1. Introduction

As previously stated, even in physiological conditions, the gut microbiota is a dynamic ecosystem. The composition of the gut microbiota is based on permanent and transitory bacterial species of 17 different phyla such as Firmicutes, Bacteroidetes and Proteobacteria, which can reach as much as 70%, 30% and 5% of the total abundance, respectively, between others^[1] [56]. This composition changes depending on the anatomic region of the gastrointestinal tract, due to pH, secretions, motility or substrate availability. A gradual increase of bacterial concentration and complexity exists through the stomach and the gut, reaching the maximum in the colon. Moreover, GM experiments with taxonomical and functional changes during the life of an individual since the prenatal period. The microbiota colonization on the gastrointestinal tract may be started in utero with the placenta and amniotic fluid microbial communities of the mother, as recent research has observed when comparing these microbial populations with the meconium ones^[2] [57]. Microbiota profile constitution is affected by numerous factors, such as genetic components, type of delivery (vaginal or cesarean), the feeding (breast-feeding or formula-feeding) or antibiotics and/or probiotics consumption during the first days of life. The initial gut microbiota of infants is a quite instable simple structure dominated by bifidobacteria^[3] [58] and is in continuous change until the age of three years. At this moment, the microbiota profile is established and acquires an adult pattern that is relatively stable over time. Nevertheless, there are many causes that can modify this adult profile, for instance lifestyle, exercise, dietary patterns, stress or pathophysiology. Microbiota changes drastically in the elderly and these age-related changes are directly correlated with an inflammatory pattern linked with many diseases. Generally, these changes are orientated to a loss of diversity, a reduction of the abundance of beneficial bacteria such as those which produce short-chain fatty acids (SCFAs)^[4] [59], a change in the dominant species or an increase of enteropathogens^[5] [60]. All of these modifications are associated with physiological changes in the gastrointestinal tract and in dietary patterns, and with a decrease in the immune system function^[6] [61], an increase in the inflammatory state and a feasible contribution to the progression of diseases^[4] [59] and frailty^[6] [61]. Regarding the changes in dietary choices in the elderly, reductions in taste, dentition, chewing ability and intestinal transit time are factors that contribute considerably^[7] [62].

2. Latest Research

Some researchers have focused on establishing the specific age-related microbiota profile. At phylum level, Firmicutes is predominant in adults, being reduced in the elderly, whereas there is some discrepancy about the increase or decrease of Bacteroidetes phylum with age^[6][8][9] [61,63,64]. Moreover, high levels of Proteobacteria phylum especially Enterobacteriaceae family^[8] [63] and Clostridia class^[9] [64]), as well as a decrease of Actinobacteria (especially Bifidobacterium, a genus with intestinal protective capacity) have been reported in old people^{[6][8][9][10]} [61,63–65]. In fact, inflammatory markers such as IL-6 or IL-8 have been associated with an enrichment in Proteobacteria phylum, which increases with age^[11] [66]. Biagi et al.^[11] [66] identified in an elder population in Italy a decrease in bacterial diversity, as well as a change in the relative proportion of Firmicutes phylum, an increase of Bacili and low levels of Clostridium cluster XIVa. This reduction in the abundance of Clostridium cluster XIVa was corroborated by later studies^[3] [58]. Moreover, Rahayu et al.^[9] [64] analyzed the gut microbiota composition of 80 volunteers from Bali and Java arranged in two groups depending on the age (25–45 age old and 70 years old), identifying a reduction of Bifidobacterium, Prevotella and Lactobacillus plantarum taxa and an increase in Enterobacteriaceae and Lactobacillus reuteri in the elderly subjects). Furthermore, Bian et al.^[12] [67] developed a study with 1095 healthy volunteers from different cities of China and showed a decrease of Bifidobacterium and Bacteroides genera in older subjects, whereas Dorea, Clostridium and Marvinbryantia genera were increased in that population. In this research, Faecalibacterium genus was identified as a core and stable microorganism among life. Additionally, Claesson et al.^[13] [68] observed that low levels of diversity were correlated with inflammatory markers, frailty and impaired health parameters, as well as diet patterns. Frailty has also been associated with a low abundance of butyrate-producers like Faecalibacterium prausnitzii^[8][14] [63,69], Lachnospiraceae family and Roseburia genus, whereas there are some species that associate positively with frailty, such as Eggerthella dolichum or E. lenta^[14] [69].

In spite of the great inter-variability among studies, there are some taxa which may be less susceptible to be modified by external factors and may constitute the core of gut microbiota composition in the elderly. The reduction in the abundance of Ruminococcus, Blautia or Clostridium cluster XIVa and Clostridium cluster IV and the major prevalence of facultative anaerobes like Escherichia coli are changes that have been observed in the elderly population across many studies^[15] [70]. Even so, it is difficult to establish a unique aging gut microbiota composition profile, due to many factors that modulate this internal ecosystem such as the ethnicity, lifestyle, dietary patterns, host genetics, the presence of comorbidities or even methodological tools. Those reasons reveal the importance to do more studies to reach a homogeneous aging gut microbiota signature.

In the elderly, the presence of comorbidities is a very common situation that requires polypharmacy in order to improve the health status. Thus, not only the comorbidities but also the polypharmacy are factors that modify drastically the composition and diversity of microbiota. In fact, Ticinesi et al.^[16] [71] studied the differences between a cohort of 76 elderly hospitalized and multimorbid patients and a group of 25 healthy active elderly volunteers. The β-diversity index showed that the microbiota profile of hospitalized patients was significantly different in comparison with non-hospitalized group. The number of drugs was negatively correlated with Chao-index α-diversity and with the taxa Massilia and Lachnospiraceae. Furthermore, Coprobacter, Helicobacter and Prevotella were positively correlated with polypharmacy. The hospitalization is another factor that modifies gut microbiota composition, characterized by a substantial decrease in Faecalibacterium prausnitzii, Desulfovibrio spp. or Bifidobacterium, between others, and a major increase of the abundance of enterobacteria^[8] [63]. Moreover, Claesson et al. ^[13][68] and Jeffery et al.^[7] [62] identified in a study which compared the gut microbiota of Irish elderly by their type of residence (community-dwelling, one day at hospital, short-term rehabilitation and residential care) a relationship between the institutionalization of elderly people and an increase of Firmicutes phylum and Parabacteroides, Eubacterium, Anaerotruncus and Coprobacillus genus, as well as a reduction in bacterial diversity and the abundance of short-chain fatty acid (SCFAs) producers. These results are in agreement with previous reports, indicating that the microbiota profile related to age is aggravated by polypharmacy, reducing the number of SCFAs producers such as Lachnospiraceae family and increasing the abundance of some enteropathogens like Helicobacter.

It is important to consider the importance and the difference between biological and chronological age, being first physiological age, which takes into consideration many issues such as lifestyle or environmental and genetic factors, and the second one the number of years a person has been alive. Bacterial diversity has been negatively correlated with biological age, but not with chronological age. Moreover, Ruminococcus, Coprobacillus and Eggerthella genera have been associated positively with biological age, independently of the chronological one^[4] [59]. Related to that, many studies have identified the microbiota profile of centenarians—those people close to 100 years old—showing a specific healthy composition closer to adults’ pattern and remarkably different to that commonly observed in elders over 65 years. Wang et al.^[17] [72] described the composition of gut microbiota of centenarians in East China and observed that the α-diversity was significantly increased, as well as the genus Escherichia and Roseburia in centenarians. Moreover, volunteers more than 100 years old also showed a decrease in the abundance of Lactobacillus, Butyricimonas, Coprococcus, Parabacteroides, Akkermansia, Sutterella and Faecalibacterium genera compared with the groups between 80 and 99 years old. Afterwards, Wang et al.^[18] [73] conducted a similar study in a larger population and described that community richness and α-diversity was significantly lower in the 65–70 years age group compared with the 90–99 and the 100+ year age groups. An increase in the relative abundance of Synergistetes phylum (with special mention of Prevotellaceae, Lachnospiraceae and Porphyromonadaceae) was observed in the longevity group compared with the younger elderly group. Similar results related to the increase of microbial diversity and Porphyromonas genus in centenarians were observed in a study of 367 Japanese volunteers^[10] [65]. Furthermore, Kim et al.^[19] [74] identified a minor relative abundance of Faecalibacterium and Prevotella, as well as an increase of Escherichia and Proteobacteria in centenarians of South Korea. Additionally, Kong et al.^[20] [75], considering the results of their own Chinese cohort and the results previously reported by Biagi et al.^[21] [76], identified an enrichment of Clostridium cluster XIVa, Akkermansia, Ruminococcaceae and Christensenellaceae in long-living groups. While many genera of Clostridium cluster XIVa are producers of SCFAs, Akkermansia and Chistensenellaceae have been identified as good metabolic health-related bacteria, associated with healthy homeostasis and immunomodulation. This suggests a tendency in the microbiota profile of centenarians towards a healthy and anti-inflammatory status^[19][20] [74,75]. Moreover, related to SCFAs producers, the microbiota profile of centenarians showed an increase in some butyrate producers (Anaerotruncus colihominis and Eubacterium limosum) and a decrease in others (Ruminococcus obeum, Roseburia intestinalis, E. ventriosum, E. rectale, E. hallii, Papillibacter cinnamovorans and Faecalibacterium prausnitzii), suggesting with these differences the presence of bacteria characteristics of longevity^[22] [77]. The association of longevity with Ruminococcus, a genus known as a SCFAs producer and with an important role in gut protection, is still contradictory^[18] [73]. All of these findings related to gut microbiota composition in elderly and in centenarians are summarized in Table 1.

Table 1. Gut microbiota composition of the elderly (≥60 years old) and centenarians (≥99 years old).

F: female; M: male. Changes (↑: increase; ↓: decrease) in the relative abundance of selected microbial taxa and in bacterial diversity with age. Names in bold denote each group for the corresponding study and are defined in the table.

In these terms, not only the composition but also the metabolic pathways of microbiota change with age. Collino et al.^[23] [78] identified some alterations in a Northern Italian population linked to age, such as low concentrations of tryptophan and lysophospatidylcholines and increased levels of sphingomyelins and phospatidylcholine 32:0. On the other hand, some plasma metabolomic patterns such as lipids and amino acids have been related to health span markers in elderly^[24] [79]. Nevertheless, it has been observed that phosphatidylinositol, glycosphingolipid and N-glycan biosynthesis signaling pathways are increased in centenarians, all of them being associated with anti-inflammation and healthy status of gut microbiota^[19] [74]. Low levels of markers of lipid peroxidation, as 9-hydroxy-octadecadienoic acid (9-HODE) and 9-oxo-octadecadienoic acid (9-oxoODE), have been identified in longevity phenotype in a population of Italy^[23] [78], while centenarians in China showed high levels of SCFAs and total bile acids^[25] [80]. These results seem to reinforce the existence of a specific altered microbiota pattern in the elderly with the particularity of a healthy microbiota composition and functionality in centenarians, with more research being necessary to elucidate such patterns.