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metabolic, and immunological functions [142]. Aging associated changes in the physical and cognitive status of the host lead to life style alternations. Consequently, they impact the niche that microbes inhabit. Aging accompanied by the alternation of the immune response state directly interfaces with the microbiota and enhances susceptibility to infection [143, 144]. For instance, the elderly are marked susceptibility to dermatologic disorders caused by infection [145]. With aging, the microbiota in humans co-evolves with the host to adapt to the niche alternation. Interestingly, many clinical issues accompanied with aging, such as Bowel disorder, cardiovascular disease, constipation and Parkinson‟s disease, are also closely correlated with perturbations in gut microbiome composition and functions [49, 88, 89, 96, 146, 147]. Given that the gut microbiome is closely associated with several features of gut barrier integrity, intestinal inflammatory balance, immune and metabolic health, and gut-brain axis [69, 148, 149], these old-age-related clinical issues could clearly contribute to the increased the susceptibility to various infectious and gut-associated diseases by causing alterations in the microbiota of elderly people . Investigation into the baseline of aging-related microbiota alternation in different body habitats enhances our understanding of the biological insights of aging and microbiota, ultimately making it possible to promote healthy aging through the intervention of the microbiota in human.

4.1 Aging related changes in gut microbiota

Since the aging population is a global issue, prolonging a healthy lifespan has become a vital challenge for modern medical research. Gut microbiota, widely regarded as associated with health and aging, has become a new focus for research on aging. With the aging process, the natural decline in physical function which, along with dietary change and immune response changes, may cause gradual alterations of gut microbiota. Aging related alternation in gut microbiota was observed in different cohorts [57, 150, 151]. Early data from the ELDERMET cohorts showed the core microbiota of the elderly was distinct from the young adults, and later, demonstrated the association of the gut microbiota in the elderly with diet and health [65, 152]. Their research indicated that the chronological aging is not the cause of gut microbiota alternation, but the loss of diversity in core microbiota groups is associated with increased frailty in the elderly [62]. Recently, a survey of gut microbiota in a large healthy cohort in China showed that the gut microbiota of healthy elderly Chinese is similar to that of the healthy young [150], further emphasizing the important role health plays in shaping the gut microbiota. While there are also certain signatures of aging related to the alternation of gut microbiota that is shared between populations, such as the reduction in Faecalibacterium and Bifidobacterium abundance and the increase in Enterobacteria abundance. Gut microbiota composition alternations cause functional shifts which lead to the change in energy utilization and the abundance of bacterial metabolites production. Functional annotation of the gut

microbiota in the aging process is critical for the utilizing future therapeutic modulation of gut microbiota to promote healthy aging. Although alternations in the composition and function were observed, till now we still do not have a clear understanding of the causative relationship between the altered gut microbiota and decreased heath during the aging. It has been hinted that gut microbiota homeostasis is crucial for healthy aging and hence restoration of this homeostasis might be supportive for human longevity [153]. Further longitudinal research following the aging process is eagerly needed to help our understanding of aging and gut microbiota.

4.2 Gut microbiota character of longevity

Evidence shows that gut microbiome impacts host longevity in animal models such as

Caenorhabditis elegans and Turquoise Killifish which have short and easily

monitored lifespan [154, 155]. Moreover, longitudinal study in a large human cohort has also found the association between the distinct metabolomics signatures and longevity of humans [156]. Thus human gut microbiota may act as the modulator between longevity and the genetic and environmental factors by affecting the host metabolism. During a life time, gut microbiota undergoes a co-evolution with the human host, adapting to the progressive changes of the host gut environment, the longevity is a successful outcome of human host and gut microbiota symbiosis. Centenarians represent a population with an extremely long lifespan, and have been

used by several groups as a model to study aging and gut microbiota [57, 63, 64, 151, 157, 158]. These studies have focused on the compositional feature of gut microbiota in centenarians with younger groups as controls. As a dynamic ecological system, gut microbiota composition is various for individuals. The variation may cause by different populations with diverse genetic, dietary, environmental factors even with different methodologies of processing the samples and data. Certain compositional features of centenarians‟ gut microbiota have been found, including accumulation of some subdominant species. Among the variations, some seem universal, such as the decrease in abundance of Faecalibacterium, it shows an aging dependent decrease in trajectory. Other changes are unique to the defined population; for example, the enrichment of Roseburia in Chinese centenarians but a decrease in Italian and Japanese centenarians [57, 63, 151]. The variation of the changes may be caused by the different populations with different genic backgrounds, diets, and lifestyle. Noticeably, metabolic function of gut microbiota in centenarians has not yet been explained yet.