Letter to the Editor: Trimetazidine modulates gut microbiota-lipid metabolism axis: A novel avenue for anti-aging interventions

Abstract

The study by Wang et al, published in the recent issue of the World Journal of Gastroenterology, which on the age-related gut microbiome profile and reversal of microbial imbalance using trimetazidine therapy. This study provided compelling evidence that the gut microbiota undergoes significant age-dependent changes, particularly an enrichment of fatty acid oxidation-related microbes in older populations. The authors successfully demonstrated that trimetazidine restored the gut microbial balance and reduced senescence markers in ageing rats, indicating that it exerts potential anti-ageing effects by modulating the microbiota and metabolism. We commend the innovative multi-cohort design of the study, in which human cross-sectional data were integrated with longitudinal rat models to enhance our understanding of microbial dynamics across the organism lifespan. However, we also acknowledge limitations of the study, including the need to further explore causal mechanisms, the lack of metabolomic data, and potential geographical bias from sample collection. Future multicentre studies are warranted to validate and expand the clinical applicability of the findings regarding the gut microbiota-fatty acid oxidation axis in ageing.

Key Words: Gut microbiome; Aging; Trimetazidine; Microbial balance; Metabolism; Senescence; Predictive model

Core Tip: In this letter, we discuss a study by Wang et al on the age-related gut microbiome profile and reversal of microbial imbalance using trimetazidine therapy. This study provided compelling evidence that the gut microbiota undergoes significant age-dependent changes, particularly an enrichment of fatty acid oxidation-related microbes in older populations. The authors successfully demonstrated that trimetazidine restored the gut microbial balance and reduced senescence markers in ageing rats, indicating that it exerts potential anti-ageing effects by modulating the microbiota and metabolism.

TO THE EDITOR

We read with great interest the original article by Wang et al[1] titled “Age-related gut microbiome profile and reversal of microbial imbalance by trimetazidine intervention” published in the recent issue of the World Journal of Gastroenterology, which showed that the gut microbiota undergoes age-dependent remodeling, with microbes associated with fatty acid oxidation (FAO) being significantly enriched in ageing populations, and we would like to submit this letter to share our comments on their findings. Notably, the authors demonstrated that trimetazidine (TMZ), an FAO inhibitor, suggests a potential could restoration restore the gut of microbial balance and suppresses markers of senescence in rats, may indicate indicating that it exerts an anti-ageing potential effects through the modulating of the gut microbiota and metabolism.

This work is distinguished by its multi-cohort design, which integrated human cross-sectional data (n = 300, ages 0-100 years) and longitudinal rat models to elucidate gut microbial dynamics across the organism lifespan. The non-linear trajectory of microbial diversity (i.e., increasing until adolescence, stabilizing until age 70, and then decreasing thereafter) - not only aligns with prior findings but also extends them by revealing a biphasic pattern throughout the human lifespan[2]. Importantly, this study identified Luteipulveratus and Catenulispora as key age-associated related microbes associated with linked to lipid metabolism, highlighting a previously under-appreciated role of FAO in driving ageing.

The intervention using TMZ is particularly innovative. By inhibiting FAO, TMZ not only reshaped the gut microbiota (e.g., decreasing Prevotella and increasing the Ruminococcaceae) but also down-regulated hepatic senescence markers (P21) and FAO enzymes (HADHB) in ageing rats. These findings suggest that position TMZ can serve as a dual-action agent for targeting both the microbial composition and host metabolism, offering a novel approach to for mitigate mitigating age-related decline[3]. The role of mitochondrial FAO as a driver of cellular senescence further supports the mechanistic basis or the TMZ’s effects.

However, this study had several limitations warrant attention. First, while although the study results suggests that the TMZ’s effects are mediated through the gut microbiota, the causal mechanisms remain speculative. Fecal microbiota transplantation experiments could clarify whether the benefits of TMZ are microbiota-dependent on the gut microbes, as demonstrated in a study in where which the transfer of the young microbiotas from young mice to older mice transfers reversed ageing phenotypes[4]. Second, the lack of metabolomic data limits the direct validation of microbial metabolic outputs (e.g., short-chain fatty acids or oxylipins). Metabolomics should be integrated into future studies that integrate metabolomics would to verify the mechanistic link between microbial shifts and host ageing, as observed in a centenarian study revealing in which a complex remodeling of lipids and the microbiota was revealed[5]. We suggest that future research should integrate metabolomics studies would also help to elucidate the functions of specific metabolites, such as short-chain fatty acids[6]. Third, we advocate for future multicenter studies are warranted to validate and expand the clinical applicability of the findings regarding the gut microbiota-FAO axis in ageing.

Despite these limitations, Wang et al[1] have provided a foundational framework for targeting the gut microbiota-FAO axis in ageing. Their findings should encourage the initiation of clinical trials to evaluate the efficacy of TMZ in promoting healthy ageing, especially in populations with metabolic disorders. Their study findings aligns with emerging evidence that lipid metabolism enzymes are regulated by longevity pathways[7], underscoring the potential of metabolic interventions in mitigating ageing-related metabolic diseases.