Currently, adults 60 years of age or more outnumber children under 5 years of age, and by 2050 adults ages 60+ are expected to outnumber adolescents and young people between the ages of 15 and 24 (1). As the pace of ageing population continues to accelerate, the United Nations General Assembly has declared 2021–2030 as the “Decade of Healthy Ageing.” Healthy ageing is defined as developing and maintaining the functional ability that enables well-being in older age (1). Ageing is inevitable and happens at both cellular and molecular levels. It is a complex process and manifests itself differently in different individuals. Human lifespan and health span are determined by various factors, including genetics, epigenetics, diet, and lifestyle (2). There is accumulating evidence suggesting a healthy lifestyle in early years is critical to maintaining health and curtailing the risk of age-related disorders later in life.
The human gut microbiome is increasingly being studied as an important contributing factor of healthy ageing due to its key role in both physical and mental health. The human microbiome is a complex ecosystem, and due to its critical role in human biology, it is sometimes referred to as a separate virtual organ. A healthy gut microbiota plays a key role in overall health and its microbial diversity is linked to several human diseases. A higher microbial diversity in the gut is associated with a healthier microbiota (3) while low diversity is linked to various disorders including obesity and gastrointestinal pathologies like inflammatory bowel disease (4). The diversity of microbes can be defined as the number and distribution of distinct types of organisms within the body. The gut microbiota of the elderly differs in composition and diversity from young and middle-aged adults (5) and this shift is described as one of the primary causes of ageing-related disorders. The composition and diversity of gut microbiota is influenced by several factors, such as diet, physical activity, geography, and general lifestyle.

The human microbiome has a symbiotic relationship with its host. Diet is a critical modifiable factor for optimal health. Adherence to a healthy and balanced diet plays a major role in maintaining a lower frailty index. Diet is also a known modulator of gut microbiota, its composition, diversity, function, and metabolism activity (6). The overall output of microbial metabolites is significantly dependent on the intake of dietary components. The microbial metabolites include short chain fatty acids (SCFAs), neuroactive molecules, vitamins, epigenetic factors, hormones, neurotransmitters, and probably hundreds of other unidentified factors (7). These metabolites are known to influence both local intestinal tissues and peripheral tissues via various bidirectional communications referred to as gut-brain axis, gut-muscle axis, and gut-skin axis to name a few (8). It is estimated that approximately 10% of energy from diet is obtained due to gut microbial fermentation and subsequent short chain fatty acid production (9).
There is a linear relation between physical activity and health of an individual. Physical activity in older age may not only help prevent and mitigate falls, but also health conditions like sarcopenia, osteoporosis, and cognitive impairment, promoting healthy ageing (10). Studies indicate a bidirectional relationship between exercise and the gut microbiota composition (8). Exercise during older age can also assist with optimal composition of the gut microbiota in addition to improving cardiovascular fitness (11).   

Changes throughout the lifespan

Core gut microbiota is known to change during old age. Increase in biological age results in a reduction in overall gut microbiota richness, while advancing chronological age increases phylogenetic richness with more diverse gut microbiota (12). Measuring biological age has been proposed as an important factor in ageing. Figure 1 depicts the changes in host when the core microbiota shifts (12). When biological age is used with adjustment for chronological age, the microbiota richness decreases and results in increased gut dysbiosis and ultimately unhealthy ageing (12).   During ageing, there is an attenuation of Bifidobacterium and Lactobacilli species which are crucial in health maintenance (13). Reduced abundance of healthy microbes may open space for opportunistic pathobionts. Akkermansia, Bifidobacterium, and Christensenellaceae in the gut have been associated with longevity (14). 

Gut dysbiosis

The gut microbiome and its metabolites that act as cofactors in various pathways can directly influence epigenetics (15). Microbial dysbiosis, which is a result of altered microbiota, impacts ageing and is linked to various diseases.  A few of those maladies include obesity (16), diabetes (17), cancers (18), inflammatory diseases (19), and cardiovascular diseases (20). It is also implicated in the diseases of the central nervous system such as Parkinson’s (21). A decrease in Bifidobacteria has been postulated as one of the prominent factors in a variety of health disorders (22) suggesting its importance in health. Today, Bifidobacterium probiotics are widely used for health management through dysbiosis rectification. Obesity can cause inflammation and impair the intestinal epithelial integrity by shifting the microbial composition in the gut (23). The microbial changes in obesity are also known to occur in ageing and are the prime cause of various pathologies and disorders including frailty, diabetes, cancer, cardiovascular disease, and neurodegeneration (23). 

Immunity and inflammaging

It is believed that the development of immune functions and gut microbiota may be mutually dependent and influenced by each other. The microbiota is fundamental in induction, training, and function of the immune system , and this starts at birth (24). Early life immune-microbiota interactions have long-lasting impact on health later in life (25). The strong link between gut microbiome and immune system has already formed the basis of microbiome-mediated therapeutic strategies in immune-mediated diseases. For example, fecal microbiome transplantation has been used as a potential treatment to restore a healthy microbiome in Clostridium difficile infections (25). 
Age related immune dysfunction or immunoscence compromises both innate and adaptive immune responses, which play a primary role in chronic low-grade inflammation or inflammaging (26). This is associated with elevated pro-inflammatory cytokines that lead to a higher risk of morbidity and mortality. They are also indicative of various organ specific, age-related physical and cognitive disorders such as sarcopenia, osteoporosis, type 2 diabetes, atherosclerosis, dementia, Alzheimer’s disease, and Parkinson’s disease (27,28). Interleukin-6 (IL-6) is the proinflammatory cytokine that is most associated with ageing. It is significantly increased in the elderly (29) due to aged biome and accounts for increased susceptibility to infections and various phenotypic changes of ageing (30). 

Mental and cognitive health

There is mounting evidence implicating the role of gut microbiota in central nervous system disorders. Gut dysbiosis is associated with a decreased level of brain-derived neurotrophic factor (BDNF), which can be regulated by butyrate, a metabolite of gut microbiota (31). Reduced levels of BDNF are directly linked to depression and brain stress (32). Impaired microglia cells are linked to neurodegeneration and several central nervous system disorders (33). Responsible for regulating brain development, maintaining neural network, and repairing injuries, they are pivotal in neuroinflammation modulation (34). Animal studies have demonstrated regulation of microglia cells by the gut microbiota, where age-related impaired gut barrier can influence microglia dysfunction (35). Chronic inflammation, which is influenced by the gut microbiota, is also considered as an important risk factor in the pathogenesis of mental disorders (36). Imbalance in the gut microbiota is associated with impaired cognition (37). The microbiome-gut-brain-axis may be able to explain the pathogenesis of various psychiatric disorders including depression (31). It is one of the most studied pathways that highlights the constant communication between the gut and the brain to modulate cognitive function in ageing. Cognition is important for functional independence, especially in older age. Cognitive abilities are believed to weaken with age. Based on current cumulative evidence, it can be determined that a healthy gut microbiota may potentially play a role in decreasing the rate of age-related cognitive decline. 

Telomeres and microbiota

Ageing is also linked to the length of telomeres. Telomeres are at the end of chromosome and are vital in its structure and function. With each cell division, telomeres shorten in length and progressively shortening telomeres are linked to activation of DNA damage and cell senescence. The rate of telomere shortening may suggest the rate of ageing (38). Diet and lifestyle are well studied factors that impact telomeres (38). Similar to the microbial diversity and population, there are various factors that are implicated in negatively impacting the telomeres, such as obesity (38), stress (39), depression (40), smoking (41), environmental pollution (42), and gut dysbiosis (43), thus directly affecting the rate of ageing. 
Targeting telomere shortening in the gut during ageing may potentially be a strategy to extend life and health span (44). Telomerase is an enzyme that can counter telomere shortening (44). Expression of telomerase in the gut to counteract systemic ageing has been successfully studied in zebrafish. Not only was telomerase able to reduce inflammation to restore a healthy gut environment, but its positive impact was also extended to other organs via the gut (44). Physical activity and exercise have been strongly connected to preserved telomeres (45). Exercise increases the biodiversity of gut microbiota and reduces telomere attrition in addition to decreasing inflammation and oxidative stress, further highlighting the interconnectedness of these factors in health and ageing (46). Antioxidants can help prevent oxidative damage that leads to telomere shortening (49). A diet rich in vitamins C and E and beta-carotene is linked to longer telomeres (47). 
In addition, omega 3 fatty acid consumption is associated with reduced telomere attrition (48). Omega 3 fatty acids have also been found to significantly impact the intestinal environment and gut microbiota composition. These polyunsaturated fatty acids have shown a positive influence on the gut-brain axis, acting through gut microbiota composition (49).

The microbial ecosystem is fundamental to life and health. Ageing is largely associated with inflammation and immune system dysfunction. The ability of gut microbiota to influence proinflammatory cytokines to control inflammation indicates its critical role in ageing. The gut microbial diversity decreases with ageing, contributing to various age-related disorders. This directly implicates the role of gut microbiota in a longer lifespan. A compromised intestinal barrier has a negative effect on nutrient absorption and pathogen defense, both of which can lead to an array of health disorders. Gut dysbiosis disrupts the microbial communication with the host, which is associated with both age- related physical and cognitive health decline. It is also implicated in telomere shortening, thus negatively impacting longevity. 
Based on our current scientific understanding, there is an untapped potential in the human gut. There is substantial data that suggest that our intestinal microbiota can be exploited to promote health, hence the rapidly advancing commercially available biotics. Continued clarity of the microbiome and its overall impact on the host and vice versa will present various opportunities to shape host health and design effective therapeutic strategies, potentially for a longer life and health span. A lot of questions remain unanswered: What does the “core set” of microbiota in its healthiest form look like? Can the microbiome be successfully modulated early in life to maximize chances of a healthy and disease-free life? This begs the question, does the answer to healthy ageing lie in a healthy ageing gut?