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Understanding Aging through the Lense of Gut Microbiome

  • Rashmi Ira,
  • Jitesh Adwani,
  • Arjun Orkkatteri Krishnan,
  • Gurunathan Subramanian,
  • Sandhya Yadav,
  • Saumya Shukla,
  • Snehlata Rao and
  • Tulika Prakash* 
Exploratory Research and Hypothesis in Medicine   2024

doi: 10.14218/ERHM.2024.00008

Received:

Revised:

Accepted:

Published online:

 Author information

Citation: Ira R, Adwani J, Krishnan AO, Subramanian G, Yadav S, Shukla S, et al. Understanding Aging through the Lense of Gut Microbiome. Explor Res Hypothesis Med. Published online: Aug 2, 2024. doi: 10.14218/ERHM.2024.00008.

Abstract

Aging is an intricate process driven by various factors, including the dynamic interplay between the host microbiome and aging. The gut microbiome undergoes several changes throughout the entire lifespan of a healthy human. Numerous factors, ranging from the mode of childbirth and sex differences to lifestyle, are known to impact the gut microbiome in healthy individuals. As a result, the gut microbiome varies widely among individuals and exhibits robustness after early childhood. However, as one ages, the human body undergoes several important changes, and so does the gut microbiome. This review addresses the relationship between aging and the dynamics of the host microbiome from in utero to over 100 years of age. Additionally, we attempted to untangle this intricate relationship between the gut microbiome and aging by presenting various microbiota-dependent mechanisms involving intrinsic and extrinsic factors such as metabolic, neurological, immunological, dietary, and lifestyle factors that potentially regulate aging. Furthermore, we aimed to highlight microbiome-based aging intervention studies focused on modulating or rejuvenating the microbiota for healthy aging and longevity.

Keywords

Aging, Gut microbiota, Immunity, Gut metabolites, Neurological disorders, Stem-cell aging

Introduction

All organisms undergo the natural process of aging, which vastly regulates their body shape, health, and functioning. An aging phenotype is characterized by nine genetic hallmarks: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication.1 As one ages, the body experiences numerous physical and biochemical changes. On average, people >30 years old experience cell loss in various organs such as muscles, liver, and kidneys. Aging is also accompanied by the demineralization of bones, which reduces their density, and changes in the body’s water content, which influence overall health.2 Another key process during aging is the accumulation of body fat in middle age. This results in the accumulation of around one-third of extra fat in this age group as compared to youngsters, leading to an increased risk of insulin resistance.3 Eventually, aging may result in the development of numerous diseases and disorders.2 However, this physical decline varies due to several factors, including the organism itself, gender, geographical location, lifestyle, etc.2

The collection of genomes from all microbes (including bacteria and fungi) and viruses, as well as microbial structural elements that inhabit the host, is termed the “microbiome”. However, the terms “microbiome” and “microbiota” are often used interchangeably, though there are important differences between the two. Microbiota refers to the living microorganisms present in a defined environment, such as the gut, oral, skin, etc. The human gut microbiota (GM) comprises a rich and diverse microbial community consisting of more than a trillion microorganisms that live in harmony with each other.4 Several studies have highlighted the significant role of GM in human health and disease.5 Many studies have focused on the relationship between changes in GM and aging, considering various physiological aspects of this process, such as alterations in beneficial metabolite producers and increased susceptibility to disease due to a weakened immunological response.5 Indeed, significant associations between the gut microbiome and both gastrointestinal and extra-intestinal diseases have been reported.6 In this review, the importance of both intrinsic and extrinsic factors associated with the gut microbiome and aging is comprehensively discussed. Additionally, the interactions of gut microbes with various host-associated processes, such as sex differences, neurology, and immune responses, are highlighted in detail. Finally, intervention studies on modulating or rejuvenating the microbiome for healthy aging and longevity are reviewed to understand the associations between the gut microbiome and the aging process.

Dynamics of gut microbiome during humans’ lifespan

The gut microbiome and aging processes are influenced by various intrinsic (gender, genetics, and ethnicity) and extrinsic factors (geographical location, demographic factors, physical activity, diet, medications, smoking, reduced social contact, and others).7 The aging process involves specific changes in GM and metabolic composition (Fig. 1). The gut microbiome transduces environmental signals, modulates disease risk factors in all age groups, and varies with host age. Overall richness of the gut microbiome declines while a particular frailty-linked bacterial group increases when measures of biological age are applied with adjustments for chronological age.8

Gut microbiome alterations from infancy to old age in humans.
Fig. 1  Gut microbiome alterations from infancy to old age in humans.

The composition of the gut microbiome exhibits genus-level variations across different age groups. The early-age gut microbiome is shaped by the embryonic environment, type of delivery, and exposure to microbes through breast/formula feeding. During weaning, the microbiome undergoes changes from a simple (less diverse) to a complex (more diverse) microbial mixture and attains stability until adulthood. During puberty, the microbiota differentiates based on the sex of the host due to associated hormonal changes. In elderly individuals, the microbiota is affected by lifestyle, dietary habits, and immunosenescence of the intestinal immune system. In this age group, the microbiome is mainly dominated by pathogenic and opportunistic microbes. The major changes in the metabolites associated with human GM and the length of the intestine concerning the aging process are also shown. Created by biorander.com. GM, gut microbiota; HMOs, human milk oligosaccharides; IgA, immunoglobulin A; SCFA, short-chain fatty acids; TGF-β, transforming growth factor-β.

Gut microbiome alterations in infancy and early childhood

At birth, a sterile environment is transformed into a rich and active microbial ecology.9 Although the embryo is considered sterile, the presence of germs in semen, placenta, amniotic fluid, umbilical cord blood, and meconium indicates that the fetus is colonized by microbes in utero.10 This suggests that the transmission of the maternal microbiome to the offspring might occur vertically. The gestational age at birth, delivery method, feeding strategy, and maternal variables are known to impact the infant’s GM colonization process.10

The GM of infants (<1 year old) is known to be less diverse,11 while that of adults is relatively stable.12 The core GM of infants can be categorized into six groups based on the prevalent population and makeup.13 Group 1 includes Bifidobacteriales, Lactobacillales, Anaerostipes, Clostridiales, and Faecalibacterium; Group 2 includes Verrucomicrobiales and Bacteroidales; Group 3 includes Clostridiales; Group 4 includes Enterobacteriales; Group 5 includes Pasteurellales; and Group 6 primarily includes Selenomonadales. More recently, the GM of infants has been found to involve core species from the genera Bifidobacterium, Bacteroides, Clostridium, Lactobacillus, Streptococcus, Veillonella, Akkermansia, and Collinsella.14

Newborns are exposed to vaginal microorganisms during birth, which are mainly dominated by Prevotella and Lactobacillus.14 Contrarily, infants delivered by cesarean section (c-section) have a prevalence of Corynebacterium, Staphylococcus, and Propionibacterium spp. (Fig. 1), resembling the microbial composition found on the skin.14 Immediately after birth, species of the genus Lactobacillus (L. gasseri and L. rhamnosus) are predominantly found in the GM of infants.15,16 Since meconium contains several species of the genus Lactobacillus, such as L. reuteri, L. plantarum, L. sakei, L. brevis, and L. casei, the relative abundance of these taxa is substantially greater in infants delivered vaginally than by c-section.17 This maternal-to-offspring transmission of the microbial community is a crucial early-life checkpoint because when a baby exits the umbilical cord-supported uterine environment, commences respiration, and actively seeks a meal, the baby faces a significant metabolic shift. The early-life microbiome is crucial for the development of the brain and immune system of offspring which have an impact on the infant as well as the long-term health.14

In breastfed infants, the GM is predominated by Bifidobacterium, whereas Bacteroides and Bifidobacterium predominate in the gut microbiome of formula-fed infants.18 However, in the feces of vaginally delivered and formula-fed infants, the abundance of Bacteroides is relatively higher compared to c-section-delivered (p < 0.01) and breastfed babies.19 Furthermore, the c-section delivery causes a delayed colonization of Bacteroides, which may be linked to the Th1 response.20 Nursing exposes the baby to the mother’s microorganisms, antibacterial agents, and nutrients crucial to the baby’s well-being. Human milk oligosaccharides (HMOs), natural prebiotics present in breast milk, specifically influence the development of beneficial bacteria in an infant.18 HMOs do not directly provide nutrients for infants; instead, they influence the development of the infant’s gut microbiome and promote long-term health.21 Bifidobacteria play a crucial role in the ability of an infant’s intestinal tract to absorb HMOs.22 However, there is also evidence of a negative correlation between the amount of bifidobacteria and the concentration of HMOs in newborn feces.21 Importantly, the stool samples of infants show a higher relative abundance of Bifidobacterium, which is associated with the risk of later acquiring non-communicable diseases like asthma and obesity. Additionally, the development of innate and acquired immunity in early infancy can be promoted by Bifidobacterium and Lactobacillus.23

In the first year of life, up to weaning, opportunistic microbes frequently colonize the gut ecosystem based on the surroundings the baby is exposed to.24 Such early colonization shows the primary predominance of aerobes like Staphylococcus, Streptococcus, and enterobacteria, followed by anaerobic colonizers such as clostridia and eubacteria. It is commonly believed that Bifidobacterium dominates the microbiota of breastfed newborns after these earliest stages.9 After weaning or ablactation, the intestinal immune system and gut mucosa undergo developmental changes. These changes, along with the introduction of solid food, cause the transformation of the human GM into an adult-like composition that is resilient and characterized by increased microbial diversity,9 which remains largely constant throughout healthy adulthood.25 These observations suggest that the composition of the GM alters as the host ages.

Gut microbiome alterations during puberty and adulthood

The adult microbiome acquires characteristics related to gender due to the influence of sex hormones associated with puberty (Fig. 1). Numerous studies on animal models and humans have shown different microbiome compositions in males and females. A study on pre-obese diabetic mice reported similar microbiota compositions in both sexes before puberty. However, after puberty, the male mice’s GM showed shifts in composition, with increased abundance in the families Porphyromonadaceae, Veillonellaceae, Kineosporiaceae, Peptococcaceae, Enterobacteriaceae, Lactobacillaceae, Cytophagaceae, Peptostreptococcaceae, and Bacteroidaceae.26 Org et al.27 conducted a study on the GM of 89 inbred mice, showing distinct composition and diversity between sexes of each strain, with a high abundance of Actinobacteria and Tenericutes in males. However, the biological definition of aging differs between humans and mice and remains debatable.

Sex-based microbiome differences have also been observed in humans. Sex hormones, including estrogen and testosterone, play significant roles in influencing the GM during adolescence or puberty (age group of 13–17 years). For instance, Adlercreutzia, Clostridium, Dorea, Parabacteroides, and Ruminococcus have all been associated with testosterone levels.28 An investigation of the fecal microbiota of opposite-sex twins aged 13 to 17 years showed the highest variations between them compared to same-sex twins (Fig. 1).29 A large-scale investigation of more than 2,500 Chinese individuals discovered sex-specific markers, which become less pronounced with age.30 Similar observations were made in two other studies based on large cohorts from Israel, the Netherlands, and the American Gut Project.30–32 Sex-dependent changes in microbiome composition (β-diversity) were more pronounced in younger individuals compared to older ones, with females having higher GM α-diversity than males.31 Apart from distinct microbial communities, differences in the abundance of bacterial genes and metabolic pathways have also been reported between males and females. For example, metabolic pathways associated with carbohydrates, lipids, and proteins were prominent in the gut microbiomes of females,33 showing the possibility that metabolites such as fatty acids may be involved in adipose tissue remodeling during puberty.34

In adulthood, the gut microbiome reaches its highest level of complexity and richness, with the development of a strong “core microbiome” that increases adaptability and decreases sensitivity to both internal and external stresses.35 The maturity of the microbiome occurs concurrently with the growth of the host organs, particularly the gut, which lengthens with age and creates new habitats for the microbiome to diversify and multiply.14 A gut ecosystem of a healthy adult is estimated to include around 1,000–1,200 phylotypes up to the species level, of which 75–82% are considered unculturable.9,36 However, this notion was challenged by a recent study using a broad-range yeast casitone fatty acid agar-based culturing approach for massive bacterial identification and discovery.37 A substantial percentage of this diversity (90–99%) is restricted to the bacterial phyla Firmicutes (including major genera Clostridium, Faecalibacterium, Lactobacilli, Ruminococcus) and Bacteroidetes (Bacteroides, Prevotella), where the dominating Firmicutes (50–80%) are predominantly composed of bacteria from Clostridium clusters XIVa and IV.38 The human gut also contains other bacteria belonging to the phyla Actinobacteria (3–15%), mainly genus Bifidobacterium; Proteobacteria (1–20%), mainly Escherichia, Helicobacter, Shigella; Verrucomicrobia (0.1%), mainly Akkermansia, Cyanobacteria, Fusobacteria, Lentisphaerae, and Spirochaetes.9,38,39 Although the changes from youth to adulthood may not be considered aging, the changes in the body and microbiome during these stages can influence later life stages. For example, Valeri and Endres summarized differences in the sex-associated GM throughout the human lifespan, from infancy to elderly age (>75 years).28

Gut microbiome alterations in the elderly age group

The elderly microbiota is generally characterized by a decline in microbial diversity, the emergence of Bacteroidetes phyla at the expense of Firmicutes, a rise in the abundance of opportunistic enteropathogens, and a decrease in species that produce short-chain fatty acids (SCFAs), particularly butyrate.9,40 A recent study found that an increase in fecal Christensenellaceae, Porphyromonadaceae, and Rikenellaceae was specifically linked to more favorable body composition in old age, namely decreased abdominal obesity.41 Additionally, the microbiome has been linked to alterations in bone density with age. Lactobacillus reuteri has shown promising results in maintaining and increasing bone mineral density in murine models and an increase in tibial bone density in elderly women.42,43 These studies provide valuable insights that L. reuteri may be an effective treatment for osteoporosis.42 The aged-type microbiota exhibits a less diverse microbial community, similar to what occurs during the initial stages of our lives. It is characterized by a rise in environmental facultative aerobes, such as Staphylococcus, Streptococcus, and Enterobacteriaceae, along with a decrease in anaerobes like Bacteroidetes and Clostridium clusters IV and XIVa. In contrast to the microbiota of newborns, the old type of microbiota is marked by a lower abundance of Bifidobacterium.9 Additionally, longevity and slower aging may also be influenced by the gut microbiome. Christensenella, Akkermansia, and bifidobacteria were reported in greater abundance in the gut of exceedingly older people (above 99 years old; known as centenarians Fig. 1), suggesting potential life-extension effects.44 These gut microbiome members may be crucial in defending against pathogenic infection and various other environmental stresses.

Interesting associations have been observed between aging and microbiome diversity in terms of the number of distinct species and their relative abundance (richness and evenness) in a given microbial ecosystem or between ecosystems (known as α-diversity and β-diversity, respectively). For example, an increase in the frailty index, which is regarded as a quantitative indicator of biological age, was found to be associated with a decrease in the diversity of the core microbiome.45 In contrast, a higher taxonomic α-diversity of the gut is linked with longer lifespans and better aging,46 while a decrease in gut microbial diversity has been linked to hospitalization.47 Notably, numerous studies have demonstrated that α-diversity, or more specifically microbial richness, is not negatively associated with chronological age but is adversely correlated with the frailty index (biological age).7

Factors affecting the aging-related alterations in hosts and their gut microbiomes

The gut microbiome plays an essential role in host health by educating the immune system and producing health-promoting microbial metabolites like SCFAs, which are signature metabolites of healthy aging as found in studies on centenarians.40 Perturbations in gut homeostasis are common with aging, causing a condition termed “leaky gut”, defined as increased permeability of the gut and unregulated tight junction blockade.48 Elderly people suffer from GM dysbiosis, with increased expression of proteolytic rather than saccharolytic genes, which intensifies inflammation due to an increase in pathobionts.49 The enhanced gut permeability allows foreign substances to enter the bloodstream and then circulate throughout the body, leading to systemic inflammation. This causes “inflammaging”, which supports the growth of aerobic and facultative aerobic pathobionts and restricts strict anaerobes (such as the Firmicutes phylum), sustaining inflammatory conditions and increasing inflammation mediators. For instance, enteric pathogens such as Clostridium difficile and Helicobacter pylori disintegrate the intestinal barrier through different mechanisms and trigger chronic inflammation, which further aggravates microbial dysbiosis and gastrointestinal infections, including diarrhea, gastritis, stomach cancer, pseudo-membranous colitis, and periodontitis.38 Inflammaging is linked to various age-related pathologies (Fig. 2), such as Alzheimer’s disease (AD), Parkinson’s disease (PD), obesity, heart disease, Type 2 diabetes, and cancer.31

Summary of age-related pathophysiological changes in host associated with gut microbiome.
Fig. 2  Summary of age-related pathophysiological changes in host associated with gut microbiome.

BBB: blood-brain barrier. Created by biorander.com.

According to a recent study, immunity, metabolism, and survival were all strongly impacted by variations in the gut microbiome of mice after exposure to antibiotics in their early lives.50 Similarly, in humans, associations have been observed between the usage of antibiotics in early life and increased risk factors for shorter life expectancies, such as susceptibility to infections and obesity.31 In addition, excessive antibiotic use by residents of aged care facilities is shown to lower colonization resistance and increase the prevalence of antibiotic-resistant bacteria, which may put the elderly at risk for fatal infections.51

Muscle mass, power, and functionality decrease by 3–8% per decade in individuals aged 30–60, with the decline rate being higher for those over 60 years.52 With aging, several changes at the cellular level contribute to sarcopenia pathology.53 These changes include a reduction in cell number and metabolism, twitch force and time, basal muscle protein synthesis (regulates muscle mass), disorganized sarcomere spacing, lower calcium transport capacity, mitochondrial dysfunction, and the accumulation of fats within and around muscle cells. The gut microbiome contributes to the determination of skeletal muscle mass, function, and architecture as part of the aging process. Butyricicoccus and Clostridium XIVa are SCFA producers positively correlated with muscle mass.54 These bacteria also produce host metabolites, including vitamin B12, lipids, folate, and microbial metabolites essential for muscle development. Gut dysbiosis and leaky gut are known to have a negative association with muscle protein synthesis due to inflammation and declined defense action upon infection.54 Dysbiosis might also contribute to sarcopenia pathology, as changes in microbial diversity have led to reduced metabolites for muscle development in sarcopenic rats.55

The skin, the largest body organ, is part of innate immunity, being the first line of defense. With age, skin becomes dry, stiff, and inflexible, losing some of its fatty tissues, making it thin with impaired sweat glands. The gut microbiome influences the skin microbiome via the gut-skin axis and gut-skin-brain axis. Skin resembles the gut in the presence of epithelial cells, which are in contact with microbes, and a low adherence of microbes occurs due to a higher rate of cellular turnover, thereby reducing infection. Several studies have shown that gut microbial dysbiosis is related to various skin diseases such as psoriasis, rosacea, and acne vulgaris, indicating a combined action of gut and skin microbiomes.56

Interplay between immunity and gut microbiome in aging

The immune system is the major host defense mechanism that protects against harmful stimuli, including microbes. The in utero environment is relatively sterile, and the immune system of the fetus exhibits tolerance to maternal alloantigens. The immune system gradually matures as the infant grows, attaining full maturity by late childhood. As one reaches old age, their immune system declines, leading to a variety of diseases. This strongly suggests that aging impacts the recognition of stimuli and may trigger several pathogenic processes linked with aging.31,48 Immunosenescence and inflammaging are two important hallmarks of the immune system in the elderly.57 Immunosenescence represents a decline in immune response in aging cells and is a complex biological process. It predisposes the elderly population to infections and comorbidities, and the elderly exhibit weaker vaccination responses than young and middle-aged adults.58 Functional and phenotypic modifications in aging immune cells result in decreased immunosurveillance and cytotoxic effector functions.59 Inflammaging refers to the rise in inflammation commonly observed with the development of some chronic inflammatory conditions as aging occurs. It also includes chronic low-grade inflammation that increases the risk of common non-communicable diseases.60 With advancing age, the microbiome affects immunity and predisposes elderly people to oxidative and inflammatory disorders. Thus, an intricate link exists between immunity and the microbiome in aging, especially the gut microbiome.61

From infancy to old age, gut microbiome composition and development are essential for the functioning, maturation, and regulation of the host immune system. Many of the bacteria that colonize the gut and other mucosal sites, besides being essential for a healthy life, also impact the development of the immune system.62 Loss of gut microbial diversity or modifications in the composition of the gut microbiome (often referred to as dysbiosis) may potentiate aging and disease.63 The mechanisms of the involvement of gut microbiome members in the development of immunity are well documented and reviewed.57,60,64,65

During aging, the host microbiome influences the local immune system in addition to epigenetics and host metabolism alterations.61 Recent studies confirmed that immune cells are responsible for the bidirectional regulation of changes in the diversity of the gut microbiome. For instance, changes in the gut microbiome’s composition, including a decrease in Faecalibacterium prausnitzii and an increase in Proteobacteria, are both linked to inflammatory disorders brought on by aging.66 One notion is that maintaining a “healthy” gut microbiome composition as one ages can aid in slowing down or ceasing the inflammatory aging process. It is known that several gut bacterial species, which belong to the genera Bifidobacterium, Faecalibacterium, and Lactobacillus, have the potential to suppress the pro-inflammatory response at the gut epithelium level or indirectly block the transcription of pro-inflammatory genes, for example, by Bacteroides thetaiotaomicron.9,67,68 Similarly, Akkermansia muciniphila, one of the few known species of the phylum Verrucomicrobia, is known for its potential to degrade mucin and promote intestinal integrity by reducing toxicity levels associated with high-fat diets. An increase in the abundance of Verrucomicrobia is also associated with better-quality sleep.69 Badal et al.69 highlighted in their study that Christensenellaceae, Verrucomicrobia, and Akkermansia may support healthy aging and gut homeostasis by decreasing adiposity, inflammation, and the future risk of developing metabolic disorders.

Associations of host metabolic alterations, gut microbiome, and aging

Microorganisms produce a wide range of organic and inorganic molecules that can interfere with the host’s metabolism and affect aging (Table 1).1,39,70–83 Flint et al.84 have reviewed variations in metabolism due to gut microbial metabolites such as SCFAs, cholesterol, lipids, vitamins, gasses, and atherogenic compounds, which may alter host sensitivity towards metabolic syndromes, obesity, cardiovascular disease, and irritable bowel syndrome.

Table 1

Microbial-produced metabolites associated with the aging process

MetabolitesEffectMicrobes associatedReference
Nicotinic acidPositively affects stem cell proliferation in the colon helping in intestinal epithelium renewal. Advantageous for healthy aging.Bacillus subtilis 2978470,71
Lipopolysaccharide (LPS)Insulin resistance due to immune dysregulation causes inflammation and disturbed metabolic and biochemical pathways leading to metabolic diseases. Disadvantageous for healthy aging.Bacteroidetes and Proteobacteria (produce LPS). Firmicutes and Actinobacteria (increases LPS absorption)72,73
Colibactin & Bacteroides fragilis toxinDNA damage by these toxins increases the chances of colon tumorigenesis which may lead to mortality observed in colorectal cancer-associated murine models also inflammation pathway role is recorded. Disadvantageous for healthy aging.E. coli and Bacteroides fragilis70
Short-chain fatty acids (SCFA)SCFAs act as follows: (I) Neurodegeneration, (II) Energy homeostasis, (III) Immunomodulatory effect, (IV) Gut function and immunity regulation, (V) Anti-cancerous, (VI) Anti-inflammatory, and (VII) Gut dysbiosis prevention. Advantageous for healthy aging.Butyrate producers (Fusobacterium, Clostridium, Eubacterium, and Faecalibacterium)74
Nitric oxideShown to increase organismal lifespan (C. elegans model study) in a gene DAF-16 a solo FoxO (forkhead box transcription factor class O), i.e. FoxODAF-16-dependent signaling pathway. Advantageous for healthy aging.Lactobacilli, bifidobacteria, and E.coli70,75
Reactive oxygen species (ROS)Induced oxidative stress and important signaling pathways modulation which produced diversified results on different model organisms related to aging. The role remains unclear.Lactobacillus rhamnosus caused the rapid generation of epithelial ROS1,70
Hydrogen sulfideSmaller concentrations are used by colonocytes and are observed to be associated positively with longevity in model organisms. Advantageous for healthy aging in a concentration-dependent manner.Sulfate-reducing bacteria residing in the human intestine70
Bacterial polysaccharide colonic acidMitochondrial homeostasis improvement in C. elegans and D. melanogaster studies helping in longevity. Advantageous for healthy aging.E. coli K-12 and other mutants of E. coli39,76
PolyaminesPolyamines help in the following: (I) Age-related markers improvement, (II) Age-induced memory impairment protection, (III) Longevity increment, (IV) Intestinal barrier integrity and function enhancement, (V) Intestinal and systemic adaptive immune system maturation, (VI) Cancer development due to dysregulated polyamine metabolism, and (VII) Pro-inflammatory M1 macrophage activation inhibition by spermine. Advantageous for healthy aging.Bifidobacterium lactis LKM51276,77
Indole derivativesIndole-3-Propionic Acid acts as (I) A powerful antioxidant; (II) Amyloid-beta fibril formation inhibitor (III) Neuroprotective and cytoprotective agent against a variety of oxidotoxins (IV) Intestinal barrier function, intestinal permeability, and mucosal integrity regulator. Advantageous for healthy aging.E. coli, Bacteroides spp., lactobacilli, Clostridium sporogenes, Fifty-one species of Bifidobacterium, probiotic Lactobacillus spp., Lechevalieria aerocolonigenes. Various Peptostreptococcus spp. and Clostridium spp. play’s role in promoting the synthesis of indoleacrylic acid (IA) and indole propionic acid (IPA)7881
Phenolic derivativesHelp in (I) oxidative stress protection, (II) Urolithin exhibits anti-inflammatory and cancer prevention, (III) Chemo-preventive effects. Advantageous for healthy aging.Proteus sp., Streptococcus faecalis, Bacteroides fragilis, Fusobacterium sp., and Clostridium sp.82,83

The associations of these microbial metabolites with host aging have been explored extensively. Colon bacteria produce SCFAs, which are a subset of fatty acids, by fermenting dietary fibers and resistant starch.85 Butyrate, propionate, acetate, and valerate are common SCFAs derived from the gut microbiome. Butyrate plays a significant role in preventing physiological decline during aging. It prevents inflammation by downregulating adipogenesis, enhancing the intestinal barrier, preventing insulin resistance, regulating B1 cell activity to prevent cancer, inhibiting histone deacetylase, and facilitating apoptosis by counteracting amyloidosis and neuro-inflammation while also preventing cellular senescence.70,86

Microbes like Akkermansia muciniphila produce acetate and facilitate the growth of butyrate-producing microorganisms.31 Biagi et al.87 observed that the presence of Faecalibacterium prausnitzii, a gut inflammation-protectant species, along with Anaerotruncus colihominis and Eubacterium limosum, which are butyrate producers, is characteristic of long-lived people. Additionally, the gut microbiome profiles of the offspring of elderly parents were found to be more similar when they cohabited with their parents compared to those who lived separately. This has escalated the incidence of pathobionts and opportunistic species in the gut microbiome of cohabiting family members, indicating an environmental influence.

Epigenetic modifications such as DNA methylation, histone modifications, noncoding RNA action, and chromatin remodeling affect living organisms throughout their lives.1 Commensals alter histone-changing enzymes by modifying their activity or substrates, affecting cell fate and development. High concentrations of SCFAs like propionate inhibit histone deacetylase activity and protect against colorectal cancer. Butyrate also induces hyperacetylation of histones and stimulates cell differentiation.70

Polyamines are small organic molecules involved in various physiological processes, including cell growth, differentiation, and apoptosis.88 These gut microbiome-derived metabolites are essential for normal cellular function and play an important role in aging (Table 1). Several studies have suggested that polyamines not only increase longevity but promote healthy aging by improving age-related markers and protecting against age-induced memory impairment.88 Levels of polyamines decline with age in various tissues, including the liver, kidney, and brain. Additionally, studies in animal models have found that increasing levels of polyamines can extend lifespan and improve healthspan.70

Reactive oxygen species (ROS) are metabolites containing partially reduced oxygen, primarily produced by the mitochondria inside a cell.89 These molecules can cause oxidative stress and damage cellular components such as proteins, lipids, and DNA, leading to various age-related diseases and the overall aging process.1Lactobacillus rhamnosus causes rapid ROS generation in the epithelial lining and induces oxidative stress. ROS also act as signaling molecules in inflammatory response generation, the ubiquitin-proteasome pathway, and regulate post-translational modifications such as SUMOylation and neddylation. When commensal bacteria contact gut epithelial cells, they produce ROS.70 As we age, the body’s ability to regulate ROS production decreases, leading to an increase in oxidative damage. This can result in the accumulation of mutations and errors in cellular function, causing the gradual deterioration of tissue and organ function, ultimately resulting in age-related diseases.

Extracellular amyloid is produced by gut microbes and can alter proteostasis, forming insoluble aggregates that speed up the development of cerebral amyloidosis. The bacterial amyloid load increases due to the gastrointestinal system and immune modification with age, which affects immune homeostasis. As we age, the body’s ability to clear amyloid decreases, leading to its accumulation and aggregation in the brain. These amyloid plaques can interfere with the normal functioning of brain cells, causing inflammation, oxidative stress, and ultimately, cell death.90 The accumulation of amyloid in the brain is strongly associated with the development of AD. Studies have shown that SCFAs can inhibit the formation and aggregation of amyloid protein in the brain, potentially helping to prevent or slow the progression of AD. Additionally, SCFAs have been shown to promote the clearance of amyloid protein from the brain by enhancing the activity of immune cells that remove these toxic proteins.70

Age-related neuro-pathologies and GM variations

The brain is separated from the rest of the organs by the blood-brain barrier. The central and enteric neuronal systems communicate bidirectionally through the gut-brain axis (also known as the microbiome-gut-brain axis), which connects the brain’s cognitive and emotional regions with the peripheral functions of the intestine.91 The vagus nerve directly connects the gut to the brain, sensing changes in the gut microbiome and influencing brain activity based on metabolites released by normal gut flora (Table 1).92 Recent reports suggest that aging, host-microbiome diversity, and aging-associated diseases may have a close relationship.59 The human gut microbiome has been associated with the origin and treatment of multiple neurological disorders such as multiple sclerosis, AD, and PD. Interestingly, the incidence and severity of these diseases also increase with age.

Behavior is regulated by gastrointestinal hormones released locally or by bacterial fragments and metabolites that interact with the central nervous system, directly impacting the hypothalamus. Additionally, it has been demonstrated that the blood-brain barrier’s permeability and serotonin release are controlled by gut bacteria.91 Despite the anatomical separation between the gut and the brain, numerous studies indicate that intestinal health substantially impacts neurodegeneration.93 There may be gastrointestinal roots to neurodegenerative conditions, including amyotrophic lateral sclerosis and AD.93 Notably, primary symptoms in a mouse model with amyotrophic lateral sclerosis included disease-specific disruption to intestinal restrictive junctions, higher gut permeability, and decreased levels of butyrate-producing bacteria (Butyrivibrio fibrisolvens).94

Age-related alteration in the morphology of microglia is termed dystrophic microglia and has been intimately linked to neurodegenerative disease.95 Several studies conducted on animal models to explore the relationship between AD and gut microbiome changes have indicated a strong connection between altered gut microbes and the progression of the illness.96 A study exploring the association of gut microbiome alterations with preclinical AD in patients with and without cerebral Aβ deposition in cognitively normal individuals.97 It was found that certain genera categorized as opportunistic pathogens, including Megamonas, Serratia, Leptotrichia, and Clostridium (family Clostridiaceae), were increased in Aβ+ cases. However, commensal genera with the ability to synthesize lactic acid and probiotic potential, including Victivallis, Enterococcus, Mitsuokella, and Clostridium (family Erysipelotrichaceae), were decreased in Aβ+ cases.97 An altered gut microbiome was observed in AD patients compared to controls, with a lower abundance of Firmicutes and Actinobacteria and a higher relative abundance of Bacteroidetes.98 In AD patients, families of Firmicutes namely Ruminococcaceae, Turicibacteraceae, Peptostreptococcaceae, Clostridiaceae, and Mogibacteriaceae, along with the genera SMB53 (family Clostridiaceae), Dialister, Clostridium, Turicibacter, and cc115 (family Erysipelotrichaceae), were less prevalent. However, the families Gemella, Bacteroidaceae, and Rikenellaceae, along with genera Bacteroides and Alistipes, were more prevalent in the patient cohort. A decline in Actinobacteria resulted in a decline of Bifidobacteriaceae at the family level and Adlercreutzia and Bifidobacterium at the genus level. Additionally, those with AD had a higher abundance of the genera Proteobacteria and Bilophila.98

PD is a peculiar neurodegenerative condition marked by the loss of substantia nigra cells and has recently been linked to gut microbial dysbiosis. In PD patients with motor complications, the relative abundance of the genus Blautia of the Lachnospiraceae family was decreased, while an increase in the genus Lactobacillus was observed.99 Similarly, Lachnospiraceae incertaes edis and Faecalibacterium prausnitzii were less abundant in PD patients, while most taxa of the phylum Proteobacteria, especially Enterobacteriaceae, were more abundant.99 A study comparing the alpha and beta diversity of PD patients and healthy controls after 14 months of clinical observation showed that the alpha and beta diversity was stable in PD patients and healthy controls, with no significant change in diversity with respect to disease pathology. However, the richness parameter of alpha diversity was reduced in both healthy individuals and PD patients.100 It was previously reported that Desulfovibrio bacteria were more prevalent in the gut of PD patients compared to healthy controls.99 Furthermore, the severity of PD was associated with the quantity of Desulfovibrio species. These bacteria produce H2S, lipopolysaccharide, and various types of magnetite, which likely cause the oligomerization and aggregation of the α-synuclein protein, leading to PD.100

Stem cell aging and gut microbiome

Intestinal stem cells play an important role in maintaining intestinal homeostasis and repairing damaged epithelial tissue. These cells function in a regenerative manner to generate new tissue throughout the growth phase and repair damaged tissue during the aging process.101 The interactions between the gut microbiome and intestinal stem cells are crucial because, if this interaction is comprehended, it may be possible to address various disorders that require stem cell therapy, heal wounds, and improve the durability of organ transplants.101 A recent study showed a connection between hematopoietic stem cells and the microbiome through altering metabolic stress.66 Therefore, the microbiota is crucial for maintaining microbial homeostasis, regulating metabolism, and the innate and adaptive immune systems.101 Furthermore, the study reveals that compositional alterations in the gut microbiome driven by dysbiosis are related to stem cell aging, metabolic dysregulations, stem cells’ epigenetic instability, and abnormal immune system activation.66

In the field of anti-aging, stem cells are regarded to have great potential. In numerous organs, it has been demonstrated that as we age, stem cells lose their capacity for self-renewal and differentiation and run out of resources.89 The emergence of anti-aging medications should address the dysregulation caused by aging that affects stem cells’ capacity for differentiation and self-renewal by re-regulating intrinsic and extrinsic variables. The host microbiome, hormones, local immune system, systemic inflammation, and niche structure are just a few examples of microenvironmental and systemic factors that influence stem cell aging.66

Endogenous ethanol is a class of microbiological metabolites. Proteobacteria, including E. coli and other Enterobacteriaceae, produce ethanol with bacterial origins. High endogenous ethanol levels in the human hippocampus inhibit proliferating stem cells and reduce progenitor and stem cells.102 Additionally, when more ethanol accumulates in the gut, it enhances the permeability of the gut by disrupting epithelial tight junctions, particularly zonula occludens. This enables the movement of pathogenic microbes, their endotoxins, and ethanol across the epithelial layer, causing more immediate and adverse effects on tissues. As a result, the stem cell reserve depletes, hastening the aging process and compensating for damaged tissues.103

The host microbiome regulates the generation of aging-associated stem cells via various pathways, namely Wnt, transforming growth factor beta, Notch, JUN N-terminal kinase, and mitogen-activated protein kinases (p38) signaling pathways. However, it is still unclear how the host microbiome influences stem cell functioning in terms of aging.66

Modulation of microbiome for a healthy aging

Over a century ago, Russian microbiologist and Nobel Laureate E. Metchnikoff observed that having the wrong kind of intestinal microflora could adversely affect health over time.104 He proposed that gastrointestinal metabolisms cause putrefactive effects on the body, gradually contributing to illness and aging, which can be mitigated by regularly consuming fermented dairy products.105 Although his concept initially gained popularity among the masses, it only caught mainstream medical attention in the mid-1990s.

Currently, several studies report that aging is associated with increased dysbiosis in the gut, where proinflammatory microbes are enriched at the expense of beneficial gut commensals.106 The gut microbial composition of elderly individuals and centenarians is characterized by a reduction in bacterial diversity and depletion of health-promoting genera such as Bifidobacterium and Lactobacillus.107 As a result, aging populations may be more prone to inflammation and morbidity. The administration of pre- and probiotic supplements is recommended as an approach to correct such dysbiotic changes in the aging intestinal microbiota.108

Most probiotics used today are bifidobacteria and subpopulations of lactobacilli, widely considered the health-promoting constituents of the human microbiome. Several strains of these organisms have exhibited anti-aging properties in nematode models. Strains such as Bifidobacterium longum BB68,109Lactobacillus gasseri SBT2055,110L. fermentum MBC2,111 and B. infantis ATCC15697 have been shown to enhance the lifespan of C. elegans by modulating DAF-16,112 a transcription factor that controls multiple signaling pathways associated with aging and longevity. Other strains of lactobacilli, such as L. rhamnosus CNCM I-3690,113L. salivarius FDB89,114 and L. fermentum LA12, have been shown to improve the life expectancy of C. elegans by exhibiting antioxidative properties.115

In rodent models, the administration of the L. brevis OW38 strain resulted in reduced expression of senescence markers p16, p53, and SAMHD1, which contributed to anti-inflammatory effects in aged mice.116 In another study, the L. paracasei PS23 strain showed promising effects in delaying sarcopenia progression during aging by preserving mitochondrial function.117 Additionally, Lactobacillus strains such as L. fermentum DR9, L. plantarum DR7, and L. reuteri 8513d significantly reduced telomere shortening, while strains L. plantarum AR501 and L. helveticus KLDS1.8701 reduced hepatic oxidative stress by elevating the gene expression of Nrf2 and other antioxidant genes.118,119 The outcomes of these studies directly impact the central hallmarks of aging.

Probiotics are generally recognized as safe for human consumption and can impart substantial health benefits to the elderly. These benefits include modulation of the microbiome, prevention of inflammatory intestinal disorders, enhanced intestinal barrier function, stimulation of the innate immune system, and improvements in cognitive function and quality of life.120 Human dietary intervention studies involving probiotic supplements have been documented to increase beneficial microbes such as bifidobacteria, lactobacilli, and enterococci species in the elderly population.121 Daily consumption of the probiotic strain Bacillus coagulans GBI-30, 6086 among aged adults has been shown to improve immune and gut-related functions by increasing levels of butyrate-producing species such as Fecalibacterium prausnitzii. Administration of certain probiotics can induce favorable responses from the residents of the elderly human gut, such as Lactobacillus rhamnosus GG, which was found to mediate interactions between key members of the gut microbiome and the host epithelium by promoting anti-inflammatory pathways in the resident microbes.122

The administration of probiotics has been observed to manage many age-related pathophysiological conditions affecting the immune system. Studies on elderly human subjects show that probiotic intake can boost immunity and improve several immune-related markers.123 Dietary supplementation with a mixture of B. longum Bar33 and L. helveticus Bar13 strains in elderly humans improved their immune response by increasing regulatory T cells, B cells, and natural killer cells while decreasing memory T cells.123 In another study, consumption of L. gasseri KS-13, B. bifidum G9-1, and B. longum MM-2 produced a less inflammatory cytokine profile by maintaining CD4+ lymphocyte levels in elderly hosts.124 Other studies examining immune-related markers found a decrease in levels of the proinflammatory cytokine IL (interleukin)-8 and C-reactive protein among the elderly with probiotic intake.125 Furthermore, these studies observed that probiotic supplementation could counteract reduced naïve T cell production and increase less-differentiated T cell populations in aging populations.123

Aside from enhancing immune function and longevity, probiotic interventions have been used to improve the quality of life in the elderly. Probiotic therapy has been shown to reduce abdominal pain,126 improve bowel movements,127 enhance oral health,128 and increase vitamin levels in the blood.129 Studies have also demonstrated that probiotics can positively impact the general well-being of the elderly by decreasing anxiety and depression, improving cognitive functions,130 and alleviating stress.131

Bifidobacterium is one of the potential candidates for boosting longevity by producing polyamine biosynthesis observed in animal models.132 When Lactobacillus rhamnosus GG and soluble corn fiber were fed to healthier elderly participants, there was a reduction in chronic inflammation and an improvement in the microbial profile.125 In addition to probiotic interventions, physical activity plays a pivotal role in modulating the gut microbiome. Regular exercise has been linked to a diverse and balanced gut microbiome, which is crucial for maintaining overall health and preventing age-related diseases. Studies indicate that regular exercise can modify the gut microbiome composition of older individuals towards a more favorable state by increasing the populations of beneficial bacteria, such as SCFA producers, and by reducing the prevalence of potential pathogens.107 This interplay between exercise and the gut microbiome can be effectively harnessed to enhance overall health and well-being among the elderly. The microbial outline and host health have a shared functional relationship; therefore, it is recommended to adopt a healthy lifestyle, exercise regularly, and maintain a proper diet to balance the beneficial microbiome. This balance contributes to longevity and reduces morbidities associated with aging. For instance, the deteriorating physiology of the alimentary canal inevitably impacts the gut microbiome. These alterations include elevated inflammation linked to aging, cellular malfunction (including mitochondrial dysfunction), genomic instability, epigenetic dysregulation, and diminished proteostasis, which further contribute to the onset of metabolic disorders, chronic illnesses, and altered gut-brain communication.7

Future directions

With the introduction of novel molecular biological techniques and advances in next-generation sequencing technologies, we finally have a snapshot of the gut microbiome and its taxonomical and functional constituents. Understanding factors that bridge the gut microbiome and long healthy life is a significant challenge. Initially, animal models have been used to understand the molecular mechanism of aging. Such studies have identified several genes associated with both the microbiome and aging. Knock-out studies involving these genes can further explore the effects of microbes on healthy aging. Various studies have been conducted on healthy elderly individuals to characterize their gut microbiome composition and identify alterations that help delay the onset of age-associated disorders.133 Many age-related pathophysiological conditions are known to influence older adults’ dietary habits, causing compositional changes in the gut microbiome that ultimately lead to senescence. At the DNA level, microbial function can only be predicted or assessed based on genetic components that can potentially produce or degrade specific compounds, such as metabolites or engage in other enzymatic activities. Evaluating mRNA (metatranscriptomics), small molecule (metabolomics), and protein levels (metaproteomics) is necessary for a more comprehensive evaluation of microbial functions. Considering that metabolic alterations are associated with aging, presumably reflecting changes in the biological roles of the host and microbiome, metabolic profiling may serve as a promising method for determining the biological age of a person.134 By analyzing the circulating microbial metabolites, a biological aging clock can be established, although this research field is still in its beginnings.135 For example, Johnson et al.136 used the plasma metabolite profiles of individuals aged 18 to 80 and reported 21 metabolites connected to biological aging, many of which had previously been recognized as “microbe-associated metabolites”.137 Elevated levels of indole-3-acetate and putrescine are linked to biologically younger ages, while a high concentration of phaseolic acid is associated with elderly age groups.136 Similarly, metabolites secreted in urine and feces have been investigated in relation to aging clocks, such as phenylacetylglutamine (PAG),138 trimethylamine-N-oxide,139 4-cresyl sulfate,138 and p-cresol sulfate (PCS),140 etc. In addition to innovations in metabolomics, proteomic studies are increasingly helpful in comprehending the composition and functioning of microbial proteins in various health aspects. More comprehensive studies are required to evaluate the relationship between the proposed metabolic-proteomic aging clock and the resident microbiome.

Advancements in the different “omics” fields have provided us with a clear understanding of various host-microbe interactions and their influences on aging. Enrichment of certain taxa, such as Bifidobacterium, Christensenellaceae, and Akkermansia, has been shown to promote longevity and improve quality of life during senescence. To improve the gut microbiome and encourage healthy aging, techniques such as fecal microbiome transplantation (FMT) and oral probiotic treatment have been used. Administration of pre- and probiotics may mitigate age-related alterations linked to sarcopenia and longevity.31 Further studies in this area can potentially enhance such taxonomic profiles, imparting positive health benefits to the host. More focused studies on metagenomic exploration of the aged population would help identify species-level microbial information positively associated with the healthy aging process. However, these methods suffer from the major limitations of predicting metagenomic diversity till the genus level, missing out on species and strain-level differences.141 Therefore, whole metagenome-based shotgun sequencing methods can be used to address these issues and explore the strain/species-level diversity of the gut microbiome.

Microbes generally do not exist in isolation and exhibit a bidirectional relationship with several other microbial members in an environment. Most current studies focus on identifying individual microbial members associated with the aging process. However, it may be useful to explore the social behavior of gut microbiome members by adopting tools and pipelines to identify co-occurring taxa or those taxa that do not occur together. To explore the activity of such beneficial taxa and how they are co-associated with each other, culturomics or culture-based methods are an alternative approach. Recent methods such as yeast casitone fatty acid agar can be employed to cultivate more than 90% of members of the gut microbiome under lab conditions.37

Since age-related disorders are known to increase intestinal permeability, regaining intestinal permeability by FMT may be a regenerative and successful medicinal technique in producing stem cells for the elderly. Nevertheless, more research is needed to determine whether FMT to old recipients from young donors restores the ability of stem cells to self-renew, regenerate, and differentiate, thereby improving lifespan. To pave the way for discovering therapeutic medications for extending lifespan and treating disorders linked to aging, more research into the interactions between intestinal stem cells and the microbiome is necessary.

Constructing a reliable aging model based on microbiomes can only be possible by integrating different types of approaches and data sources. Additionally, novel and advanced computational methods are needed considering the heterogeneity and complexity of aging and the microbiome. Machine learning models trained on metagenomic, transcriptomic, proteomic, and metabolomics data can predict microbial behaviors associated with aging. These models can also account for external factors such as geographical features and lifestyle, further refining our understanding of biological and chronological aging.142 Furthermore, such advancements can assist in modulating the gut microbiome and developing personalized longevity therapies in a clinical context. Therefore, adopting a healthy lifestyle with proper nutrition and exercise, along with positive modulation of GM through probiotics, can bring us closer to prolonged healthy lives.

Conclusions

Hippocrates’ emphasis on the importance of gut health resonates through the centuries to our modern understanding of the pivotal role of the gut microbiome in human health and aging. Although aging is a complex biological process that has yet to be fully understood, we have an increasing volume of evidence supporting the existence of a dialogue between the gut microbiome of a host and its aging process. Aging brings about changes in the gut microbiome, disrupting its balance and functionality, which can accelerate senescence through inflammatory processes and reduced production of beneficial metabolites. Advancements in the various “omics” fields have provided us with a clear understanding of various host-microbe interactions, their influences on aging, and the enrichment of certain longevity-associated taxa, such as Bifidobacterium, Christensenellaceae, and Akkermansia, offering promising avenues for interventions such as FMT and probiotic treatments. Although we are still far from solving the “curious case of aging” or finding “the path to longevity”, it is possible that a healthy aging process with less morbidity and frailty can be achieved through a healthy diet and proper modulation of the gut microbiome.

Declarations

Acknowledgement

We thank the Indian Institute of Technology Mandi and Ministry of Human Resource Development. Figures were created using biorander.com.

Funding

This research received no external funding.

Conflict of interest

The authors declare no conflict of interests.

Authors’ contributions

Conceptualization (RI), original draft writing (RI, JA, AOK, GS, SY, SS, SR), review and editing (RI, JA, AOK, GS, SR, TP), and supervision (TP). All authors have read and agreed to the published version of the manuscript.

References

  1. López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell 2013;153(6):1194-1217 View Article PubMed/NCBI
  2. Walston J. Goldman-Cecil Medicine. 26th ed. Philadelphia, PA: Elsevier; 2020 View Article PubMed/NCBI
  3. Holloszy JO. The biology of aging. Mayo Clin Proc 2000;75 Suppl:S3-S8 View Article PubMed/NCBI
  4. Khan M, Mathew BJ, Gupta P, Garg G, Khadanga S, Vyas AK, et al. Gut Dysbiosis and IL-21 Response in Patients with Severe COVID-19. Microorganisms 2021;9(6):1292 View Article PubMed/NCBI
  5. Choden T, Cohen NA. The gut microbiome and the immune system. Explor Med 2022;3:219-233 View Article PubMed/NCBI
  6. Salvo-Romero E, Stokes P, Gareau MG. Microbiota-immune interactions: from gut to brain. LymphoSign Journal. LymphoSign Journal Limited Partnership 2020;7(1):1-23 View Article PubMed/NCBI
  7. Ratiner K, Abdeen SK, Goldenberg K, Elinav E. Utilization of Host and Microbiome Features in Determination of Biological Aging. Microorganisms 2022;10(3):668 View Article PubMed/NCBI
  8. Ghosh TS, Rampelli S, Jeffery IB, Santoro A, Neto M, Capri M, et al. Mediterranean diet intervention alters the gut microbiome in older people reducing frailty and improving health status: the NU-AGE 1-year dietary intervention across five European countries. Gut 2020;69(7):1218-1228 View Article PubMed/NCBI
  9. Biagi E, Candela M, Fairweather-Tait S, Franceschi C, Brigidi P. Aging of the human metaorganism: the microbial counterpart. Age (Dordr) 2012;34(1):247-267 View Article PubMed/NCBI
  10. Collado MC, Rautava S, Aakko J, Isolauri E, Salminen S. Human gut colonisation may be initiated in utero by distinct microbial communities in the placenta and amniotic fluid. Sci Rep 2016;6:23129 View Article PubMed/NCBI
  11. Arrieta MC, Stiemsma LT, Amenyogbe N, Brown EM, Finlay B. The intestinal microbiome in early life: health and disease. Front Immunol 2014;5:427 View Article PubMed/NCBI
  12. Claesson MJ, Cusack S, O’Sullivan O, Greene-Diniz R, de Weerd H, Flannery E, et al. Composition, variability, and temporal stability of the intestinal microbiota of the elderly. Proc Natl Acad Sci U S A 2011;108(Suppl 1):4586-4591 View Article PubMed/NCBI
  13. Vallès Y, Artacho A, Pascual-García A, Ferrús ML, Gosalbes MJ, Abellán JJ, et al. Microbial succession in the gut: directional trends of taxonomic and functional change in a birth cohort of Spanish infants. PLoS Genet 2014;10(6):e1004406 View Article PubMed/NCBI
  14. Kundu P, Blacher E, Elinav E, Pettersson S. Our Gut Microbiome: The Evolving Inner Self. Cell 2017;171(7):1481-1493 View Article PubMed/NCBI
  15. Yang B, Chen Y, Stanton C, Ross RP, Lee YK, Zhao J, et al. Bifidobacterium and Lactobacillus Composition at Species Level and Gut Microbiota Diversity in Infants before 6 Weeks. Int J Mol Sci 2019;20(13):3306 View Article PubMed/NCBI
  16. Solís G, de Los Reyes-Gavilan CG, Fernández N, Margolles A, Gueimonde M. Establishment and development of lactic acid bacteria and bifidobacteria microbiota in breast-milk and the infant gut. Anaerobe 2010;16(3):307-310 View Article PubMed/NCBI
  17. Nagpal R, Tsuji H, Takahashi T, Kawashima K, Nagata S, Nomoto K, et al. Sensitive Quantitative Analysis of the Meconium Bacterial Microbiota in Healthy Term Infants Born Vaginally or by Cesarean Section. Front Microbiol 2016;7:1997 View Article PubMed/NCBI
  18. Harmsen HJ, Wildeboer-Veloo AC, Raangs GC, Wagendorp AA, Klijn N, Bindels JG, et al. Analysis of intestinal flora development in breast-fed and formula-fed infants by using molecular identification and detection methods. J Pediatr Gastroenterol Nutr 2000;30(1):61-67 View Article PubMed/NCBI
  19. Gregory KE, LaPlante RD, Shan G, Kumar DV, Gregas M. Mode of Birth Influences Preterm Infant Intestinal Colonization With Bacteroides Over the Early Neonatal Period. Adv Neonatal Care 2015;15(6):386-393 View Article PubMed/NCBI
  20. Jakobsson HE, Abrahamsson TR, Jenmalm MC, Harris K, Quince C, Jernberg C, et al. Decreased gut microbiota diversity, delayed Bacteroidetes colonisation and reduced Th1 responses in infants delivered by caesarean section. Gut 2014;63(4):559-566 View Article PubMed/NCBI
  21. Underwood MA, German JB, Lebrilla CB, Mills DA. Bifidobacterium longum subspecies infantis: champion colonizer of the infant gut. Pediatr Res 2015;77(1-2):229-235 View Article PubMed/NCBI
  22. Sakanaka M, Gotoh A, Yoshida K, Odamaki T, Koguchi H, Xiao JZ, et al. Varied Pathways of Infant Gut-Associated Bifidobacterium to Assimilate Human Milk Oligosaccharides: Prevalence of the Gene Set and Its Correlation with Bifidobacteria-Rich Microbiota Formation. Nutrients 2019;12(1):71 View Article PubMed/NCBI
  23. Björkstén B, Sepp E, Julge K, Voor T, Mikelsaar M. Allergy development and the intestinal microflora during the first year of life. J Allergy Clin Immunol 2001;108(4):516-520 View Article PubMed/NCBI
  24. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol 2007;5(7):e177 View Article PubMed/NCBI
  25. Vanhoutte T, Huys G, Brandt E, Swings J. Temporal stability analysis of the microbiota in human feces by denaturing gradient gel electrophoresis using universal and group-specific 16S rRNA gene primers. FEMS Microbiol Ecol 2004;48(3):437-446 View Article PubMed/NCBI
  26. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity 2013;39(2):400-412 View Article PubMed/NCBI
  27. Org E, Mehrabian M, Parks BW, Shipkova P, Liu X, Drake TA, et al. Sex differences and hormonal effects on gut microbiota composition in mice. Gut Microbes 2016;7(4):313-322 View Article PubMed/NCBI
  28. Valeri F, Endres K. How biological sex of the host shapes its gut microbiota. Front Neuroendocrinol 2021;61:100912 View Article PubMed/NCBI
  29. Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature 2012;486(7402):222-227 View Article PubMed/NCBI
  30. Zhang X, Zhong H, Li Y, Shi Z, Ren H, Zhang Z, et al. Sex- and age-related trajectories of the adult human gut microbiota shared across populations of different ethnicities. Nat Aging 2021;1(1):87-100 View Article PubMed/NCBI
  31. Ghosh TS, Shanahan F, O’Toole PW. The gut microbiome as a modulator of healthy ageing. Nat Rev Gastroenterol Hepatol 2022;19(9):565-584 View Article PubMed/NCBI
  32. de la Cuesta-Zuluaga J, Kelley ST, Chen Y, Escobar JS, Mueller NT, Ley RE, et al. Age- and Sex-Dependent Patterns of Gut Microbial Diversity in Human Adults. mSystems 2019;4(4):e00261-19 View Article PubMed/NCBI
  33. Yuan X, Chen R, Zhang Y, Lin X, Yang X. Sexual dimorphism of gut microbiota at different pubertal status. Microb Cell Fact 2020;19(1):152 View Article PubMed/NCBI
  34. Moreira-Pais A, Ferreira R, Neves JS, Vitorino R, Moreira-Gonçalves D, Nogueira-Ferreira R. Sex differences on adipose tissue remodeling: from molecular mechanisms to therapeutic interventions. J Mol Med (Berl) 2020;98(4):483-493 View Article PubMed/NCBI
  35. Saffrey MJ. Aging of the mammalian gastrointestinal tract: a complex organ system. Age (Dordr) 2014;36(3):9603 View Article PubMed/NCBI
  36. Xu J, Mahowald MA, Ley RE, Lozupone CA, Hamady M, Martens EC, et al. Evolution of symbiotic bacteria in the distal human intestine. PLoS Biol 2007;5(7):e156 View Article PubMed/NCBI
  37. Browne HP, Forster SC, Anonye BO, Kumar N, Neville BA, Stares MD, et al. Culturing of ‘unculturable’ human microbiota reveals novel taxa and extensive sporulation. Nature 2016;533(7604):543-546 View Article PubMed/NCBI
  38. Conway J, A Duggal N. Ageing of the gut microbiome: Potential influences on immune senescence and inflammageing. Ageing Res Rev 2021;68:101323 View Article PubMed/NCBI
  39. Han B, Sivaramakrishnan P, Lin CJ, Neve IAA, He J, Tay LWR, et al. Microbial Genetic Composition Tunes Host Longevity. Cell 2017;169(7):1249-1262.e13 View Article PubMed/NCBI
  40. Biagi E, Rampelli S, Turroni S, Quercia S, Candela M, Brigidi P. The gut microbiota of centenarians: Signatures of longevity in the gut microbiota profile. Mech Ageing Dev 2017;165(Pt B):180-184 View Article PubMed/NCBI
  41. Tavella T, Rampelli S, Guidarelli G, Bazzocchi A, Gasperini C, Pujos-Guillot E, et al. Elevated gut microbiome abundance of Christensenellaceae, Porphyromonadaceae and Rikenellaceae is associated with reduced visceral adipose tissue and healthier metabolic profile in Italian elderly. Gut Microbes 2021;13(1):1-19 View Article PubMed/NCBI
  42. Britton RA, Irwin R, Quach D, Schaefer L, Zhang J, Lee T, et al. Probiotic L. reuteri treatment prevents bone loss in a menopausal ovariectomized mouse model. J Cell Physiol 2014;229(11):1822-1830 View Article PubMed/NCBI
  43. Nilsson AG, Sundh D, Bäckhed F, Lorentzon M. Lactobacillus reuteri reduces bone loss in older women with low bone mineral density: a randomized, placebo-controlled, double-blind, clinical trial. J Intern Med 2018;284(3):307-317 View Article PubMed/NCBI
  44. Biagi E, Franceschi C, Rampelli S, Severgnini M, Ostan R, Turroni S, et al. Gut Microbiota and Extreme Longevity. Curr Biol 2016;26(11):1480-1485 View Article PubMed/NCBI
  45. O’Toole PW, Jeffery IB. Gut microbiota and aging. Science 2015;350(6265):1214-1215 View Article PubMed/NCBI
  46. Kong F, Hua Y, Zeng B, Ning R, Li Y, Zhao J. Gut microbiota signatures of longevity. Curr Biol 2016;26(18):R832-R833 View Article PubMed/NCBI
  47. Claesson MJ, Jeffery IB, Conde S, Power SE, O’Connor EM, Cusack S, et al. Gut microbiota composition correlates with diet and health in the elderly. Nature 2012;488(7410):178-184 View Article PubMed/NCBI
  48. Takiishi T, Fenero CIM, Câmara NOS. Intestinal barrier and gut microbiota: Shaping our immune responses throughout life. Tissue Barriers 2017;5(4):e1373208 View Article PubMed/NCBI
  49. Rampelli S, Candela M, Turroni S, Biagi E, Collino S, Franceschi C, et al. Functional metagenomic profiling of intestinal microbiome in extreme ageing. Aging (Albany NY) 2013;5(12):902-912 View Article PubMed/NCBI
  50. Lynn MA, Eden G, Ryan FJ, Bensalem J, Wang X, Blake SJ, et al. The composition of the gut microbiota following early-life antibiotic exposure affects host health and longevity in later life. Cell Rep 2021;36(8):109564 View Article PubMed/NCBI
  51. Rogers GB, Papanicolas LE, Wesselingh SL. Antibiotic stewardship in aged care facilities. Lancet Infect Dis 2018;18(10):1061-1063 View Article PubMed/NCBI
  52. Melton LJ, Khosla S, Crowson CS, O’Connor MK, O’Fallon WM, Riggs BL. Epidemiology of sarcopenia. J Am Geriatr Soc 2000;48(6):625-630 View Article PubMed/NCBI
  53. Volpi E, Nazemi R, Fujita S. Muscle tissue changes with aging. Curr Opin Clin Nutr Metab Care 2004;7(4):405-410 View Article PubMed/NCBI
  54. Thevaranjan N, Puchta A, Schulz C, Naidoo A, Szamosi JC, Verschoor CP, et al. Age-Associated Microbial Dysbiosis Promotes Intestinal Permeability, Systemic Inflammation, and Macrophage Dysfunction. Cell Host Microbe 2017;21(4):455-466.e4 View Article PubMed/NCBI
  55. Siddharth J, Chakrabarti A, Pannérec A, Karaz S, Morin-Rivron D, Masoodi M, et al. Aging and sarcopenia associate with specific interactions between gut microbes, serum biomarkers and host physiology in rats. Aging (Albany NY) 2017;9(7):1698-1720 View Article PubMed/NCBI
  56. De Pessemier B, Grine L, Debaere M, Maes A, Paetzold B, Callewaert C. Gut-Skin Axis: Current Knowledge of the Interrelationship between Microbial Dysbiosis and Skin Conditions. Microorganisms 2021;9(2):353 View Article PubMed/NCBI
  57. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A. Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 2018;14(10):576-590 View Article PubMed/NCBI
  58. Bosco N, Noti M. The aging gut microbiome and its impact on host immunity. Genes Immun 2021;22(5-6):289-303 View Article PubMed/NCBI
  59. Sharma R. Emerging Interrelationship Between the Gut Microbiome and Cellular Senescence in the Context of Aging and Disease: Perspectives and Therapeutic Opportunities. Probiotics Antimicrob Proteins 2022;14(4):648-663 View Article PubMed/NCBI
  60. Clements SJ, Carding SR. Diet, the intestinal microbiota, and immune health in aging. Crit Rev Food Sci Nutr 2018;58(4):651-661 View Article PubMed/NCBI
  61. Zheng D, Liwinski T, Elinav E. Interaction between microbiota and immunity in health and disease. Cell Res 2020;30(6):492-506 View Article PubMed/NCBI
  62. Simon AK, Hollander GA, McMichael A. Evolution of the immune system in humans from infancy to old age. Proc Biol Sci 2015;282(1821):20143085 View Article PubMed/NCBI
  63. Xue J, Ajuwon KM, Fang R. Mechanistic insight into the gut microbiome and its interaction with host immunity and inflammation. Anim Nutr 2020;6(4):421-428 View Article PubMed/NCBI
  64. Wiertsema SP, van Bergenhenegouwen J, Garssen J, Knippels LMJ. The Interplay between the Gut Microbiome and the Immune System in the Context of Infectious Diseases throughout Life and the Role of Nutrition in Optimizing Treatment Strategies. Nutrients 2021;13(3):886 View Article PubMed/NCBI
  65. Tibbs TN, Lopez LR, Arthur JC. The influence of the microbiota on immune development, chronic inflammation, and cancer in the context of aging. Microb Cell 2019;6(8):324-334 View Article PubMed/NCBI
  66. Tan Y, Wei Z, Chen J, An J, Li M, Zhou L, et al. Save your gut save your age: The role of the microbiome in stem cell ageing. J Cell Mol Med 2019;23(8):4866-4875 View Article PubMed/NCBI
  67. Tien MT, Girardin SE, Regnault B, Le Bourhis L, Dillies MA, Coppée JY, et al. Anti-inflammatory effect of Lactobacillus casei on Shigella-infected human intestinal epithelial cells. J Immunol 2006;176(2):1228-1237 View Article PubMed/NCBI
  68. Kelly D, Campbell JI, King TP, Grant G, Jansson EA, Coutts AG, et al. Commensal anaerobic gut bacteria attenuate inflammation by regulating nuclear-cytoplasmic shuttling of PPAR-gamma and RelA. Nat Immunol 2004;5(1):104-112 View Article PubMed/NCBI
  69. Badal VD, Vaccariello ED, Murray ER, Yu KE, Knight R, Jeste DV, et al. The Gut Microbiome, Aging, and Longevity: A Systematic Review. Nutrients 2020;12(12):3759 View Article PubMed/NCBI
  70. Bana B, Cabreiro F. The Microbiome and Aging. Annu Rev Genet 2019;53:239-261 View Article PubMed/NCBI
  71. Choi P, Rhayat L, Pinloche E, Devillard E, De Paepe E, Vanhaecke L, et al. Bacillus Subtilis 29784 as a Feed Additive for Broilers Shifts the Intestinal Microbial Composition and Supports the Production of Hypoxanthine and Nicotinic Acid. Animals (Basel) 2021;11(5):1335 View Article PubMed/NCBI
  72. Pedersen HK, Gudmundsdottir V, Nielsen HB, Hyotylainen T, Nielsen T, Jensen BA, et al. Human gut microbes impact host serum metabolome and insulin sensitivity. Nature 2016;535(7612):376-381 View Article PubMed/NCBI
  73. d’Hennezel E, Abubucker S, Murphy LO, Cullen TW. Total Lipopolysaccharide from the Human Gut Microbiome Silences Toll-Like Receptor Signaling. mSystems 2017;2(6):e00046-17 View Article PubMed/NCBI
  74. Valdes AM, Walter J, Segal E, Spector TD. Role of the gut microbiota in nutrition and health. BMJ 2018;361:k2179 View Article PubMed/NCBI
  75. Tiso M, Schechter AN. Correction: Nitrate Reduction to Nitrite, Nitric Oxide and Ammonia by Gut Bacteria under Physiological Conditions. PLoS One 2015;10(5):e0127490 View Article PubMed/NCBI
  76. Rooks MG, Garrett WS. Gut microbiota, metabolites and host immunity. Nat Rev Immunol 2016;16(6):341-352 View Article PubMed/NCBI
  77. Pérez-Cano FJ, González-Castro A, Castellote C, Franch A, Castell M. Influence of breast milk polyamines on suckling rat immune system maturation. Dev Comp Immunol 2010;34(2):210-218 View Article PubMed/NCBI
  78. Wikoff WR, Anfora AT, Liu J, Schultz PG, Lesley SA, Peters EC, et al. Metabolomics analysis reveals large effects of gut microflora on mammalian blood metabolites. Proc Natl Acad Sci U S A 2009;106(10):3698-3703 View Article PubMed/NCBI
  79. Venkatesh M, Mukherjee S, Wang H, Li H, Sun K, Benechet AP, et al. Symbiotic bacterial metabolites regulate gastrointestinal barrier function via the xenobiotic sensor PXR and Toll-like receptor 4. Immunity 2014;41(2):296-310 View Article PubMed/NCBI
  80. Li X, Zhang B, Hu Y, Zhao Y. New Insights Into Gut-Bacteria-Derived Indole and Its Derivatives in Intestinal and Liver Diseases. Front Pharmacol 2021;12:769501 View Article PubMed/NCBI
  81. Ye X, Li H, Anjum K, Zhong X, Miao S, Zheng G, et al. Dual Role of Indoles Derived From Intestinal Microbiota on Human Health. Front Immunol 2022;13:903526 View Article PubMed/NCBI
  82. Selma MV, Espín JC, Tomás-Barberán FA. Interaction between phenolics and gut microbiota: role in human health. J Agric Food Chem 2009;57(15):6485-6501 View Article PubMed/NCBI
  83. Iizuka R, Kawakami K, Chiba K. Gut bacteria producing phenols disturb keratinocyte differentiation in human skin. Microb Ecol Health Dis 2009;21(3–4):221-227 View Article PubMed/NCBI
  84. Flint HJ, Scott KP, Louis P, Duncan SH. The role of the gut microbiota in nutrition and health. Nat Rev Gastroenterol Hepatol 2012;9(10):577-589 View Article PubMed/NCBI
  85. Silva YP, Bernardi A, Frozza RL. The Role of Short-Chain Fatty Acids From Gut Microbiota in Gut-Brain Communication. Front Endocrinol (Lausanne) 2020;11:25 View Article PubMed/NCBI
  86. Kim M, Benayoun BA. The microbiome: an emerging key player in aging and longevity. Transl Med Aging 2020;4:103-116 View Article PubMed/NCBI
  87. Biagi E, Nylund L, Candela M, Ostan R, Bucci L, Pini E, et al. Through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians. PLoS One 2010;5(5):e10667 View Article PubMed/NCBI
  88. Dobi A, Gasque P, Guiraud P, Selambarom J. Irinotecan (CPT-11) Canonical Anti-Cancer Drug Can also Modulate Antiviral and Pro-Inflammatory Responses of Primary Human Synovial Fibroblasts. Cells 2021;10(6):1431 View Article PubMed/NCBI
  89. Ermolaeva M, Neri F, Ori A, Rudolph KL. Cellular and epigenetic drivers of stem cell ageing. Nat Rev Mol Cell Biol 2018;19(9):594-610 View Article PubMed/NCBI
  90. Friedland RP, Chapman MR. The role of microbial amyloid in neurodegeneration. PLoS Pathog 2017;13(12):e1006654 View Article PubMed/NCBI
  91. Carabotti M, Scirocco A, Maselli MA, Severi C. The gut-brain axis: interactions between enteric microbiota, central and enteric nervous systems. Ann Gastroenterol 2015;28(2):203-209 View Article PubMed/NCBI
  92. Raimondi I, Izzo L, Tunesi M, Comar M, Albani D, Giordano C. Organ-On-A-Chip in vitro Models of the Brain and the Blood-Brain Barrier and Their Value to Study the Microbiota-Gut-Brain Axis in Neurodegeneration. Front Bioeng Biotechnol 2019;7:435 View Article PubMed/NCBI
  93. Molinero N, Antón-Fernández A, Hernández F, Ávila J, Bartolomé B, Moreno-Arribas MV. Gut Microbiota, an Additional Hallmark of Human Aging and Neurodegeneration. Neuroscience 2023;518:141-161 View Article PubMed/NCBI
  94. Boddy SL, Giovannelli I, Sassani M, Cooper-Knock J, Snyder MP, Segal E, et al. The gut microbiome: a key player in the complexity of amyotrophic lateral sclerosis (ALS). BMC Med 2021;19(1):13 View Article PubMed/NCBI
  95. Shahidehpour RK, Higdon RE, Crawford NG, Neltner JH, Ighodaro ET, Patel E, et al. Dystrophic microglia are associated with neurodegenerative disease and not healthy aging in the human brain. Neurobiol Aging 2021;99:19-27 View Article PubMed/NCBI
  96. Harach T, Marungruang N, Duthilleul N, Cheatham V, Mc Coy KD, Frisoni G, et al. Erratum: Reduction of Abeta amyloid pathology in APPPS1 transgenic mice in the absence of gut microbiota. Sci Rep 2017;7:46856 View Article PubMed/NCBI
  97. Jung JH, Kim G, Byun MS, Lee JH, Yi D, Park H, et al. Gut microbiome alterations in preclinical Alzheimer’s disease. PLoS One 2022;17(11):e0278276 View Article PubMed/NCBI
  98. Vogt NM, Kerby RL, Dill-McFarland KA, Harding SJ, Merluzzi AP, Johnson SC, et al. Gut microbiome alterations in Alzheimer’s disease. Sci Rep 2017;7(1):13537 View Article PubMed/NCBI
  99. Takahashi K, Nishiwaki H, Ito M, Iwaoka K, Takahashi K, Suzuki Y, et al. Altered gut microbiota in Parkinson’s disease patients with motor complications. Parkinsonism Relat Disord 2022;95:11-17 View Article PubMed/NCBI
  100. Cerroni R, Pietrucci D, Teofani A, Chillemi G, Liguori C, Pierantozzi M, et al. Not just a Snapshot: An Italian Longitudinal Evaluation of Stability of Gut Microbiota Findings in Parkinson’s Disease. Brain Sci 2022;12(6):739 View Article PubMed/NCBI
  101. Ahmad Sophien AN, Jusop AS, Tye GJ, Tan YF, Wan Kamarul Zaman WS, Nordin F. Intestinal stem cells and gut microbiota therapeutics: hype or hope?. Front Med (Lausanne) 2023;10:1195374 View Article PubMed/NCBI
  102. Le Maître TW, Dhanabalan G, Bogdanovic N, Alkass K, Druid H. Effects of Alcohol Abuse on Proliferating Cells, Stem/Progenitor Cells, and Immature Neurons in the Adult Human Hippocampus. Neuropsychopharmacology 2018;43(4):690-699 View Article PubMed/NCBI
  103. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56(7):1761-1772 View Article PubMed/NCBI
  104. Hamilton-Miller JM. Living in the ‘post-antibiotic era’: could the use of probiotics be an effective strategy?. Clin Microbiol Infect 1997;3(1):2-3 View Article PubMed/NCBI
  105. Mackowiak PA. Recycling metchnikoff: probiotics, the intestinal microbiome and the quest for long life. Front Public Health 2013;1:52 View Article PubMed/NCBI
  106. Ragonnaud E, Biragyn A. Gut microbiota as the key controllers of “healthy” aging of elderly people. Immun Ageing 2021;18(1):2 View Article PubMed/NCBI
  107. Ramos C, Gibson GR, Walton GE, Magistro D, Kinnear W, Hunter K. Systematic Review of the Effects of Exercise and Physical Activity on the Gut Microbiome of Older Adults. Nutrients 2022;14(3):674 View Article PubMed/NCBI
  108. Bischoff SC. Microbiota and aging. Curr Opin Clin Nutr Metab Care 2016;19(1):26-30 View Article PubMed/NCBI
  109. Zhao L, Zhao Y, Liu R, Zheng X, Zhang M, Guo H, et al. The Transcription Factor DAF-16 is Essential for Increased Longevity in C. elegans Exposed to Bifidobacterium longum BB68. Sci Rep 2017;7(1):7408 View Article PubMed/NCBI
  110. Nakagawa H, Shiozaki T, Kobatake E, Hosoya T, Moriya T, Sakai F, et al. Effects and mechanisms of prolongevity induced by Lactobacillus gasseri SBT2055 in Caenorhabditis elegans. Aging Cell 2016;15(2):227-236 View Article PubMed/NCBI
  111. Schifano E, Zinno P, Guantario B, Roselli M, Marcoccia S, Devirgiliis C, et al. The Foodborne Strain Lactobacillus fermentum MBC2 Triggers pept-1-Dependent Pro-Longevity Effects in Caenorhabditis elegans. Microorganisms 2019;7(2):45 View Article PubMed/NCBI
  112. Sun J, Deng Z, Yan A. Bacterial multidrug efflux pumps: mechanisms, physiology and pharmacological exploitations. Biochem Biophys Res Commun 2014;453(2):254-267 View Article PubMed/NCBI
  113. Grompone G, Martorell P, Llopis S, González N, Genovés S, Mulet AP, et al. Anti-inflammatory Lactobacillus rhamnosus CNCM I-3690 strain protects against oxidative stress and increases lifespan in Caenorhabditis elegans. PLoS One 2012;7(12):e52493 View Article PubMed/NCBI
  114. Zhao Y, Zhao L, Zheng X, Fu T, Guo H, Ren F. Lactobacillus salivarius strain FDB89 induced longevity in Caenorhabditis elegans by dietary restriction. J Microbiol 2013;51(2):183-188 View Article PubMed/NCBI
  115. Lee J, Yun HS, Cho KW, Oh S, Kim SH, Chun T, et al. Evaluation of probiotic characteristics of newly isolated Lactobacillus spp.: immune modulation and longevity. Int J Food Microbiol 2011;148(2):80-86 View Article PubMed/NCBI
  116. Jeong JJ, Kim KA, Hwang YJ, Han MJ, Kim DH. Anti-inflammaging effects of Lactobacillus brevis OW38 in aged mice. Benef Microbes 2016;7(5):707-718 View Article PubMed/NCBI
  117. Chi C, Xue Y, Lv N, Hao Y, Liu R, Wang Y, et al. Longitudinal Gut Bacterial Colonization and Its Influencing Factors of Low Birth Weight Infants During the First 3 Months of Life. Front Microbiol 2019;10:1105 View Article PubMed/NCBI
  118. Lew LC, Hor YY, Jaafar MH, Lau ASY, Ong JS, Chuah LO, et al. Lactobacilli modulated AMPK activity and prevented telomere shortening in ageing rats. Benef Microbes 2019;10(8):883-892 View Article PubMed/NCBI
  119. Li B, Evivie SE, Lu J, Jiao Y, Wang C, Li Z, et al. Lactobacillus helveticus KLDS1.8701 alleviates d-galactose-induced aging by regulating Nrf-2 and gut microbiota in mice. Food Funct 2018;9(12):6586-6598 View Article PubMed/NCBI
  120. Ale EC, Binetti AG. Role of Probiotics, Prebiotics, and Synbiotics in the Elderly: Insights Into Their Applications. Front Microbiol 2021;12:631254 View Article PubMed/NCBI
  121. Patel PJ, Singh SK, Panaich S, Cardozo L. The aging gut and the role of prebiotics, probiotics, and synbiotics: A review. J Clin Gerontol Geriatrics 2014;5(1):3-6 View Article PubMed/NCBI
  122. Eloe-Fadrosh EA, Brady A, Crabtree J, Drabek EF, Ma B, Mahurkar A, et al. Functional dynamics of the gut microbiome in elderly people during probiotic consumption. mBio 2015;6(2):e00231-15 View Article PubMed/NCBI
  123. Finamore A, Roselli M, Donini L, Brasili DE, Rami R, Carnevali P, et al. Supplementation with Bifidobacterium longum Bar33 and Lactobacillus helveticus Bar13 mixture improves immunity in elderly humans (over 75 years) and aged mice. Nutrition 2019;63-64:184-192 View Article PubMed/NCBI
  124. Spaiser SJ, Culpepper T, Nieves C, Ukhanova M, Mai V, Percival SS, et al. Lactobacillus gasseri KS-13, Bifidobacterium bifidum G9-1, and Bifidobacterium longum MM-2 Ingestion Induces a Less Inflammatory Cytokine Profile and a Potentially Beneficial Shift in Gut Microbiota in Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study. J Am Coll Nutr 2015;34(6):459-469 View Article PubMed/NCBI
  125. Costabile A, Bergillos-Meca T, Rasinkangas P, Korpela K, de Vos WM, Gibson GR. Effects of Soluble Corn Fiber Alone or in Synbiotic Combination with Lactobacillus rhamnosus GG and the Pilus-Deficient Derivative GG-PB12 on Fecal Microbiota, Metabolism, and Markers of Immune Function: A Randomized, Double-Blind, Placebo-Controlled, Crossover Study in Healthy Elderly (Saimes Study). Front Immunol 2017;8:1443 View Article PubMed/NCBI
  126. Macfarlane S, Cleary S, Bahrami B, Reynolds N, Macfarlane GT. Synbiotic consumption changes the metabolism and composition of the gut microbiota in older people and modifies inflammatory processes: a randomised, double-blind, placebo-controlled crossover study. Aliment Pharmacol Ther 2013;38(7):804-816 View Article PubMed/NCBI
  127. Aoyagi Y, Amamoto R, Park S, Honda Y, Shimamoto K, Kushiro A, et al. Independent and Interactive Effects of Habitually Ingesting Fermented Milk Products Containing Lactobacillus casei Strain Shirota and of Engaging in Moderate Habitual Daily Physical Activity on the Intestinal Health of Older People. Front Microbiol 2019;10:1477 View Article PubMed/NCBI
  128. Lee X, Vergara C, Lozano CP. Severity of Candida-associated denture stomatitis is improved in institutionalized elders who consume Lactobacillus rhamnosus SP1. Aust Dent J 2019;64(3):229-236 View Article PubMed/NCBI
  129. Valentini L, Pinto A, Bourdel-Marchasson I, Ostan R, Brigidi P, Turroni S, et al. Impact of personalized diet and probiotic supplementation on inflammation, nutritional parameters and intestinal microbiota - The “RISTOMED project”: Randomized controlled trial in healthy older people. Clin Nutr 2015;34(4):593-602 View Article PubMed/NCBI
  130. Inoue T, Kobayashi Y, Mori N, Sakagawa M, Xiao JZ, Moritani T, et al. Effect of combined bifidobacteria supplementation and resistance training on cognitive function, body composition and bowel habits of healthy elderly subjects. Benef Microbes 2018;9(6):843-853 View Article PubMed/NCBI
  131. Kim CS, Cha L, Sim M, Jung S, Chun WY, Baik HW, et al. Probiotic Supplementation Improves Cognitive Function and Mood with Changes in Gut Microbiota in Community-Dwelling Older Adults: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. J Gerontol A Biol Sci Med Sci 2021;76(1):32-40 View Article PubMed/NCBI
  132. Imaoka A, Matsumoto S, Setoyama H, Okada Y, Umesaki Y. Proliferative recruitment of intestinal intraepithelial lymphocytes after microbial colonization of germ-free mice. Eur J Immunol 1996;26(4):945-948 View Article PubMed/NCBI
  133. Shapira M. Gut Microbiotas and Host Evolution: Scaling Up Symbiosis. Trends Ecol Evol 2016;31(7):539-549 View Article PubMed/NCBI
  134. Johnson AA, Shokhirev MN, Wyss-Coray T, Lehallier B. Systematic review and analysis of human proteomics aging studies unveils a novel proteomic aging clock and identifies key processes that change with age. Ageing Res Rev 2020;60:101070 View Article PubMed/NCBI
  135. Robinson O, Chadeau Hyam M, Karaman I, Climaco Pinto R, Ala-Korpela M, Handakas E, et al. Determinants of accelerated metabolomic and epigenetic aging in a UK cohort. Aging Cell 2020;19(6):e13149 View Article PubMed/NCBI
  136. Johnson LC, Parker K, Aguirre BF, Nemkov TG, D’Alessandro A, Johnson SA, et al. The plasma metabolome as a predictor of biological aging in humans. Geroscience 2019;41(6):895-906 View Article PubMed/NCBI
  137. Sonowal R, Swimm A, Sahoo A, Luo L, Matsunaga Y, Wu Z, et al. Indoles from commensal bacteria extend healthspan. Proc Natl Acad Sci USA 2017;114(36):E7506-E7515 View Article PubMed/NCBI
  138. Swann JR, Spagou K, Lewis M, Nicholson JK, Glei DA, Seeman TE, et al. Microbial-mammalian cometabolites dominate the age-associated urinary metabolic phenotype in Taiwanese and American populations. J Proteome Res 2013;12(7):3166-3180 View Article PubMed/NCBI
  139. Psihogios NG, Gazi IF, Elisaf MS, Seferiadis KI, Bairaktari ET. Gender-related and age-related urinalysis of healthy subjects by NMR-based metabonomics. NMR Biomed 2008;21(3):195-207 View Article PubMed/NCBI
  140. Collino S, Montoliu I, Martin FP, Scherer M, Mari D, Salvioli S, et al. Metabolic signatures of extreme longevity in northern Italian centenarians reveal a complex remodeling of lipids, amino acids, and gut microbiota metabolism. PLoS One 2013;8(3):e56564 View Article PubMed/NCBI
  141. Gupta S, Mortensen MS, Schjørring S, Trivedi U, Vestergaard G, Stokholm J, et al. Amplicon sequencing provides more accurate microbiome information in healthy children compared to culturing. Commun Biol 2019;2:291 View Article PubMed/NCBI
  142. Chen Y, Wang H, Lu W, Wu T, Yuan W, Zhu J, et al. Human gut microbiome aging clocks based on taxonomic and functional signatures through multi-view learning. Gut Microbes 2022;14(1):2025016 View Article PubMed/NCBI