Cell. Mol. Life Sci. DOI 10.1007/s00018-017-2674-y Cellular and Molecular LifeSciences MULTI-AUTHOR REVIEW Gut microbiota changes in the extreme decades of human life: a focus on centenarians Aurelia Santoro1,2 · Rita Ostan1,2 · Marco Candela3 · Elena Biagi3 · Patrizia Brigidi3 · Miriam Capri1,2 · Claudio Franceschi4 Received: 25 September 2017 / Accepted: 29 September 2017 © The Author(s) 2017. This article is an open access publication Abstract The gut microbiota (GM) is a complex, evo- such as Parkinson’s and Alzheimer’s, and its possible thera- lutionarily molded ecological system, which contributes peutic use, taking advantage of the fact that centenarians to a variety of physiological functions. The GM is highly are characterized by an extreme (healthy) phenotype versus dynamic, being sensitive to environmental stimuli, and its patients sufering from age-related pathologies. Finally, it composition changes over the host’s entire lifespan. How- is argued that longitudinal studies combining metagenom- ever, the basic question of how much these changes may be ics sequencing and in-depth phylogenetic analysis with a ascribed to variables such as population, diet, genetics and comprehensive phenotypic characterization of centenarians gender, and/or to the aging process per se is still largely and patients using up-to-date omics (metabolomics, tran- unanswered. We argue that comparison among studies on scriptomics and meta-transcriptomics) are urgently needed. centenarians—the best model of healthy aging and longev- ity—recruited from diferent geographical areas/populations Keywords Gut microbiota · Aging · Centenarians · Gut– (diferent genetics and dietary habits) can help to disentangle brain axis · Host genome the contribution of aging and non-aging-related variables to GM remodeling with age. The current review focuses on the role of population, gender and host genetics as possible driv- The study of the human gut microbiota: ers of GM modifcation along the human aging process. The methodological aspects feedback impact of age-associated GM variation on the GM– brain axis and GM metabolomics is also discussed. We like- The human gut microbiota (GM) is a highly diverse eco- wise address the role of GM in neurodegenerative diseases system made up of trillions of bacteria populating the gas- trointestinal tract. This niche establishes a complex, multi- species apparatus in which every occupant plays a role and Aurelia Santoro and Rita Ostan contributed equally to this work. modulates its own activity in response to signals coming from inside and outside the human host [1]. The composition * Aurelia Santoro [email protected] of the GM is afected by a plethora of individual, popula- tion and environmental variables, e.g., age, gender, genetic 1 Department of Experimental, Diagnostic and Specialty background, biography (type of delivery, breastfeeding or Medicine (DIMES), Alma Mater Studiorum-University formula feeding, use of antibiotics), immuno-biography of Bologna, Via San Giacomo 12, 40126 Bologna, Italy 2 (lifelong immunological experience) and geography (ethnic- Interdepartmental Centre “L. Galvani” (CIG) Alma Mater ity, cultural habits, nutrition). These factors over a lifetime Studiorum-University of Bologna, Via San Giacomo 12, 40126 Bologna, Italy impinge on the GM, resulting in huge variability and het- erogeneity of this ecosystem in human beings. This adaptive 3 Department of Pharmacy and Biotechnology (FABIT), Alma Mater Studiorum-University of Bologna, Via Belmeloro 6, nature of the GM is functional to calibrating the immune 40126 Bologna, Italy and metabolic pathways in response to individual needs, and 4 Institute of Neurological Sciences (IRCCS), Via Altura 3, has a profound impact on health and disease. Indeed, the 40139 Bologna, Italy GM has emerged as a dynamic community able to adapt its Vol.:(0123456789)1 3 A. Santoro et al. composition and functionality to the varying conditions in age-related environmental (lifestyle, diet, etc.) and endog- which the human host lives to meet the changing demands enous changes, contributing to the maintenance of metabolic of host metabolism [2]. Thus, a healthy adult GM structure and immunological homeostasis and promoting survival [1, is properly defned as a set of many possible confgurations 8]. which, even when difering in composition, share a compa- Human longevity has a strong familial and genetic com- rable degree of diversity and evenness (meaning the number ponent [12, 13]. Data from diferent populations have shown of species with an equal distribution in the ecosystem), and that relatives (parents, siblings and ofspring) of long-lived the ability to preserve the homeostasis of the human host [3]. subjects have a signifcant survival advantage, a higher prob- In this elaborate scenario, the most informative approach for ability of being or becoming long-lived and a lower risk understanding the role of the GM in its lifelong maintenance of undergoing major age-related diseases [14–17]. Family of host homeostasis would clearly be by longitudinal stud- genealogy data from Sardinian centenarian women have ies monitoring individuals over time (years and decades) confrmed that maternal longevity is associated with lower to identify and follow the specifc trajectories of their age- infant mortality in ofspring [18] suggesting that parents/ related GM modifcations. To date, this kind of analyses has mothers who will later become centenarians very likely not been possible because attention towards the GM is quite adopt healthier lifestyles for their children. Considering that a recent development, while the most reliable and robust the study of centenarians has some obvious limitations (rar- longitudinal studies have not collected stool samples across ity, lack of an age-matched control group and frailty related the full life span of individuals. Hopefully, new life-long to extreme age), centenarians’ ofspring, representative of longitudinal studies or continuations of existing ones will the elderly age bracket whose lifestyle can still be modifed cover this gap. to attain better health, may provide a useful model to study At present, the best way of grasping the adaptive pat- both genetic and environmental/lifestyle determinants of tern of human GM as humans age is represented by cross- healthy aging [14]. sectional studies embracing a wide age range in well-defned Starting from observation of the profound changes in populations that are relatively homogeneous in genetics and immune responses with age (immunosenescence, i.e., the lifestyles. Inclusion of “extreme phenotypes”, i.e., individu- overall age-related remodeling of the immune system [19]) als who are at the extreme ends of a trait distribution (healthy and taking into account the increasing amount of experi- subjects versus patients sufering from diseases), can help in mental data on genetics, proteomics, epigenetics, metabo- identifying specifc signatures within overall age-related tra- lomics, glycomics, etc. [20], one may conceptualize the jectories, regarding genetics, epigenetics, metabolomics, and aging process as a continuous lifelong remodeling of the including metagenomics, among other things [4–8]. Such whole human organism [21]. The exceptional phenotype of is the case of centenarians who represent a clearly defned centenarians has been revealed as unexpectedly complex and and highly informative “super-control” group, since, unlike very dynamic, being a unique mixture of adaptive robustness younger controls, most of them achieved their remarkable and accumulating frailty [21–26] resulting from the ability age by avoiding or perhaps postponing major age-related of the centenarian’s organism to respond/adapt to damaging diseases. The strategy of focusing on individuals from well- stimuli. defned populations and including the “extreme phenotypes” According to the dynamics of world population aging, such as centenarians increases one’s power to identify physi- a lifelong approach including the last decades of life is ological age trajectories, including the last 20–30 years of extremely important if we are to understand the basis of the human life which are usually neglected [9]. Comparison longevity process, considering that the oldest-old are the between data sets obtained from diferent populations will fastest growing segment of the population in many countries. allow us to disentangle changes related to specifc genetic or It is also interesting to note that the birth cohort is crucial lifestyle habits, including diet, from changes related to the in the health outcome of long-lived people. A comparison aging process itself. of two Danish cohorts born 10 years apart (1905 and 1915) showed that the younger cohort had longer survival and The model of centenarians scored signifcantly better on both cognitive tests and the activities of daily living scale than the cohort born in 1905, Centenarians represent the best model of “successful” aging despite being 2 years older at the time of assessment. This showing a lower incidence of chronic illness, a reduction of fnding suggests that more people are living to older ages morbidity and an extension of health span in comparison to with better overall functioning [27]. octogenarians and nonagenarians from the same cohort [10, Demographic projections suggest that there will be 3.7 11]. Thus, the study of the GM of exceptionally long-lived million centenarians across the globe in 2050. In particular, individuals is providing insights into how the GM