy and lactation. The results showed persistent alterations in the offspring's gut microbiota, including increased Firmicutes and Lachnospiraceae, larger adipocytes, VAT fibrosis, and elevated inflammatory markers. However, these negative effects were observed to be reversed by supplementing a diet rich in omega-3-rich flaxseed oil. There, the production of beneficial microbial metabolites, like Hippurate, increased, thereby enriching the Clostridium, Oscillospira, and Rikenellaceae species [74].

When considering unsaturated fatty acids, especially when fish and plant oils rich in omega-3 polyunsaturated fatty acids (PUFAs) are consumed, they exert protective effects on both the gut and the brain, but not all studies agree on high-fat diet effects, and the context of overall diet and baseline microbiota matters. The growth of beneficial microbes, including Bifidobacterium, Roseburia, and Faecalibacterium prausnitzii, has been shown to be promoted by omega-3 fatty acids while enhancing mucosal barrier integrity and reducing gut-derived endotoxin levels, including lipopolysaccharides (LPSs) [72,73,75]. Other than that, improvement of metabolic regulation, cognitive function, and reduction in inflammation have also been observed through modulation of the gut–brain axis while reducing the risk of age-related cognitive decline.

In a study, after six weeks of consuming a modified Mediterranean ketogenic diet (MMKD), older adults with mild cognitive impairment exhibited significant changes in gut microbiota composition, including increased abundance of Enterobacteriaceae, Akkermansia, Slackia, and Christensenellaceae, and decreased levels of Bifidobacterium and Lachnobacterium [76].

Long-term consumption of high-fat diets, especially those rich in saturated fats, leads to gut dysbiosis characterized by reduced levels of beneficial bacteria, like Bifidobacterium and Akkermansia, and increased pro-inflammatory species, such as Firmicutes and Proteobacteria. These changes contribute to systemic inflammation and metabolic disorders. In contrast, short-term dietary interventions, even brief exposure to emulsifiers or high-fat meals, can already reduce microbial diversity and compromise gut barrier integrity. The type of fat also matters. Unsaturated fats promote microbial balance and anti-inflammatory effects, while saturated fats consistently disrupt microbial richness and elevate inflammation-related taxa. Chronic inflammation driven by these microbial shifts accelerates aging by promoting immunosenescence and tissue degeneration [13].

Despite the source, animal and plant proteins play a key role in shaping gut microbiota-mediated outcomes associated with aging in different ways. Red meat and dairy, prominent sources of animal proteins, enhance the production of trimethylamine (TMA), which is then converted into trimethylamine-N-oxide (TMAO), a metabolite linked to cardiovascular disease and metabolic aging. But, while promoting the production of SCFAs, plant proteins support lipid regulation, microbial diversity, and potentially healthier aging trajectories [77,78].

Proteins and their derivatives, like peptides and hydrolysates, possess prebiotic potential. By skipping the full digestion in the upper gastrointestinal tract, these compounds reach the colon and promote the growth of beneficial microbes by serving as nitrogen-rich substrates. The viability, acid resistance, and enzymatic activity of Lactobacillus and Bifidobacterium-like species are enhanced by protein-derived oligopeptides from whey, casein, and soy. This is one of the examples that proves proteins' ability to support a favorable microbial profile during aging [79].

Pulses are also a type of plant-based protein source that contain fermentable fibers and resistant starch. These pulse-based proteins promote the growth of longevity-associated taxa. Pulses are further considered as a sustainable source of protein associated with gut-centered strategies in aging due to their ability to increase SCFA production [80]. Proving the above fact, a study reports that red lentils, which are rich in protein, non-digestible carbohydrates, and polyphenols, have enhanced gut microbial diversity and SCFA levels in mice, specifically increasing Roseburia, Prevotella, and Dorea, which are linked to gut health and resilience [81].

Even though plant proteins are beneficial, not all plant proteins exert the same level of benefits for each individual. In line with this, a study demonstrated that glycated lentil proteins showed donor-specific shifts in microbial composition rather than significantly affecting the metabolite output [82].

However, animal proteins, mainly high-protein diets rich in sulfur-containing amino acids, have shown an increase in microbial production of hydrogen sulfide (H₂S). H₂S influences gut barrier disruption and metabolic stress associated with aging. Although short-term dietary changes in sulfur intake did not significantly alter sulfate-reducing bacteria, like Desulfovibrio and Bilophila, individual microbial stability appeared to mediate the response, suggesting that inherent microbiota composition may modulate the effects of dietary sulfur [83].

However, translating animal studies on protein intake and gut microbiota to human health presents key challenges. Differences in microbial composition, digestive physiology, and immune responses between species limit direct applicability. Animal models often use purified proteins and exaggerated doses, which do not reflect human dietary complexity. Additionally, microbial metabolites, like TMAO and ammonia, may behave differently in humans. Environmental, genetic, and lifestyle factors further complicate extrapolation, underscoring the need for well-controlled human trials to validate mechanistic insights.

Exposure of gut microbes from early childhood to elderly life shapes the development of the immune system, mucosal tolerance, and the regulatory function of lymphocytes. This lays a foundation for long-term beneficial health outcomes [112]. Even though the early stages of life have better compositional changes in the microbiome, when a person ages, the relationship becomes dysregulated, leading to immune dysfunction. With aging, beneficial anaerobes, like Faecalibacterium prausnitzii and Bifidobacteria, tend to decline while facultative anaerobes, such as Enterobacteriaceae, increase [113,114].

The gut dysbiosis related to aging may cause different losses, including anti-inflammatory strains, such as Faecalibacterium prausnitzii, Eubacterium hallii, and Roseburia, and diminished regulatory T cell output. Due to these compositional changes, systemic immune remodeling is accelerated through senescence-associated secretory phenotypes [115]. Further, these disruptions cause the development of lymphoid follicles, an intestinal immune structure, thereby interfering with the feedback loop between microbiota and immune maturation, including impaired dendritic and regulatory T cell development [116]. The loss of Bacteroidetes, Lactobacillus, and Bifidobacteria due to aging can further worsen the immune consequences associated with aging.

The spatial gradients of the gastrointestinal tract, including pH, oxygen, and mucus levels, tend to change when the hist ages. The niche specialization of anaerobic bacteria, such as Faecalibacterium and Lachnospiraceae, gets affected by these changes, leading to weakened microbial–host signaling required for nutrient metabolism, immune coordination, and endocrine responses, especially in the small intestine [117].

Leaky gut is one key manifestation of this disruption. When the gut becomes leaky, the intestinal barrier becomes compromised, allowing the passage of pathogens, toxins, and undigested food into circulation. Upregulation of Zonulin, a tight junction regulator, happens due to the microbial imbalance occurring with aging, thereby weakening epithelial barriers and activating immune responses, such as T helper 17 cell differentiation. These changes may fuel different illnesses with aging, mainly chronic inflammation, type 1 diabetes, and celiac disease [118,119].

Frailty is a condition marked by reduced physiological reserve and increased vulnerability to stress. This has proven to be associated with compositional changes of the gut microbiome. A study demonstrated that lower levels of Lactobacilli, Bacteroides/Prevotella, and Faecalibacterium prausnitzii have been identified among older adults with different levels of frailty, while they showed elevated counts in Enterobacteriaceae [120]. Hence, microbial composition may both reflect and influence frailty status in aging populations [121].

The gut barrier consists of several layers that maintain intestinal integrity and regulate host–microbe interactions. The layers, namely, are the mucus layer, epithelial cell layer, and immune components in the lamina propria. These three layers act together to provide physical protection and immunological communication in the gut. The goblet cells secrete MUC2 mucin to compose the mucus layer. The mucus layer comprises two sub-layers in the colon, which are stratified, where the inner layer is a dense layer free of microbes and the outer layer is a loose layer colonized by commensals. Under this layer, another layer called the epithelial monolayer can be seen. Enterocytes, goblet cells, Paneth cells (in the small intestine), enteroendocrine cells, tuft cells, and microfold (M) cells are the components of this epithelial monolayer. Absorption of nutrients and the secretion of antimicrobial peptides and sample luminal antigens are the main roles of this layer. Tight junctions, adherens junctions, and desmosomes together seal the intercellular junctions while regulating the tissue permeability. Lamina propria, which contains immune cells, such as dendritic cells, macrophages, and lymphocytes, as well as organized lymphoid structures, like Peyer's patches, supports this physical structure of the epithelial monolayer. Therefore, the gut barrier is a main dynamic interface between host immunity and microbial populations, which coordinate immune responses to promote tolerance or defense [122].

This complex barrier system tends to compromise with aging. In line with this, a mouse model study has demonstrated a six-fold reduction in colonic mucus thickness, leading to an increased microbial contact with the epithelial surface. The expression of tight junction proteins such as occludin, ZO-1, and TJP2 has also been shown to be reduced [114,123].

Another factor that impairs the gut barrier function is microbial dysbiosis. Faecalibacterium prausnitzii is considered a beneficial taxon that produces butyrate, which is crucial for maintaining tight junction integrity and epithelial energy supply. Dysbiosis may lead to a reduction in the abundance of these taxa [124]. Lactobacillus royi is also such a beneficial taxon that contributes to reducing microbial support for epithelial structure and function [113].

Restoring microbial balance by therapeutic interventions is considered a remedy to rejuvenate barrier integrity. A study that was performed using aged mice identified an upregulation of TJP2 at both mRNA and protein levels and an increment in goblet cell counts and enhanced mucus thickness through the intervention of Gastrodia elata and its active compound parishin, suggesting a reinforcement of both the chemical and physical aspects of the barrier [125].

However, epithelial integrity and alleviating age-related pathology can be improved by transplanting microbiota from young donors, confirming a causal role of gut microbial balance in preserving the gut barrier during aging [126].

Fibers, bile acids, and amino acids that are transferred from the intestine to the gut are metabolized into bioactive compounds that modulate host physiology by gut microbiota. The most important among them are short-chain fatty acids (SCFAs) and bile acid derivatives. These compounds influence epithelial renewal and immune responses [111]. The disruption of microbial metabolism with aging happens particularly through the decline of SCFA-producing bacteria, such as Clostridium clusters IV and XIV and Bifidobacterium [114]. Other than that, with aging, the occurrence of saccharolytic metabolism reduces while it increases the proteolytic metabolism, thereby reducing SCFA levels while increasing less beneficial metabolites. As an example, reduced production of indole, a tryptophan-derived compound essential for epithelial renewal, is linked with decreased health span and elevated mortality risk.

Butyrate is an SCFA that utilizes different epigenetic mechanisms to influence host immunity. Butyrate has the ability to enhance the regulatory T cell differentiation and promote anti-inflammatory cytokines, such as IL-10, through the inhibition of histone deacetylases (HDACs). Through this action, epithelial regeneration improves, and chronic inflammation tends to decline, highlighting the immune-modulatory role of SCFAs in aging [126]. Further, anti-aging dietary interventions, such as calorie restriction and intermittent fasting, have been proven to enrich SCFA-producing bacteria, like Lactobacillus, Bifidobacterium, and Roseburia, which contribute to the improvement of beneficial metabolic output and may delay age-associated dysfunction [125].

Bile acid is also a microbial-derived metabolite. Primary bile acids are synthesized from cholesterol in the liver. These bile acids serve as signaling molecules once converted into secondary bile acids by gut microbes. In addition to that, they aid fat digestion. These secondary bile acids influence glucose metabolism, energy expenditure, gut barrier function, and inflammation by activating host receptors, like the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5). Gut dysbiosis significantly shifts bile acid pools and signaling capacity, linking this axis to metabolic disorders, such as type 2 diabetes and liver disease [117].

Diet plays an important role in modulating the biological processes that drive aging, influencing longevity and disease risk through multiple molecular pathways. The Mediterranean diet has emerged as a model that promotes healthy aging by influencing both biological and clinical dimensions of the aging process. It has been shown to support longevity through epigenetic mechanisms such as DNA methylation, histone modification, and microRNA regulation. While being rich in bioactive compounds, such as polyphenols from olive oil and sulfur-containing molecules found in cruciferous vegetables, this dietary pattern helps regulate the cell cycle, mitigate oxidative damage, and temper key processes, like inflammation and carcinogenesis. The Mediterranean diet promotes longevity by reducing chronic disease risk. In the Seven Countries Study of 12,000 men (40–59 years), coronary heart disease incidence was much lower in Greece (32/10,000 person-years) and Yugoslavia (53/10,000) than in the U.S. (177/10,000) and Finland (198/10,000). The PREDIMED (short for Prevención con Dieta Mediterránea) trial (7018 participants) further showed that high adherence reduced stroke risk in genetically predisposed individuals to levels comparable with low-risk groups. A smaller interventional study (12 healthy subjects, 12 metabolic syndrome patients) confirmed that polyphenol-rich olive oil improved insulin sensitivity and gene regulation. Collectively, these findings link the Mediterranean diet to longer life through cardiovascular protection and molecular benefits [127]. The modified Mediterranean diet supports longevity and healthy aging by prioritizing plant-based foods, unsaturated fats, and modest alcohol intake. A multi-center prospective cohort study across nine European countries followed 74,607 adults aged ≥60 years who were free from coronary heart disease, stroke, or cancer at enrolment. Adherence to a modified Mediterranean diet was scored on a 10-point scale. Each two-point increase in the score was linked to an 8% reduction in overall mortality (95% CI: 3–12%), with consistent results across countries and stronger effects in Greece and Spain. After dietary calibration, the reduction remained 7% (95% CI: 1–12%), confirming that the Mediterranean diet promotes increased survival and longevity in older Europeans [128].

Oxidative stress plays a central role in vascular aging, largely by impairing endothelial function. As we age, the vascular lining becomes a key site of reactive oxygen species (ROS) production from sources like NAD(P)H oxidase and mitochondria, which degrades nitric oxide (NO) and forms harmful by-products, such as peroxynitrite. This redox imbalance contributes to vascular stiffness and dysfunction. Diets high in saturated fats worsen the issue by increasing oxidative and inflammatory stress, while those rich in polyphenols and unsaturated fats may help preserve NO availability and support healthy endothelial aging [129].

The Mediterranean diet may contribute to slow biological aging by positively influencing the DNA repair mechanisms and reducing the DNA damage due to oxidative stress. The Mediterranean diet's rich content of bioactive compounds (melatonin, phytosterols, carotenoids, polyphenols, resveratrol, hydroxytyrosol, and glucosinolates) works together to preserve telomere length and enhance genomic stability. Correspondingly, individuals following this diet often exhibit lower levels of oxidative stress markers, like 8-OHdG, underscoring its potential protective role in the aging process. In a randomized crossover trial involving 20 hypercholesterolemic individuals, daily consumption of a Mediterranean-type meal rich in olive oil, fruits, and vegetables for four weeks significantly reduced plasma oxidized LDL levels by 25% compared to a Western-type diet, highlighting improved antioxidant defense. Similarly, an interventional study with 30 patients with metabolic syndrome reported that adherence to a Mediterranean diet supplemented with extra virgin olive oil for 12 weeks lowered malondialdehyde (MDA) concentrations by 22%, a key marker of lipid peroxidation. These findings suggest that the diet's antioxidant-rich profile directly mitigates oxidative damage, contributing to healthier aging [130].

The CALERIE (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy) trial was the first randomized study to examine how cutting calories affects aging in healthy, non-obese adults. By reducing intake by 25% over two years, participants showed slower biological aging, marked by lower DNA methylation age and oxidative stress. Echoing earlier animal studies, the results suggest that restriction of high-calorie intake can improve mitochondrial function, curb inflammation, and delay aging [131].

A review underscores that plant-forward eating patterns like the Mediterranean, DASH (Dietary Approaches to Stop Hypertension), and MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay) diets are linked to better physical and cognitive health. High adherence to these diets has been associated with slower memory loss, fewer mood issues, sharper senses, improved fitness, and reduced frailty. These benefits are largely credited to their anti-inflammatory, antioxidant-rich nature and strong overall nutritional balance [132].

Nutrition plays a key role in physical and cognitive health during aging, thereby preserving functional abilities. In particular, the Mediterranean diet itself is linked to reduced rates of neurodegenerative diseases, cardiovascular issues, and general frailty by enhancing the physical and cognitive function of people. As an example, the synergetic action of foods, such as tomatoes and olive oil, where enhanced bioavailability of lycopene can be observed when tomatoes are eaten along with olive oil, helps maintain metabolic and neurological health in aging individuals [127].

Long-term adherence to a nutrient-rich Mediterranean-style diet may help preserve functional capacity in older age. A dietary pattern rich in vegetables, fruits, and whole grains alongside moderate consumption of fish and dairy appears to support energy balance, nutritional sufficiency, and sustained mobility. This aligns with observed links between greater adherence to this diet and a lower risk of early mortality [128]. Traditional Mediterranean dietary patterns characterized by olive oil, vegetables, fish, and moderate wine intake have been linked to a lower risk of age-related neurodegenerative diseases, such as Alzheimer's and Parkinson's. These protective effects are largely attributed to neuroactive compounds, like omega-3 fatty acids, which may help slow cognitive decline and preserve memory and executive function in later life [64].

Evidence from the NU-AGE project suggests that adherence to a Mediterranean diet may support cognitive function in older adults, although effects can vary between individuals. In this multi-center, interventional study, 612 non-frail or pre-frail participants aged 65–79 from five European countries (UK, France, the Netherlands, Italy, and Poland) were assigned to a 12-month MD tailored to elderly subjects. Gut microbiota profiling before and after the intervention revealed that diet adherence increased the abundance of specific bacterial taxa, which were positively associated with markers of lower frailty and improved cognitive performance and negatively associated with inflammatory markers, such as C-reactive protein and interleukin-17. While the associations were observed independently of age or body mass index, individual responses may differ due to baseline microbiota composition and other host factors. Collectively, the findings suggest that dietary modulation of the gut microbiome via the Mediterranean diet has the potential to support cognitive health in aging, but benefits may not be uniform across all individuals [32].

The gut microbiota can positively affect aging by regulating immune responses, maintaining gut barrier integrity, and producing anti-inflammatory metabolites, like short-chain fatty acids (SCFAs). Among these SCFAs, butyrate is significantly important for diminishing systemic inflammation, promoting colon health, and modulating brain function. Dysbiosis or change in the microbial composition in the gut in older adults tends to increase gut permeability and chronic inflammation, which also contribute to neurodegenerative diseases, like Alzheimer's and Parkinson's. Furthermore, changed microbiota can impair brain-derived neurotrophic factor (BDNF) expression and synaptic plasticity, negatively impacting memory and cognition [144].

Host physiology is further affected by gut microbiota towards enhancing aging. The key functions related to this are biosynthesis of vitamins (e.g., thiamine, niacin), metabolism of carbohydrate and fiber, and development of the immune system. During childhood, species like Bifidobacterium longum predominate, and they can support nervous and immune development via vitamin production. With aging, microbial enzymes that are involved in metabolizing fiber become more dominant, mainly due to dietary changes, and they possibly help regulate inflammation and metabolic health [145].

An increase in Gram-negative bacteria is observed with aging, which decreases microbial diversity. The release of lipopolysaccharides by these bacteria tends to enhance inflammation. Reduced fiber intake, antibiotic use, and immune-senescence are the factors that contribute to this shift. As a result, the production of beneficial SCFAs is reduced and immune and metabolic functions get impaired, which accelerates aging in return [144].

Furthermore, some core gut species, such as B. longum, tend to decline, while microbes in taxa like Faecalibacterium, Roseburia, and Ruminococcus may rise with advancing age. Additionally, Akkermansia and Clostridium cluster IV, like some beneficial microbiota, also show a drop in count, thereby notably weakening both immune and metabolic functions. Therefore, both compositional and functional changes are considered to be associated with aging, which changes the gut microbiota ecosystem [145].

A beneficial gut microbial composition is enhanced by high levels of fiber. Gut microbes can ferment these dietary components into short-chain fatty acids (SCFAs), like butyrate, which are essential for the regulation of immune responses, maintenance of gut barrier integrity, and reduction in inflammation, which are considered the key factors affecting healthy aging [126]. On the other hand, Western diets that are rich in saturated fats, red meat, and low in fiber lead to dysbiosis in gut microbial composition. As a result of this imbalance, the production of harmful metabolites, like trimethylamine-N-oxide (TMAO), is enhanced, thereby increasing gut permeability ("leaky gut"), and chronic inflammation is a main factor attributed to accelerated aging [146].

However, age-related oxidative stress and inflammation, the drivers of cellular aging, can be reduced using a vegetarian diet that is rich in antioxidants, mainly vitamin C, carotenoids, and polyphenols. Reduced DNA damage, lipid peroxidation, and higher plasma antioxidant concentrations have been observed in elderly people who have followed a vegetarian diet, suggesting that diet can mitigate oxidative damage typically associated with aging. Further, a healthier gut function can be promoted by the high antioxidant intake from plant-based foods while preserving physical and cognitive function in older ages [147].

While diet can influence aging, on the other hand, aging also influences diet through biological and behavioral changes. Insulin signaling, mitochondrial efficiency, and nutrient sensing (like mTOR and AMPK-like mechanisms) in the human body tend to shift with age, affecting the way food behaves inside the body. Restriction of high calories is a promising method for elderly people to endure these metabolic changes. Furthermore, appetite, taste, and physical activity can also be affected by aging, while altering personal food choices and nutrient intake suggest that personalized diets are important for promoting health and longevity in later life [131].

Refined grains, sugars, saturated fats, and low fiber are characteristic dietary components of a Western diet. These components disrupt microbial diversity while leading to gut dysbiosis and thereby enhance the pro-inflammatory species. An increase in intestinal permeability ("leaky gut") is another function of these dietary components, where they allow microbial products, like lipopolysaccharides (LPSs), to enter circulation and trigger systemic inflammation. On the other hand, the growth of beneficial microbes that produce anti-inflammatory short-chain fatty acids (SCFAs), such as butyrate, is promoted by vegetarian diets that are rich in unprocessed plant foods, fiber, and polyphenols (like ancestral or Paleolithic diets) [4,148].

A study demonstrates that the regulation of host energy harvest and nutrient availability is mainly influenced by gut microbiota. The breakdown of complex carbohydrates and the increase in absorption of short-chain fatty acids are performed by certain microbial communities, thereby contributing to energy extraction from otherwise indigestible fibers. Other than that, satiety hormones and lipid metabolism are also subtly shaped. Therefore, rather than just responding to diet, the gut microbes actively shape how the bodies process and respond to what is consumed [4].

Supporting the previous fact, another study showed that the way nutrients are metabolized and the way our body responds to dietary components are typically influenced by the gut microbiota. Proving this fact, it has been identified that the digestion of complex polysaccharides and the synthesis of vitamins (like B and K vitamins) are enhanced by beneficial species. However, dysbiotic microbiota promote chronic low-grade inflammation, insulin resistance, and oxidative stress by impairing nutrient metabolism, which suggests that even a moderate diet can be more harmful to the host [145].