Can our gut microbiota be a firm of longevity? A day with a Centenarian… (Part II)

When asked how old you are, you likely answer based on the number of years that have passed since you were born. That represents your chronological age. This is the primary way people define their age. However, our physical appearance is not always the reflection of our age, since we can really feel older or younger than we really are. In fact, chronological age is just a number that counts the path of life since your birth, a calendar transcribed in your DNA. However, does the chronological age really represent you today? Try to do this exercise in front of the mirror and ask yourself about your biological age, the one which most likely reflects your current state of health, and ask: "how old do I feel?- How old am I?”

In the attempt to do this by myself, despite being 39 years old as chronological age, I can confidently say that I feel only 28 or 30 years on my back! I'll be optimistic maybe (??) but I am sure that my inflammatory, metabolic and fitness parameters can confirm it... what's still missing to investigate is my gut microbiota! Well, yes, because several recent studies confirm that the microbiota-longevity binomial exists and that aging in a state of health, compared to one of instability, changes the microbiota consortium significantly. Is it a cause or a consequence? Is it possible to act on our gut microbiota to move back the hands of time of our biological age?

Try to remember this, through your reading: “The first person to live to 150 has already been born” Dr. Aubrey de Grey (Biogerontologist).

We are indeed not far-fetched to move the hands of chorological time. Life expectancy will soon reach the 200 years, and we have to be ready to reconsider our health, food, lifestyle, sleep, exercise and overall habits in life, as well as including artificial intelligence in our daily routine… It is a fascinating story, called the “Longevity Revolution”, which deserves an in-depth, separate discussion (which I promise I’ll do!) following Dr Sergey Young’s forecasts.

Successful aging was defined by Rowe and Kahn’s model (1998) and includes the following five indicators:

1.??????no major diseases;

2.??????no disability;

3.???????high cognitive functioning;

4.???????high physical functioning;

5.???????active engagement with life

Successful aging is more than absence of disease, and even more than the maintenance of functional capacities. Both are important contributors to successful aging, of course, but it is their synergy with active, positive engagement with life and society that represents the full concept of successful aging.

The way we do age strictly depends on our choices and lifestyle and it is affected by the same things that control our biological or functional age: nutrition, drug abuse, alcohol, smoke, genetic, exposome environment, disease in life, physical activity, social life, stress management and meditation… and so on! The list is getting longer and longer thanks to the increasing scientific contributions to the longevity science, but for sure we can’t omit the gut microbiota’s interaction with our systemic health and its impact on aging. The basic idea behind biological aging is that aging occurs as you gradually accumulate damage to various cells and tissues in the body. It depends on several variables that are continuously changing, sometimes under human control, other times, not. While chronological age is a factor, a number, a predictable information, you may not end up having the same biological age as you age: you can grow older or younger, it is 90% your choice, responsibility, and interest.

Centenarians represent so far, the best model of successful aging. Demographic estimates suggest that there will be 3.7 million centenarians across the globe in 2050, between China, Japan, the United States, Italy and India (Santoro et al., 2018). The analysis of the gut microbiota of exceptionally long-lived individuals, or centenarians, is useful to deepen how the microbiota successfully adapts to their environmental (lifestyle, diet, community, etc.) as well as endogenous changes, contributing to the maintenance of metabolic, immunological, and biochemical homeostasis at the bottom of their long-term health and survival.

Centenarian vs Elderly: focus on lifestyle and gut microbiota

The human gut microbiota “metacommunity” is a highly diverse ecosystem made up of trillions of bacteria, archaea, eukarya and viruses, albeit mostly bacteria are populating the gastrointestinal tract. Over 1000 different microbial species, belonging to 5 predominant phyla, colonize our intestine: Firmicutes (Clostridium, Faecalibacterium, Lactobacilli, Ruminococcus) and Bacteroidetes (Bacteroides, Prevotella) followed by Actinobacteria (Bifidobacterium), Verrucomicrobia (Akkermansia) and Proteobacteria (Escherichia, Helicobacter, Shigella). Bacteroidetes and Firmicutes are the most abundant, representing over 90 % of gut microbes (Santoro et al., 2018). Sequencing analyses of human fecal metagenomes from four countries (Danish, French, Italian and Spanish individuals) identified well-defined and robust microbial communities (enterotypes) represented by different levels of three genera: Bacteroides, Prevotella and Ruminococcus (Arumugam et al., 2011).

The enterotype-based classification however is still debated, and it has not been identified in a large study of healthy and frail elderly people, where diet was assumed to be the main drive of microbial classification (Claesson ?etal., 2012). According to the authors, the microbiota of older people displays greater variation than that of younger adults, while the individual microbiota of people in long-stay care was significantly less diverse than that of community residents. Loss of microbiota diversity correlated with increased frailty. ?Frailty has been negatively associated with microbial diversity, and Eubacterium dolichum and Eggerthella lenta have been found to be more abundant among ?frail individuals, while Faecalibacterium prausnitzii was ?less abundant, determining a signature of frailty (Jackson et al., 2016).

The study of Biagi and colleagues on Italian centenarians (99–104 old), and semi-supercentenarian (105–109 old) suggested the presence of a different core microbiota dominated by Ruminococcaceae, Lachnospiraceae and Bacteridaceae families, which decreases with aging (Biagi et al., 2016). Independent studies on Chinese centenarians revealed a negative association between extreme aging and the abundance of Coprococcus, Roseburia and Faecalibacterium genera, belonging to the Lachnospiraceae and Ruminococcaceae families (Wang N, et al. 2019; Kong F, et al 2016).

Both the Italian and Chinese study on centenarians showed how longevity increases microbial community richness (Chao index and observed operational taxonomic units, OTUs) and the abundance of subdominant but health-related bacterial genera and families, such as Oscillospira, Christensenellaceae, Akkermansia and Bifidobacterium (Biagi et al., 2016; Kong et al., 2016). In another study on Sardinian Centenarian from Wu et al., (2019), an enrichment of Methanobrevibacter and Bifidobacterium was detected, in agreement with a previous study on another Italian cohort, in the Emilia Romagna (Biagi et al., 2016). However, the enrichment of Methanobrevibacter and Bifidobacterium was not found in the Sichuan and Guangxi cohorts in China or in a national Japanese cohort and a Manipur, Indian cohort (Tuikhar et al., 2019; Kong et al., 2016). Conversely, Akkermansia was detected in abundance in the centenarians from Emilia Romagna, Italy, and Manipur, India (Biagi et al., 2016, Tuikhar et al., 2019), but not in the centenarians of Sardinia in the cohort of Wu et al., (2019) and in the Guangxi, China cohort (Wang et al., 2015).

Does this consortium of bacteria contribute to the healthy aging typical of Centenarian?

It presumably contributes to a healthy state of the elderly cohorts because Oscillospira and Christensenellaceae control leanness and decrease certain inflammatory diseases in humans (Konikoff et al., 2016; Waters et al., 2019). Akkermansia muciniphila and its outer membrane protein Amuc_1100* also stimulate intestinal epithelial cells to induce mucus production and thus protects the intestinal epithelial integrity avoiding the risk of metabolic endotoxemia and circulating LPS, supports beneficial SCFA (short chain fatty acids)-producing bacteria and counteracts inflammation and metabolic impairments such as insulin resistance (Schneeberger et al., 2015). It does so as a consequence of oligosaccharides release from the mucus layer, feeding synergistic bacteria and inducing butyrate production from Anaerostipes caccae, Eubacterium hallii, and Faecalibacterium prausnitzii. Interestingly E. hallii upregulates vitamin B12 to stimulate propionate production from A. muciniphila in a vicious cycle which feed it upstream. Bifidobacterium generates lactate and acetate, drastically reducing pro-inflammatory bacteria. The Bifidobacterium genus dominance declines after the first year of infancy where it is the dominant genera due to the abundance of human milk oligosaccharides (HMOs) in infant diets, which Bifidobacterium species utilize and convert into lactate and acetate. Their presence decline with time, when the diet of the infant ?start to be more solid and varied, and intestine colonization with other microbes is facilitated and the microbial diversity increases. However, in centenarians their presence rises up again, in particular the species B. longum and B. adolescentis. B. adolescentis presence in centenarians suggests a possible association between gut microbiota and inflammatory status in the gut of centenarians because it has been shown to directly influence Th17 cell generation (Wu et al., 2019). However, it also has a positive synergy with Anaerostipes caccae and Faecalibacterium prausnitzii, both butyrate-producers, starting from lactate and acetate respectively. Butyrate improves the intestinal epithelial cells barrer protecting them from C. difficile toxin through the activation of the hypoxia-inducible factor 1α, at least in animal model (Fachi et al., 2019). This probably explains why the gut of centenarians shows high levels of butyrate and hosts increased variety of the butyrate producers such as Anaerotruncus colihominis (from Clostridium cluster IV), Eubacterium limosum (from Clostridium cluster XV), Bifidobacterium and other the health-associated bacteria, such as Akkermansia and Christensenellaceae (Ragonnaud et al., 2021).

All SCFAs are very important for human health. They provide energy to commensal microbes, immune cells, and the colonic epithelium. They induce production of the natural mucus, strengthening the epithelial barrier functions; they support the growth of various beneficial commensal microbes, and promote immune tolerance and gut homeostasis. SCFAs also regulate immune responses by directly stimulating immune cells. They are essential for human systemic health, and they relative abundance in centenarians can easily explain their healthy aging (Ragonnaud et al., 2021).

Wu et al., (2019) found a reduced capacity of carbohydrate and dietary fibre metabolism in Sardinian Centenarian. Their results revealed that the relative abundance of the pathways related to carbohydrate degradation was similar for the elderly and young groups but significantly lower in the centenarians. The only exception was the starch degradation pathway III, adopted by Archaea, who could contribute to the ATP generation. Interestingly, the galactose degradation related pathways were also extremely low in the centenarian. The increased SCFA production via glycolysis as well as amino acid fermentation in the centenarian gut microbiota could be a pivotal beneficial factor for healthy aging and contribute to longevity. Moreover, their metabolic machinery is enriched in microorganisms that can generate unique secondary bile acids, including various isoforms of lithocholic acid (LCA): iso-, 3-oxo-, allo-, 3-oxoallo- and isoallolithocholic acid (Sato et al., 2021). The authors of a study on Japanese centenarians identified Odoribacteraceae strains as effective producers of isoalloLCA, both in vitro and in vivo, by screening 68 bacterial isolates from the faecal microbiota. Interestingly, IsoalloLCA reported potent antimicrobial effects against Gram-positive multidrug-resistant pathogens, such as Clostridioides difficile and Enterococcus faecium. Their abundance in centenarians seems to play a pivotal role in reducing the risk of infection with pathobionts, meanwhile contributing to the maintenance of intestinal homeostasis (Sato et al., 2021).

Does the Mediterranean Lifestyle intervention shape the gut microbiota in the path to longevity?

As a microbial ecosystem and additional endocrine organ (as a new emerging definition), the gut microbiota can respond and adapt its community members and functional pathways to external stimuli such as diet, environment, lifestyle, antibiotic treatments, cultural habits, ethnicity, biography, genetic background and stress. Its plasticity is pivotal to optimize the metabolic and immune performance of the host in response to environmental and physiological changes, such as immunosenescence and “infammaging”, the chronic low-grade inflammatory status typical of the elderly that strongly impact host health and quality of life.

Diet is a pivotal factor that regulates the gut microbiota. In elderly, diet could differ substantially from the young and elderly’s habits due to physiological changes. Either reduced gastrointestinal tract function and compromised ability to masticate certain foods may alter food preference and eating habits (Wu et al., 2019). A reduced ability to taste and smell may also alter food preferences. In agreement with this assumed risk, the pathway analysis on Sardinian centenarian specifically reported a lower abundance of genes encoding components of pathways involved in degradation of dietary fiber such as starch, pectin, and cellulose (Wu et al., 2019). The poor capacity for fiber degradation suggests that the dietary fiber-deprived gut microbiota in an extreme-aging population may contribute to the risk of inflammation and gut barrier disruption. Normally, in elderly people, the level of SCFAs from carbohydrate fermentation is decreased while metabolites from protein fermentation (branched fatty acids, ammonia and phenols) are increased, as a proof of a shift from saccharolytic fermentation to more proteolytic activities. This change can be further accelerated upon the use of antibiotics or with low-fiber diets (especially in assisted healthcare housing for elderly people). However, as reported for the Sardinian centenarians, some alternative metabolic pathways can move on, to confirm their capacity to generate SCFA, such as glycolysis and related pathways, pyruvate fermentation to propionate, and lysine fermentation to acetate and butanoate, as well as an increase in the anaerobic energy metabolism pathway (releasing propanoate and acetate). That is why the centenarian gut microbiota is not poor in genes encoding components involved in glycolysis and SCFA production, although being deficient in carbohydrate degradation genes. The high abundance of B. adolescentis, M. smithii, Escherichia, and Lactobacillus well support this working model in a taxonomic view.

Interestingly, but somewhat contradictory to as previously mentioned in the study of Wu and colleagues, ?Ghosh et al., (2020) observed that increased adherence to the Mediterranean Diet in elderly (65–79 years) during 1 year intervention and across 5 European Countries?(UK, France, Netherlands, Italy and Poland), modulates specific components of the gut microbiota that were associated with a reduction in risk of frailty, improved cognitive function and reduced inflammatory status (C-reactive protein and IL-17). Inferred microbial metabolite profiling indicated that the diet is the main drive of the microbiome change, promoting an increase in SCFA production and decrease of secondary bile acids, p-cresols, ethanol and carbon dioxide, all deleterious metabolites. On a global basis, the majority of elderly people do not consume a Mediterranean Diet and, in fact, a major challenge in elderly healthcare is the consumption of a restricted diet which is associated with a low-diversity gut microbiome, especially in subjects in long-term residential care. Adherence to the NU-AGE MedDiet (Berendsen et al., 2018) was characterised by an increase in the consumption of fibres (vegetables, fruits), carbohydrates (wholegrains), plant proteins (legumes), polyunsaturated fatty acids (fish), vitamins such as vitamin C (fruits) and a concomitant decrease in the consumption of fats, alcohol, sodium and sugar (sweets). The OTUs associated with a high adherence to the diet, were mainly assigned to Faecalibacterium prausnitzii, along with Roseburia (R. hominis), Eubacterium (E. rectale, E. eligens, E. xylanophilum), Bacteroides thetaiotaomicron, Prevotella copri and Anaerostipes hadrus. These bacteria can be associated to a major production of SCFAs and antiinflammatory markers, while a negative association can be seen with diseases like type 2 diabetes and colorectal cancer.

Several evidence suggests that important principles of the Mediterranean Diet (or better calling it Mediterranean Lifestyle?), such as the moderate protein consumption, low glycemic index, and abundance of fibre-rich foods and polyphenols, may promote healthy aging through positive, synergistic effects on nutrient sensing pathways. A whole diet, devoid of refined flours and processed, industrial food is always a precious source of antioxidants, macronutrients and micronutrients that we cannot afford otherwise (Donati Zeppa et al., 2023). The Mediterranean Diet can greatly affect senescence and related aspects, at a cellular and molecular level, laying the foundations for a healthy, worth-living aging.

Moving back to our initial question: Is it possible to act on our gut microbiota to move back the hands of time of our biological age?

I think we can easily say, we can, through dietary and lifestyle intervention, precision probiotic intake as biotherapeutic agents, and daily activity outdoor. The gut microbiota consortium can be shaped according to our dietary habits and social environment as the study of NU-AGE MedDiet confirmed. Being aware of its impact on health already in an early stage of life will allow to take the right corrective measures (both in diet and lifestyle) towards the path of longevity. According to me, a day with a centenarian is the best prescription ever!

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