The Novel Microbiome of Centenarians

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Introduction

Centenarians, or individuals over 100 years of age, exhibit relatively low susceptibility to inflammation-linked illness such as heart disease, arthritis, and certain cancers . A variety of factors contribute to this longevity, including a lack of genetically inherited disorders and beneficial diet and exercise choices earlier in life. Exercise and nutrition – as well as specific genetic differences, such as relative levels of growth factor present in adults – have been linked with ultimately determining an individual’s lifespan (CITE). Beyond these well-documented contributors to overall health, however, another key biological factor has recently been examined as a contributor to the medical resiliency of these long-lived individuals: their unique microbial gut composition. While aging is generally associated with a reduction in microbial diversity and a reduced ability to fight infection, analysis of the gut microbiome of centenarians has revealed specific trends in the relative abundance of consequential microbial species compared to the general population.

Due to developments in healthcare and quality of living, centenarians represent the most rapidly expanding age group in many regions, and are projected to exceed 3.5 million in number globally by 2050 . Because they live lives generally free of chronic ailments and severe medical conditions, centenarians often use fewer medical resources and incur fewer medical expenses compared to their counterparts who die an earlier death – making the study of centenarian microbiome features beneficial to not only individuals who wish to extend their lifespan, but to those who wish to reduce elderly contributions to hospital patient volume and insurance claims (CITE). Consequently, the unique features of centenarian microbiomes, as well as the gut changes that accompany aging and the time period that precedes death – have been recent areas of research, especially for the potential of artificially extending longevity through probiotic intervention.

The Gut Microbiome and Immune Implications

The human gut microbiome features a balance of both pathogenic and beneficial bacteria -- many of which perform critical daily functions in maintaining the body's metabolism and homeostatic ability. The shaping of this microbiome begins in infancy and embryonic development, when maternal nutrition, mode of delivery, and infant diet introduce several key flora (CITE). As one ages, chemicals introduced from diet, as well as repeated or improper use of antibiotics, have the potential to kill biome-balancing species and bring about immune havoc. WIth the gut being estimated as composing over 70% of the human immune system and production of a majority of the body’s antibiotics, the degree to which the gut is in balance is heavily consequential in an individual’s overall health.(CITE)

The gut microbiome plays a vital role in the immune response by nature of regulating a range of immune-associated elements. Namely, gut microbes are instrumental in producing B and T-cells, mucosal cells, and antimicrobial proteins including lectins and cathelicidins. (CITE) Certain bacteria accomplish a range of longevity-promoting tasks within the gut biome; for example, species such as _____ have the capacity to bind with carcinogens and interfere with the enzymatic conversion of molecules into carcinogens, support cancer-destroying cells, and suppress inflammation within the body (cite). In the realm of immune support, metabolic products of gut bacteria -- including these antimicrobial proteins and lactic acid -- are crucial components of a lytic defense against pathogenic bacteria. (CITE)

Generally, individuals have a single dominant bacterial genus -- Bacteroides, Prevotella, or Ruminococcus, as well as a variety of other viral and bacterial organisms in a highly unique biome (CITE). Deviations from the norm can result in health conditions associated with fluctuations or proportional shifts within the gut microbiome. For example, obesity is linked with a reduction of Bacteroidetes and an upregulation of Firmicutes; this causes an inflammatory response in host cells and can result in the development of metabolic syndrome (CITE). Furthermore, different strains belonging to the same bacterial family can have differing effects: Bacteroides ovatus abundance is linked with several health conditions, including diabetes and multiple sclerosis, while Bacteroides fragilis is linked with a decreased occurrence of these genes. (CITE)

In any study of the gut microbiome and its consequential health impacts, the highly individualistic nature of a person’s gut, immune, and environmental history ensures that there is not one standard model of a healthy gut. Certain bacteria strains may prove highly beneficial in certain environmental or dietary conditions and neutral in impact in others – for example, in those living in regions where diets are often high in carbohydrates, certain strains of bacteria may be more beneficial in the digestion of their everyday diet (CITE). Furthermore, those who are not genetically predisposed to certain gastrointestinal and immune conditions may not benefit from an increased presence of specific strains. A highly individualized blend of genetic, epigenetic, and other factors contribute to an individual’s microbiome and longevity – however, the preliminary study of especially long-lived individuals highlights several unique species that experience changes in abundance.

Consequential Species

The species composition that accompanies aging does not follow a linear trajectory; while people tend to maintain a relatively stable gut microbiome from ages 20 to 60, then experience a decrease in diversity–centenarians have adapted a novel composition that is not consistent with a decrease in diversity related to aging. While certain species–namely Ruminococcaceae, Lachnospiraceae, and Bacteroidaceae, do experience reductions in centenarians, individuals over 100 generally display an increased presence of 3 specific consequential species: Akkermansia, Bifidobacterium, and Christensenellaceae.

Akkermansia

Akkermansia is a gram-negative Verrucomicrobia bacteria which is capable of anaerobic respiration, and is frequently involved in the process of mucus degradation . It is capable of secreting an enzyme that downregulates specific inflammasomes, and creates metabolic products that contribute to the production of short chain fatty acids (SCFAs) – which aid in reducing inflammation, and are linked with a decreased presence of diabetes and irritable bowel syndrome . Akkermansia strains also have roles in stimulating goblet cell and macrophage production -- in addition to antimicrobial products and proper insulin secretion. Specifically, it regulated pancreatic lymphocyte production in rodents that mitigated the bodily impact of diabetes.

Because of the specific roles it plays in the body (and those the subsequent consequences of those roles for diseases such as diabetes, Akkermansia is linked with longevity and decreased presence of inflammatory gut-linked ailments found in centenarians. The presence of Akkermansia is typically correlated with a lower body weight (a trait common to centenarians, who typically do not suffer from high-weight related ailments), and studies involving the introduction of Akkermansia as a probiotic have shown potential in weight mitigation and diabetes prevention.

Bifidobacterium

Bifidobacteria is a gram-negative bacterium thought to be consequential in several gut linked health conditions -- namely, asthma and allergic disease . While an overall increased presence of Bifidobacteria is linked with centenarians, there are regional nuances regarding the most abundant strain; for example, while B. longum is the dominant strain of bifidobacteria amongst Italian centenarians, B. dentium is the prevalent strain amongst Chinese centenarians.

Bifidobacteria are thought to have immune stimulating potential, as well as to be linked with decreased cholesterol due to their ability to hydrolyze bile salts. They have been studied as a gut regulator of specific mental health conditions, with a reduction of conditions such as depression and anxiety when introduced with mice; furthermore, one strain, B. longum, demonstrated anti anxiety effects in subjects with stimulation of enteric gut neurons and subsequent pathways.

Because of their role in stimulating an uptake of T-cell activity in rodent tumors, Bifidobacterium are currently being studied as a mechanism of targeted tumor treatment. The increased presence of Bifidobacterium in centenarians may be partially contributory to the relatively low cancer rates – as well as lower rates of severe mental health conditions and their physiological consequences – in centenarians.

Christensenellaceae

Christensenellacae is a Firmicute bacteria -- the presence of which is considered highly genetic in nature, with an estimated 30-60% heritability amongst humans. Christensenellacae has been linked with decreased risk of Chrohn's disease and decreased risk of high visceral fat (a type of fat that heavily contributes cardiovascular health conditions). Additionally, adults diagnosed with colorectal cancer (globally, one of the most common types of cancers) exhibit decreased Christensenellaceae presence, although the specific biological mechanisms underlying the bacterial mitigation of this cancer are currently ill-understood and highly dependent on the type of mutation present.

Bacterium such as Christensenellacae, with a highly heritable component, may be contributory factors for centenarian “clusters” – i.e., why those with centenarian and long-lived relatives tend to have a higher chance of reaching the same advanced age. Christensellacae has also been shown to be highly responsive to higher levels of dietary fiber and protein – proliferating in response to beneficial dietary increases of these nutrients and subsequently aiding individuals in maintaining a lean body mass.

Clostridium scindens

One general area in which centenarians differ from the general population is bile acid synthesis and secondary metabolite presence. While many pathways of bile acid catabolism yield toxic byproducts, species found in centenarians are capable of synthesizing beneficial products linked with an increase in immune defense, Specifically, they harbor strains of Odoribacteracae effective at synthesizing isoalloLCA, a secondary bile acid associated with gram-positive pathogen defense and boosted immune ability.

One such bacterium is Clostridium scindens. Beyond synthesis of secondary metabolites that aid in a general increased immune response, Clostridium scindens is novel in its ability to convert inflammatory glucocorticoids such as cortisol to sex hormones. It accomplishes this by operon-induced synthesis of an enzyme capable of cleaving cortisol's side chain in aerobic condition, a relatively rare function for gut bacteria. This specific bacteria demonstrates a link between not only the novel gut microbiome of centenarians and the immune system, but between the microbial features and regulation of bile acid, stress-induced metabolic products, and hormones within the body.

Probiotic Upregulation of Healthy Aging

Supplementary probiotic intake has been linked with reducing a variety of deleterious conditions linked with aging and early death. However, because longevity studies involving probiotics involve an extensive timeframe and continual probiotic supplementation, data is both limited and difficult to achieve regarding which specific strains would be effective in extending one’s lifespan. Even so, the study of bacterial components of fermented foods and local longevity can provide some insight as to the potential dietary regulation of beneficial gut bacteria. The introduction of specific probiotic supplements and the balancing of an individual’s microbial fingerprint have been associated with a decrease in insulin resistance, ______, and even a decrease in the abnormal cells present in individuals with colon cancer.

Prebiotic fermentation within the gut microbiome consists of complex relationships between several species of bacteria; products synthesized by one species often act as substrates for other species. Although metabolism of proteins can result in toxic byproducts, many strains of bacteria are capable of degrading such byproducts and minimizing health impacts on host organisms.

Certain bacteria--such as B. subtilis--are being examined as potential pathways for extending human lifespans. In several invertebrate species,-introduction of B-subtilis has allowed for the formation of life-extending metabolic structures. Namely, it forms a biofilm that produces several molecules associated with anti-aging activity and reduces insulin receptor activity. These molecules trigger a pathway which eventually results in the upregulation of several longevity linked transcription factors, including DAF-16 and HSF. While current studies involving B. subtilis are largely confined to worms and flies, links between longevity clusters in areas wher B. subtilis is consumed (via natto in Japan, for example), suggest that longer studies involving humans will yield promising results.

Research has also linked the presence of specific probiotic species with improved memory retention and decreased stress on the brain; however, presently, these studies are largely confined to rodents. The species examined in these studies were primarily linked with dietary probiotic consumption, rather than a genetic difference resulting in varying gene transcription. For example, rodent exposure to Lactobacillus, a species present in a variety of milk based products, resulted in decreased levels of neurological disorders analogous to dementia in humans (CITE).

Difficulties in Studying the Centenarian Microbiome

With many studies focused on centernarians within the context of a “western” lifestyle (i.e. ________), it can be difficult to distinguish between consequential commonalities present within the cetenarian microbiome and the results of typical regional nutrition, exercise, and chemical presence. To account for this, researchers took the results of several studies done across multiple geographic areas–namely, Japan, Italy, and China–and examined which bacteria common to all centenarians were effective in separating the gut fingerprint of centenarians from their local younger counterparts.

In different locations, different metabolic elements were linked with varying levels of longevity. For example, while Chinese citizens displayed a direct correlation between high bile acid levels and longer lifespan, Italian elders displayed the inverse. Discrepancies such as these, in addition to evolving definitions of an “elderly” individual, make it difficult to categorize and identify commonalities and predictive factors of healthy aging.

Microbial Changes Prior to Death

When centenarians do eventually die, the microbial changes in their gut microbiome prior to death can provide an indication of when their physical decline began. In these relatively ailment-free elders, the period preceding death is often marked by sharp and rapid decline over the course of weeks and months, rather than an extended period of suffering – this decline is reflected by the simultaneous decline of several beneficial species of bacteria.

In a study of Hainan centenarians, researchers cataloged a reduction in ten key bacterial species that accompanied the three months preceding when individuals eventually did die. This period of time, which typically was accompanied by a sharp and sudden decline in food intake and physical capabilities, was accompanied by the reduction of several strains -- including alisipes, bacteroides, and bifidobacterium. When charted for a year prior to their deaths, these changes began their downward trajectory around seven months prior to death and often preceded the onset of noticeable symptoms.

However, the results of this study are highly limited in scope. This focused on a single region with a limited sample size of ___ centenarians. The rapid decline following a seven month inflection point in bacterial species abundance could also be reflective of general cultural and medical care practices involving end of life, and could differ in a region with differing care value.

Implications for the Future

The longevity of centenarians is linked with a variety of unique microbial gut features – namely, while certain key species are found in increased presence in the centenarian gut microbiome, others are reduced. The longevity-supporting composition of their gut microbiome is likely shaped by an optimal blend of genes, environmental circumstances, diet, and lifestyle choices; however, the centenarian microbiome offers insight as to beneficial dietary choices (such as supporting _____ growth through high protein/fiber choices and reducing sugar), as well as promising probiotics.

The use of probiotic intervention that models the centenarian dominant species composition may be an effective course of action in treating conditions such as obesity and diabetes, and increasing the overall lifespan of individuals. While it is impossible to perfectly identify or emulate the circumstances that contribute to centenarian’s longevity, probiotic supplementation or dietary support of important bacterial strains may be a first step in extending an individual’s lifespan through microbial intervention.

References

Sato, Y., Atarashi, K., Plichta, D.R. et al. Novel bile acid biosynthetic pathways are enriched in the microbiome of centenarians. Nature 599, 458–464 (2021). https://doi.org/10.1038/s41586-021-03832-5

Authored for BIOL 238 Microbiology, taught by Joan Slonczewski, 2023, Kenyon College