Microbial Imbalance as a Roadblock to Longevity: A Review

In the past, research aimed at comprehending and enhancing human lifespan has concentrated on genetic, metabolic, and environmental factors associated with aging, alongside significant social determinants of health such as Socio-Economic Status (SES), dietary quality, and healthcare access [1-5]. Although these elements continue to be crucial, new studies emphasize the gut microbiome as a significant and modifiable factor impacting healthspan-a vital component influencing human longevity [6-10]. This vibrant and diverse microbial community is vital for maintaining immune homeostasis, metabolic equilibrium, and cognitive capabilities-key physiological functions that are especially vulnerable to the impacts of aging [11-13]. Microbial dysbiosis-characterized by reduced diversity and the loss of beneficial microorganisms-has recently been identified as a significant factor contributing to age-related deterioration, receiving growing acknowledgment from researchers [14-17]. It impacts several hallmarks of aging, such as genomic instability, the shortening of telomeres, dysfunction of mitochondria, and the loss of proteostasis, thereby amplifying its far-reaching influence on the aging process [18-20]. Additionally, dysbiosis, which is characterized by diminished microbial diversity, a reduction in commensal and beneficial species, and an increase in opportunistic pathobionts, contributes to the persistence of a chronic, lowgrade inflammatory state known as inflammaging, which is significant in various age-related conditions, including Neurodegenerative Diseases (NDs), metabolic disorders, and immune dysregulation [21-25]. Disrupting the interconnected systems associated with the hallmarks of aging, dysbiosis diminishes physiological resilience, hastens the decline of healthspan, and obstructs the compression of morbidityultimately leading to a shortened lifespan [14-16,26,27]. As awareness of the gut microbiome’s function as a crucial regulator of systemic aging increases, its significant potential as a target for therapies aimed at fostering healthy aging and preventing agerelated diseases is considerable [28,29].

Traditionally viewed as having a passive role, the human gut microbiome is now recognized as an active and crucial regulator of host physiology, influencing a range of biological functions throughout an individual’s life [30,31]. The development of microbial colonization in the gut and the interactions between the host and microbiota start in the womb, shaped by maternal influences such as diet, metabolic health, psychosocial stress, and the transfer of microbial components and metabolites via the placenta [32-34]. Following birth, the gut microbiome continues to develop, influenced by factors like the delivery method (vaginal or cesarean), breastfeeding habits, antibiotic consumption, and early dietary selections [35,36]. Compounds produced by gut microbes from the diet, including Short-Chain Fatty Acids (SCFAs) and polyphenol derivatives, are crucial in directing the host’s epigenetic programming, affecting gene expression, and impacting long-term disease susceptibility [37-39]. During childhood, adolescence, and into early adulthood, the gut microbiota generally develops into a state marked by high diversity, metabolic adaptability, and ecological stability [40,41]. It forms the basis for crucial functions that affect and regulate the development of the immune system, uphold the integrity of the intestinal epithelium, hinder the establishment of harmful pathogens in the gut, and aid in maintaining energy balance [42,43]. The stability of microbial communities strengthens the host’s capacity to cope with both internal and external stressors, facilitating the preservation of homeostasis and fostering health during early and midlife stages [44,45].

The gut microbiota, which was once a resilient and varied ecosystem, undergoes changes with aging, a phenomenon referred to as dysbiosis [14-17]. In older individuals, helpful gut bacteria that generate SCFAs, including butyrate-such as Faecalibacterium prausnitzii and some Roseburia species-are typically diminished, whereas pro-inflammatory members of the Enterobacteriaceae family increase in number [46-48]. The alterations in microbial diversity linked to aging are now understood as significant factors in physiological deterioration, rather than just a byproduct of the aging process [49,50]. Importantly, the gut microbiome that develops with age can affect the host’s epigenetic environment by changing the availability of microbial metabolites-such as SCFAs, folate, and polyamines-which are critical cofactors for epigenetic enzymes like Histone De Acetylases (HDACs) and DNA Methyl Transferases (DNMTs) [51-53]. By influencing DNA methylation patterns, histone Post-Translational Modifications (PTMs), and the expression of non-coding RNAs (ncRNAs), changes in the gut microbiome associated with aging can lead to long-term epigenetic reprogramming in host cells [54,55]. This process may reinforce dysfunctional cellular states, contributing to the functional decline associated with aging. The ongoing reprogramming of gene expression results in a pro-inflammatory state characterized by a mild but chronic inflammation, referred to as “inflammaging,” which destabilize immune equilibrium and increase susceptibility to various diseases linked to aging [22-25]. Furthermore, metabolites produced by the microbiome, such as polyamines, bile acids, and tryptophan catabolites, influence the host’s aging by affecting crucial nutrient-sensing and longevity pathways like mTOR (Mechanistic Target of Rapamycin), sirtuins, and AMPK (AMP-Activated Protein Kinase) [56,57]. Consequently, the microbiome plays a dual role as both a metabolic integrator and an epigenetic modulator, actively influencing the aging process in response to environmental factors and signals originating from the host [58-60]. The imbalance in the communication between organs mediated by the microbiome increases the likelihood of metabolic disorders and NDs, partly by dysregulating the Gut-Brain Axis (GBA) [61-63]. Additionally, disturbances in the gut-heart axis have been associated with Cardio Vascular Diseases (CVDs) [64-66]. Emerging research indicates that changes in the microbiome may worsen dysfunction in various organ systems through the gut-lung and gut-pancreas-liver pathways, highlighting the widespread effects of microbial imbalance [67-70]. To summarize, changes in the microbiome related to aging have a significant impact on the physiology of the host by both sensing and modulating age-associated biological processes. In essence, functioning as a persistent epigenetic modulator, the microbiome has the ability to alter gene regulatory networks, which increases the host’s vulnerability to various chronic diseases associated with aging.

Historically, changes in the gut microbiome linked to aging were mainly viewed as effects of natural aging processes and chronic diseases. However, an increasing number of longitudinal studies in humans, along with interventional experiments in animals, suggest that gut dysbiosis serves both as a cause and a consequence, affecting key features of the aging phenotype [30- 71]. Rodent studies suggest that shifts in the composition of gut microbial communities precede the onset of cognitive decline [72], immunosenescence, and metabolic dysfunction-signs of aging [73,74]. Notably, these age-related impairments appear to be at least partially reversible through the restoration of microbial homeostasis [75,76]. Transferring fecal microbiota from younger mice to older ones via a method called Fecal Microbiota Transplantation (FMT) has demonstrated the ability to restore the integrity of the intestinal barrier, lower systemic inflammation, stimulate neurogenesis in the hippocampus, and improve cognitive abilities, especially those associated with learning and memory [77-82]. Notably, these results are relevant beyond just preclinical studies. In human observational studies, certain microbial profilessuch as a decrease in the quantity of SCFA-producing bacteria (for instance, Faecalibacterium prausnitzii and Roseburia spp.) alongside an increase in pro-inflammatory pathobionts (like Enterobacteriaceae)-have been strongly linked to age-related issues, including frailty, sarcopenia, systemic inflammation, cognitive decline, and multimorbidity [83-86]. Specifically, gnotobiotic mouse models, which are free from microorganisms and are populated by targeted microbial communities, have produced causal proof for these connections [87-89]. Introducing gut microbiota from elderly or frail human donors to Germ-Free (GF) mice results in signs of inflammaging, increased gut permeability, and neurocognitive deficits in otherwise young hosts, demonstrating that ageassociated microbial profiles are not merely byproducts of host aging but actively contribute to biological decline [48-90].

Research on healthy centenarians, especially those living in longevity hotspots such as Okinawa [91] (Japan) and certain regions of Italy, has uncovered specific microbial patterns that correlate with the maintenance of physiological function in older age [92-94]. These individuals generally exhibit a high presence of SCFA-producing and anti-inflammatory bacterial species like Akkermansia muciniphila, Christensenella, and Bifidobacterium spp., as well as other unique microbes such as Odoribacter and Subdoligranulum, which are associated with preserving mucosal integrity and immune balance [95-97]. The characteristics associated with the microbiome are thought to contribute to a systemic state of low-grade inflammation and enhanced metabolic robustness, both of which are indicators of healthy aging, marked by preserved physiological functions and a lower incidence of diseases in elderly individuals. Furthermore, studies focusing on older adults have shown that modifying the gut microbiome-through increased consumption of fermentable fibers, diets abundant in polyphenols, or specific probiotic use-can boost microbial diversity, increase the production of SCFAs, improve metabolic indicators, and lower inflammatory markers in the blood [98-100]. Indeed, multiple lines of evidence from observational research, animal model studies, and interventional trials suggest that gut dysbiosis is not simply a byproduct of aging but rather a changeable factor that plays an active role in the decline of physiological function associated with aging [101,102].