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Xu et al. Microbiome Res Rep 2024;3:13 https://dx.doi.org/10.20517/mrr.2023.68 Page 5 of 11

Nutrient metabolism regulation
Nutrition is the main common factor that links both gut microbes and hosts; thus, the microbiome may
influence lifespan and health by supplementing nutrition or regulating the body’s nutritional metabolic
signaling pathways . Cellulose, for instance, can be decomposed into short-chain fatty acids by
[43]
Ruminococcus and Butyrivibrio, etc., converting from being unavailable for intestinal absorption to
indispensable bioactive molecules. These bacterial-derived metabolites have been shown to be effective in
the amelioration of basic diseases in the elderly, such as type 2 diabetes and obesity . Insulin/insulin-like
[44]
growth factor 1 (IGF-1) signaling (IIS), the first signaling proven to be involved in aging regulation, was
found to be somewhat relevant to the nutrient metabolism of gut bacteria . Caenorhabditis elegans model
[45]
with healthy bacterial composition features proper intestinal nutrient supply and sensory capacity, and the
IIS pathway is sustained in low activation, thus mitigating the host aging . Similar situations also occur on
[46]
[47]
other nutritional metabolic pathways associated with the IIS, such as Sirtuins, Forkhead Box O (FOXO) ,
[48]
and mammalian TOR pathways . For instance, Δhns Escherichia coli administration could extend the
lifespan of C. elegans by activating decay accelerating factor-16 (DAF-16)/FOXO family transcription
[49]
factors, and this effect is independent of the IIS pathway .
Neuroprotection
Neurodegeneration is the typical feature of individual aging in the central nervous system, mainly
manifested as motor and cognitive decline, for which the onset of Parkinson’s disease and Alzheimer’s
[50]
[51]
disease is most common. For the gut-brain axis, a figurative perception defines it as the collection of
signaling pathways between the central and enteric nervous systems that enable a bidirectional connection
between the gut and the brain through immune, metabolic, and neuroendocrine mediators . Studies have
[52]
shown that healthy gut microbiota could prevent Alzheimer’s disease through the gut-brain axis, an effect
that relies on the interaction and signaling of microecology-associated neurological and humoral factors. In
particular, the restriction of trimethylamine oxide levels inhibits β-amyloid formation, neuroinflammation,
and tau phosphorylation, mitigating the further progression of mild cognitive impairment to organic lesions
[53]
in older individuals . In addition, metabolites of gut microbes such as secondary bile acids and tryptophan
derivatives can modulate the bile acid profile, serotonin synthesis pathway, and the number of brain-derived
neurotrophic factors, which, in turn, yield positive guidance for the learning behavior, memory recognition,
and emotional expression in the organism [54,55] .

INTERVENTIONS FOR HEALTHY AGING: GUT MICROBIOTA TARGETED
Fecal microbiota transplantation
The mechanism of gut microbiota-host interaction provides another perspective on anti-aging research,
that is, in addition to marking aging, gut microbes themselves or strategies targeting gut microbes possess
the potential for anti-aging effects. FMT transplants functional microbiota from the feces of healthy donors
into the gut of patients, treating both intestinal and extra-intestinal diseases through microecological
remodeling. Initially, FMT was tentatively applied in Clostridium difficile infection, stubborn constipation,
and intestinal immune deficiency, with demonstrable efficacy . As standardized FMT takes hold, there is
[56]
growing evidence to support its anti-aging effect. In a premature aging mice model, the experimental group
transplanted with fecal bacteria from wild-type mice showed a 13.5% prolonged average lifespan and a 9%
enhanced maximum survival rate . After transplantation of fecal bacteria from long-lived elders into mice,
[57]
alleviation of aging indicators and improved richness of Lactobacillus spp. and short-chain fatty acid-
producing bacteria were observed compared to controls . Another study then illustrated that FMT
[58]
improved aging-related signatures in the eye, brain, and gut by repairing intestinal barrier, reversing
systemic inflammation, and refining nutrient metabolism .
[59]