The human microbiota, a complex ecosystem of microorganisms inhabiting various body sites, particularly the gut, plays a crucial role in maintaining health and influencing disease susceptibility. Dysbiosis, characterized by alterations in microbial composition and diversity, has been implicated in numerous diseases, including those associated with aging. This review examines the complex relationship between gut microbiota and aging, highlighting the age-associated gut microbiota alterations, the factors contributing to these changes, the links between microbiota and age-related diseases, and the potential of interventions targeting the microbiome to extend lifespan and improve health outcomes in the elderly. Further research is needed to unravel the intricate mechanisms underlying the interplay between the microbiome and aging, paving the way for innovative strategies to promote healthy aging.
1 Introduction
Since the early 1900s, when researchers discovered numerous microorganisms—including bacteria, yeasts, and viruses—in various parts of the human body, the human microbiota has intrigued scientists . The term “microbiota” refers to the community of living microorganisms that inhabit a particular environment. The gut microbiota is the most extensive component, comprising more than 1,000 species of microorganisms. The highest density is found in the colon, which, according to recent estimates, hosts more than 3.9 × 1013 microbial cells. To a lesser extent, the human microbiota is also present in other areas, including the oral cavity, lungs, vagina, and skin.
Over the past decades, the field of human microbiota has attracted great scientific interest because of its critical influence on health and disease. Often referred to as “the hidden organ,” the gut microbiota forms a symbiotic relationship with the intestinal epithelium in healthy individuals, showcasing vital metabolic, immunological, and protective functions.. For example, these microorganisms metabolize dietary components, xenobiotics, and drugs, while producing short-chain fatty acids (SCFAs), vitamins (such as K, B12, biotin, folic acid, and thiamine), secondary bile acids, and antimicrobial peptides (including defensins, cathelicidins, and lectins). They also provide antimicrobial protection by producing lactic acid and mucin and by stimulating the innate immune system and immunoglobulin A secretion.
Αlterations in the composition and diversity of the gut microbiota, known as dysbiosis, are implicated in numerous diseases, including irritable bowel syndrome, inflammatory bowel disease, allergies, diabetes, and obesity. Dysbiosis has also been related to aging, an unavoidable, irreversible process characterized by noticeable changes in an organism’s physical appearance and function. The proportion of the European population aged 65 and over increased from 14.9% in 1996 to 19.2% in 2016, with forecasts indicating a rise to 29% by 2070. As life expectancy rises, aging populations face declines in both physical and cognitive abilities, often experiencing multiple health conditions. This demographic shift places significant strain on global healthcare systems.
López-Otín et al. identified a set of biological processes contributing to the aging of cells, tissues, and the entire organism. A decade later, these were expanded to include twelve key hallmarks of aging. They include genomic instability, telomere shortening, epigenetic changes, loss of proteostasis, disrupted nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell depletion, impaired intercellular communication, macroautophagy, chronic inflammation, and dysbiosis. These hallmarks provide a foundational framework for understanding the aging process and are deeply interconnected. For instance, dysbiosis and chronic inflammation are closely linked, as the altered gut microbiota in elderly individuals is associated with increased intestinal permeability and immune system activation, resulting in chronic inflammation.
Given the gut microbiota’s significant impact on health and its contribution to aging, understanding its alterations in elderly individuals and its complex association with age-related diseases could provide valuable insights. Understanding these complex interactions may reveal strategies for modulating and potentially slowing down aging through gut microbiota interventions. The current review explores the existing literature on the relationship between gut microbiota and aging, examines age-associated conditions, and proposes the potential of novel microbiota-targeting interventions for extending lifespan. However, further research is needed to illuminate the intricate interplay between the microbiome and aging.
2 Shaping of the gut microbiota across age
The gradual colonization of the gut by microbes may begin during the prenatal period, through a unique microbiota present in the placenta and amniotic fluid. Factors pertaining to the mother, such as health, dietary habits, and exposure to antibiotics, can influence the fetal microbiome during pregnancy. Postnatally, factors like delivery mode, breastfeeding, and diet further shape the microbiota, leading to a relatively stable composition by the age of 3–4 years, though some suggest that it is not fully established until the age of 5
FIGURE 1
Gut microbiota shaping across age and influencing factors. F/B = Firmicutes/Bacteroidetes. Upward arrows indicate an increase and downward arrows indicate a decrease.
Vaginally born infants possess a distinct microbiota, with early and enhanced colonization by Lactobacilli, Bacteroides, and Prevotella, similar to the maternal vagina, whereas infants delivered via caesarean section often exhibit delayed or reduced carriage of Bacteroides, Bifidobacteria, and Lactobacilli and are more frequently colonized with Clostridium difficile, Clostridium perfringens, Escherichia coli, Staphylococcus, and Streptococcus, similar to the maternal skin and the hospital environment. Breastfeeding promotes high levels of Bifidobacterium, aiding oligosaccharide metabolism found in breast milk, Staphylococcus, Bacteroides, Streptococcus, and Lactobacillus. In contrast, infants fed with a formula show a higher prevalence of Proteobacteria and Clostridium species.
A major change in microbiota diversity occurs between 9 and 18 months, including an increase in Bacteroidetes, and a decrease in Lactobacillus spp. and Enterobacteriaceae. At the age of 9–36 months, an increase in butyrate-producing Clostridium leptum, Eubacterium hallii, and Roseburia has been observed. By age 1, Akkermansia muciniphila, Bacteroides, Veillonella, Clostridium coccoides spp., and Clostridium botulinum spp. are prevalent. Actinobacteria abundance significantly declines after weaning and keeps decreasing with age, with Firmicutes becoming the most dominant phylum.
The onset of weaning signals a gradual transition of the infant gut microbiota toward that of adults, which highlights the determining role of diet on microbiota composition. Comparative studies reveal that dietary habits profoundly shape the gut microbiota. African children on a high-fiber diet have increased Bacteroidetes and decreased Firmicutes, with higher levels of short-chain fatty acids and unique bacteria like Prevotella and Xylanibacter, unlike European children on a western diet. Similarly, Bangladeshi children, whose diet is rich in carbohydrates and rice, exhibit a prevalence of Prevotella, while US children consuming more meat and protein show a prevalence of Bacteroides .
In healthy adults, the dominant phyla are Firmicutes and Bacteroidetes, which constitute over 90% of the intestinal flora, followed by Actinobacteria, Proteobacteria, and Verrucomicrobia . Aging further alters the gut microbiota, with the elderly showing increased E. coli and other Proteobacteria and decreased beneficial anaerobes like Bacteroides and Bifidobacteria . The oldest-old typically have lower Firmicutes levels and higher Bacteroidetes levels, with the Firmicutes/Bacteroidetes ratio rising during adulthood and decreasing in older age. An increase in genera like Akkermansia has also been observed in centenarians, potentially linked to longevity.
Extended adherence to plant-based diets is linked to a more diverse and abundant phylogenetic composition of fecal microbiota compared to Western diets. The Mediterranean diet, characterized by high consumption of fruits, vegetables, and legumes, has been demonstrated to be a healthy diet pattern that is beneficial for the gut microbiota. A study found that Lachnospira and Prevotella were higher in individuals on plant-based diets, whereas L-Ruminococcus was linked to omnivorous diets . The same study showed that the Mediterranean diet had a positive impact on fecal SCFA levels, likely reflecting the presence of Firmicutes and Bacteroidetes that degrade indigestible carbohydrates. Strong adherence to this diet has also been associated with lower E. coli levels, increased Bifidobacteria/E. coli ratio, which is regarded as a crucial marker of gut microbiota balance and overall health, and higher levels of Bacteroidetes, with a lower Firmicutes/Bacteroidetes ratio.
Lifestyle and environmental factors, such as physical activity, stress, smoking, and traveling, also influence the gut microbiota Athletes and individuals with a low body mass index seem to have higher levels of A. muciniphila compared to those with a high body mass index, which has a positive effect on metabolic health . Six weeks of guided endurance exercise training has been shown to positively affect the gut microbiota by increasing the abundance of A. muciniphila and decreasing the abundance of Proteobacteria. Daily exercise in the elderly can alleviate age-related gut microbiota differences by increasing Actinobacteria and decreasing Cyanobacteria levels. Stress reduces the number of Lactobacilli, while it promotes the growth of gram-negative pathogens such as E. coli and Pseudomonas. Smoking, another lifestyle factor, impacts the gut microbiota by raising Bacteroides-Prevotella. Other environmental factors, like exposure to infectious gastrointestinal diseases while traveling, may have long-term effects on gut microbiota and health. Additionally, traveling and shift work can disrupt the circadian rhythm, further influencing the gut microbiome.
Antibiotics significantly disrupt the gut microbiota by reducing the overall diversity, enhancing the growth of opportunistic organisms like Enterococcus faecalis, and elevating the risk of C. difficile infection. The impact varies with antibiotic type, dosage, and duration. Broad-spectrum antibiotics can disrupt the balance between Firmicutes and Bacteroidetes. For instance, a 7-day treatment with broad-spectrum β-lactam antibiotics doubled the microbial load in patients’ fecal samples and increased the ratio of Bacteroidetes/Firmicutes , while macrolides decreased Actinobacteria and increased Bacteroides and Proteobacteria levels.
Other medications, including osmotic laxatives, hormones, benzodiazepines, antidepressants, antihistamines, inflammatory bowel disease medications, proton pump inhibitors (PPIs), metformin, and statins, also significantly influence gut microbiota composition . Research indicates that PPIs, a commonly used medication, are associated with notable microbiota changes. For example, 20% of bacterial taxa are substantially altered in PPI users compared to non-users. Families like Bifidobacteriaceae, Ruminococcaceae, and Lachnospiraceae are often reduced, while others like Actinomycetaceae and Staphylococcus spp. may increase. Also, PPIs impose a great risk of susceptibility to infections such as C. difficile, Salmonella, and Campylobacter, by reducing gastric acidity. The stomach’s acidic environment—primarily maintained by hydrochloric acid—creates a low pH that effectively kills many pathogens that might otherwise survive and increase the risk of infections.
3 Age-related alterations in the composition and function of the gut microbiota
Age-related alterations in the composition and function of the gut microbiota have been extensively studied, although results vary due to differences in study populations, sample sizes, methodologies, and designs. Next, we will mention several studies from the existing literature on intestinal microbiota alterations with increasing age (Table 1).
A reduction in Bacteroides levels and species diversity was observed in elderly groups.
A similar reduction and shift were seen with Prevotella species.
Bifidobacteria species and diversity decreased in elderly, especially in hospitalized patients.
Fusobacteria, Propionibacteria, and Clostridia
increased in antibiotic-treated elderly.
Short-chain fatty acids decreased with increased age.
Infants: Bifidobacteria was the most abundant group.
Four dominant bacterial groups in adults: C.leptum, C.coccoides, Bacteroides and Bifidobacterium.
In elderly: increased E. coli, decreased beneficial anaerobes like Bacteroides and Bifidobacteria. Firmicutes/Bacteroidetes ratio for infants, adults and elderly: 0.4, 10.9 and 0.6, respectively.
Summary of studies on gut microbiota alterations across age.
A study comparing fecal microbiota among infants, adults, and the elderly revealed continuous changes with aging . In infants, Bifidobacterium was the most abundant group. In adults, the dominant bacterial groups included Clostridium leptum, Clostridium coccoides, Bacteroides, and Bifidobacterium, with sub-dominant groups including Lactobacilli, Enterobacteriaceae, and others. In elderly subjects, there was a significant increase in Escherichia coli counts and a noted decrease in beneficial anaerobes like Bacteroides and Bifidobacteria. The Firmicutes/Bacteroidetes ratio for infants, adults, and elderly subjects was estimated at 0.4, 10.9, and 0.6, respectively.
Another study in Italy found microbiota similarities between young adults and seventy-year-olds but significant differences in centenarians (individuals surpassing 100 years old). Centenarians displayed a rearrangement in Firmicutes population and an abundance of facultative anaerobes, predominantly from Proteobacteria (including E. coli, Klebsiella pneumoniae, and Pseudomonas) and Bacilli (such as Bacillus and Staphylococus). The rearrangement in Firmicutes included lower levels of Clostridium cluster XIVa, such as Roseburia intestinalis and Ruminococcus obeum, higher levels of Bacilli, and alterations in the composition of Clostridium cluster IV, such as a decrease in Faecalibacterium prausnitzii. This also reflected a decrease in butyrate producers, such as R. intestinalis, R. obeum, and F. prausnitzii. The mucin-degrading Akkermansia muciniphila was found to be enhanced in older people. Akkermansia muciniphila is recognized for its ability to break down mucin and enhance intestinal integrity by lowering toxicity levels linked to high-fat diets; thus it has beneficial effects on preventing and improving metabolic disorders and obesity (. Researchers also noted an increase in Eubacterium limosum (Clostridium cluster XV) in centenarians, suggesting that it could be an indicator of longevity .
Other research involving elderly subjects has demonstrated core microbiota differences compared to young adults, with a lower proportion of Firmicutes and a shift towards Clostridium cluster IV, specifically within the Ruminococcaceae family, including Faecalibacterium, Sporobacter, and Ruminococcus species . A study comparing urbanized regions with longevity villages—specific regions where residents tend to live significantly longer compared to global averages—revealed a lower Firmicutes to Bacteroidetes ratio in longevity villages residents, along with higher levels of Bacteroides, Prevotella, and Lachnospira . Notably, some Bacteroides spp. and Faecalibacterium spp. were found only in longevity villages residents. In contrast, lipopolysaccharide (LPS) was found higher in urbanized towns residents, a finding that is associated with greater consumption of animal-based foods, reduced vegetable intake, and increased intestinal bacteria. LPS promotes chronic low-grade inflammation, a known contributor to aging and related diseases. Conversely, longevity villages residents exhibited higher levels of anti-inflammatory Faecalibacterium spp., which may help reduce LPS production and inflammation.
Another study about the gut microbial composition of residents from longevity villages of South China revealed higher amounts of Enterococcus, Lactobacillus, Enterobacteriaceae, Clostridium perfringens, and Bacteroides compared to a control group. Additionally, some unique species, such as Methanobacterium, Butyricimonas, Deinococcus, and members of the Streptococcaceae family, were detected in the villagers’ gut microbiota.
Differences have also been detected between the gut microbiota of centenarians in rehabilitation hospitals and those living at home. Centenarians residing in rehabilitation hospitals had higher levels of Bacteroidetes and Proteobacteria, lower bacterial diversity, and a lower abundance of Faecalibacterium compared to those living in the community . This contrast indicates the impact of the environment and diet on the gut flora composition.
Moreover, a large-scale study conducted in Ukraine indicated age-related variations in intestinal flora. In particular, the Firmicutes/Bacteroidetes ratio increased from ages 0–9 to 60–69), followed by a decrease in the advanced age group (70+). These findings are consistent with previous studies.
At both the metagenomic and functional levels, the gut microbiota of centenarians exhibits an abundance of genes involved in glycolysis and SCFA production, despite a limited capacity for carbohydrate degradation and amino acid synthesis. This model is supported by a high presence of Bifidobacterium adolescentis, Methanobrevibacter smithii, Escherichia, and Lactobacillus, along with a lower presence of F. prausnitzii, Eubacterium hallii, Eubacterium ventriosum, and Eubacterium rectale. SCFAs possess anti-inflammatory action by regulating cytokine secretion and immune cell function by mechanisms like direct action on immune cells and inhibition of nuclear factor kappa B (NF-κB) activity . Among them, butyrate has been highlighted for its anticarcinogenic properties, maintaining the intestinal barrier integrity as well as the modulation of oxidative stress by regulating oxidoreductase activity and inhibiting the production of reactive oxygen and nitrogen species.
Additionally, genes involved in menaquinone (vitamin K2) and riboflavin (vitamin B2) biosynthesis are increased in centenarians. Menaquinone supports bone health, reduces the risk for coronary heart disease, and decreases the overall cancer incidence and mortality, while riboflavin is vital for various redox reactions in human metabolism. Decreased trimethylamine (TMA) levels, a metabolite associated with cardiovascular disease, cancer, and metabolic disease, have also been reported among centenarians, possibly mediated by M. smithii. Centenarians also possess a unique gut microbiome enriched with microorganisms capable of producing distinctive secondary bile acids, including various forms of lithocholic acid (LCA) such as iso-, 3-oxo-, allo-, 3-oxoallo-, and isoallolithocholic acid. These are reported to suppress pro-inflammatory T helper 17 cells and induce Treg cells .
4 Factors contributing to age-related gut microbiota dysbiosis
Taking into account the influence of diet on gut microbiota composition, alterations in the nutritional habits and lifestyles of older individuals contribute to age-related imbalances in the intestinal microbial community. The elderly experience a decreased chewing ability, tooth loss, and diminished taste perception, factors affecting appetite and dietary choices, that can ultimately impact their gut microbiota composition. In particular, they prefer foods richer in sugar and fat while reducing the consumption of plant-based foods. However, a balanced diet, rich in micronutrients and low in saturated fats, is crucial for longevity, as evidenced by populations in regions with high life expectancies). Centenarians in longevity villages are reported to maintain regular and diverse dietary habits, typically eating three meals a day with appetite. Their intake of protein and other nutrients is similar to that of adults in the same region.
Furthermore, the elderly experience reduced intestinal function compared to younger individuals, which may lead to constipation and impact digestion, nutrient absorption, and immune activity . Moreover, shifts in body mass index (BMI) during aging may be reflected in the observed microbiota changes. An increased BMI is associated with a higher proportion of Firmicutes and a lower proportion of Bacteroidetes.
Multiple other factors explain the age-related microbiota alterations, such as shifts in immune response, hospital stays, extended intestinal transit times, decreased physical activity, recurrent infections, and the frequent use of antibiotics and other medications (Figure 2) . It has been reported that long-term care residents lose their health-associated components and gain elderly-associated microbes over time . The comparison of the gut microbiota between centenarians living in the community and those in rehabilitation hospitals has shown higher proportions of Bacteroidetes and Proteobacteria, a lower proportion of Faecalibacterium, and lower bacterial diversity in the latter . Similarly, long-stay residents exhibited a decrease in Ruminococcus and Prevotella and an increase in Oscillibacter compared to community-dwelling subjects. These microbiota alterations were associated with the composition and variety of their diets.
Factors contributing to age-related gut microbiota dysbiosis.
