Introduction
Aging is a multifaceted biological phenomenon characterized by a progressive decline in cellular and physiological functions, affecting all organisms universally.1,2 This process undermines resilience to stress, the capacity for injury recovery, and the maintenance of internal stability, critical facets tightly intertwined with aging.3–5 Recent scientific inquiries have illuminated an intriguing intersection between aging and the human microbiome—an intricate ecosystem of microorganisms cohabiting within our bodies.6,7 In particular, the relationship between the microbiome, notably the gut microbiota, and aging has emerged as a focal point of research, unveiling profound implications for human health and longevity.8–10
DNA damage is widely considered one of the hypothesized hallmarks of aging.11,12 It is influenced by various cumulative factors, including exposure to environmental agents such as ultraviolet radiation, pollution, and toxins.13–15 Additionally, aging is associated with increased production of reactive oxygen species (ROS) due to declining mitochondrial function.16–18 Furthermore, as cells divide, telomeres shorten, contributing to cellular senescence.19,20 Moreover, age-related declines in DNA repair efficiency, epigenetic modifications affecting gene expression in DNA repair, and replication stress further exacerbate DNA damage.21–23 Chronic inflammation, known as “inflammaging,” which is associated with aging and induced by pro-inflammatory cytokines, exacerbates oxidative stress and the accumulation of DNA damage.24–28 Genomic instability resulting from accumulated mutations and chromosomal abnormalities further contributes to age-related DNA damage.29,30
As individuals age, their microbiome undergoes substantial transformations characterized by diminished diversity and shifts in bacterial composition.6,31 These changes involve an increase in opportunistic pathogens and a decline in beneficial bacteria.32 Factors such as altered metabolic activity, which influences the production of essential short-chain fatty acids (SCFAs) crucial for gut health, contribute to these shifts.8,33,34 Furthermore, aging-related immunosenescence, marked by diminished immune function, promotes chronic low-grade inflammation and compromises the integrity of the gut barrier, thereby disrupting the microbiome.35–37 Oxidative stress, compounded by these changes, also influences the microbiome’s composition and functionality.38–40 Additionally, dietary shifts, lifestyle modifications, increased antibiotic usage, and chronic diseases impact the microbiome’s ability to synthesize vitamins, degrade complex polysaccharides, and regulate host metabolism.41,42
Importantly, this exploration of microbiota-mediated regulation of DNA damage and its implications for human health and aging reveals striking parallels in the mechanisms underlying age-related DNA damage and microbial dysregulation. An understanding of these complexities could pave the way for innovative therapeutic strategies aimed at fostering healthy aging and combating age-related diseases. Hence, this review aimed to critically examine the complex interactions between the microbiome, DNA damage, and aging, with a specific focus on their interrelationship and their broader implications for human health and disease. By exploring these interactions, we seek to deepen our understanding of the biological mechanisms that underlie human longevity and, more importantly, healthspan—the portion of life spent in optimal health.
An extensive literature search was performed to identify pertinent studies for this review. The search covered multiple academic databases, including PubMed, Scopus, Web of Science, and Google Scholar, with a focus on laboratory, in vivo, and clinical research. The search strategy was designed to align with the central themes of the review, utilizing targeted keywords and phrases relevant to the research focus. A total of 993 papers were identified through database searches. After removing 24 duplicates, 969 papers remained for screening. Of these, 600 papers were excluded based on title and abstract screening, primarily due to irrelevance to the narrative review, lack of methodological rigor, insufficient data or analysis, duplicate entries, or non-availability of full text. Ultimately, approximately 300 papers were included for full-text review. In this context, duplicates refer to instances where the same paper appeared multiple times across different database search results, either due to indexing in multiple databases or different versions of the same paper, as shown in the flowchart (Fig. 1).
The interplay between gut microbiota and immune function in health and disease
The human gut microbiome plays a crucial role in overall health, with its composition influenced by multiple factors such as genetics, immune system effectiveness, age, gender, and lifestyle choices, including diet, pregnancy, and stress management. Maintaining a balanced microbiome (eubiosis) is vital for optimal health, as it helps produce essential metabolites and boosts immune functions.43,44 In contrast, dysbiosis occurs when there is an imbalance, resulting in the growth of harmful microorganisms while beneficial ones decline, which can lead to various health issues.45,46
An increasing number of studies are highlighting the link between gut bacteria and diverse health outcomes.44,47,48 For instance, a research study conducted in Poland explored the impact of polyphenols, lignans, and herbal sterols on immune-modulating bacteria such as Escherichia coli and Enterococcus spp. in a group of 95 non-obese individuals. The findings suggested that a higher intake of these compounds might be linked to a lower risk of COVID-19, likely due to beneficial changes in gut microbiome composition.49 This implies that altering the microbiome could be useful in preventing infections, particularly respiratory diseases like COVID-19. However, the authors stress the importance of conducting additional research to confirm these results and to investigate microbiome-centered approaches for tackling various health challenges.
Importantly, the gut microbiome plays a pivotal role in modulating immune responses, a factor of particular relevance in the context of COVID-19, where dysregulation of immune function is central to the pathophysiology and progression of the disease.50,51 An excessively pro-inflammatory response can lead to severe complications. Proteins known as Toll-like receptors play a crucial role in detecting pathogens such as SARS-CoV-2 and initiating immune responses, including the release of type I interferons and inflammatory cytokines.52,53 Nevertheless, an overly aggressive or delayed immune response during viral respiratory infections, including COVID-19, may worsen the severity of the disease. The gut microbiome is essential for regulating immune responses, including the activation of Toll-like receptors via the gut-lung axis, which links gut health to lung function.54,55 A well-balanced microbiome enhances immune activation, ensuring an effective response to pathogens, whereas a disrupted microbiome may increase inflammation and the risk of severe disease.43–46 Additionally, beneficial gut bacteria generate SCFAs, which help manage inflammation and maintain immune balance, potentially resulting in improved outcomes for various diseases.8,33,34,56
Recent studies also highlight the significant influence of the microbiome on overall well-being. Research linking intestinal bacteria to lung diseases such as asthma, chronic bronchitis, COPD (chronic obstructive pulmonary disease), and pulmonary arterial hypertension reveals distinct associations between certain gut bacteria and the risk of developing these diseases.57–59 This emphasizes the microbiome’s vital importance in both digestive and respiratory health. Furthermore, investigations into autoimmune diseases like juvenile idiopathic arthritis and uveitis indicate that changes in gut microbiota may play a role in these disorders.60,61 Mendelian randomization studies provide new insights into their underlying mechanisms and possible treatments.62 In addition to immune responses, the microbiota-gut-brain axis has gained interest for its influence on mental health.63,64 Studies suggest that gut microbiota can influence psychological issues such as post-traumatic stress disorder, highlighting notable differences in SCFAs and bacterial populations in those affected.65,66 Research involving probiotics and fermented foods has shown promising results, indicating that modifying the gut microbiome might improve mental health treatments.67,68 This connection underscores the essential role of gut health in our psychological state. Importantly, a significant factor linking gut microbes to overall well-being is systemic inflammation.69,70 This relationship is becoming more important in the realm of predictive, preventive, and personalized medicine, as it unveils health risks and aids in effective care strategies. By using the microbiome and inflammation as indicators, we can develop early intervention strategies and tailored therapies to enhance health outcomes and individual treatments.
Research into the role of gut microbiota in zoonotic diseases like leptospirosis is currently ongoing.71,72 This infection leads to approximately 1 million reported cases each year, with a mortality rate of 6.86%, translating to roughly 60,000 deaths globally.73,74 The nature of the relationship between leptospirosis and gut microbiota is not yet fully understood; however, recent research has shown that a Leptospira infection alters the composition of gut microbes, notably raising the Firmicutes/Bacteroidetes ratio.75,76 While antibiotics and steroids are frequently prescribed, there is increasing interest in probiotics as a potential treatment alternative.77 Studies indicate that the use of antibiotics, which reduce gut microbiota, can worsen the infection’s impact on various organs, whereas fecal microbiota transplantation may alleviate these effects.77,78 This suggests that preserving or restoring a balanced gut microbiota could be vital for effectively managing leptospirosis. Therefore, probiotics, which help reestablish gut balance, may be advantageous in lessening the severity of the infection, improving immune responses, and aiding recovery.
Together, these studies highlight the crucial impact that gut microbiota has on various health issues, including immune response, respiratory illnesses, mental health, and infections. Growing evidence emphasizes the necessity for additional research into microbiome-focused therapies, which present exciting opportunities for disease prevention, health enhancement, and personalized treatment alternatives.
DNA repair, maintenance, and microbiome interconnections
DNA repair and maintenance are fundamental to genetic stability and represent pivotal elements within biological systems.79 It is widely acknowledged that the accumulation of DNA damage, which is presumed to occur progressively over time, can potentially be mitigated through the microbiome’s modulatory impact on DNA repair pathways.80–82 Thus, fostering a robust microbiota capable of supporting optimal DNA repair mechanisms holds promise for potentially attenuating the aging process and enhancing genetic stability.83–85
Notably, cancer patients afflicted with erysipelas, a skin infection caused by Streptococcus pyogenes, experienced spontaneous regression of tumors due to the infection.86–88 Additionally, Escherichia coli emerged as the first microorganism identified to demonstrate mutagenic properties.89 Colibactin, a compound derived from Escherichia coli, has been found to induce double-strand DNA breaks through the alkylation of adenine residues, potentially leading to direct mutations associated with colorectal cancer.90 Intriguingly, genotoxins secreted by the gut microbiota exhibit DNase activity.91 Upon release in close proximity to gastrointestinal (GI) epithelial cells, these toxins induce double-strand DNA breaks, triggering a transient cell cycle arrest in host epithelial cells.92,93 Alongside colibactin, a variety of other bacterial toxins that cause genetic damage can lead to considerable harm to the host’s DNA. Cytolethal distending toxins (CDTs), secreted by Gram-negative bacteria such as Escherichia coli, Shigella dysenteriae, and Campylobacter jejuni, act as potent DNA-damaging agents.94,95 These toxins cause genotoxic effects by interfering with the cell cycle and resulting in DNA fragmentation, which contributes to genomic instability. This process is crucial for the onset of colorectal cancer, where E. coli strains that produce CDTs play a role in DNA damage and the formation of tumors.96 Another notable genotoxic toxin is typhoid toxin, which is generated by Salmonella typhi, Salmonella paratyphi, and other Salmonella subspecies (such as arizonae and javiana).97 The toxin associated with typhoid harms DNA and plays a vital role in the development of typhoid fever, a widespread infection that causes serious digestive issues and other complications.98 Moreover, shigellosis, which is caused by Shigella dysenteriae, along with campylobacteriosis from Campylobacter jejuni, also involves CDTs, which lead to severe GI inflammation and can sometimes result in complications outside the intestines, such as Guillain-Barré syndrome.99,100 These observations underscore the crucial role of microbial toxins in perturbing the genomic stability of hosts, contributing to the emergence and progression of various infections and cancers.
On another front, the transcription factor tumor protein,53 p53, well-known for its tumor-suppressing abilities, binds to distinct DNA sequences, activating transcription, regulating the cell cycle, and facilitating the repair of damaged genes.101,102 Interestingly, a significant portion of p53 mutations commonly associated with cancer initiation are attributed to metabolites produced by the gut microbiota.103,104 Furthermore, Shigella flexneri, using secretases like virulence gene A and inositol phosphoinositide 4-phosphatase, induces degradation of the host cell’s p53, thereby elevating the incidence of DNA mutations.105–107 Moreover, anaerobic Gram-negative bacteria such as Fusobacterium nucleatum are frequently observed in the microbiomes of individuals with colorectal cancer.108,109 There is a general consensus that ROS and pro-inflammatory substances may contribute to the Fusobacterium nucleatum oncogenic process. ROS could potentially lead to alterations in 5′—C—phosphate—G—3′ site methylation, resulting in microsatellite instability and other epigenetic changes.110,111 Concurrently, pro-inflammatory agents and ROS may induce DNA damage. Similarly, Helicobacter pylori triggers the production of hydrogen peroxide and ROS via spermine oxidase, potentially causing DNA mutation and promoting carcinogenesis.112,113 Lastly, clinical investigations revealed a correlation between highly pathogenic mutations in the Adenomatous Polyposis Coli tumor suppressor gene in the intestinal cells of patients, an increase in Fusobacterium mortiferum, and a notable decrease in Clostridium geniculatum and Bifidobacteria.114–116 These studies are among the numerous pieces of evidence linking the microbiome to DNA integrity. Additional pertinent studies are listed in Table 1.117–121
Table 1Studies on DNA repair, maintenance, and microbiome interconnections
| Study title | Authors | Year | Main findings | Reference |
|---|
| Bacterial phenotypic heterogeneity in DNA repair and mutagenesis | Vincent et al. | 2020 | The article highlights how variation in DNA repair pathways can affect mutation rates and genome stability in bacteria, especially under antibiotic stress | 117 |
| Gut Microbiota as Important Mediator Between Diet and DNA Methylation and Histone Modifications in the Host | D’Aquila et al. | 2020 | The review highlights that gut microbiota, through its metabolites, plays a crucial role in shaping the host’s epigenome by influencing DNA methylation and histone modifications, thereby affecting cellular activities | 118 |
| Bacterial DNA excision repair pathways | Wozniak et al. | 2022 | This article highlights newly discovered bacterial DNA repair pathways, including EndoMS and MrfAB, advancing our understanding of genome maintenance | 119 |
| DNA Damage and the Gut Microbiome: From Mechanisms to Disease Outcomes | Hsiao et al. | 2023 | This article explores how DNA damage impacts the gut microbiome, linking impaired microbial DNA repair to dysbiosis, disrupted host interactions, inflammation, and disease outcomes like gastrointestinal disorders, metabolic dysfunction, and cancer | 120 |
| Colibactin-induced damage in bacteria is cell contact-independent | Lowry et al. | 2025 | This study reveals that colibactin-induced DNA damage in bacterial cells occurs over long distances without direct contact. Using a fluorescent reporter system, researchers found that genotoxic effects saturated within 12 h and were detectable hundreds of microns away, challenging previous delivery assumptions | 121 |
Dysbiosis, aging, and immunosenescence: mechanisms at the gut interface
As the body’s ability to repair itself diminishes over time, chronic inflammation and immunosenescence create conditions conducive to increased DNA damage.122,123 This convergence of factors sets the stage for a vicious cycle, where each element exacerbates the effects of the others.124,125 Dysbiosis, an imbalance in the gut microbiota, accelerates immunosenescence, thereby accelerating DNA degradation associated with aging.45,46,126,127 Alternatively, DNA damage escalates inflammation, perpetuating a self-reinforcing loop of decline.128–130 Research indicates that dysbiosis may contribute to age-related immunosenescence through various mechanisms. One crucial aspect involves the modulation of the gut-associated lymphoid tissue (GALT), a pivotal component of the immune system residing in the GI tract, often regarded as the body’s largest immune organ.131–133 As people age, the functionality of GALT diminishes, leading to a weakened immune response and a higher risk of infections and diseases. Recent research has shown that aging results in a decrease in both the quantity and functionality of key immune cells found in GALT, such as naive T cells, B cells, and dendritic cells (DCs), which are vital for triggering immune responses.134,135 This age-related reduction in immune cell populations is associated with an elevated vulnerability to GI cancers and systemic inflammation in older adults.136,137 Within GALT, innate immune cells act as the frontline defenders of the gut mucosa, playing essential roles in pathogen recognition, initiating the innate immune response, and presenting antigens to activate the adaptive immune system downstream.138–140 Moreover, GALT is integral in maintaining immunological tolerance to commensal bacteria, serving as a crucial link between the systemic immune response and the local immunological environment of the gut. Alterations in microbiota composition can profoundly influence the development and function of immune cells within GALT, thereby potentially impacting systemic immune responses.141–143 This intricate interplay underscores the importance of gut microbiota in modulating immune function and highlights its relevance in the context of aging and immunosenescence (Fig. 2).
Additionally, there is compelling evidence connecting the loss of DC tolerance to gut dysbiosis.144,145 Recent clinical studies have demonstrated that gut microbiota dysbiosis profoundly impacts DC-mediated immune tolerance, contributing to immune dysfunction.144,146 In patients with inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis, dysbiosis characterized by an overgrowth of pro-inflammatory bacteria impairs DC function, leading to a failure to induce tolerance to gut antigens and subsequent inflammation.147,148 These patients also exhibit a reduction in T cells (Tregs) in the gut, further exacerbating immune dysregulation and promoting chronic inflammation. Similarly, individuals with autoimmune conditions like rheumatoid arthritis and systemic lupus erythematosus show altered gut microbiota profiles, which skew DC activation, promoting pro-inflammatory responses that drive autoimmune pathogenesis.149,150 Furthermore, studies have demonstrated that microbiome-based interventions, such as probiotics, can restore DC function and enhance regulatory Treg induction, reducing inflammatory markers in elderly individuals with dysbiosis.151,152 Collectively, these findings highlight the critical role of gut microbiota in modulating DC-mediated immune responses and underscore the potential of microbiome-targeted therapies to restore immune tolerance, reduce inflammation, and mitigate autoimmune diseases, offering promising strategies to counteract age-related immune dysfunction.
DCs also play a crucial role in maintaining immunological tolerance by orchestrating mechanisms such as inducing anergy, clonally deleting T cells, and promoting the generation of Tregs to suppress immune responses against self-antigens.153–155 These processes collectively ensure that the immune system avoids harmful responses to its own tissues. Importantly, dysbiosis can disrupt the production of SCFAs, compromising the integrity of the gut barrier and facilitating the translocation of harmful microbial products.156,157 Consequently, this triggers the activation of immune cells and contributes to systemic inflammation, ultimately culminating in immunosenescence. Notably, various signaling pathways, including SCFA synthesis by specific bacteria, mediate communication between the gut microbiota and the immune system.158,159 SCFAs not only support intestinal barrier integrity but also possess anti-inflammatory properties, further underscoring their role in immune regulation.160–162 Moreover, recent research has elucidated how dysbiosis influences T cell diversity, a crucial aspect of adaptive immune function.163 With aging, individuals may experience a decline in the capacity of their T cells to respond effectively to new infections and vaccinations due to alterations in the composition of their gut flora.164–166
New research emphasizes the considerable role that imbalances in gut microbiota play in the processes associated with aging. Dysbiosis is linked to increased oxidative stress, mitochondrial dysfunction, and inadequate immune responses, all of which can accelerate the aging process.167–169 Moreover, this imbalance in microbes heightens the likelihood of infections and weakens immune defenses in older adults, exacerbating the decline in immune function. Clinical trials indicate that probiotics such as Lactiplantibacillus plantarum may help alleviate inflammation and oxidative stress, which are significant factors in age-related deterioration.170,171 These investigations encourage approaches to restore a balanced gut microbiota, which could enhance immune function and promote healthier aging by combating chronic inflammation. Overall, this research highlights the crucial importance of the gut microbiome for aging and immune health, pointing to the potential for microbiome-centric treatments to improve immunity and foster longevity among the elderly. Further evidence related to this is provided in Table 2.172–176
Table 2Microbiome-centric strategies for enhancing immunity and promoting longevity in the elderly
| Study title | Authors | Year | Main findings | Reference |
|---|
| The Gut Microbiome, Aging, and Longevity: A Systematic Review | Badal et al. | 2020 | Aging is associated with distinct gut microbiota alterations, including reduced Faecalibacterium, Bacteroidaceae, and Lachnospiraceae, increased Akkermansia, and functional shifts in carbohydrate metabolism, amino acid synthesis, and short-chain fatty acid production, particularly in the oldest-old adults | 172 |
| Gut microbiota changes in the extreme decades of human life: a focus on centenarians | Sontoro et al. | 2018 | Centenarians provide a unique model for disentangling aging-related and non-aging-related gut microbiota changes, highlighting the influence of population, gender, and genetics, with implications for the gut-brain axis, neurodegenerative diseases, and microbiome-based therapies | 173 |
| Lactic Acid Bacteria and Aging: Unraveling the Interplay for Healthy Longevity | Liu et al. | 2023 | Lactic Acid Bacteria (LAB) may promote healthy aging by modulating key molecular pathways (e.g., IL-13, TNF-α, mTOR, Sirtuin-1, TLR2), enhancing gut balance, antioxidant potential, and cognitive health, though further human trials and mechanistic studies are needed to validate their anti-aging benefits | 174 |
| Microbiota medicine: towards clinical revolution | Gebrayal et al. | 2022 | The gut microbiota plays a crucial role in immunity, nutrient absorption, and disease prevention, with its dysbiosis linked to various systemic disorders, highlighting the need for targeted microbiome-based strategies in future medical treatments | 175 |
| The aging gut microbiome and its impact on host immunity | Bosco & Noti | 2021 | Aging disrupts the co-evolved gut microbiome-immune system axis, leading to microb-aging, inflammaging, and immunosenescence, increasing disease susceptibility and weakening vaccine responses, while emerging microbiome-targeted interventions like prebiotics and probiotics aim to restore microbial balance, reduce systemic inflammation, and rejuvenate immune function to enhance healthspan and longevity | 176 |
In essence, the complex interplay between immunosenescence and dysbiosis underscores the critical role of maintaining a diverse and balanced gut microbiota for optimal immune function as individuals age. However, the precise mechanisms linking age-related microbial dysbiosis to immunosenescence and inflammaging processes remain largely unclear. Therefore, further comprehensive research is essential to uncover these intricate connections and understand their broader implications for age-related immune dysfunction. By elucidating the relationship between dysbiosis, loss of immune tolerance, and inflammation, we can better understand the mechanisms underlying age-related immune decline. This understanding is vital for developing targeted interventions to mitigate the impact of immune dysfunction on health and aging. Continued research is crucial for identifying effective strategies to support older individuals in maintaining a healthy gut microbiome and a robust immune system. Comprehensive studies are essential to uncover these intricate connections and their broader implications for age-related immune dysfunction.
Understanding the dynamic relationship of immunosenescence and inflammation in aging
An intriguing aspect of the interplay between inflammation and immunosenescence is their mutually reinforcing relationship. While chronic inflammation is both a consequence and a contributor to immunosenescence, the sustained release of pro-inflammatory molecules, termed cytokines, can disrupt immune regulation and exacerbate age-related immune decline.177,178 Although the immune system predominantly regulates the levels of pro- and anti-inflammatory cytokines, recent research in fibroblasts and epithelial cells has unveiled a correlation between cellular senescence and a significant increase in the secretion of 40–80 factors involved in intercellular signaling, collectively known as the “senescence-associated secretory phenotype”.179–181 Immune cells, like macrophages and natural killer cells, are typically recruited to eliminate senescent cells (SCs).182,183 However, they may eventually lose their ability to do so, leading to an accumulation of SCs and heightened inflammation. Thus, within the intricate fabric of human health, the relationship between inflammation and immunosenescence emerges as a crucial component. This dynamic interaction underscores the importance of understanding how aging processes impact immune function and vice versa, offering potential insights into therapeutic strategies aimed at mitigating age-related immune dysfunction and chronic inflammation. Additional supporting evidence on this topic is presented in Table 3.184–188
Table 3The link between inflammation and immunosenescence across aging
| Study title | Authors | Year | Main findings | Reference |
|---|
| Immunosenescence and Inflamm-Aging: Clinical Interventions and the Potential for Reversal of Aging | Kumar et al. | 2024 | Immunosenescence, driven by inflammaging and lifelong pathogenic exposure, weakens immune resilience, while interventions like immunomodulation, vaccination, nutrition, microbiome therapy, stem cells, and exercise aim to slow or reverse age-related immune decline | 184 |
| Inflammation and aging: signaling pathways and intervention therapies | Li et al. | 2023 | Aging is driven by chronic inflammation (inflammaging), where the senescence-associated secretory phenotype (SASP) sustains a cycle of immune dysfunction, organ damage, and age-related diseases, highlighting the need for dimensionality reduction approaches, single-cell technologies, and targeted anti-inflammatory strategies to mitigate aging and enhance longevity | 185 |
| Immunosenescence: Aging and Immune System Decline | Goyani et al. | 2024 | Immunosenescence, marked by thymic involution, inflammaging, metabolic and hematopoietic changes, weakens immune responses in aging by impairing macrophages, neutrophils, T cells, dendritic cells, B cells, and NK cells, underscoring the need for strategies to counteract age-related immune decline | 186 |
| Immune-Inflammatory Response in Lifespan—What Role Does It Play in Extreme Longevity? A Sicilian Semi- and Supercentenarians Study | Accardi et al. | 2024 | Analysis of inflammatory scores (INFLA-score, SIRI) and ARIP in 249 individuals aged 19–111 years revealed age-related increases in inflammation but no significant differences in immune-inflammatory markers between semi- and supercentenarians and other age groups, suggesting that immune regulation may contribute to extreme longevity | 187 |
| The 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience | Wrona et al. | 2024 | Immunosenescence, characterized by a decline in innate and adaptive immunity, chronic inflammation, and increased disease susceptibility, is influenced by aging hallmarks, sex, social determinants, and gut microbiota, with potential mitigation strategies including lifestyle interventions and gerotherapeutics to enhance immune resilience in the elderly | 188 |
As individuals age, various factors contribute to the complex interplay between inflammation and immunosenescence, impacting the functionality of the immune system. First, alterations in immune cell function occur, particularly in T cells, which play a pivotal role in directing immune responses. This decline in T cell efficacy may lead to diminished control over inflammation, resulting in prolonged and exaggerated inflammatory reactions.189 Second, dysregulation of cytokines—crucial proteins for immune cell communication—ensues due to immunosenescence, favoring the production of pro-inflammatory cytokines and perpetuating a chronic inflammatory state associated with age-related disorders.177–179 Third, the accumulation of SCs, known to release a mixture of pro-inflammatory molecules termed the SASP, further fuels both local and systemic inflammation. This process is facilitated by the persistence of these cells under conditions of immunosenescence.179–181 Additionally, impaired immune surveillance, a consequence of immunosenescence, compromises the immune system’s ability to detect and eliminate damaged cells. This compromise leads to inflammatory responses aimed at controlling potential threats. Finally, epigenetic changes induced by both inflammation and immunosenescence contribute to alterations in gene expression.190–192 These changes exacerbate the pro-inflammatory condition and establish a reciprocal relationship between immunosenescence and epigenetic modifications.193–195 Together, these interconnected processes underscore the intricate relationship between inflammation and immunosenescence, shaping the immune landscape in aging individuals.
Orchestrated insights into cellular interactions: gut microbiome, inflammation, and aging
The gut microbiome plays a crucial role in modulating immune and epithelial cell activities, significantly affecting the aging process through its involvement in inflammation—a key concept in cell biology. As we age, dysbiosis emerges, compromising the integrity of the gut epithelial barrier. Enterocytes (the cells that line the gut) typically maintain tight junctions that create a selective barrier against microbial products and toxins.196 However, with age, oxidative stress and cellular senescence weaken these junctions, leading to increased gut permeability and allowing microbial endotoxins, such as lipopolysaccharides, to enter the bloodstream, initiating immune activation. Immune cells, such as macrophages, DCs, and T cells, play essential roles in this process.197,198 In a healthy gut, macrophages maintain a tolerogenic state, preventing excessive immune responses to commensal bacteria.199,200 However, with dysbiosis and aging, macrophages acquire a pro-inflammatory M1 phenotype, releasing cytokines like tumor necrosis factor (TNF)-α, interleukin-6, and interleukin-1β, which amplify systemic inflammation.201,202 T cells, especially the balance between Tregs and pro-inflammatory T cells such as Th17, are crucial for immune homeostasis.203,204 Aging and dysbiosis shift this balance toward pro-inflammatory states, exacerbating inflammation. DCs, responsible for antigen presentation and immune modulation, become less effective at distinguishing harmful from harmless microbes with aging, further impairing immune regulation and promoting inflammation.36,37,40 Aging is also characterized by the presence of SCs that secrete pro-inflammatory molecules known as the SASP, which fuel ongoing inflammation and hinder cellular functions.124,177,179–181 In the GI tract, senescence disrupts the repair of epithelial cells and enhances gut permeability, escalating inflammation further. Moreover, fibroblasts and myofibroblasts in the gut wall become activated due to inflammation, resulting in extracellular matrix remodeling that causes fibrosis and tissue scarring. This adversely affects tissue regeneration, nutrient absorption, and motility.205,206 From a neurobiological standpoint, the enteric nervous system interacts with the brain through the gut-brain axis.207 Dysbiosis initiates neuroinflammation by activating immune responses within the gut, affecting the enteric nervous system, and modifying gut motility and pain perception.208 These alterations become more significant with aging, establishing a connection between gut dysbiosis and neurodegenerative diseases linked to age, such as Alzheimer’s disease.209,210 At the molecular level, beneficial bacteria produce microbial metabolites like SCFAs, which are essential for maintaining the health of the gut epithelium and modulating immune responses.156,158 Conversely, dysbiosis leads to a decrease in SCFA production and an increase in microbial products like lipopolysaccharides, which compromise gut function and activate inflammatory pathways. Over the years, the reduction of beneficial microorganisms coupled with the increase of harmful bacteria creates a pro-inflammatory environment that exacerbates age-related issues such as cardiovascular diseases, diabetes, and neurodegenerative diseases.211,212 The gut microbiome plays a crucial role in a complex interaction that includes immune system activation, cellular aging, remodeling of the extracellular matrix, and neuroinflammation, all of which accelerate the aging process.213,214 This connection between dysbiosis, inflammation, and cellular dysfunction highlights the profound influence of the gut microbiome on inflammaging and diseases related to aging (Fig. 3).
The interplay of DNA damage and inflammation in aging dynamics
The intricate relationship between DNA damage and inflammation within the body signifies a close interconnection.215,216 These processes engage in reciprocal signaling, exerting influence across a range of physiological and pathological contexts. Notably, chronic inflammation poses a significant threat to DNA stability. Inflammatory agents, like ROS, induce DNA damage by triggering oxidative stress, resulting in the formation of lesions such as base modifications and strand breaks.217,218 Furthermore, specific inflammatory mediators, including TNF-α and interleukins, activate pathways that exacerbate DNA damage.219,220 For instance, TNF-α stimulates the production of ROS, intensifying DNA damage.221
Conversely, DNA damage activates the DNA damage response, a multifaceted cellular mechanism involving signaling pathways aimed at repairing damaged DNA and preserving genomic integrity.222,223 Intriguingly, DNA damage response also influences inflammatory pathways. The activation of nuclear factor-kappa B by DNA damage leads to the generation of pro-inflammatory cytokines.224,225 Additionally, immune cells, which are pivotal in both inflammation and DNA repair, significantly contribute to this bidirectional communication. Macrophages exemplify this dual role, participating in both inflammation and tissue repair. However, persistent inflammation may drive macrophages toward a phenotype that exacerbates DNA damage and disrupts repair mechanisms.226–229
Furthermore, SCFAs, such as butyrate, propionate, and acetate, produced by the gut microbiota through dietary fiber fermentation, play a crucial role in epigenetic modifications that affect DNA repair mechanisms.230,231 SCFAs act as histone deacetylase inhibitors, increasing histone acetylation and thereby relaxing chromatin structure to facilitate DNA repair enzyme access to damaged sites. Additionally, SCFAs influence DNA methylation patterns by serving as substrates for enzymes involved in one-carbon metabolism, such as DNA methyltransferases.232,233 This dual action of SCFAs enhances the expression of genes crucial for DNA repair pathways, like base excision repair and nucleotide excision repair, promoting efficient DNA damage repair and maintaining genomic stability (Fig. 4).234,235 Moreover, SCFAs exert anti-inflammatory effects by inhibiting nuclear factor-kappa B activation and reducing pro-inflammatory cytokine production, indirectly supporting DNA repair mechanisms that might be impaired under inflammatory conditions.236,237 Understanding these mechanisms holds promise for developing therapeutic interventions targeting chronic diseases and cancer by modulating SCFA levels through dietary adjustments or microbiome-targeted therapies to enhance epigenetic and DNA repair processes in clinical settings.
In summary, this article offers a focused perspective on key aspects, including the interplay between dysbiosis, immunosenescence-driven inflammation, and DNA damage in aging. Nevertheless, it acknowledges the complexity and breadth of this subject, aiming to spark further dialogue and deeper investigation into how the microbiome intricately links with aging. By discussing and emphasizing these mechanisms, the article highlights their interconnected nature, particularly how dysbiosis, inflammation, immunosenescence, and DNA repair collectively impact the health of elderly individuals (Fig. 5). This foundational understanding highlights the critical need for ongoing research to uncover precise interventions that can mitigate these multifaceted interactions, promoting better health outcomes for aging populations.
Future directions
Further exploration of the intricate interplay between the microbiota and DNA damage offer potential strategies to support healthy aging and address microbiome-related disorders in later life stages. The burgeoning field of research on the connection between the human microbiome and genomic stability presents promising avenues for unraveling the complexities of aging. Recent studies emphasize the correlation between gut microbiota dysbiosis and heightened DNA damage, underscoring the significance of microbiome management in preserving genomic integrity. Accumulating evidence suggests that cultivating a robust and diverse microbiome may positively impact genomic stability and contribute to graceful aging. By expanding our understanding of how microbial dysbiosis influences genomic instability during aging, future investigations could focus on refining targeted interventions to restore and preserve a healthy gut microbiome and mitigate age-related DNA damage. This may involve identifying specific microbial strains or metabolites that enhance DNA repair mechanisms or mitigate oxidative stress-induced DNA damage.
Cutting-edge technologies like metagenomics, metatranscriptomics, and metabolomics can provide profound insights into the interactions between the host, microbiome, and DNA damage pathways during aging. Combining multi-omics approaches with long-term studies of aging populations could identify biomarkers of microbial health and DNA integrity, serving as early indicators of age-related disease risk or therapeutic intervention effectiveness. Recognizing the linkages between the gut microbiome, systemic inflammation, immune function, and age-related DNA damage, future research could explore synergistic approaches targeting inflammation, immunosenescence, and microbial dysbiosis comprehensively. This might involve developing lifestyle interventions, dietary strategies, or pharmacological agents that modulate both host and microbial factors implicated in aging. Promising intervention avenues are emerging from research on probiotic strains that reduce inflammation and promote DNA repair mechanisms.
However, several limitations should be acknowledged in the current body of research. While the exploration of the interplay between the microbiota and DNA damage holds great promise, the complexity and variability of the human microbiome across individuals presents challenges in drawing universal conclusions. Microbial composition can be influenced by a range of factors, including diet, lifestyle, genetics, geographic location, and environmental exposures, making it difficult to establish standardized biomarkers or treatments. Furthermore, most research on microbiome-DNA damage interactions has been conducted in preclinical models or under controlled conditions, which may not fully replicate the complexities of human aging. Translating these findings to humans requires careful consideration of confounding factors and the need for longitudinal studies to account for the long-term effects of microbiome alterations.
While advanced multi-omics technologies, such as metagenomics, metatranscriptomics, and metabolomics, provide powerful tools to study the microbiome and its role in aging, these approaches can be technically challenging and resource-intensive. The integration of large datasets across different omics layers also poses significant bioinformatics challenges, requiring sophisticated algorithms and computational models to discern meaningful relationships. Additionally, the precise mechanisms through which the microbiome influences DNA damage and repair remain underexplored. Despite promising correlations, causality has not yet been definitively established, and more mechanistic studies are needed to elucidate how microbial dysbiosis directly impacts genomic stability during aging.
Moreover, clinical trials investigating the role of the microbiome in DNA damage and aging are currently limited, and there is insufficient evidence to support therapeutic applications. Most studies to date have been preliminary or small-scale, and larger, well-designed clinical trials are necessary to substantiate the role of the microbiome in aging-related DNA damage. The lack of long-term, large-scale human studies and the challenge of controlling for confounding variables further complicate efforts to validate microbiome-based interventions for aging and associated diseases. Finally, the potential for therapeutic interventions—whether through probiotics, diet, or pharmacological agents—remains largely untested in the context of aging. While early studies suggest potential benefits, large-scale, long-term clinical trials are needed to validate these strategies and assess their safety and efficacy in diverse aging populations.
To this end, while this field holds significant promise for improving health during aging, further research, particularly through large-scale clinical trials, is needed to overcome these limitations and develop effective, personalized interventions that target the microbiome to preserve genetic integrity and promote healthy aging. As we continue to deepen our understanding of this intricate symbiotic relationship, new possibilities will emerge, presenting opportunities for innovative interventions aimed at improving health through precise adjustments to the microbiome. Drawing on insights from advancing research in this area, we are well-positioned to uncover strategies that enhance vitality and resilience throughout the aging process.
Conclusions
The microbiome’s subtle yet profound influence on DNA damage and aging unveils a complex and dynamic interplay that significantly governs human health and longevity. As aging progresses, the accumulation of DNA damage, coupled with a decline in repair mechanisms, accelerates cellular senescence, while alterations in the microbiome drive persistent inflammation and immune dysregulation. Dysbiosis, through its modulation of immune responses and exacerbation of chronic low-grade inflammation, emerges as a critical instigator of the aging process. The microbiome’s pivotal role in regulating DNA repair and inflammatory pathways—particularly through SCFAs and immune modulation—presents promising therapeutic avenues for mitigating age-related diseases. By fostering gut microbiome stability, we may enhance DNA repair mechanisms and attenuate the inflammatory cascade that accelerates aging. Targeted interventions, including microbiome-based therapies and dietary strategies, offer substantial potential to improve DNA repair, restore immune function, and ultimately promote healthier aging, thereby extending both healthspan and lifespan.
Declarations
Funding
This research is supported by Bandhan, Kolkata, India.
Conflict of interest
The authors state that they have no conflicts of interest regarding 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).