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Page 4 of 11 Xu et al. Microbiome Res Rep 2024;3:13 https://dx.doi.org/10.20517/mrr.2023.68

Gut microbiota as reactive biomarkers
Response to interventions is another major criterion for screening aging-related biomarkers. Utilizing diet
and drug interventions as the primary means of anti-aging has become a consensus, in which gut microbial
alterations as reactive biomarkers make sense. Modification of dietary strategies such as caloric restriction
(CR) and intermittent fasting (IF) has been proven to maintain health and prolong lifespan in a target
[30]
[31]
of rapamycin (TOR) signaling pathway-dependent or -independent manner, and this is, at least partially
due to gut improvement. Therefore, the detection of α-diversity and β-diversity, which indicate microbiome
[32]
abundance and diversity, can well reflect the intervention effect . Furthermore, biased diets fortified with
substances such as phenols and fiber intake have been observed to exhibit dual benefits of delaying aging
and regulating the gut microbiota. The above effect can be signified by the enhanced abundance of
probiotics such as Bifidobacterium and Lactobacillus . In addition, medications contribute to the anti-
[33]
aging campaign. TOR signaling inhibitor Rapamycin , chronic disease targeting drug Resveratrol , and
[34]
[35]
the Chinese pharmaceutical preparation FuFang Zhenshu TiaoZhi (FTZ) have all been adopted in the
preventive healthcare of the elderly. Unexpectedly, gut microbial changes can also describe drug efficacy.
The FTZ-administered aging mice model showed an extended lifespan, along with a decline in the level of
Clostridium erysipelae, and the raised abundance of probiotics such as A. muciniphila and Clostridium
butyricum existed at the same time . However, the problem is that the causal association between the anti-
[36]
aging capacity of the above interventions and the altered microbiota remains unknown.

THE INVOLVEMENT OF GUT MICROBIOTA IN HEALTHY AGING
Inflammatory immunity
The capacity of gut microbiota to mark aging is inextricably linked to the biological mechanisms by which it
acts on the body, dominated by immunomodulation. Intestinal stem cells (ISCs), located in the crypts, serve
[37]
as the cellular basis for intestinal epithelial renewal and mucosal permeability . Gut microbes in healthy
adults can interact with ISCs through their bacterial components and metabolites, on the one hand
activating the dual oxidase to generate reactive oxygen (ROX) in response to bacterial uracil , and on the
[38]
other hand initiating the immune deficiency (IMD)/Relish pathway to enhance the expression of
antimicrobial peptides (AMP) , which together mediate the maintenance of the balance between gut and
[39]
microbiome, as well as normal immune state. The intestinal mucus layer also depends on the commensal
microbiota to induce the release of secretory immunoglobulin A and inflammatory factors such as
interleukin-6, interleukin-10, and tumor necrosis factor-α, thereby achieving immune suppression and
killing of opportunistic pathogens .
[40]

Due to the hyperfunction of pro-inflammatory T-cell populations (e.g., TH1 and TH17 cells), defects in
immune surveillance, and loss of self-tolerance, the intrinsic immunity of the elderly is susceptible . In this
[41]
case, unhealthy aging accompanied by intestinal dysbiosis directly disrupts the delicate balance that exists in
the gut of healthy individuals, as described above, which may at least partially explain the onset of systemic
low-grade inflammation. Specifically, the upregulated expressions of ROX and AMP should be blamed.
ROX is a key molecule mediating cellular senescence, while sustained ROX production also leaves the
intestinal epithelium in a state of chronic oxidative stress damage . Impaired intestinal barrier integrity
[38]
and elevated mucosal permeability not only hinder the digestion and absorption of nutrients in the elderly,
but also accelerate the leakage of pathogens and harmful substances into the circulation, raising the
incidence of aging-related diseases . Studies have also confirmed that in Drosophila, the upregulation of
[37]
AMP would make the peptidoglycan recognition protein-dependent gut development and longevity
modulation difficult to achieve . All of the above prompt that the imbalance of gut symbiotic microbiota-
[42]
host interactions may induce a chain reaction of aging and short lifespan via activating conserved immune
pathways. Therefore, surveillance and maintenance of normal intestinal microecology are required for
healthy aging.