Microbiome-Engineered Herbal Synbiotics for Regulating Ferroptosis and Mitochondrial Dysfunction in Age-Related Sarcopenia: A Mechanistic Review and Research Roadmap

Abstract

Sarcopenia – the age-associated progressive decline in muscle mass, strength, and functionality, predicted to impact over 200 million elderly people on the planet in four decades – has the following two converging cellular mechanisms of development: ferroptosis – an iron-mediated, lipid peroxidation-induced form of cell death recently shown to occur in sarcopenic mouse muscles by virtue of p53/SLC7A11/GPX4 pathway; and progressive mitochondrial malfunction, manifested by compromised mitochondrial biogenesis, defective mitophagy, and reduced oxidative activity. The two aforementioned cellular mechanisms are interrelated: dysfunctional mitochondria and mitochondrial fission lead to ferroptotic lipid peroxidation, and the latter results in further damage to the mitochondria – hence a vicious cycle mechanistically proven to exist in non-skeletal muscle tissue. In addition, there is quite a lot of evidence of the presence of gut-muscle axis, where certain microbial taxa of the gut, as well as short-chain fatty acids produced by them, determine muscle mass and functionality, whereas several plant-derived phytometabolites – curcumin, tannic acid, polydatin, and catechin among them – inhibit ferroptosis through the same p53/SLC7A11/GPX4 and Nrf2 pathway. The current review aims to hypothesise that engineered synbiotics (probiotics in combination with anti-ferroptosis herbal phytometabolites encapsulated in a plant-based matrix for targeted delivery to the colon, which is a technology that has already been validated in the case of another metabolic disease) would be capable of correcting age-related dysbiosis and delivering anti-ferroptosis and mitochondria protective phytometabolites to the skeletal muscles, thereby addressing both parts of the sarcopenia-driving mechanism via the single formulation. This strategy will be called microbiome-engineered herbal synbiotics. The review ends with a stepwise roadmap including in vitro, animal, and initial clinical translation stages. No novel experimental findings are provided; all the proposed links between mechanisms are formulated as hypotheses based on the existing evidence.