Buettner’s 20-year longevity research led him to identify the world’s five blue zones described as “communities whose elders live with vim and vigor to record-setting age”. Some of the answers may also lie deeper within – in the unique gut microbiome composition of these blue zone centenarians, converting them into potential gold mines (or, in this case, bacteria, fungi and virus mines) of information.
The ongoing quest to unravel the secrets behind long and healthy living converges with reports that U.S. life expectancy is declining at a historic rate. Beyond mainstream media, the scientific community continues to explore the possibilities of reverse-engineering aging or at least of understanding what may prove to be a more complicated paradigm.
NutraIngredients-USA caught up with Mark Haupt, MD, chief medical officer at International Flavors & Fragrances (IFF) Health – who led off the session “Aging: What can we learn from centenarians?” at this year's Probiota Americas Conference – to find out more about whether the centenarian microbiome could indeed be the fountain of youth.
NIU: How did you become interested in the centenarian microbiome?
MH: When considering opportunities to improve healthspan (not just lifespan), we need to consider sources of unique insights that can help us understand where health-related factors could go wrong, and then to assess which elements are modifiable, measurable, or simply differentiated. Evaluating opportunities that impact health and wellness through the lens of aging, immediately presents two unique sources of insights: infants/children and centenarians.
To evade the typical age-related morbidities (i.e., cardiovascular disease, diabetes, etc.), centenarians could possess a unique physiology to extend both their health and lifespan. Centenarian populations tend to cluster in unique communities and environments, which informs broader thinking about nutrition, social engagement, community and other components of health and wellness – all of which really sparked my curiosity to see what can be learned from this truly remarkable population to enable health in others.
NIU: What can we learn about the mechanism of aging from the microbiomes of centenarians? (Does the diverse microbiome translate to a unique composition of immune cells for example in a healthy centenarian microbiome?)
MH: Globally, the microbiota of centenarians is more diverse compared to young or even elderly populations. There also appears to be a clear reduction in the abundance of core taxa. The specific makeup of the changes in the diversity varies, and may be influenced by host factors, diet, environment, etc. Included in that diversification is the increase in pro-inflammatory or less health-associated organisms.
This increase, however, is balanced by an increase in health-associated organisms, meaning, balance of the entire system is maintained. This is akin to what is seen with inflammatory markers in the blood. Beyond this balance, there are clear metabolic differences seen in the microbiome of the centenarian population, such as an increase in activity of metabolic pathways related to short chain fatty acid (SCFA) fermentation.
We also see a change in the resilience of centenarians with diverse microbiota in the setting of viral illnesses. This shows that the microbiota is a key contributor to maintaining inflammatory balance in these individuals, as well as support in recovering from physiologic insults to the individual, allowing them to maintain a state of health rather than crossing the threshold of accelerated aging.
NIU: What does a youthful centenarian microbiome look like and are there unique youth-associated signatures? Could this explain why people who are not necessarily champions of health live so long?
MH: This is an area where more data is going to be helpful. Much of the data we have are from cross- sectional studies or collected samples in a specific population at a specific moment in time. We need to better unravel the temporal changes that occur during the ‘healthy’ periods in life.
Are the seeds of the centenarian microbiome identifiable at an earlier age? Most likely yes. We do know that the children of centenarians tend to become centenarians and their microbiota resemble those of their parents. Certainly, several factors contribute to that fact, but this at a minimum, suggests that earlier identification of a unique prognostic microbial signature may be possible. This concept of microbiota prognostication is at the heart of the work by Thomas Wilmanski and colleagues, who were able to predict survival in their cohort based on microbial composition.
Regarding resiliency, health status is not static throughout life. We all have dips and declines. How we respond to those may be influenced by lifestyle, diet, sleep, environment, host factors and perhaps the microbiome. The microbiome is also dynamic and responsive to health status. More work needs to be done to understand the role of the microbiome when it comes to its impact on overall health; to what degree it provides a protective mechanism during general sickness – supporting resilience – or if it has preventive effects.
NIU: Given what is known so far about the bacteria, fungi and viruses in the centenarian gut, what opportunities are there to modulate the microbiome to expand healthspan and lifespan? Could there be a one-size-fits all approach?
MH: With respect to microbiome modulation, based on what we know so far, diversity seems to be the key, and we need to evaluate all available tools to encourage that diversity, which may include: pre-biotics, probiotics, symbiotics, novel microbiome modulators, activity, and environment. A single probiotic strain will not be the solution as there are a spectrum of mechanisms that drive the aging process, and demonstrating the impact of the mentioned tools on aging is not a simple task either; novel approaches are needed, to tie meaningful change to the aging process.
When it comes to healthspan and lifespan, unfortunately, a single, universal solution isn’t the answer, but rather a confluence of concepts: consuming a diverse diet, getting sufficient sleep, being active, engaging with others and one’s community, maintaining cognitive health and agility, avoiding external stressors, and many other variables, are foundational pillars to promote health and healthy aging. The time at which ‘aging’ begins and the rate at which it occurs is different for every individual and even within different organ systems.
Having said that, perhaps there is a one-size-fits-all set of principles to promoting health in general, but it’s unlikely there is a single one-size-fits-all product to promote healthy aging; physiology is much more complex than that.
NIU: Are there specific probiotic strains that have a greater potential to reverse the hallmarks of aging? Could these be mined from the centenarian microbiome for novel strains to support healthspan in other individuals?
MH: Further mining of the centenarian microbiome is needed. The literature suggests a variety of species that are increased or decreased in centenarians – some are on both sides of the equation – and some are perhaps not beneficial microbes. This again reflects the heterogeneity of the populations studied.
Promoting diversity within the context of the individual’s environment appears to be key. And, when does that process of diversification begin? Again, there are elegant studies with incredible insights, but we are looking at different individuals at different time points. Longitudinal data will be pivotal to a more comprehensive understanding of which probiotic strains may help support health span and lifespan.
NIU: Are there any specific changes in composition and diversity that occur at specific times in our lives that are linked to healthspan? Special windows of opportunity?
MH: The most dramatic changes in the intestinal microbiota occur during infancy/early childhood, and in the elderly. During infancy and early childhood, we establish the microbiota we will have for the remainder of adulthood. The first 1000 days concept – this is a critical period during which the microbiome can influence health. We’re continuing to harness greater insights into the ways in which changes in early life influence health at later outcomes. We are collaborating with the University College Cork/APC Microbiome Ireland to investigate this period of life further, in the Missing Microbes in C-Section Study (MiMiC). We aim to understand how various environmental factors from birth influence health outcomes at later ages.
The second window of opportunity is when the diversity of the microbiota declines at some point in adulthood. When exactly that happens is yet to be known and will differ for every individual. There are changes in the microbiome associated with the onset of frailty. Frailty can begin as early as 55-60 years of age, therefore, perhaps the window to intervene is just before that.
NIU: What is most compelling about the current knowledge/research on the centenarian microbiome? What is most interesting for future study?
MH: The fact that the centenarian microbiome is so unique, even from healthy individuals in their 80s, is what makes it so exciting. That diversity is the foundation for all the other interesting questions and opportunities that arise from it, like metabolic function, immune interactions, nutrient absorptions and so on. We still need to further unravel the metabolic profile of this unique environment. SCFA fermentation appears to be different when compared to younger individuals, and we know it’s more diverse than in younger populations. But how dynamic is it? What is the resiliency of it in response to challenges or illness? Further understanding of these elements will provide greater insight into what opportunities may be available to influence healthspan via microbiota modulation.
NIU: Can microbiome health predict longevity? Is the centenarian microbiome the fountain of youth?
MH: The definition of dysbiosis still lacks clarity, but we are becoming more precise in being able to categorize a healthy microbiome versus non. When it comes to longevity prediction capabilities, the technology isn’t quite there yet. Saying you will live to 113 if your microbiota looks like ‘x’ or ‘y’ at age 30 seems beyond our current ability and understanding.
Perhaps though, if you can do all the things to maintain the microbiome of a ‘healthy’ 30-year-old (healthy diet, exercise and sleep) throughout your lifetime, means you might have a higher probability of living a long and healthy life – that seems more feasible. I don’t think the centenarian microbiome is the fountain of youth…but I do think it is one of its sources.
