Introduction
In recent years, research on human aging has placed greater emphasis on the biological processes that underlie it.1 This shift has been driven by technological advances and a deeper understanding of the intricate cellular and molecular interactions that regulate aging.2,3 Central to this exploration is the recognition that aging is not a singular event but a complex interaction of numerous inherent and external factors that together shape the timing and nature of the process.4,5 Among these factors, the human microbiome has emerged as an important influence on host physiology and health outcomes.6–8 Consisting of a diverse array of microorganisms that inhabit various areas of the body, the microbiome significantly impacts metabolic functions, immune responses, and even brain health.9 Dysbiosis, or imbalances in the microbiome, is linked to age-related conditions such as cardiovascular diseases (CVDs), neurodegenerative diseases (NDs), and metabolic syndromes.10 DNA repair mechanisms and cell cycle checkpoints protect genetic material, ensuring its stability across cell generations.11 However, internal and external factors—such as reactive oxygen species (ROS), radiation, and environmental toxins—continuously threaten this stability by causing DNA damage.12 As DNA damage accumulates over time, it can result in mutations, chromosomal abnormalities, and, eventually, cellular dysfunction and aging.13–15 An important factor in cellular aging is the progressive shortening of telomeres, repetitive DNA sequences found at the ends of chromosomes.16 Telomeres protect chromosomal ends, preventing them from being mistaken for DNA breaks and maintaining genomic stability.17 However, with each cell division, telomeres shorten because DNA polymerase cannot fully replicate the lagging strand. As a result, telomeres act as a molecular timer, restricting the ability of cells to proliferate and leading to replicative senescence.18,19 Understanding how the human microbiome, genomic stability, and telomere shortening are interconnected is crucial to uncovering the mechanisms of aging and developing strategies for healthy aging.20–25
Thus, this review aimed to integrate current studies and provide a comprehensive understanding of the complex interactions among various factors that contribute to the aging process. In particular, we emphasize genomic instability and telomere attrition—two crucial primary hallmarks of aging outlined by López-Otín C and colleagues.26 These hallmarks are essential to the biology of aging and are closely linked to cellular dysfunction and the emergence of age-related diseases. Genomic instability, resulting from the buildup of DNA damage and mutations, accelerates aging at the cellular level, whereas telomere attrition, which limits cellular replication, plays a key role in cellular senescence.20–25,27 While epigenetic changes and the loss of proteostasis also qualify as primary hallmarks of aging, their inclusion would significantly expand the scope of this review.27 Considering the complexity of these processes and their evolving connections with the microbiome, we have chosen to focus specifically on genomic instability and telomere attrition. This targeted approach allows for a more detailed and precise investigation of these well-established aging mechanisms, which are directly affected by the microbiome, without delving into the complex interactions with other hallmarks. Through this strategy, we aimed to provide valuable insights into the evolving relationship between aging and the microbiome, a growing area of interest in gerontological studies.
Key hallmarks that shape our journey through life
The phenomenon of biological aging is complex and gradual, marked by a steady decline in both physiological and cellular functions, resulting in reduced resilience to stress, slower healing, and disrupted homeostasis in the organism.1–5,28 Scientists are actively exploring the molecular and cellular foundations of aging, identifying twelve distinct hallmarks associated with this process.26,28–31 This growing body of knowledge highlights the intricate nature of aging and drives ongoing efforts to unravel its essential mechanisms and develop strategies that promote healthier aging trajectories. The proposed hallmarks of aging involve various cellular and molecular mechanisms that are crucial in the aging process of diverse organisms. These features include genomic instability, telomere shortening, epigenetic changes, a decline in proteostasis, disrupted nutrient sensing, mitochondrial dysfunction (MD), cellular senescence, stem cell depletion, altered cell communication, dysbiosis, chronic inflammation, and impaired macroautophagy.28–31 Genomic instability refers to the buildup of DNA damage, whereas telomere attrition involves the progressive shortening of the protective ends of chromosomes.20–25 In contrast, epigenetic modifications change gene expression without altering the DNA sequence, while loss of proteostasis disrupts the structure and function of proteins.27,32,33 Disruption of nutrient sensing negatively impacts metabolic pathways, and MD results in diminished energy output and increased production of ROS.34,35 Cellular senescence halts cell growth permanently, stem cell decline reduces tissue regeneration, and altered intercellular communication disrupts tissue balance.36–38 Dysbiosis disrupts gut microbe balance, chronic inflammation keeps the immune system overactive, and impaired macroautophagy leads to the accumulation of cellular waste, exacerbating age-related decline.39–41 These hallmarks reveal the complex interactions of cellular, molecular, and microbial processes in aging, highlighting the potential for targeted interventions to promote healthier aging.26 It is important to emphasize that each hallmark should be present during normal aging, with their exacerbation potentially speeding up aging and their alleviation possibly extending a healthy lifespan.28–31
Microbiome and hallmarks of aging
The human microbiome, especially the gut microbiota, develops in tandem with its host, and changes within it are significantly linked to the aging process. The microbiome consists of a wide range of microorganisms inhabiting various regions of the body, and it undergoes ongoing transformations in harmony with its host— a trend supported by many scientific investigations exploring its complex relationship with aging.21–25 Research has revealed that alterations in gut microbiota composition can affect how individuals respond to stress and their overall health as they age. Recent empirical studies suggest an innovative method focused on gut microbiota to alleviate symptoms associated with brain aging and improve cognitive health.42 Experimental data shows that gut microbiota metabolism changes with age, suggesting a possible link to age-related metabolic disorders.23,43,44 Studies tracking specific groups over time have shown that the composition of gut microbiota evolves gradually as a person ages, and these changes are linked to the onset of age-related diseases.45,46 These findings highlight the strong impact of the gut microbiota on aging and the need for further study into the mechanisms behind this connection. Research also shows that maintaining a balanced gut microbiota is crucial for encouraging optimal physical and mental development during infancy and childhood.47,48 Aging causes physiological changes that alter gut microbiota composition and function, highlighting their role in dysbiosis and the aging process.49,50 Furthermore, dysbiosis-related changes in gut microbiota can impact various aspects of aging through the body’s interconnected ecosystem.51–53
Thus, this review article takes an important initial step in exploring the complex connection between the microbiome and critical aspects of aging, including genomic instability and telomere shortening. Acknowledging the difficulties inherent in this subject, the following sections aim to clarify the nuanced interaction between these elements. By initiating this journey of exploration, this review paves the way for further research and advancements in this vibrant and rapidly evolving field.
Evolving interaction between the microbiota and genomic instability
In the intricate realm of human biology, the relationship between the human microbiome and the stability of our genes is a fascinating topic that warrants further exploration. Recent pioneering research has illuminated the considerable impact that the microbial populations residing within us have on various health and disease factors. As our understanding grows, an engaging narrative unfolds: the evolving connection between genetic stability and these microorganisms.21–24,42–44 One common characteristic observed in numerous diseases is genomic instability, which refers to the increased frequency of genetic alterations, including DNA mutations, chromosomal rearrangements, and aberrant recombination events. In biomedical research, understanding the causes and factors contributing to this instability has been essential.54 However, new findings are revealing a crucial, yet previously overlooked, element affecting genetic stability: the complex microbial communities within both our internal and external environments.11–15
Central to this investigation is a pivotal shift in perspective: microbiota are now recognized not merely as passive bystanders but as active contributors to the development of host physiology, including the optimal maintenance of the host genome, a process intricately linked to aging. The dynamic interplay between the microbiota and the genome introduces additional complexity, as environmental factors, diet, antibiotic use, and host genetics combine to shape microbial communities, influencing genomic stability in diverse ways.55–58 This convergence of genetic and microbiological research represents a transformative shift in our understanding, emphasizing the microbiota’s crucial role in human health and disease. Embracing this comprehensive perspective not only enhances our insight into the origins of diseases but also opens avenues for new treatments and personalized medicine aimed at preserving genomic balance. For instance, studies have demonstrated the profound effects of Helicobacter pylori infection on the gastrointestinal (GI) system, unveiling DNA-damaging processes triggered by this pathogenic bacterium.59,60 These studies revealed the detrimental impacts of H. pylori on host cells and provided preliminary evidence linking microbial infections to the activation of DNA damage responses (DDR).59–61 Moreover, they highlighted the disruption of the host’s DNA repair mechanisms in the presence of H. pylori, underscoring the potential threat to genomic stability posed by pathogenic bacteria and the urgent need to explore targeted therapeutic strategies to mitigate microbial-induced DNA damage. Similarly, Fusobacterium nucleatum, a bacterium frequently found in the human digestive system, causes persistent inflammation, leading to the production of ROS, which damage cellular components, including DNA.62,63 Over time, this accumulation of DNA damage may hasten the aging process by promoting cellular senescence, weakening DNA repair functions, and contributing to the hallmarks of aging.64,65 Additionally, Enterococcus faecalis produces superoxide anions and hydrogen peroxide during metabolism, both of which can cause oxidative damage to DNA, resulting in base modifications, strand breaks, and cross-linking.66 Over time, the continuous cycle of DNA damage and repair leads to the accumulation of mutations and chromosomal instability, indicators of aging that reduce cellular functionality and increase the risk of degenerative diseases, including cognitive deterioration.64,65 Gut microbiota also play a critical role in processing bile acids, which is vital for preserving DNA integrity.67 Gut microbiota convert primary bile acids into secondary forms, including deoxycholic acid, which can produce ROS and directly interact with DNA, causing strand breaks and genetic mutations.67–69 This DNA damage is particularly significant as we age, as the accumulation of damage can overwhelm the cells’ repair capabilities, impairing function in critical organs like the colon and liver. As a result, chronic exposure to dysbiosis-induced altered bile acid compositions may contribute to inflammation related to aging and tissue degeneration.70,71 Moreover, the role of Clostridium difficile further exemplifies how gut bacteria contribute to DNA damage. This bacterium secretes powerful toxins, such as Toxin A and Toxin B, which enzymatically modify Rho GTPases, impairing the actin cytoskeleton and cellular signaling.72,73 The resulting disruption of cellular integrity activates DDR pathways, initiating repair or inducing cell death when the damage is irreparable. Prolonged exposure to these toxins induces inflammation, exacerbating cellular stress and accelerating the accumulation of DNA damage. Over time, these chronic assaults can overwhelm DNA repair mechanisms, causing genomic instability and mutations that hinder tissue function.64,65 The intestinal epithelium, with its rapid turnover rate, is particularly vulnerable to accelerated aging and degeneration as DNA damage disrupts regeneration and organ function.74,75 Furthermore, the synthesis of genotoxins, such as colibactin and Bacteroides fragilis toxin, by commensal bacterial strains like Escherichia coli and Bacteroides fragilis presents a significant concern for cellular health.76,77 Interestingly, the healthy GI tract is predominantly inhabited by obligate anaerobic bacteria, including Bacteroides, Bifidobacterium, Clostridium, and Ruminococcus,78–80 which help maintain gut health and support essential metabolic functions. However, dysbiosis—an imbalance in the microbiota—leads to an increase in facultative anaerobes such as Escherichia, Enterobacter, Enterococcus, and Klebsiella.81,82 Unlike obligate anaerobes, facultative anaerobes can thrive in both oxygen-rich and oxygen-poor environments, and their proliferation triggers gut inflammation, resulting in ROS production and DNA damage. This cascade of events accelerates genomic instability, particularly in the GI tract, and increases the risk of age-related disorders.83–85 Furthermore, older individuals exhibit elevated oxidative stress markers, such as 8-oxoguanine and γ-H2AX, which indicate DNA damage that worsens with dysbiosis, contributing to neurodegeneration and systemic aging.86,87 Dysbiosis also promotes MD, further exacerbating mtDNA damage and cellular aging. This process is characterized by impaired energy production and immune responses—hallmarks of aging.88,89
Recent research has reinforced the connection between gut microbiota, genomic instability, and aging, emphasizing the pivotal role of inflammation in this process. Studies have found that aging impairs DNA double-strand break repair in mouse livers following diethylnitrosamine exposure, with gut microbiota-induced inflammation playing a crucial role.90,91 Age-related microbiota changes lead to dysregulated innate immunity, heightened inflammatory cytokine levels, and reduced DNA repair efficiency.92,93 Notably, interventions such as antibiotic treatment, MyD88 gene (myeloid differentiation primary response gene 88) deletion, or germ-free conditions have been shown to reduce inflammation and enhance DNA repair in older mice.94–96 Conversely, pro-inflammatory factors, such as a high-fat diet, exacerbate DNA repair deficiencies; however, antibiotic treatment mitigates this effect, highlighting the microbiota’s significant influence.97,98 These findings suggest that modifying inflammatory responses, rather than directly targeting DNA repair mechanisms, may help prevent genomic instability during aging.99,100
Clinical trials investigating the microbiota-genomic instability link are also exploring potential therapeutic avenues. For example, the Canakinumab trial, which targets interleukin-1β to reduce inflammation, demonstrated benefits in managing age-related diseases like hypertension and diabetes, further confirming inflammation’s role in genomic instability.101–103 Similarly, the Metformin Aging Study suggests that metformin, a diabetes drug, may enhance genomic stability and slow cellular aging, positioning it as a potential anti-aging therapy.104,105 Additionally, fecal microbiota transplantation trials aim to restore a healthy microbiome, potentially improving genomic stability and mitigating aging-related issues.106,107 Trials examining rapamycin, a drug believed to delay menopause, further suggest that modulating immune responses and cellular aging mechanisms can help combat genomic instability.108–110 Collectively, these studies underscore the significant role of microbiota and inflammation in aging, offering insights into novel therapies that could enhance healthspan and reduce the impact of genomic instability. In summary, microbial metabolites and toxins contribute to DNA damage through oxidative stress, genotoxic by-products, and direct interactions with DNA. The accumulation of this damage over time drives genomic instability. While the relationship between the microbiome and aging remains complex, growing evidence suggests that microbial effects on DNA integrity play a pivotal role in the aging process. This underscores the importance of maintaining a balanced microbiome for healthy aging and minimizing the risk of age-related diseases.
Intricate interplay between microbiome dynamics and telomere attrition
At the ends of each chromosome, there is a protective structure called a telomere, which consists of repeating DNA sequences of the motif TTAGGG.17,18 Telomeres play an essential role in protecting genetic information during cell replication, as the processes responsible for copying DNA encounter challenges in fully replicating the ends of chromosomes.17–20 Additionally, telomeres are composed of repetitive DNA sequences and are capped by a unique protein complex known as shelterin.111–114 This shelterin assembly includes six specific proteins: telomeric-repeat binding factor (TRF) 1, TRF2, tripeptidyl peptidase 1, protection of telomerase 1, TRF1-interacting nuclear factor 2, and repressor activator protein 1. The shelterin complex is essential for protecting telomeres and executing several critical functions. First, it acts as a shield, preventing the identification of telomeres as sites of DNA damage. This blockage of DDR pathways helps prevent undesirable biological reactions, such as cell cycle arrest or apoptosis. Second, shelterin plays a vital role in preserving the integrity of telomeres, stopping the cellular machinery responsible for DNA repair from mistakenly identifying them as damaged. This action helps prevent the fusion of telomeres with the ends of other chromosomes, ultimately reducing the risk of genomic instability or rearrangement. Lastly, shelterin modulates the telomerase enzyme, which restores lost telomeric DNA during cellular division by managing its availability and function. This regulation ensures that telomerase is active only when needed, avoiding excessive elongation of telomeres that could result in age-related disorders. Together, the shelterin complex plays a crucial role in maintaining telomere integrity by striking a balance between shielding them from damage and ensuring they function correctly in essential biological activities like replication and repair.111–117 Although telomerase activation is typically inhibited in mature somatic cells, it peaks during the developmental phases of humans.118 Throughout embryonic growth, telomerase remains highly functional to promote effective cell division and tissue development.119 However, as cells specialize and mature, the activity of telomerase is generally reduced in most somatic cells.120 Nevertheless, specific cell types, such as stem cells and immune cells, retain their telomerase activity throughout an individual’s life.121–123 This persistent activity allows stem cells to continually divide and differentiate into different cell types, repairing damaged or aging cells. Similarly, immune cells rely on telomerase to aid in their rapid growth and effective function when responding to pathogens and ensuring ongoing immune monitoring.124,125 The persistence of telomerase activity within these essential cell types enables the body to maintain tissue balance, healing, and regeneration over time. This highlights the importance of telomerase not just for enhancing lifespan but also for safeguarding tissue quality and functionality as aging occurs.126,127
Research indicates that dysbiosis initiates a cascade of events leading to shortened telomeres in host cells through various pathways.128–130 Initially, dysbiosis triggers chronic, low-grade inflammation, which produces ROS and other damaging substances that accelerate telomere shortening.131,132 This inflammation also increases cellular turnover and oxidative stress, further hastening telomere loss. Additionally, dysbiotic microbiota produce metabolites and byproducts that contribute to oxidative stress in host cells.133 Interestingly, certain beneficial microorganisms, such as those generating short-chain fatty acids (SCFAs), have been identified as potential protectors of telomeres.133–135 SCFAs influence both oxidative stress and inflammation, which are closely linked to telomere shortening.136,137 Thus, microbial metabolites like SCFAs may mitigate telomere loss, creating a favorable environment for maintaining telomere length and cellular vitality. Additionally, an imbalanced microbiota disrupts the host immune system, leading to irregular immune responses, including impaired T cell activity and increased production of pro-inflammatory cytokines. These changes amplify inflammation and oxidative stress, which, in turn, accelerate telomere shortening.138–140 Moreover, dysbiosis impacts host metabolism, leading to complications such as insulin resistance and dyslipidemia.141,142 These metabolic disturbances exacerbate systemic inflammation and oxidative stress, contributing to accelerated telomere attrition. Furthermore, microbial imbalances could influence the host’s epigenetic processes, including changes in DNA methylation and histone modifications.143–145 These epigenetic alterations can disrupt telomere regulation, accelerating telomere shortening. For instance, modifications in DNA methylation at genes associated with telomeres might impair telomerase function or affect telomere structure, exacerbating telomere loss.146,147
Numerous studies reinforce the link between dysbiosis, telomere shortening, and the onset of diseases. Research shows that metabolic diseases, like type 2 diabetes, are associated with accelerated aging due to shortened telomeres, which may result from disrupted gut microbiota.148,149 Changes in diet or weight-loss surgery can alter gut microbiota composition, reducing inflammation caused by gut-derived Gram-negative bacterial fragments known as endotoxins.150,151 This shift may similarly influence the gradual shortening of telomeres over time. A distinct study further demonstrated that enhancing telomerase activity, particularly in the GI tract, could counteract aging processes. This intervention extended the lifespan of telomerase-deficient zebrafish and alleviated age-related symptoms in wild-type counterparts.152,153 This finding underscores the potential of strategic interventions to mitigate the impacts of aging and improve health outcomes. Additionally, research into the gut microbiome’s role in mental health, particularly depression, reveals a connection between telomere shortening and an imbalance of beneficial gut bacteria.154,155 These studies contribute to the growing body of evidence suggesting that changes in gut microbiota composition play a crucial role in the acceleration of telomere shortening, especially in mood disorders like depression. Further research highlights the gut microbiome’s critical role in regulating telomere length and the development of age-related diseases, primarily through inflammation and oxidative stress. Studies show that a diverse microbiota helps preserve telomere length, while imbalances or dysbiosis accelerate telomere loss and exacerbate aging-related issues.156,157 For instance, individuals with less diverse microbiota exhibit significantly shorter telomeres, indicating that microbial imbalances increase the risk of age-related conditions. Animal models support these findings, with germ-free mice showing notably shortened telomeres due to abnormal immune responses and increased oxidative stress.158,159 In humans, an imbalanced microbiome is correlated with higher inflammatory markers, such as C-reactive protein, which contribute to telomere shortening.160 Conversely, correcting dysbiosis in animal models has been shown to reverse telomere shortening, likely by reducing inflammation and oxidative stress through beneficial SCFAs.161,162 A balanced microbiome, supported by dietary interventions or probiotics, has also been associated with longer telomeres, suggesting that such strategies could slow telomere loss and delay aging.163,164 These studies strongly suggest that maintaining a balanced microbiome is essential for preserving telomere length and preventing age-related diseases.
Recent human studies have further established a link between gut microbiome changes and telomere shortening, emphasizing the importance of gut health in aging. Research indicates that individuals with a more diverse microbiome tend to have longer telomeres, suggesting that a balanced microbiota can protect against aging.165,166 Diet, particularly fiber-rich foods, plays a key role by promoting beneficial bacteria that produce SCFAs, such as butyrate.163,164 These SCFAs reduce inflammation and oxidative stress—major contributors to telomere shortening—and enhance immune function. The microbiome also significantly influences immune cells like T-cells, which in turn affect telomere length. Imbalances in microbiota can weaken immune responses and accelerate telomere loss. Overall, these findings demonstrate that the microbiome’s regulation of inflammation, oxidative stress, and immune function is vital for preserving telomere length and slowing aging.167,168
In summary, imbalances in the microbiota trigger a series of physiological changes, including inflammation, oxidative stress, immune dysfunction, metabolic issues, and genetic modifications. Together, these factors lead to shorter telomeres and genomic instability, accelerating cellular aging and increasing the risk of aging-related diseases. However, a comprehensive analysis of how disruptions in microbial balance influence these interconnected factors goes beyond the scope of this article. Nonetheless, this section aims to shed light on the intricate relationship between microbiota, telomere shortening, and aging, emphasizing the need for continued research in this evolving field.
Microbiome and aging: interplay between genome stability and telomere attrition
In the complex field of human health and aging, an important molecular-level topic emerges: the relationship between genome stability and the gradual deterioration of telomeres. This section explores this connection comprehensively by summarizing findings from key studies in the literature, with a focus on how genome stability and telomere attrition impact human health and aging, particularly in relation to the microbiome. For example, Werner syndrome (WS) is an inherited disorder characterized by the early onset of aging symptoms.169 At the molecular level, WS results from a mutation in the Werner protein, which is a crucial member of the RecQ helicase family involved in DNA replication, repair, and recombination.170,171 Consequently, WS is associated with heightened genomic instability, accelerating the development of aging and age-related diseases. Cells obtained from WS patients exhibit limited growth in culture, entering a senescent state after a certain number of cell divisions, indicating telomere dysfunction.172 Nevertheless, bypassing p53- and retinoblastoma protein-dependent tumor-suppressing mechanisms allows for enhanced cell division and an extended replicative lifespan, further emphasizing the link between telomere dysfunction and the accelerated aging observed in WS.173,174 Critically short telomeres in humans initiate signaling through the p53 and retinoblastoma protein tumor suppressor pathways, exacerbating genomic instability.175 This relationship highlights why individuals with WS face a higher risk of age-related diseases, given the close connection between genomic instability and aging, likely stemming from telomere dysfunction. It underscores the increasing recognition of the interconnections among the hallmarks of aging, particularly in the context of accelerated aging in WS. Although direct links between microbial dysbiosis and WS are still emerging, numerous studies suggest that dysbiosis may exacerbate aging-related conditions, potentially impacting WS.176,177 For instance, research has shown that an imbalance in the microbiome can lead to increased levels of pro-inflammatory cytokines and ROS, both of which can negatively affect cell health and intensify concerns tied to premature aging, such as in WS.178,179 Impaired DNA repair mechanisms are a hallmark of WS, and factors triggered by dysbiosis, such as oxidative stress and inflammation, might indirectly impede these repair processes, potentially worsening genomic instability in WS patients. Additional studies present intriguing results regarding the efficacy of telomeric DNA repair across different cell types.180,181 Comparisons indicate that as individuals age, their cells exhibit diminished repair efficiency, particularly in those from older adults.182 This reduction is notably severe in cells from individuals with WS. While repair efficiency in cells from Alzheimer’s patients meets expectations, there is a slight drop in efficiency observed in WS cells.183,184 These findings prompt inquiries into the possible functional ramifications of compromised telomeric repair mechanisms in relation to the genomic instability linked to aging. Furthermore, the connection between reduced DNA repair capacity and age-associated alterations in the microbiome underscores a complex interplay between cellular aging mechanisms and microbial dynamics, highlighting how these factors may collectively influence the aging process and age-related diseases.185–189
The role of the gut microbiome in longevity: insights from centenarians
Centenarians, those who live to be 100 years old or more, demonstrate remarkable longevity and resilience to age-related health challenges.190,191 Recent research has highlighted how their gut microbiome composition may play a critical role in sustaining their long lives.192,193 Studies suggest that the microbiomes of centenarians differ significantly from those of younger individuals, exhibiting greater diversity of beneficial microbes.192,194,195 Notably, centenarians tend to have increased levels of gut bacteria such as Akkermansia, Bifidobacterium, and Christensenellaceae, which are linked to anti-inflammatory effects and improved gut health. These microbial compositions likely play a pivotal role in maintaining immune homeostasis, reducing systemic inflammation, and modulating metabolic pathways, all of which are crucial for promoting healthy aging and extending lifespan. Moreover, centenarians possess a broader variety of microbes that produce beneficial compounds like SCFAs, which support both gut health and overall physiological balance.196,197 While the evidence remains limited, primarily due to small sample sizes and observational studies, current findings suggest significant correlations between specific gut microbiota profiles in centenarians and factors such as SCFA production and gut health. However, these studies do not yet establish definitive causal relationships, and further research is needed to clarify how the microbiome connects with the hallmarks of aging. Understanding these microbial patterns could offer valuable insights for developing strategies to promote healthy aging and potentially extend lifespan in broader populations. This exploration of the microbiome’s influence on aging intersects with broader biological processes like telomere shortening and genetic stability. Telomeres, the protective caps at the ends of chromosomes, naturally shorten as we age, and this genetic instability is a key driver of age-related decline. The relationship between the microbiome, telomere preservation, and genome stability is a fascinating area of study. Researchers are increasingly focused on understanding how the microbiome may help protect telomeres, which could open new avenues for therapies aimed at promoting healthy aging. These studies highlight that the gut microbiome plays a crucial role in protecting overall well-being, offering a pathway to improve longevity and health through its potential interactions with genome stability and telomere length.198–200
Studies on centenarians from around the world reinforce these concepts, highlighting specific microbial features linked to longevity. For instance, research on Okinawan centenarians has found that their microbiomes are enriched with Akkermansia muciniphila, a bacterium known for enhancing gut barrier function and reducing inflammation.201,202 This microbe, along with others like Bifidobacterium, is associated with improved metabolic health, a balanced immune system, and lower levels of inflammation—factors crucial for aging well.203,204 Similarly, Italian centenarians possess a microbiome with greater diversity, including strains like Faecalibacterium prausnitzii and Bifidobacterium, which are recognized for their anti-inflammatory properties.205 These microbes may help reduce chronic inflammation, a key driver of age-related diseases such as CVDs and type 2 diabetes.206 The microbial diversity in these populations suggests that a varied and balanced gut microbiome may be protective against these diseases and contribute to healthy aging. In Sardinia, a region known for its significant number of centenarians, studies have revealed that these individuals possess microbiomes that generate higher levels of SCFAs, such as butyrate, which are crucial for preserving gut health, immune responses, and metabolic balance.205,207 The microbiome of Sardinian centenarians strengthens the gut barrier and aids in diminishing inflammation, further supporting the notion that a robust gut microbiome is a vital component of healthy aging.208 Additional research indicates that centenarians exhibit greater microbial diversity compared to younger people and older individuals who do not live to 100.209 This diversity, along with a prevalence of bacteria such as Bifidobacterium and Prevotella, is linked to enhanced metabolic health and reduced inflammation, implying that these microbial characteristics shield centenarians from the typical diseases related to aging, thus bolstering their overall well-being.210,211 A recent cross-sectional study involving 1,575 participants ranging from 20 to 117 years of age in Guangxi province, China, which included 297 centenarians, further examined the relationship between the gut microbiome and increased longevity.198 This research found that centenarians have microbiomes commonly found in younger people, dominated by Bacteroides species, showing increased species diversity and enrichment with potentially beneficial Bacteroidetes. Additionally, the microbiomes of centenarians demonstrated a reduction in potential pathobionts, which are thought to help lower systemic inflammation and improve metabolic health—key elements in preserving genomic stability and reducing telomere shortening.212,213 Although current findings indicate that the microbiome plays a role in promoting conditions favorable for genomic stability and telomere maintenance, conclusive studies directly comparing telomere length and genomic stability in centenarians with younger or similarly aged non-centenarians are still required. The results show a strong link but do not yet confirm that enhanced genomic stability or longer telomeres are defining traits of centenarians. Across these studies, one clear theme emerges: centenarians tend to have gut microbiomes rich in specific, beneficial microbes that support immune function, reduce inflammation, and regulate metabolic processes. These factors are critical for promoting healthy aging and may help extend lifespan. While much of the evidence remains correlational rather than causal, the research underscores the significant role the microbiome plays in aging. It may hold the key to understanding longevity at a microbial level, offering a promising path forward in efforts to improve health and extend longevity (Fig. 1).
Future directions
Future investigations into how the microbiome influences aging have the potential to significantly enhance our comprehension of personal health while also delivering substantial benefits to society. By elucidating the molecular mechanisms involved in aging, we can reduce the financial burden that age-related diseases place on healthcare systems. This research could lay the foundation for innovative treatments aimed at prolonging both lifespan and healthspan. Such advancements could transform healthcare systems worldwide, alleviating the pressure of aging-related challenges and promoting a healthier, more active aging population. Furthermore, expanding our understanding of genome stability and telomere health is essential for understanding the complex relationships between these elements, aging, and the microbiome. Exploring these relationships could reveal new avenues for interventions, ultimately improving public health. Importantly, the close anatomical connection between the gut microbiota and immune cells in the intestine underscores the potential effects of telomere shortening and genomic instability in these immune cells on the fragile balance of the gut microbiome. Disruptions to this balance may lead to microbial imbalances, further complicating the ongoing interactions between the microbiome, telomere attrition, and genomic instability. This interconnectedness highlights the critical need for thorough studies to enhance our understanding of how these elements influence overall health. The convergence of microbiome research and aging biology presents an exciting new realm in biomedical science, offering the potential for significant advancements in aging studies. However, the field must also account for the complex interactions between genomic stability, telomere attrition, and the other hallmarks of aging to better understand the independent role these factors play in the aging process. Grasping the microbiome’s impact on each hallmark of aging requires comprehensive research to unravel the intricate network of interactions that drive aging processes. In essence, this review has focused on two primary hallmarks of aging—genomic instability and telomere degradation—and their potential interactions, elucidating their roles within the broader framework of aging biology. While these hallmarks are inherently interrelated, their connections with other aging mechanisms remain inadequately explored, indicating the need for further inquiry. Future studies should strive to unravel the individual contributions of each hallmark to longevity, providing deeper insights into their singular and synergistic impacts on the aging process. Furthermore, the meta-hallmark framework, which examines the interconnections between various aging mechanisms, offers a crucial perspective for enhancing our comprehension of the aging process.214,215 This approach acknowledges that aging arises not from isolated biological events but from intricate interactions among diverse cellular and systemic systems. By focusing on meta-hallmarks, scientists can gain deeper insights into how distinct hallmarks—such as genomic instability, telomere shortening, epigenetic changes, and loss of proteostasis—interrelate, affecting each other in ways that can either accelerate or decelerate the aging process. This comprehensive framework is crucial for pinpointing potential therapeutic targets capable of addressing multiple dimensions of aging concurrently, rather than isolating a single factor. In addition, the meta-hallmark framework has substantial implications for the research of age-related diseases. Many chronic conditions linked to aging, including NDs and CVDs, arise from complex, multifaceted disturbances in cellular and systemic processes. Gaining insights into the interconnections of these disruptions through the lens of meta-hallmarks could facilitate the development of more comprehensive and effective strategies for disease prevention, intervention, and treatment.216 By recognizing that aging is a systemic process shaped by the interactions of multiple biological pathways, we can more accurately pinpoint the root causes of age-related diseases and formulate therapies targeting these fundamental mechanisms. Moreover, the meta-hallmark perspective encourages a more integrated approach to understanding aging, healthspan, and lifespan. By reframing these aspects as interconnected rather than isolated phenomena, this perspective creates a cohesive framework in which the interactions among biological processes influence not only the aging trajectory but also the overall quality of life during aging. This approach underscores the importance of a multi-faceted understanding of aging that encompasses not just cellular health but also the systemic balance and resilience required to promote healthy aging and extend lifespan.
This review synthesizes findings from existing literature, forming a foundation for future studies aimed at refining this framework and investigating the interrelationships among aging mechanisms. As the field evolves, this comprehensive approach will be critical for devising targeted strategies that promote human health, enhance healthspan, and ultimately extend longevity. Considering the complex nature of aging and the intricate interplay of biological factors, ongoing research is imperative for deepening our understanding and developing interventions that foster healthier aging and improved quality of life across various populations.
Conclusions
The hallmarks of aging—genome stability and telomere shortening—serve as crucial indicators of the complex aging process, underscoring the intricate relationship between cellular health and the passage of time. Their close connection to a variety of human diseases reveals the significant complexity of aging. Within this complexity, the host microbiome plays a critical role, creating a dynamic and reciprocal relationship that influences the course of aging and longevity. The interdependent relationship between the microbiome and the hallmarks of aging is not merely coincidental; it forms a central axis around which the aging process unfolds. This two-way communication emphasizes the interconnectedness of various physiological functions and presents an exciting opportunity for therapeutic strategies. Understanding and manipulating this interplay could hold significant potential for preventing and managing age-related diseases. By altering the composition and activity of the microbiome through dietary modifications, probiotics, or targeted microbial approaches, it may be possible to mitigate the adverse effects of genome instability and telomere attrition. Additionally, combining these microbiome-focused strategies with methods aimed at directly improving genome stability and preserving telomere length could provide a holistic approach to addressing the fundamental causes of age-associated conditions.
Declarations
Acknowledgement
This research is supported by Bandhan, Kolkata, India.
Funding
None.
Conflict of interest
The authors affirm that they have no conflicts of interest to disclose in relation to the publication of this research.
Authors’ contributions
Conceptualization (SKC), formal analysis (SKC), original draft preparation (SKC), writing—review and editing (SKC, DC), supervision (SKC), project administration (SKC), and funding acquisition (SKC).