Part 1 Aging Series: Longevity Starts In the Gut

Microbiome diversity in older age is associated with reduced inflammation, and longer lifespan—suggesting gut composition as a key aspect of healthy aging.

Diet-driven modulation of the gut microbiome can extend healthspan by influencing immune function, nutrient metabolism, and disease resistance.

Centenarians are seen to display youthful and stable gut microbiota profiles, supporting the role of microbiome-targeted interventions in promoting longevity.

Changes in the gut microbiome as we age may influence healthy aging and longevity. Microbiome diversity is considered a “hallmark of aging” and the gut follows predictable patterns throughout life: rapid changes in early childhood, stability in middle age and accelerated shifts in late adulthood.

In a study analyzing genetic sequences and health data from over 9,000 people (including 900 older adults), researchers found that individuals with more unique microbiome changes in older age were healthier, more mobile and lived longer. This growing "uniqueness" was characterized by a progressive shift away from the common, core microbial composition typically shared by younger and middle-aged adults. Instead, the microbiomes of healthier older adults displayed a greater presence of rare, individual-specific bacterial taxa and a reduction in the prevalence of more universal species. These participants also had lower LDL cholesterol, higher vitamin D levels, and more beneficial blood metabolites, such as tryptophan-derived-indole, which reduces inflammation and promotes longevity (Wilmanski et al., 2021).

 The mTOR pathway is a central nutrient-sensing system that helps cells decide whether to grow and build new components or shift into maintenance and repair mode. It is especially activated when the body has plenty of nutrients, particularly amino acids.  (López-Otín, et al., 2013). Accordingly, mTOR has been implicated in many of the processes that are associated with aging, including aging at the cellular level, immune responses, cell stem regulation, autophagy, mitochondrial function, and protein homeostasis. 

Inhibition of mTOR has been shown to extend lifespan by improving stress resistance, promoting autophagy (natural cell removal), and suppressing inflammation. Gut bacteria like Escherichia coli K-12 reduce the toxic metabolite methylglyoxal (MG), which inhibits the TOR pathway, whose activity is often linked to increased cellular stress and aging when overactive. By reducing MG, these bacteria help prevent cellular damage and promote longevity. Inhibition of TOR activates DAF-16, which enhances stress resistance, autophagy, and cellular repair (Shi et al., 2024).

Thus, longevity may be linked to a more adaptable and stable gut microbiota, with successful aging marked by a healthy composition of core microbes and a proper regulation of pro- and anti-inflammatory responses. 

Healthspan is best described in comparison to lifespan. While lifespan refers to the total number of years a person lives, healthspan represents the portion of that life spent free from disease and chronic illness. The average gap between healthspan and lifespan is roughly 9 years.

The gut microbiome plays a key role in influencing healthspan due to its dynamic nature and ability to respond to dietary changes. Unlike the human genome, which is fixed at birth, the gut microbiome is highly adaptable, with rapid cellular turnover. This makes it a promising target for dietary interventions aimed at slowing or even reversing aspects of aging. Since the gut microbiome composition changes significantly in many age-related diseases, such as osteoporosis and arthritis (Paturel, 2024) modifying it through diet may help prevent or mitigate these conditions, thereby extending healthspan.

Research shows that diet is a stronger determinant of gut microbial composition than genetics, highlighting the potential of personalized nutrition to promote healthy aging. The interaction between diet and gut microbes regulates both the structure and function of the microbiome, which in turn influences the metabolism and bioactivity of food-derived compounds (Low et al.,2021). This diet-microbiome axis has a direct impact on organ function, immune response, and overall health.

Long-term adherence to healthy dietary patterns during mid-life is strongly associated with greater odds of healthy aging in later life, according to a large, 30-year follow-up study of US adults. The Alternative Healthy Eating Index (AHEI) showed the strongest link to healthy aging, with individuals in the highest adherence group having 86% greater odds of reaching age 70 in good health and 2.24 times greater odds of doing so by 75, compared to those with the lowest adherence. Other effective dietary patterns included the Mediterranean diet (aMED), DASH, MIND, and plant-based diets (hPDI and PHDI), all of which promoted better physical function, mental health, and reduced chronic disease risk (Tessier et al., 2025). 

Centenarians offer valuable insights into the link between gut microbiome and longevity. A study of 1,575 individuals (ages 20–117) in Guangxi, China, including 297 centenarians, found that centenarians had gut microbiome traits resembling those of younger adults. Their microbiomes were dominated by Bacteroides, showed greater species evenness, and were enriched with beneficial Bacteroidetes while lacking potential pathogens. Longitudinal analysis over 1.5 years revealed that centenarians with more even microbiomes experienced greater stability, while those with low evenness were prone to instability (Pang et al., 2023).

A study of Estonian centenarians revealed significant gut microbiota differences compared to younger adults. The centenarians’ diet, rich in starch, fibers, and polyphenols, was linked to higher levels of lactic acid bacteria and butyric acid-producing species, which promote gut health. Notably, centenarians had more Christensenellaceae, a family linked to longevity and lower cardiometabolic risk. A diverse gut microbiome, shaped by diet and lifestyle, may support healthy aging and longevity (Sepp et al., 2022).

Personalized dietary interventions that support a healthy gut microbiome could be a key strategy for extending healthspan and slowing down age-related decline. By tailoring diets to boost gut microbial diversity and encourage beneficial metabolic activity, it may be possible to promote healthier aging. One promising approach involves focusing on whole, minimally processed foods and complex carbohydrates. These foods spend more time in the large intestine (Low et al., 2021), which encourages gut microbes to shift from breaking down proteins to fermenting carbohydrates—a process linked to short-chain fatty acid production and furthermore regulation of important biological processes (Kim, 2023).

For example, a common personalized medicine approach, based on evaluating individuals' unique microbiota profiles, is key to optimizing weight loss efforts, which can be achieved by changes in the gut microbiome as well as aid in promoting a longer healthspan. Calorie restriction , which involves reducing caloric intake while maintaining optimal nutrition, is currently one of the most effective lifestyle interventions for extending healthspan, slowing biological aging, and enhancing quality of life (Kebbe et al., 2021). By assessing gut composition before starting a dietary regimen, interventions can be better tailored for effectiveness. Establishing clear links between specific microbes and dietary ingredients is essential for designing targeted, successful weight loss strategies (Hernández-Calderón et al., 2021). Microbiome-based interventions like prebiotics, synbiotics, and health-linked diets like longevity diets, aim to promote health, though their effectiveness varies based on an individual's microbiome composition.

Maintaining a healthy lifestyle with a diet rich in unrefined, natural foods, along with regular physical activity, can help restore and preserve a healthy gut microbiota, even in old age. Diets rich in fruits, vegetables, whole grains, unsaturated fats, nuts, and legumes—while low in trans fats, sodium, and red and processed meats—are key to promoting longevity and healthy aging (Tessier et al., 2025). This, in turn, promotes healthy aging and may delay the onset of age-related diseases.

Regular physical activity, ranging from low-intensity walking to more vigorous sports and resistance exercises, has been shown to be safe for both healthy and frail older adults. It significantly reduces the risk of major cardiovascular and metabolic diseases, obesity, cognitive decline, osteoporosis, and muscle weakness, making it a key component of successful aging strategies (McPhee et al., 2016).

Active ageing, as defined by the World Health Organization, is the process of optimizing health, participation, and security to enhance quality of life as people age. It emphasizes continued engagement in social, economic, cultural, and civic activities, not just physical activity or workforce participation. This approach promotes autonomy, independence, and intergenerational solidarity while recognizing the rights of older individuals to participate fully in society. Aging experiences vary, and fostering healthy choices throughout life can help prevent or delay major chronic conditions such as cardiovascular disease, diabetes, osteoporosis, and neurodegenerative disorders like Alzheimer’s and Parkinson’s. Preventing and managing these conditions reduces personal and societal burdens, improving overall well-being in later life (WHO, 2014).