Achieving healthy aging through gut microbiota-directed dietary intervention: Focusing on microbial biomarkers and host mechanisms

Graphical abstract

Highlights

• •This review has provided a comprehensive synthesis of evidences on aging-related/caused gut microbiota features.
• •The gut microbiota of centenarians has been emphasized in revealing healthy-aging related microbial and metabolic properties.
• •This review has depicted aging-related gut microbiota features in higher resolution (at species, and even strain levels).
• •This review has explored and proposed potential dietary approaches including specific dietary components that target aging-associated microbiota biomarkers.
• •This review has updated new findings on microbial-related aging (e.g., new microbial-derived biomarker including δ-valerobetaine).

Abstract

Background

Population aging has become a primary global public health issue, and the prevention of age-associated diseases and prolonging healthy life expectancies are of particular importance. Gut microbiota has emerged as a novel target in various host physiological disorders including aging. Comprehensive understanding on changes of gut microbiota during aging, in particular gut microbiota characteristics of centenarians, can provide us possibility to achieving healthy aging or intervene pathological aging through gut microbiota-directed strategies.

Aim of Review

This review aims to summarize the characteristics of the gut microbiota associated with aging, explore potential biomarkers of aging and address microbiota-associated mechanisms of host aging focusing on intestinal barrier and immune status. By summarizing the existing effective dietary strategies in aging interventions, the probability of developing a diet targeting the gut microbiota in future is provided.

Key Scientific Concepts of Review

This review is focused on three key notions: Firstly, gut microbiota has become a new target for regulating health status and lifespan, and its changes are closely related to age. Thus, we summarized aging-associated gut microbiota features at the levels of key genus/species and important metabolites through comparing the microbiota differences among centenarians, elderly people and younger people. Secondly, exploring microbiota biomarkers related to aging and discussing future possibility using dietary regime/components targeted to aging-related microbiota biomarkers promote human healthy lifespan. Thirdly, dietary intervention can effectively improve the imbalance of gut microbiota related to aging, such as probiotics, prebiotics, and postbiotics, but their effects vary among.

Introduction

Population aging has become a critical global public health issue. According to public health organizations, the number of individuals aged 60 years and above is anticipated to double by 2050 [1]. Likewise, the number of people aged 80 years and above is anticipated to triple between 2020 and 2050. As a populous country, China faces a considerable aging issue as well [1]. Currently, the elderly in China comprises 18.1 % of the headcount, approaching 254 million and surpassing the total populations of Japan and Germany. By 2050, elderly population in China aged 60 years and above is estimated to approach 35 % of the total population [2]. Forestalling age-associated diseases and prolonging healthy life expectancies have thus emerged as worldwide priorities.

The process of aging may occur either normally or pathologically. “Normal (or healthy) ” aging refers to aging in the absence of any diagnosed metabolic disorders or declared diseases, whereas “pathological” aging refers to aging with metabolic and organ/tissue dysfunction related to disease development. Healthy aging often leads to higher life expectancy. Centenarians are a rare population of macrobian who have approached the age of 100 years without succumbing to diseases that often lead to the death of other elderly people, like cancer, type 2 diabetes, cardiovascular disease (CVD) and neurodegenerative disease [3]. However, centenarians still show signs of aging. Thus, studying the characteristics of centenarians can inspire future research on healthy aging.

The gut microbiota plays major roles in regulating metabolism, combating infection and inflammation, preventing autoimmune diseases and cancer, and modulating the brain-gut axis. To this end, the gut microbiota promotes health through the action of a balanced population of symbiotic and pathogenic bacteria. Diet, exercise, living, and working conditions, and drug treatment can affect the variety and function of the gut microbiota [4]. Recently, the gut microbiota has also served as a novel target for regulating the senescence process. Age-dependent exposures (e.g., tooth loss, difficulty in chewing and swallowing, impairment in sense of smell and taste, decreased intake of dietary fiber-rich food, and reduced rates of physical activity) can directly lead to imbalances in the gut microbiota (Fig. 1) [5], [6], [7]. For example, impairment of oral function in the elderly can affect their ability to chew and swallow food, leading them to choose soft and low-fiber foods, which can affect the composition of the gut microbiota [6]. An accumulation of evidence has revealed causal links between aging and the gut microbiota. Age-induced variations in the gut microbiota are typified by shifts in composition and function, abundance of key microbial species, and associated microbial metabolites. Conversely, changes in the gut microbiota may directly contribute to aging [8], [9]. For example, Lim et al. discovered that with increased age, the proportion of beneficial bacteria (Prevotella copri and Coprococcus eutactus) decrease, whereas that of harmful species (Bacteroides fragilis and Clostridium hathewayi) increase. Moreover, 11 metabolic pathways (including the L-tryptophan degradation pathway) were also found to be negatively associated with the Frailty Index (the Frailty Index refers to the currently used composite index for measuring frailty characteristics in old age) [10]. In addition, Lactobacillus abundance was also shown to be lower in the feces of the elderly in comparison to those of younger individuals, while pathogenic Shigella species and Escherichia coli (E. coli) showed increased abundance [11]. Lee et al. also recently showed that fecal transplantation gavage of gut microbiota from aged mice to germ-free (GF) mice inhibited short chain fatty acid (SCFA) production in the host, and led to cognitive decline [12]. These findings suggest that it is possible to intervene in aging of the host through the regulation of the gut microbiota to promote a long and healthy life. Probiotics and diet are two commonly used strategies to modulate the gut microbiota. Beneficial bacteria such as Bifidobacterium longum [13] and dietary components such as baicalin, genistein, GOS and OS-Inulin [14], [15], [16], [17] were previously shown to exert anti-aging effects by regulating the gut microbiota. This opens an opportunistic window to utilize dietary intervention in aging.

Fig. 1.

Illustration on the reported changes in host physiology and gut microbiota during the course of aging.

This review summarizes the characteristics of senescence-associated gut microbiota, identifies crucial gut species and gut microbiota-derived metabolites, and outlines the dietary factors and probiotics with potential to mitigate aging through gut microbiota modification to guide future efforts in developing dietary intervention therapies for aging.

Relationship between aging and gut microbiota

Age-associated alterations in composition of microbial species and their metabolites in the gut

Aging-associated changes in alpha and beta diversity of the gut microbiota. As people age, it is a common understanding that the alpha diversity of the gut microbiota decreases. However, current studies have shown that there is no significant difference in alpha diversity (in terms of Shannon index and species richness) in the gut microbiota between different age groups [18], [19]. Even among centenarians, alpha diversity (Chao1 index, Shannon index, PD whole tree and the number of observed specifications) was found to increase significantly [20], [21], [22], [23]. Pang et al. showed that the decrease in alpha diversity (Shannon diversity) with increasing age was only associated with the elderly, not centenarians, and that the trend of increasing alpha diversity in centenarians was only reflected in species evenness (Pielou's evenness index), but not species richness [24]. Beta diversity did not differ significantly on older versus young people (Bray-Curtis, Hellinger distance, JSD distance and Spearmen distance), but there were significant differences between centenarians versus young and old people (Bray-Curtis and unweighted UniFrac distances) [19], [21], [25], [26], [27], which indicates that the aging process may not involve overall changes in gut microbial species and their relative abundance, and that the gut microbiota of centenarians displays rearranging characteristics [25]. Decreased alpha diversity has been associated with metabolic and inflammatory diseases [28]. A study on a Chinese population has also reported a lower level of alpha diversity (Shannon index) in unhealthy elderly people compared to that in healthy elderly people, in addition to a significant difference in beta diversity [29].

Key members of gut microbiota and related microbial metabolites involved in healthy (centenarian-related) or pathological aging. Most of the previous studies conducted on “healthy aging” showed that the affection of aging on gut microbiota is characterized mainly by the loss of dominant commensal taxa (such as Faecalibacterium, Lachnospira, Prevotella, Coprococcus, Eubacterium rectale, and the health-associated genus Bifidobaterium), which are replaced by pathogenic species (such as Eggerthela, Biophila, Fusobacteria, Streptococcus, and Enteroberiaceae) and microbiota presumed to be beneficial (such as the putative beneficial Akkermansia, Christensenellacea, Butyrisimonas, Odoribacter, and Butyriciccus). In “pathological” aging (especially in age-related diseases), the loss of dominant commensal taxa is replaced by pathogenic bacteria and the microbiota presumed to be beneficial are lost [30]. Studies on the gut microbiota of elderly and centenarians in China, Russia, Italy, Japan, South Korea, and the United States revealed that in centenarians, the presence of beneficial bacteria such as Christensenaceae [31], [32], [33], Akkermansia [31], [32], [33], Clostridium [27], [33], [34], Lactobacillus [23], [32], and Bifidobacterium was positively correlated with age, however, the presence of SCFA-producing bacteria Coprococcus [19], [25], [31] and Faecalibacterium prausnitzii [19], [21], [25], [35] was negatively correlated, and pathogenic bacteria Eggerthella [25], [35], Enterobacteriaceae [23], [36] were positively correlated with age. These findings appear in contrast to previously reported alterations in gut microbiota in the elderly, in which beneficial bacteria were reported to decrease with an increase in age, which can be explained by the fact that the gut microbiota of centenarians shows rearranged taxonomic patterns that allow for a balance between health-promoting and harmful bacteria as well as pro- and anti-inflammatory species in the gut ecosystem [28]. Moreover, the aging process also effects the metabolism of gut microbiota species, as evidenced by an enrichment in SCFA producing bacteria and genes involved in tryptophan (Trp) metabolism in centenarians [19], [22], [25]. However, in the elderly, the levels of SCFAs are reduced. Furthermore, the production of Trp, indole, and spermidine decreases while the production of toxic metabolites, such as LPS, increases [26], [37], [38]. Yoshimoto et al. showed that elderly people with an 'elderly microbiota' tend to accumulate more metabolites related to age-related disease, such as choline, trimethylamine, N8-acetylspermidin, whereas those with an 'adult microbiota' tend to accumulate beneficial metabolites like cholic acid and taurocholic acid [39]. The details of variations in the gut microbiota and metabolites of centenarians and other elderly individuals are shown in Table 1 and Table S1, respectively.

Table 1.

Alterations in the gut microbiota during aging in the elderly and the long-living of different populations at the species level.

People	Country	Sequencing technique	Speculative mechanism	Comparison	Main microbiome alterations (Species)	Abundance change	Reference
Long-Living	China	16S rRNA	–	N vs. E	Clostridium perfringens Bacteroides fragilis Ruminococcus gnavus Parabacteroides merdae	↑	[27]
					Clostridium sp. AT5 Bacteroides vulgatus Ruminococcus sp.5139BFAA	↓
	China	Metagenomic sequencing	–	L vs. E and Y	Odoribacter splanchnicus Peptoniphilus lacrimalis Anaerofustis stercorihominis Porphyromonas bennonis Clostridium methylpentosum Pyramidobacter piscolens Clostridium celatum	↑	[46]
					Roseburia inulinivorans Haemophilus parainfluenzae	↓
	China	High-quality sequences	–	L vs. E	Bifidobacterium breve Bifidobacterium longum	↑	[47]
					Bifidobacterium adolescentis	↓
	Italy	Shotgun	Chronic inflammation	C vs. E and Y	Escherichia coli Akkermansia muciniphila Eggerthella lenta Methanobrevibacter smithii	↑	[25]
					Faecalibacterium prausnitzii Eubacterium rectale Coprococcus comes Bacteroides uniformis	↓
				C vs. E	Eggerthella lenta Eubacterium limosum Ruminiclostridium Clostridium leptum	↑
	Italy	Shotgun	Inflammation Health parameters	C vs. E and Y	Methanobrevibacter smithii Bifidobacterium adolescentis	↑	[17]
					Eubacterium rectale Ruminococcus sp_5_1_39BFAA Faecalibacterium prausnitzii	↓
	India	16S rRNA	Inflammation Immunosenescence	C vs. Y	Ruminococcaceae D16 Ruminococcus bromii	↑	[21]
					Faecalibacterium prausnitzii	↓
Elderly	China	Metagenomic sequencing method	–	E vs. L and Y	Megamonas funiformis Parabacteroides merdae	↑	[46]
	Switzerland	Shotgun	–	Above 65 age vs. below 65 age	Suturella wadswonthensis unclassified（below65 age） Bifidobacterium adolescentis unclassified（below65 age）	↑	[36]
	China	Shotgun	Chronic inflammation	E vs. Y	Escherichia coli Parabacteroides distasonis Ruminococcus gnavus	↑	[26]

Note: L denotes the long-lived group with age of 90 + years, N is the Nonagenarian group with an age range of 90–99, C is the centenarian group with an age range of 97 + years, E is the Elderly group with an age range of 50–90, Y is the Younger group with an age scope of under 50 years.

Confounding environmental factors affecting microbiota during aging. The composition of the gut microbiota may vary based on environmental and host factors such as diet, host genetics, antibiotics, and lifestyle [40]. In this context, diet is considered a pivotal factor affecting the gut microbiota. The dominant species in the gut microbiota of healthy Hainan centenarians at the genus and species levels were found to differ significantly from those of centenarians from the Mediterranean region of northern Italy [41]. Urbanization [42], [43], the living conditions [44], as well as the early-life environment (in the initial three years of life) [45] may also affect the composition of the gut microbiota of the elderly.

Causal links between gut microbes and aging

Gut dysbiosis denotes a decline in the number and variety of gut microbiota, and is at the center of many aging-related changes. Sirtuin 6 knockout (SIRT6 KO) mice are a typical model for premature aging research. By grafting the fecal microbiota of SIRT6 KO mice into wild-type (WT) mice, researchers observed that WT mice also exhibited the intestinal dysbiosis and premature aging observed in SIRT6 KO mice, whereas transplanting the fecal microbiota from WT mice into SIRT6 KO mice led to an extended lifespan of SIRT6 KO mice, and improvement with respect to gut dysbiosis [48]. Naturally aging mice over 24 months of age that were transplanted with the fecal microbiota of 8-week-old young mice were found to have rejuvenated gut microbiota with significant improvements in aging-related physiological changes [49]. In addition, supplementation with Akkermansia [50], Bifidobacterium [51], Lactobacillus [52] or acetic acid can beneficially alter the gut microbiota, increase the lifespan of Caenorhabditis elegans or mice, and ameliorate diseases associated with aging. These results demonstrate a causal link between aging and the gut microbiota and highlight the potential for microbiome-based intervention.

Role and mechanisms of gut microbiota and associated metabolites in aging

Host aging mechanisms associated with gut microbiota

As the host ages, the risk of gut microbiota imbalance increases as well, leading to a collection of pathological and inflammatory changes, such as altered the levels of gut microbiota metabolites, damaged the integrity of the gut barrier, and enhanced intestinal leakage. This can exacerbate systemic inflammation, resulting in dysregulation of the immune system and growth of various diseases. A comparison of young and aged gut microecosystems is shown in Fig. 2.

Fig. 2.

Mechanisms of host senescence associated with the gut microbiota The leaky intestinal barrier caused by aging allows microorganisms and other harmful substances to penetrate the intestinal barrier and come into the systemic circulation. Aging also causes shifts in the gut microbiota, which exacerbates the leaky gut barrier. These factors ultimately lead to systemic inflammation, which result in dysregulation of the immune system, and causes a range of diseases associated with aging.

Intestinal Barrier. The gut barrier plays a crucial part in preventing harmful molecules from entering other body tissues through the gut mucosa [53]. Studies in rodents and non-human primates have shown that gut permeability increases with age, and the expression of tight junction (TJ) components has been observed to change in several cases [54]. A similar phenomenon has been observed in humans as well, for example, disrupted tight junctions and reduced expression of E-cadherin and occludin proteins in colon were observed in the intestines of healthy elderly individuals [55]. Man et al. suggested that compared to young people (20–40 years old or 7–12 years old), elderly people (67–77 years old) showed higher expression of claudin-2 and intestinal permeability in the ileum, with no changes in zonula occludens (ZO)-1, occludin, and JAMA-1 mRNA and protein expression levels [56]. Although various biomarkers associated with increased gut permeability may be altered in the elderly, enhanced intestinal permeability and concurrent changes in microbiota during aging were found to be consistently observed across individuals [3]. In addition, aging can also affect the number and differentiation of intestinal stem cells (ISCs), as well as the extracellular components of the gut mucosal barrier.

Inflammageing and Immunosenescence. Decreased immune function (also known as immune aging) and chronic inflammation are also linked to age-related dysbiosis of the gut micro-ecosystem [2]. The intestinal mucosal barrier, is the largest immune chamber and is also strongly affected by aging [57]. Previous reports showed that the number of intestinal immune cells does not decrease with age. However, their functionality deteriorates with increased age [58]. For example, Thevaranjan et al. found that the aged macrophages had significantly lower bactericidal capacity compared to the younger macrophages [59]. Similar observations were made on dendritic (DC) and natural killer (NK) cells [58]. Furthermore, senescence reduces the immune function of T cells, mainly by affecting the proliferative response of CD4⁺ T cells in Peyer's patches, decreasing the expression of immunoregulatory molecules in LP CD4⁺ T cells and the frequency and function of LP CD4⁺ Th17 cells, which ultimately have a direct impact on the integrity of the mucosal barrier and the recognition of gut microbiota [57].

Inflammatory aging refers to an increased pro-inflammatory status (increased levels of the pro-inflammatory cytokines IL-1β, TNF-α and IL-6 and C-Reactive Protein and decreased levels of the anti-inflammatory cytokine IL-10) and a decreased ability to cope with various stressors during the aging process [60]. Studies have shown that systemic inflammation including accumulation of pro-inflammatory cytokines, overexpression of NF-κB transcription factor, activation of NLRP3 inflammasome, and defects in autophagy signaling pathways is associated with inflammatory aging [61], [62]. With aging, loss of autophagy directly or indirectly stimulates the NF-κB pathway, leading to activation of inflammasome, thereby creating an age-associated pro-inflammatory phenotype [62]. NF-κB, a transcription factor, play a vital role in regulation of inflammatory processes [63]. It has been shown that NF-κB activity increases with age in tissues including the liver, heart and brain, and enhances the activity of ERK, JNK, and p38 MAPK, which are the three subtypes of MAPKs, and MAPKs are the upstream signaling pathways that regulate NF-κB activity [64]. Activation of NF-κB promotes transcription of pro-inflammatory molecules such as IL-1β, TNF-α, IL-6, adhesion molecules, and specific enzymes (including iNOS and COX-2) [63]. Under normal conditions, activation of NF-κB by oxidative stimuli is transient. However, if the input signals are not well controlled, chronic inflammation can occur during aging. Activation of NF-κB results in the production of IL-1β, TNF-α, and IL-6, which in turn act as activators of NF-κB, forming an autoactivation loop [63]. Chronic inflammation is a morbidity and mortality risk factor in the aged population, whereas dysregulated gut ecology contributes to the systemic inflammatory state in the elderly. In turn, inflammation affects gut integrity and causes shifts in gut microbiota [65]. In animal experiments, aging-associated microbes promote elevated levels of IL-6, IL-10, Th1, and TNF-α, and activate TLR2, NF-κB, and mTOR [66]. Fransen et al. found that transferring aged microbiota to young GF mice promoted the leakage of microbiota and its metabolites into the circulatory system, increased intestinal inflammation, and caused episodes of chronic inflammation. In addition, this study demonstrated the presence of pro-inflammatory bacterial species in the aging microbiota [67]. This effect was mainly manifested as increases in TM7 bacteria and Proteobacteria, as well as a decrease in Akkermansia, which is relevant to elevated TNF-α levels [67]. However, contradictory levels of IL-6 (another inflammatory biomarker) were detected in the elderly population. Even among centenarians, significant differences may be observed because of the different specific populations studied [35], [68]. Nevertheless, the reduction in TNF-α level is a common characteristic of centenarians [1].

Ensuring a balance between pro- and anti-inflammatory immunity in the elderly is beneficial for healthy aging. Recent studies suggest that human longevity is significantly shorter with a disrupted balance of immunosenescence and inflammaging [69]. Maintaining a “youthful” or “healthy” gut microbiota during the aging process may delay or restrict immunosenescence and inflammaging [70].

The role of key gut microbes in aging

The abundances of Akkermansia, Christensenellaceae, Clostridium cluster IV and XIVa, Faecalibacterium prausnitzii, Bifidobacterium and Lactobacillus were found to decrease over the aging process, yet a relatively high abundance of these microbes is observed in centenarians, except for Faecalibacterium prausnitzii [21], [71], [72]. All of these microbes have been reported to promote healthy aging by facilitating homeostasis in the intestine as well as reducing inflammation through various mechanistic routes (Fig. 3).

Fig. 3.

Mechanisms on host aging alleviation by specific beneficial microbes The most important role of key bacteria such as Akkermansia is the production of SCFAs. In addition, Akkermansia can also act on the TLR-2 receptor by producing Amuc_1100; promoting increases in the amount of goblet cells, which promotes the production of mucus layer; increasing the expression of tight junction proteins (TJPs); up-regulating AhR receptor; and up-regulating RORγt⁺ T_reg cell-mediated immune response. However, recent studies have shown that Akkermansia also decreases the production of DCA and LCA. As illustrated in the figure, other bacterial species (such as Bifidobacterium animalis, Faecalibacterium prausnitzii, etc.) focuses on promoting the production of immune molecule such as IgA and anti-inflammatory cytokines by immune cells, and regulate the expression of TJPs and other mechanistic routes.

Akkermansia muciniphila and Clostridium spp. Akkermansia muciniphila (A. muciniphila) is an elliptical gram-negative and stringently anaerobic bacterium that belongs to the phylum Verrucomicrobia. A. muciniphila is also a “next-generation probiotics”. Recent research has revealed that it can tolerate hypoxia as well [73]. Bárcena et al. found that A. muciniphila was effective in prolonging the lifespan of premature mice by transplanting it into Lmna^G609G/G609G premature aging mice [74]. Further studies found that administration with A. muciniphila increased ileocecal expression of Reg3g and intestinal trefoil factor Tff3, thereby favoring the restoration and thickening of the mucosal layer. In conclusion, the positive effects of Akkermansia on aging are mainly reflected in protecting the mucus barrier function (enhancing the abundance of goblet cells and MUC2 and MUC3 proteins expressed levels [50]), changing the composition of the gut microbiota (promoting the proliferation of other beneficial symbionts [75]), playing an anti-inflammatory role (reducing the production of pro-inflammatory cytokines such as TNF-α, IL-6 and MCP-1[76]) and promoting immune function (upregulating RORγt⁺ T_reg cell-mediated immune response [77]). Additionally, studies have also shown differences in the metabolic effects of A. muciniphila and pasteurized A. muciniphila. Although few studies have evaluated their direct effects on host aging, they can change the levels of polyamines, SCFAs, bile acids (BAs), 2-hydroxybutyrate, and other metabolic pathways associated with aging and/or human health [78].

Clostridium cluster IV, XIVa, and Clostridium butyricum also have anti-inflammatory properties and maintain intestinal barrier function. For example, Clostridium cluster IV and XIVa block NF-κB and IL-8 production, induce the generation of T_reg cells, and produce bacterial antigens and TGF-β [79], [80], [81], [82], [83]. The detailed mechanistic routes involved are shown in Fig. 3. Clostridium clusters IV, XIVa, and Clostridium butyricum are enriched in centenarians. Previous studies have focused on reducing inflammation and treating colorectal cancer and diabetes with few direct links to aging [71], [80], [84], which could be further investigated in future studies to examine their roles in aging and whether they can actually mitigate aging.

Bifidobacterium and species from Lactobacillaceae. Bifidobacterium and Lactobacillus are commonly used probiotics and widely considered to promote health. Fang et al. showed that the probiotic combination including Bifidobacterium (Bifidobacterium longum SX-1326, and Bifidobacterium animalis SX-0582) and Lactobacillus (Lactobacillus fermentum SX-0718, Lactobacillus casei SX-1107) improved impaired spatial memory and motor dysfunction in aging mice, inhibited TLR4/NF-κB-induced neuroinflammation, and enhanced the expression of ZO-1 and occludin proteins to improve the gut barrier integrity [85]. Bifidobacterium play an essential function in the barrier effect [86]. For instance, Bifidobacterium animalis subsp. lactis BLa80 reduces pro-inflammatory cytokines, increases gut microbiota diversity, promotes the proliferation of beneficial bacteria [87], inhibits the activation of TLR4/MYD88/NF-κB signaling pathway, and increases the expression of TJPs [88]. Bifidobacterium bifidum exerts its anti-inflammatory effects by regulating miRNA-associated TJP and NF-κB modulation and partly recovering dysbiosis [89]. Bifidobacterium longum can alleviate colitis through the TLR-2-induced upregulation of claudin-1 and ZO-1 gene expression [90], and can enhance bacterial arginine enrichment to achieve anti-aging [13].

Christensenellaceae. Christensenellaceae of the phylum Firmicutes is one of the five taxa that are considered signatures of a healthy gut, exhibiting higher abundance in centenarians and supercentenarians [72]. Several researches have demonstrated that the presence of Christensenellaceae in older adults is correlated with visceral fat-related cardiovascular and metabolic diseases, which is a potential marker of healthy aging and possible longevity [91]. Christensenella minuta (C. minuta) of Christensenellaceae is a potential next generation probiotic. C. minuta is closely associated with weight loss, as it regulates metabolic markers associated with obesity such as blood glycemia and leptin, and results in lower levels of pro-inflammatory IL-8 cytokines through suppression of the NF-κB signaling pathway [92], [93]. Previous studies have shown that C. minuta also produces LPS, which in small amounts induces the proliferation and phagocytosis of macrophages, and produces an immune response [94]. The weight loss effect of C. minuta may be due to the promotion of an immune response, and subsequent inhibition of the proliferation of pathogens like E. coli [94]. Hence, it has been hypothesized that C. minuta also promotes healthy senescence by inducing a moderate immune response.

Faecalibacterium prausnitzii. Faecalibacterium prausnitzii accounts for approximately 5 % of fecal microbiota, and is one of the primary butyrate-producing bacteria in the intestine. Several studies have indicated that the abundance of fecal or mucosal-associated F. prausnitzii can be used as an underlying biomarker to differentiate intestinal disorders [95]. It has been shown that there is a reduction in F. prausnitzii in age-related disorders [96], and that supplementation with F. prausnitzii isolated from healthy voluntaries were shown to enhance cognitive functions in mice [97]. F. prausnitzii and its supernatant were found to shorten the severity of acute, chronic, and low-grade chemically-induced inflammation through mouse models, and its anti-inflammatory properties were mainly mediated through secretion of the anti-inflammatory cytokine IL-10 by peripheral blood monocytes, DCs, and macrophages, secreting extremely low levels of the pro-inflammatory cytokines IL-12 and IFN- γ, blocking the activation of NF-κB and the production of IL-8, and upregulating regulatory T cell production [98], [99]. Additionally, the effect of F. prausnitzii and its supernatant on reduction in gut permeability may be related to the expression of certain TJPs [100]. These anti-inflammatory properties may be partly attributed to the production of butyrate, a metabolite secreted by F. prausnitzii.

In addition to Faecalibacterium prausnitzii, Christensenella minuta (C.minuta) and Clostridium cluster IV and XIVa, which are enriched in the intestines of centenarians, what they have in common in the alleviation of aging is that these bacteria are SCFAs-producing bacteria, which can have a protective influence on the gut barrier by production of SCFAs, thereby alleviating aging [94], [101], [102], [103].

Gut microbiota-derived metabolites in aging

Concurrent with alterations in the composition of the gut microbiota, the metabolic pattern of the gut microbiota also undergoes a transformation that affects the bioavailability of functional metabolites such as SCFAs, indole derivatives, spermidine, and BAs. The cross-talk between the host, gut microbiota and diet ensures the production of the above-mentioned bioactive molecules, which in turn bind to host receptors and regulate physiological functions such as host immunity, gut barrier, and epithelial tissues. However, with age, the levels of these metabolites gradually decrease and lead to gut barrier damage, systemic inflammation, and the development of immune diseases [60]. The specific mechanisms of action of these microbially-derived metabolites in the host are shown in Fig. 4.

Fig. 4.

Mechanisms of action on host aging alleviation by key microbial-derived metabolites SCFAs, secondary BAs, Trp derivatives, and polyamines are produced by gut microbes. These compounds can be used in a variety of ways to protect the intestinal barrier, reduce inflammation, and in turn promote health. For example, SCFAs can bind to GPCR and TLR-4 to regulate the production of anti-inflammatory cytokines and inhibit the secretion of pro-inflammatory cytokines via intestinal epithelial cells (IECs) and immune cells, regulate goblet cell to promote the production of mucus layer, inhibit the activation of NF-κB via the HDAC pathway, increase the expression of TJPs, and promote an increase in the proliferation of beneficial bacteria, and suppress opportunistic pathogenic bacteria. Trp metabolites regulate IEC and ILC3 secretion of immune factors, such as IL-22, primarily through combining with PXR and AhR receptors. BAs can bind to receptors such as TGR5 and FXR to regulate the intestinal barrier and reduce inflammation through immune cells. Polyamines have been displayed to increase the number of anti-inflammatory macrophages and memory T cells, regulate TJPs and inhibit inflammation.

SCFAs. Studies have shown that the levels of SCFAs (acetate, propionate and butyrate) tend to decline with age [104]. However, higher levels of SCFAs were detected in the fecal samples of centenarians than in older adults, and the gut microbiota of centenarians has a higher glycolytic capacity [105]. Fecal transplants of the senescent microbiome into GF mice by gavage demonstrated that the senescent gut microbiota itself reduced SCFAs in the host, leading to cognitive decline [12]. Remodeling the gut microbiota of older mice by gavage of the fecal microbiota of younger mice was found to improve healthy lifespan in natural aging and to improve inflammation and intestinal barrier, with Akkermansia muciniphila and its derived acetic acid being responsible for these beneficial effects [49]. In addition, supplementation with butyrate-producing bacteria increased serum levels of butyrate in aged mice and macaques, reduced inflammation [106], and reduced muscle atrophy during aging in mice [104]. These findings provide evidence that SCFAs are associated with aging. SCFAs are mainly used in the intestine to achieve an intestinal microecological balance by lowering the intestinal pH, providing energy, forming antimicrobial peptides, and inhibiting the growth of bad bacteria [107]. Decreased levels of SCFAs during aging may adversely affect the intestinal barrier [104]. Butyrate is a potentially critical inhibitor of unhealthy aging that delays the transition to physiological decline in senescent hosts [30]. Gut microbial derived butyric acid have been shown to inhibit HDAC activity thereby modulating macrophage function in the lamina propria of mice gut [108]. In addition, it can also promote the anti-inflammatory properties of colon macrophages and DCs by activating GPR109a signaling, thereby inducing the differentiation of Treg cells and IL-10 producing T cells [109]. SCFAs (acetate and propionate) induce an immune response by activating ERK1/2 and p38 mitogen-activated protein kinase (MAPK) signaling pathways in epithelial cells through GPR41 and GPR43 [110]. In general, different SCFAs play different roles through separate pathways to alleviate aging-related immunity decline.

Tryptophan derivates. Microbiota-derived Trp derivates (tryptamine, indole propionic acid (IPA), and indole derivatives) have been revealed to be closely associated with host aging, and have great potential in the prevention of age-related diseases [111]. For example, tryptamine and its derivatives can inhibit neuronal cells and reduce neuronal damage [111], and IPA can reduce inflammation and neuronal apoptosis via the GPR30/AMPK/SIRT1 pathway, thereby attenuating neurodegeneration during aging [112]. In addition, high levels of IPA reduce the incidence of cardiovascular disease [112] and diabetes mellitus type 2 [113] in the elderly. Rampelli et al. found an increased abundance of genes associated with Trp metabolism in the gut microbiota of centenarians [114]. However, indole content and TnaA abundance were reduced in the feces of the elderly compared with young people and infants [37]. Through research on various organisms such as Drosophila melanogaster, Cryptomeria elegans, and mice, indole produced by commensal bacteria was demonstrated to prolong healthy lifespan with no impact on maximum lifespan. Thus, indole may be used to improve the process of aging but cannot extend the lifespan [115]. Gut microbiota has a direct effect on the type and level of Trp metabolites as well. Trp metabolism is pathway representing host-microbe co-metabolism, which requires the participation of both host and microbial enzymes to catabolize Trp into three types of metabolites: microbial-derived, host-derived, and microbial- and host-shared derivatives [116]. For example, Clostridium sporogenes and Ruminococcus gnavus can metabolize Trp to tryptamine via tryptophan dehydrogenase, and IPA is produced by symbiotic bacteria Lactobacillus reuteri, the genera Clostridium and Peptostreptococci, which are equipped with tryptophanase [111]. According to a previous study, IPA levels in the serum of GF mice were not detected until 5 days after Clostridium sporogenes colonization [117]. In addition, some specific species of Clostridium anomalum, Bifidobacterium spp. and Lactobacillus spp. can also produce Trp metabolites such as indole, indole-3-acetic acid, indole-3-carboxaldehyde (ICA), etc. [118]. These metabolites interact with the host's Aryl Hydrocarbon Receptor (AhR) or pregnane X receptor (PXR), which can impact the integrity of the gut barrier and immune cells in mice [119]. For example, the ICA of microbial metabolism restores the amount of goblet cells in elderly animals through the action of AhR and IL-10 [120], and IPA, also a microbial-derived metabolite, can enhance the mucus barrier by promoting the production of mucin proteins (MUC2 and MUC4) and increasing goblet cell secretion products, and the expression of inflammatory cytokines (TNF-α, IL-8 and IL-6) was downregulated by inhibiting LPS-induced PI3K/AKT/mTOR signaling [121]. Venkatesh et al. showed that the modulatory impact of IPA on the intestinal barrier are mainly mediated through PXR and TLR4 receptors [122]. Aging alters the balance of gut microbes, disrupts the gut mucosa, and promotes inflammation, which happens to be reversed by microbial-derived Trp derivates, and thus it is hypothesized that Trp derivates may be mitigate aging by activating receptors and thereby affecting the gut barrier and inflammation.

Polyamines. Polyamine metabolism has been demonstrated recently to play an important role in aging, with putrescine, spermidine, and spermine being the most studied polyamines [123]. In rodents, overall levels of spermidine and putrescine decline with age, while spermine content declines only in the brain [124]. Pucciarelli et al. found that the total polyamine content of whole blood tended to decrease and then increase with age. And the levels of spermine and spermidine in individuals over 90 years old were similar to those of people younger than 50 years old and significantly higher than those of people between the ages of 60 and 80 [125]. Recent epidemiological evidence suggests that increasing the dietary intake of spermine may reduce overall mortality, cardiovascular mortality and cancer-related mortality [126]. Additionally, it has been shown to extend lifespan and improve age-related memory impairment in yeast, nematodes, Drosophila, and mice [127]. Older adults who took a daily combination of 200 µg of putrescine, 900 µg of spermidine, and 500 µg of spermine (a total of 1600 µg) for 12 consecutive months were reported to have positive effects on cognition [128]. All of these evidences prove that polyamines are associated with aging. In addition to cellular biosynthesis in host cells, dietary intake and synthesis by gut microbiota are the main mechanisms through which the host accesses polyamines. Because food-derived polyamines are absorbed into the upper intestinal tract, most polyamines in the colon are produced by gut microbiota [129]. The ornithine decarboxylase pathway and the arginine decarboxylase (ADC) pathway are the two main polyamine metabolism pathways. The gut microbiota synthesizes polyamines mainly through the ADC pathway [130]. Current studies have shown that Bacteroides, Parabacteroides, Ruminococcus, Clostridium, Eubacterium, Latilactobacillus and other members of gut microbiota can synthesize/transport polyamines through the carboxyspermidine dehydrogenase, carboxyspermidine decarboxylase, putrescine-agmatine antiporter, SpeA, and PotB [131]. In vitro experiments revealed that deletion of the speA gene (gene related to biosynthesis of agmatine, which is a precursor for the synthesis of spermidine) in Bacteroides dorei resulted in a decrease in the concentration of spermidine in the cells and culture supernatants [132]. N-carbamoylputrescine amidohydrolase, an enzyme that biosynthesizes the precursor of spermidine, whose absence also reduced spermidine accumulation in Bacteroides thetaiotaomicron cells [133]. Metabolic synthesis of polyamines by gut microbes can occur either within individual bacterial cells or through sequential reactions of different bacterial species in the gut. For example, arginine can be converted to agmatine by the AdiA/SpeA genes of E. coli, after which the conversion of agmatine to putrescine can be performed by the AguA and AguB genes of Enterococcus faecalis [134]. Microbially derived polyamines have a broad range of effects on the intestinal environment, which includes promoting the intestinal barrier integrity by increasing the expression of colonic epithelial cells and TJPs (Claudin1 and Occludin), mediating intestinal immunity by increasing the number of anti-inflammatory macrophages in the colon, stimulating the formation of memory T cells, and inducing of autophagy in CD4 + T cells [135], [136], [137]. Ma et al. showed that spermidine restored the mRNA expression of autophagic (Lc3b, Atg4d, and Atg16l2), TJ (Cldn1, Cldn7, Tjp1, and Tjp3), mucin secretion (Reg3b, Defa, Muc1, and Muc2), and inflammatory (Tnfrsf, TNF-α, and IL6st) markers in the colon [138]. It has been suggested that the mechanism of life extension by polyamines may be related to the inhibition of chronic inflammation and enhancement of the intestinal barrier [139].

Bile acids. BAs regulate many facets of human health, particularly in maintaining homeostasis of the intestinal microbiota and balance of the mucous membrane immune system [140]. Fecal BAs were altered in centenarians, including a decrease in primary BAs and an enrichment of secondary BAs (e.g., lithocholic acid (LCA) derivatives), compared with younger or older adults [141]. Changes in composition of BAs with age have also been found in mice [142], [143]. For example, the increased ratio of conjugated to unconjugated BAs in the liver and serum of aged mice was associated with changes in the composition of the gut microbiota [143]. Transplanting feces from WT mice into progeroid mice prolonged their lifespan. The metabolomics analysis of ileal contents suggested that the restoration of the secondary BA pool may be a potential mechanism for prolonging lifespan [74]. A diet rich in cholic acid (CA) improved the health and longevity of prematurely aging mice by restoring dysregulated BA pool [144], [145]. Supplementation with LCA extended the lifespan of yeast [146] and fruit flies [147]. After hepatic conversion of cholesterol to BAs in humans, approximately 95 % of BAs are reabsorbed before reaching the end of the ileum, whereas the remaining 5 % of BAs enter the colon to be metabolized by gut microbes to secondary BAs before being passively reuptaken [148]. Bile salt hydrolase (BSH) and 7α/β-dehydroxylases are two categories of enzymes produced by gut microbiota involved in the deconjugation of conjugated primary BAs (by removing taurine or glycine) and subsequent conversion to secondary BAs [149]. The distribution of BSH in the gut microbiota is diverse and is present in Bifidobacterium, Clostridium, Lactobacillus, and the phylum Bacteroidetes [150]. Martoni et al. found that ingestion of BSH-active Lactobacillus reuteri NCIMB 30242 increased plasma levels of unconjugated BAs in healthy hypercholesterolemic adults, which may be related to intestinal BAs deconjugation [151]. A few bacteria in Clostridium cluster XIVa and XI carry bile acid-inducible (bai) genes that can encode 7α/β-dehydroxylases [149], [152]. A new strain of Faecalicatena contorta S122 was recently found to carry a putative bai operons and can convert CA/chenodeoxycholic acid to deoxycholic acid/LCA [153]. Aging-induced imbalances in the gut microbiota not only can reduce the activation of BSH, leading to diminished metabolism and deconjugation of BAs, which affects the composition of the BA pool and levels of specific BAs, but also affect the expression of the relevant receptors (e.g., the nuclear farnesoid X receptor (FXR), PXR, nuclear vitamin D receptor (VDR), and Takeda G protein-coupled receptor 5 (TGR5)), thereby increasing the probability of development of different diseases [154]. It has been shown that the expression of FXR and TGR5 declines with age and that gut microbiota-derived BAs modulate intestinal mucosal homeostasis and inflammation by specifically binding to IEC and immune cells and activating the FXR, PXR, VDR, and TGR5 [155], [156]. For example, LCA can be used as a ligand for VDR to increase the expression of TJ marker proteins (ZO-1, E-cadherin, Occludin, and Claudin1), suppress NF-κB signal transduction, and activate of the SIRT1/Nrf2 pathway [157]. Secondary BAs have anti-inflammatory, enhancing barrier integrity, and improving glucose homeostasis effects. Therefore, BAs represent a potential research area in healthy aging.

Other Metabolites. A diet rich in polyphenols is degraded in to urolithin A (UroA) by microorganisms. Research has shown that UroA can prolong the lifespan of Cryptomeria elegans [158], improve muscle health, and increase muscle endurance in the elderly [159], [160], [161]. UroA alleviates or controls inflammatory bowel disease (IBD) by upregulating the expression of epithelial TJPs through activation of the AhR-Nrf2 pathway and enhancing the intestinal barrier integrity [162]. Therefore, it is speculated that the anti-aging mechanism of UroA may also be relevant to the AhR-Nrf2 pathway. Recent studies have demonstrated that metabolites δ-valerobetaine from the gut microbiota shows an increasing trend with age, which can drive brain aging by causing changes in the activity of the mPFC neural network. In addition, it is a diet-dependent obesogen derived from gut microbiota, which can reduce cellular carnitine and inhibit mitochondrial fatty acid oxidation, exacerbating visceral obesity in WD [163], [164].

Targeted regulation of gut microbes by dietary intervention

In recent years, a growing number of studies have used dietary strategies, including dietary regimes, dietary patterns, and probiotics/prebiotics/synbiotics/postbiotics, to modulate the gut microbiota and its metabolic changes caused by aging or age-related diseases with the purpose of alleviated these physiological disorders (Table 2).

Table 2.

Summary of dietary interventions to alleviate aging and potential interventions targeted aging-associated gut microbiota biomarkers.

Diet	Disease	Experiment model	Phenotypes	Key findings		References
				Microbial changes	Changes in microbial metabolites
Animal and cell experiments
Intermittent Fasting	Obesity	C57BL/6N mice	Alleviation of immune senescence	Altered composition of the gut microbiota	↑Acetate and lactate	[202]
Intermittent Fasting	Alzheimer’s disease	5XFAD mice	Improvement of cognitive function	–	↑Sarcosine, dimethylglycine	[168]
Mediterranean diet	Alzheimer’s disease	Sprague Dawley rats	Improvement of cognitive function	↓Actinobacteria ↑Patescibacteria	–	[169]
Lactobacillus casei Shirota	Aging	SAMP8 mice	Reduction of inflammation and oxidative stress, modulation of age-related muscle damage	↑Lachnospiracae_UCG_006 ↑Erysipelatoclostridium	↑SCFAs (acetic, isobutyric, butyric, penic, and hexanoic acids)	[178]
Lactobacillus casei LC122 Bifidobacterium longum BL986	Aging	C57BL/6 mice	Enhancement of intestinal barrier function, reduction of oxidative stress and improvement of cognitive function	The administration of Lactobacillus: ↑Lactobacillus, Escherichia-Shigella, Ruminococcus 2, and Veillonellaceae UCG-001, Faecalibaculum, Lachnospiraceae NK3A20, Ruminococcaceae UCG-005 The treatment of Bifidobacterium: ↑Bifidobacterium, Ruminiclostridium, Desulfovibrio, and Alloprevotella	–	[177]
VSL#3	Alzheimer’s disease	C57BL/6 mice AppNL-G-Fmice	Improvement of the immune response, anxiolytic	–	↑SCFAs (Acetate, butyrate, and lactate) in serum	[203]
Lactobacillus plantarum DR7 L. reuteri 8513d L. fermentum DR9	Aging	Sprague–Dawley rats	–	DR9: ↑Blautia, Ruminococcus and unc.Erysipelotrichaceae; ↓Clostridium and unc._S24-7. DR7: ↑Blautia,unc. Erysipelotrichaceae, F/B ratio; ↓genus unc._Ruminococcaceae and Ruminococcus	↑SCFAs (feces), DR7 and 8513d: ↑Compounds associated with amino acid metabolism (tryptophan, valine, leucine, tyrosine, lysine, cysteine and methionine) DR9: ↑Carbohydrate metabolism-related compounds (erythritol, xylitol, and arabitol)	[204]
Bacillus licheniformis	Aging	Caenorhabditis elegans	Extended life span	–	Influence on genes involved in serotonin signaling, including tph-1 (tryptophan hydroxylase), ser-1 and ser-7 (serotonin receptors), bas-1 (serotonin- and dopamine-synthetic aromatic amino acid decarboxylase), mod-1 (serotonin-gated chloride channel)	[181]
Latilactobacillus curvatus KP 3–4	/	Germ-free mice	–	–	↑Putrescine（feces）	[205]
Bifidobacterium animalis subsp. lactis LKM512	Aging	ICR mice	Maintenance of intestinal barrier integrity, anti-inflammatory, extended life span and preventing age-related memory disorders	↑Prevotella	↑ Spermidine、spermine	[127]
Lactobacillus plantarum WcFs1	Aging	Ercc1−/Δ7 mice	Protection of the mucus barrier	Bacterial supplementation did not significantly change microbial diversity and abundance.	–	[183]
Lactobacillus helveticus KLDS1.8701	Aging	BALB/c mice	Reduction of oxidative stress in the liver	↑Lactobacillus, Faecalibacterium, Bifidobacterium, Rikenella, Alloprevotella, Butyricicoccus and Blautia ↓Desulfovibrio, Helicobacter, Alistipes, Odoribacter, Bacteroides and Parabacteroides, Escherichia Shigella	↑Butyrate ↓Endotoxin	[179]
Probiotic mixture-1 (Lactobacillus plantarum BCRC 12251, Streptococcus thermophilus BCRC 13869, Lactobacillus paracasei ssp. paracasei BCRC 12188,)	Aging	C57B/CL6 mice	Improvement of memory and learning ability as well as antioxidant capacity in aging mice	–	SCFAs maintained at normal levels	[206]
ProBiotic-4 (B. lactis, L. acidophilus, B. bifidum and L. casei)	Aging	SAMP8 and SAMR1 mice	Weakening the disruption of the gut barrier and blood–brain barrier related to aging, reducing inflammation, and improving cognitive impairment	↓F/B ratio, Lachnospiraceae_NK4A136_group and Proteobacteria, Pseudomonas	–	[182]
Lactobacillus rhamnosus	/	Sprague Dawley Rat	Enhancement of the immune system and maintenance of gut integrity	↑Limnobacter, Turicibacterales, Enterococcus, and Vagococcus. ↓ Oscillospira, Rikenellaceae, Dorea, Anaerostipes S24_7, Bacteroidia, Ruminococcaceae, Clotridiales, Roseburia, Bacteroidetes, Coprococcus, Helicobacteraceae and Lachnospira	Regulating the metabolism of energy, lipids, sugars and amino acids	[207]
Lactobacillus plantarum 69‑2 combined with Galactooligosaccharides	Aging	BALB/c mice	Antioxidant activity of the liver is restored, inflammation is reduced, and aging is mitigated.	–	↑SCFAs (Acetate, propionate, butyrate)	[52]
Grape seed proanthocyanidin extract	Aging	BALB/c mice	Improvement of antioxidant capacity, anti-inflammatory, anti-aging	↑Akkermansia, Lachnospiraceae_NK4A136, Lactobacillus, Bifidobacterium ↓Helicobacter and Alistipes	–	[189]
Bilberry anthocyanin extract	Aging	SD rats	Reduced damage to intestinal barrier function	↑Bacteroides, Lactobacillus, Aspergillus oryzae, the Lachnospiraceae_NK4A136_group, the Bacteroidales-S24-7-group and Clostridiaceae-1 ↓Verrucomicrobia and Euryarchaeota	↑SCFAs (Acetic acid, propionic acid, butyric acid)	[208]
Galactooligosaccharide	Aging	C57BL/6J mice	Intestinal permeability decreased and mucus production increased.	↑Bacteroides and Lactobacillus	–	[185]
Dietary pulses-derived resistant starches	Aging	C57B6/J mice	Reduced intestinal leakage and inflammation	Significant differences in microbiota at the level of phylum and genus ↓Enterococcus, Odoribacter, Desulfovibrio, Alistipes and Erysipelatoclostridium。	–	[184]
yuzu (Citrus junos) extracts	Aging	C57BL/6 mice	Extended life and reduced validation	Changes in the relative ratio between Bacteroidetes (Bacteroidales and Lactobacillus) and Firmicutes (Clostridiales and Erysipelotrichaceae)	↑SCFAs (acetic acid, propionic acid, and butyric acid)	[209]
Inulin	Alzheimer's disease	C57BL/6J mice	Reduction of pro-inflammatory bacteria	↑Roseburia, Akkermancia, ↓F/B ratio, pathogenic bacteria (Ruminococcaceae, Streptococcaceae, Lactococcus, and Ruminiclostridium 9)。	↑Butyric acid	[175]
Phenolic Compounds-Rich Grape Pomace	Aging	Wistar rats	Counteract the adverse effects of aging on intestinal flora	↓Clostridium Cluster I Clostridium cluster IV, Bacteroides and Enterococcus were not significantly changed	–	[210]
Genistein	Aging	C57BL/6 mice	Reducing the level of systemic inflammatory cytokines in aging mice, promoting health and longevity	↑Lachnospira (SCFA synthetic bacteria)	↑ SCFAs	[16]
Melatonin	Aging	C57BL/6J mice	Inhibition of FXR expression	–	↓TCDCA, TMAO (liver)	[211]
Fructus Ligustri Lucidi	Aging	ICR mice	Reversing the increase in oxidative stress	Restoring the gut microbiota ↓Coprococcus, Clostridium, Desulfovibrio and Sutterella ↑Lactobacillus, Bifidobacterium, and Allobaculum	↓TMAO	[212]
Ellagic Acid	Aging	Sprague − Dawley rats	–	↓Firmicutes and Bacteroidota, Akkermansia, Bifidobacterium, Clostridium_sensu_stricto_1. ↑Lactobacillus and Tubriciactor.	↑Urolithin A, GABA, and 5-HT	[213]
LAB metabolites	/	Male piglets	–	↑Faecal lactic acid bacteria	↑Faecal SCFAs	[194]
F. prausnitzii strain A2-165 and its culture supernatant (SN)	Chronic low-grade inflammation	C57BL/6 mice	Reducing inflammation	–	↓Serotonin levels	[196]
Clostridium butyricum supernatant	Colorectal cancer	Apcmin/+ mice	Suppression of the Wnt/β-catenin signaling pathway and regulation of gut microbiota composition	Inhibit the increase of pathogenic bacteria and promote the growth of beneficial bacteria.	–	[214]
Pasteurized Akkermansia muciniphila	Colorectal cancer	C57BL/6 mice	–	–	↑Polyamines, SCFAs, 2-hydroxybutyrate, multiple BAs	[78]
Betaine	Obesity	Leprdb/db miceC57BL/6 mice	Preventing HFD induced obesity	↑Akkermansia muciniphila, Lactobacillus and Bifidobacterium	↑propionate, acetate and butyrate	[215]
A fish-oil diet enriched in polyunsaturated fatty acids	Obesity	C57BL/6 mice	Reduced metabolic inflammation	↑Akkermansia muciniphila and Lactobacillus	–	[216]
Lactobacillus reuteri	/	C57BL/6J mice	Stimulating immune cells and prolonging the survival period of melanoma patients	–	↑Indole-3-aldehyde (I3A)	[217]
Inulin	Alzheimer's disease	C57BL/6 mouse	Reducing inflammatory gene expression in the hippocampus and the risk of AD in asymptomatic APOE4 carriers	↑Prevotella and Lactobacillus spp.	–	[218]
Inulin	Aging	C57BL/6J mice	–	↑Faecalibaculum	↑Butyrate	[219]
Lacticaseibacillus paracasei SD1 and Lacticaseibacillus rhamnosus SD11	Colon cancer	Caco-2 cellsHIEC-6 cells	Anti-inflammatory	–	↑Butyrate	[220]
Clinical Trial
Heat-inactivated Bifidobacterium bifidum MIMBb75 (SYN-HI-001)	Irritable bowel syndrome	Patients with IBS	Alleviating IBS			[198]
LKM512 yogurt	Hospitalized elderly people	Elderly (average age, 76.9 years)	–	↑B. animalis subsp. Lactis ↓Lactobacillus spp.	↑ SCFAs	[221]
LKM512 yogurt	Cognitive decline	Elderly (average age 78.0 years)	Inhibition of acute intestinal inflammation	–	↑Putrescine, spermidine, spermine, and cadaverine	[222], [223]
Synbiotic beverage: Soy and yacon extracts enriched with Bifidobacterium animalis ssp. lactis BB-12	Healthy elderly people	Elderly (over 65 years of age)	Does not affect inflammatory response.	–	↑Putrescine, cadaverine, spermidine (feces)	[224]
Multi-strain probiotic (alongside omega-3): L. paracasei Lpc-37, B. lactis Bl-04, L. acidophilus NCFM, B. lactis Bi-07	Aging	Elderly (aged 65–81 years)	Reduced inflammation	–	↑Isobutyric acid, valeric acid, valproic acid	[225]
Soluble Corn Fiber, Pilus-Deficient Derivative GG-PB12 and Lactobacillus rhamnosus GG	Healthy elderly people	Elderly（aged 60–80 years）	Promotion of innate immunity and reduction of inflammatory cytokines	↑Parabacteroide, Ruminococcaceae Incertae sedis ↓Oscillospira and Desulfovibrio	–	[226]
Bifidobacterium longum MM-2, Bifidobacterium bifidum G9-1 and Lactobacillus gasseri KS-13	Aging	Elderly (aged 65–80 years)	Reduction of inflammatory cytokines	↑Fecal bifidobacterial, lactic acid bacteria ↓Escherichia coli	–	[227]
A mix prebiotics (resistant starch, wheat dextrin, polydextrose, galactooligosaccharide, and soluble corn fiber)	Frailty	Men (over 20 years old)	The level of chemokine CXCL11 decreased.	↑Ruminococcaceae (Clostridium cluster IV), Parabacteroides, Phascolarctobacterium.	–	[186]
A biscuit with probiotics: Lactobacillus helveticus Bar13 and Bifidobacterium longum Bar33	Aging	Elderly (aged 71 to 88 years)	Maintenance of immune homeostasis	↓The opportunistic pathogens: Clostridium perfringens, Clostridium cluster XI, the enteropathogenic genus Campylobacter, Clostridium difficile, Enterococcus faecium.	–	[180]
Bifidobacterium lactis W51, Lactococcus lactis W19, Lactobacillus salivarius W24, Lactobacillus casei W56, Bifidobacterium lactis W52, Lactobacillus paracasei W20, Lactobacillus plantarum W62, Lactobacillus acidophilus W22, Bifidobacterium bifidum W23	Alzheimer's disease	20 outpatient patients with dementia symptoms (age 76.7 ± 9.7 years)	–	–	↑Canine uric acid (serum) No significant change in Kyn/Trp concentration	[228]
Mediterranean diet	Frailty	Elderly (aged 65–79 years)	Improvement of cognitive function and anti-inflammatory	↑ Eubacterium (E. rectale, E. eligens, E. xylanophilum), Roseburia hominis, Faecalibacterium prausnitzii, Anaerostipes hadrus, Prevotella copri and Bacteroides thetaiotaomicron ↓Veillonella dispar, Coprococcus comes, Dorea formicigenerans, Collinsella aerofaciens, Actinomyces lingnae, Ruminococcus torques, Flavonifractor plautii and Clostridium ramosum	↑SCFAs, BCFAs ↓ ethanol, p-cresols, Secondary BAs and carbon dioxide.	[171]
Mediterranean diet	Aging	Men (over 16 years old)	Anti-inflammatory	MD significantly changed the abundance of three genera (Lachnoclostridium Enterohabdus and Parabacteroides)	↑SCFAs	[229]
Bifidobacterium animalis subsp. lactis Probio-M8	Parkinson’s disease	PD patients (average 69.41 ± 6.05 years)	Enhanced clinical efficacy in treating PD	↑Bifidobacterium animalis, Ruminococcaceae, and Lachnospira. ↓Lactobacillus fermentum and Klebsiella oxytoca	↑Cholic acid and deoxycholic acid, SCFAs.	[230]

Note: PD, Parkinson’s disease; SCFAs, short chain fatty acids; BCFA, branch chained fatty acid; Kyn/Trp, kynurenine/Tryptophan; GABA, γ-Aminobutyric acid; 5-HT, 5-hydroxytryptamine; TMAO, Trimethylamine N-oxide; TCDCA, taurine chenodeoxycholic acid; F/B, Firmicutes/ Bacteroidetes.

Calorie-restricted (CR)

Experimental animal studies have shown that lifelong calorie-restricted (CR) can balance the structure of the gut microbiota and may facilitate the development of a Lactobacillus-predominated gut microbiota, and thereby promote host health. Therefore, calorie-restriction is considered the only effective experimental regimen for extending the life span in various animal models [165]. As a powerful but simple dietary modifier, CR has now been proven in many model organisms to extend lifespan and improve various senescence-related diseases, including obesity, diabetes, and cardiovascular disease. However, its application in real life is still challenging owing to psychological and social behavioral constraints. At present, interventions similar to CR have been developed, including macronutrient modulation, intermittent fasting, and time-restricted eating [166]. Li et al. observed that intermittent fasting induced significant alterations in the content and composition of the gut microbiota in mice, and caused a significantly increase in the ratio of Firmicutes/Bacteroidetes that reversed the aging-related alterations in gut microbiota [167]. Pan et al. showed that the increase in metabolic products sarcosine and dimethylglycine from gut microbiota mediated by IF can alleviate the symptoms of Alzheimer's disease [168]. In general, caloric restriction could extend lifespan or improve aging-related diseases by regulating the changes in the gut microbiota and its metabolites caused by aging or aging-related diseases.

Dietary patterns

Many researches have reported an interaction between dietary patterns and a lower risk of aging and aging-related diseases, and these dietary patterns could help mitigate aging or improve aging-related diseases by regulating aging-induced changes in the gut microbiota and its metabolites, improving the gut barrier, and reducing inflammation, such as the Mediterranean diet, which has been shown to mitigate aging as well as improve cognitive function by beneficially altering gut microbiota and promoting the production of SCFAs [169], [170]. A project called NU-AGE conducted a one-year Mediterranean diet intervention with older adults from five countries, and suggested that the presence of several species of the gut microbiota was positively correlated with health increased (e.g. Faecalibacterium prausnitzii, Roseburia, Prevotella copri, Eubacterium, Bacteroides thetaiotaomicron and Anaerostipes hadrus), and the abundance of species that are negatively correlation with diseases such as type 2 diabetes and colon cancer decreased (e.g., Dorea formicigenerans, Ruminococcus torques, Coprococcus comes, Collinsella aerofaciens, etc.), which in turn could promote healthier aging [171]. However, not all dietary patterns have beneficial effects on healthy aging. Ketogenic diets have been reported to restore healthy gut microbiota (e.g., Akkermansia muciniphila sp.), improve cognitive function, and downregulate neuroinflammatory markers [172]. However, ketogenic diets also have negative effects, such as a decrease in the variety of gut species and beneficial microbes, increased pathogenic bacteria and altered intestinal metabolism, and decreased cognitive ability, which can result in increased intestinal and systemic inflammation and disruption of the intestinal barrier [173]. Adapting the ketogenic diet to a cyclic KD diet increases the average and healthy lifespan of mice [174], and adapting the ketogenic diet to an intermittent diet schedule reduces Firmicutes and enhances Akt phosphorylation [175]. Therefore, further studies are required to demonstrate whether the ketogenic diet model, in combination with intermittent fasting or other dietary patterns, can be more effectively utilized in patients with neurodegenerative diseases. Additionally, according to the genetic background of the host, the same diet may differ significantly in terms of enrichment or depletion of specific intestinal bacteria [176].

Probiotics, prebiotics, synbiotics

Dietary strategies, such as probiotics, prebiotics, synbiotics, postbiotics, etc., have important benefits in preventing aging-related gut microbiota imbalance or restoring healthy anti-aging.

The most extensively used probiotics in anti-aging research are Bifidobacterium and Lactobacillus. These probiotics delay aging or promote healthy aging by increasing the number of beneficial bacteria in the gut, including Lactobacillus, Faecalibulum, Bifidobacterium and SCFA-producing bacterium Lachnospiracae [177], [178], [179] and inhibiting the increase of opportunistic pathogenic bacteria [180]. Probiotics are species/strain specific in mitigating aging. For example, the probiotic LKM512 has been proven to raise intestinal concentrations of polyamines and prolong lifespan in mice [51], and Bacillus licheniformis (sieved from traditional Korean foods) can prolong the lifespan of Caenorhabditis elegans by host serotonin signaling [181]. However, several probiotics can also improve immunity and cognitive ability in aging mice, change the diversity of gut microbiota, yet not directly affect the lifespan. For example, ProBiotic-4 (Bifidobacterium lactis, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus acidophilus) weakened the aging-related disruption of the intestinal and blood–brain barriers, reduced inflammation, and improved cognitive impairment, yet there was no direct evidence that it extends lifespan or delays aging [182]. In addition, several probiotics may also negatively affect hosts. For example, intake of Lactobacillus casei BL23 or Bifidobacterium breve DSM20213 exacerbated the decrease of the colonic mucus barrier in Ercc1^-/Δ7 mice and B. breve DSM20213 suppressed immune pathways [183]. Prebiotics, such as inulin and galactooligosaccharides [175], [184], [185], [186], are dietary fibers that can bypass uptake in the upper digestive tract, and enter the colon where it is optionally fermented by the gut microbiota. These probiotics cause specific changes in the composition or metabolic activity of the gut microbiota, which favors healthy aging of the host [2], [187]. Dietary polyphenols play an important regulatory part [188]. Sheng et al. showed that grape seed proanthocyanidin extract increased the abundance of Lachnospiracea NK4A136, Lactobacillus, Bifidobacterium, and Akkermansia in the gut of mice and inhibited the growth of the harmful bacteria Helicobacter and Alistipes [189]. Prebiotics can restore the imbalance in the gut microbiota, inhibit systemic inflammation, and maintain the integrity of the intestinal barrier by regulating the composition of the gut microbiota, increasing beneficial bacteria while inhibiting pathogenic bacteria, triggering the production of beneficial metabolites like SCFAs, and thereby ultimately promoting healthy aging [190]. Synbiotics are a blend of probiotics and prebiotics that have attracted attention owing to their power to enhance gastrointestinal health. The types of synbiotics are mainly complementary and synergetic, but there are relatively few studies on the affection of synbiotics on aging, and few have been proven to have clinical efficacy [191], [192].

Postbiotics

Postbiotics are functional bioactive compounds, including microbial cells, cell components and metabolites (SCFAs, Trp derivates, and polyamines.) that are produced in the form of a matrix during fermentation, and can promote health [2]. Compared with probiotics, postbiotics have better stability, environmental tolerance and safety, and the target of postbiotics is broader. Previous studies have shown that postbiotics have strong effects on improving neurodegenerative diseases, immune function, allergic reactions, and maintaining the stability of the intestinal endo-environment, as well as better stability and safety [193]. For example, feeding the supernatant of Lactobacillus plantarum (containing SCFAs) or inactivated Lactobacillus rhamnosus to pigs has been shown to increase growth performance, improve immune response, and increase SCFAs in the intestines and feces [194], [195]. Pasteurized Akkermansia muciniphila was found to increase intestinal polyamine, SCFA, 2-hydroxybutyric acid, and a variety of BAs concentrations more efficiently than live Akk [78] through experimental studies in mice, and the supernatant of F. prausnitzii was found to have a mitigating effect on intestinal epithelial barrier damage in chronic inflammation [196]. In addition, the supernatant of heat inactivated Bifidobacterium adolescentis can promote the regeneration of ISCs and alleviate colon aging through the Wnt/β-catenin pathway, and subsequently, it was demonstrated that the soluble polysaccharides of Bifidobacterium adolescentis play a role in promoting ISCs [197]. Clinical trials have shown that supplementation with inactivated Bifidobacterium bifidum MIMBb75 (SYN-HI-001) can alleviate irritable bowel syndrome (IBS) [198]. Aging can cause disruption of the gut microbiota, damage to the intestinal barrier, and chronic inflammation, and postbiotics may improve the intestinal internal environment, increase metabolites associated with aging, and enhance immunity. Therefore, it is hypothesized that postbiotics could be effective interventions for anti-aging. However, current research on postbiotics in aging populations has primarily focused on host physiological or health-related changes, such as inflammatory state and response to vaccines [199], [200], with fewer studies analyzing the changes in the gut microbiota and whether they can alleviate aging or ameliorate aging-related diseases. Furthermore, the effects of postbiotics are only temporary, and these effects fade once the intervention is stopped [201]. In conclusion, the gut microbiota is a complex population of microorganisms that requires further research to prove its effectiveness and mechanisms.

Future possibility of using diet components targeted to aging-related biomarkers to intervene aging

As mentioned above, aging is related to variations in the diversity and composition of the gut microbiota. A systematic summary has revealed that decreased abundance of in key bacterial species, such as Akkermansia, Christensenellaceae, Faecalibacterium prausnitzii, Bifidobacterium and Lactobacillus, as well as decreased amounts of key metabolites, such as SCFAs, BAs, Trp derivatives, polyamines, and inosines, are closely associated with aging. Recent studies have shown that probiotics, prebiotics, and other dietary factors can specifically enhance the levels of aging-related microbes and metabolites (Table 2), and thus may potentially be effective in alleviating aging. For example, betaine supplementation can improve the imbalance of the gut microbiota induced by a high fat diet (HFD) and increase the abundances of Akkermansia muciniphila, Lactobacillus, and Bifidobacterium [215]. In addition, supplementation with omega-3 or fish-oil rich in omega-3 PUFAs can increase the levels of Bifidobacterium, Lactobacillus, Akkermansia muciniphila, and butyric acid producing bacteria Coprococcus, which may reduce metabolic inflammation [216]. Bender et al. found that supplementation with Lactobacillus reuteri may induce the production of indole-3-aldehyde, which stimulates immune cells and prolongs the survival of patients with melanom [217]. The combination of conventional regimens (benserazide and dopamine inhibitors) and Bifidobacterium animalis subsp. lactis Probio-M8 can enhance the clinical efficacy of PD treatment, while increasing the production of secondary BAs, such as cholic acid and deoxycholic acid, as well as SCFAs [230]. Inulin, a fiber that is easily fermented by gut bacteria, can increase the levels of key butyrate producing genera (e.g. Faecalibacterium), BAs, and Trp derivatives [219] and can reverse the aging microbiota phenotype to a young adult phenotype [231], reduce the expression of inflammatory genes in the hippocampus of asymptomatic E4FAD mice, and reduce the risk of AD in asymptomatic APOE4 carriers [218]. The probiotic bacterium LKM512 has been clinically proven to increase intestinal polyamine levels, inhibit systemic inflammation in elderly people, and maintain a healthy gut microbiota [51], [127], [221], [223]. Bifidobacterium longum can enhance the ability of the gut microbiota to accumulate arginine, which is another precursor to polyamines [13]. Although the direct effects of most of these dietary components on aging phenotypes have not yet been validated, these interventions can be used to regulate the abundance of key aging-related bacteria or metabolites. Further research is required to determine whether these compounds have a more targeted and functional role in the alleviation of aging. Aging is a complex process, and these current aging-related markers may be useful in one group of people but not in others. Therefore, future research will require larger samples, longitudinal cohort studies, and a variety of methods of controlling for interfering factors to validate whether these aging-related markers can actually mitigate aging.

As mentioned earlier, there are differences in gut microbes between healthy and unhealthy aging populations. The core microbiome (Faecalibacterium prausnitzii, Akkermansia muciniphila, Coprococcus, etc.) is under abundance decrease or even lost in unhealthy aging [232]. Therefore, selecting interventions that match the individual's aging process would more effectively contribute to healthy aging. Dietary interventions targeting the aging-related markers discussed above, including probiotics, prebiotics, synbiotics, and postbiotics, could theoretically promote changes in the core microbiome, thereby having the potential to mitigate aging. However, the response of microbiota-based dietary interventions to hosts is highly individualized, which is due to differences in baseline microbiota [30], [233]. If the core microbiome or key gut microbes have not been completely eliminated from the baseline microbiota, separate dietary interventions, as described above, may be used to increase the abundance of the core microbiome or key gut microbes. For example, the abundances of key gut microbes can be increased through direct supplementation with probiotics, dietary fibers, or synbiotics [234], [235], [236]. However, in cases of gut microbial dysbiosis, certain prebiotics may not precisely target the gut microbiota due to their simple structure and low specificity, which can promote the growth of unhelpful gut microbes [233], [237]. Therefore, targeted prebiotics that align with the enzymatic capabilities of health-promoting microbes can be used to achieve precise regulation of gut microbes [233]. Unhealthy gut microbes can be altered by remodeling a healthy gut microbiota for groups that have lost their core microbiome or key gut microbes, which can be achieved through whole diet interventions or combinatorial therapy (involving diet adjustment complemented by microbial restoration of key taxa at the central node of the microbiota network). A study demonstrated that adherence to the Mediterranean diet could help to reset changes in the microbiome, maintain the diversity of the gut microbiota and the core microbiome, such as Bacteroides thetaiotamicron and Faecalibacterium prausnitzii [171]. Additionally, a machine learning technique can be utilized to customize a personalized diet based on each individual's baseline gut microbial composition and dietary information in order to restore a healthy gut microbiota [238].

Conclusion and perspectives

In conclusion, previous research has highlighted the significance of gut microbiota for health, and it represents a new target for studying and promoting healthy aging. Although age-dependent dysregulation of the gut microecosystem characterized by changes in the diversity and composition of the gut microbiota is now a well-established phenomenon following research efforts in the past few decades, recent evidence has also provided new insights by showing that different changes in the direction of alpha diversity in the elderly and in centenarians, which challenged the previous inherent cognition that alpha diversity decreases with host aging. Specifically, follow-up longitudinal studies should be carried out on a larger scale and for longer periods of on healthy elderly adults and longevity populations, and metagenomics and metabolomics approaches should be used to explore the changes in the diversity and composition of the gut microbiota. In addition, we found that current used dietary intervention strategies against aging are often arbitrarily selected without consideration on aging-associated biomarkers of gut microbiota. Therefore, we propose some dietary components that can targettedly alter those aging-associated microbiota biomarkers that have been summarized in the first few parts of the submitted review. Supplementation with probiotics or other dietary factors may increase the abundance of these species and substances. In the future, microbial genome-directed approaches should be adopted to targettedly analyze the metabolic capacity of specific probiotics/gut symbiotic bacteria for aging on specific dietary components, in this way to guide the for rational selection and development of gut microbiota-targetted food. However, the efficacy of probiotics also relies on the specificity of the strains, the dosage, the duration of the treatment, as well as on individual differences. The efficacy of prebiotics depends not only on composition and structure, but also on the composition of the pre-intervention gut microbiota. The effects of postbiotics disappear after the intervention is ceased, although they offer better stability than probiotics or prebiotics.

Compliance with ethics requirements

This article does not contain any studies with human or animal subjects.

CRediT authorship contribution statement

Yue Xiao: Conceptualization, Writing – original draft, Funding acquisition, Writing – review & editing. Yingxuan Feng: Writing – original draft, Writing – review & editing. Jianxin Zhao: Supervision, Writing – review & editing. Wei Chen: Supervision, Funding acquisition, Writing – review & editing. Wenwei Lu: Conceptualization, Supervision, Writing – review & editing, Project administration, Conceptualization, Supervision, Writing – review & editing, Project administration.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Biographies

Dr. Yue Xiao is an associate professor at the School of Food Science and Technology, Jiangnan University, and she focuses on research in the fields of probiotics, gut microbiota, and human health (H index=14, Microbiome, 2021, 9, 180; Annual Review of Food Science and Technology, 2021,12: 213–233; Clinical Nutrition, 2020, 39(5): 1315–1323).

Yingxuan Feng is a master student in School of Food Science and Technology, Jiangnan University, and her advisor is Professor Wei Chen. Her research focus is relationships among gut microbiota, probiotics, and host aging.

Professor Jianxin Zhao currently is a professor at the School of Food Science and Technology, Jiangnan University. His research interests mainly concentrated on the development and utilization of probiotic resources. He has published nearly 100 SCI papers (Environment International, 2022, 166: 107388; Carbohydrate Polymers, 2022, 287: 119304; Gut Microbes, 2022, 14(1): 2044723) and received some awards and honors.

Professor Wei Chen is an academician from the Chinese Academy of Engineering, the headmaster of Jiangnan University. His main research interests are the interaction between probiotics and the environment and hosts, the health effects of probiotics on hosts, and the relationship between gut microbiota and human health (H index=48, Trends in Microbiology, 2021, 29; Biotechnology Advances, 2022, 54: 107794; Brain, behavior, and immunity, 2022, 100: 233–241).

Professor Wenwei Lu is a professor at the School of Food Science and Technology, Jiangnan University. His research focuses on resource mining and mechanism of action research of functional probiotics (H index=19, Microbiome, 2023, 11(1): 184; npj Biofilms and Microbiomes, 2021, 7(1): 71).

Appendix A. Supplementary material

The following are the Supplementary data to this article: