Postbiotic targeting muscle aging: mechanistic insights and application prospects of urolithin A

Abstract

BACKGROUND: Urolithin A is a natural active compound produced by the metabolism of dietary polyphenols, which has multiple biological effects such as promoting mitochondrial function, antioxidation and anti-inflammation. In recent years, the development of urolithin A in delaying aging-related diseases has received extensive attention. However, the specific mechanism of its action in improving muscle aging remains unclear and further systematic research is still needed. OBJECTIVE: To systematically explore the mechanism of action of urolithin A in muscle aging, providing a theoretical basis for its potential application value in delaying muscle aging. METHODS: The Web of Science, PubMed, China National Knowledge Infrastructure (CNKI) and WanFang Database were retrieved from January 2000 to April 2025. The search terms were "urolithin A, muscle aging, mitochondrial function, mitophagy, inflammation, oxidative stress, muscle function, skeletal muscle" in English and Chinese. According to the inclusion and exclusion criteria, 80 literatures were finally selected for review. RESULTS AND CONCLUSION: (1) Urolithin A is a metabolite generated by the conversion of dietary polyphenolic compounds ellagic acid and ellagic acid under the action of intestinal microorganisms, and is widely present in pomegranates, berries and nuts. It has a unique α-benzocoumarin structure, with a small molecular weight, strong lipophilicity and easy absorption. The production of urolithin A depends on an individual’s intestinal microbiota and can be classified into different metabolic types. Moreover, this ability weakens with age, reflecting changes in intestinal function and physiological state. (2) Muscle aging is a process driven by mitochondrial dysfunction, chronic inflammation, and neuromuscular degeneration. With age, mitochondrial energy metabolism declines, reactive oxygen species accumulation aggravates cellular damage; chronic low-grade inflammation accelerates protein breakdown, inhibits synthesis, and impairs muscle repair; neuromuscular junction degeneration and signal transduction disorders lead to muscle denervation and atrophy. These factors interact, leading to a continuous decline in muscle mass and function. (3) Urolithin A improves muscle aging through multi-target mechanisms, mainly including: activating PTEN-induced kinase 1/Parkin signaling pathway to clear damaged mitochondria and enhance metabolic functions such as tricarboxylic acid cycle, fatty acid oxidation, and oxidative phosphorylation; inhibiting nuclear factor κB and protein kinase B/mitogen-activated protein kinase signaling pathways, upregulating anti-inflammatory factors such as interleukin-10 and transforming growth factor β1, downregulating pro-inflammatory factors such as interleukin-1β and tumor necrosis factor α, achieving inflammatory regulation; enhancing antioxidant enzyme activities such as catalase, superoxide dismutase, and glutathione peroxidase, inhibiting reactive oxygen species generation, and alleviating oxidative stress. (4) Urolithin A promotes the proliferation and differentiation of muscle stem cells, activates anabolic pathways, enhances protein synthesis, improves muscle strength, and regulates molecular mechanisms related to endurance and anti-fatigue, thereby comprehensively improving muscle performance. (5) Urolithin A shows broad prospects in delaying muscle aging and promoting muscle health, but existing studies are limited by small sample sizes, short durations, and individual differences. Future large-scale, long-term clinical studies are urgently needed to clarify dose-response relationships, explore individualized and combined intervention strategies, and focus on the potential of urolithin A as a sports nutrition supplement in enhancing physical fitness and healthy aging.

1. Introduction

Aging is the result of multiple interacting factors and has extremely complex biological mechanisms. Cellular senescence, telomere attrition, genomic alterations, and mitochondrial dysfunction drive the progression of aging and promote the development of related diseases [1]. Muscle aging, as a key part of the aging process, manifests as loss of muscle strength and mass [2]. Current main therapeutic approaches for muscle aging include gene therapy, nutritional supplements, physical activity, anabolic hormones, endurance and resistance training, anti-inflammatory drugs, and antioxidants [3].

In this context, urolithin A, a postbiotic metabolite derived from dietary polyphenols, has emerged as a promising candidate. It is produced by the gut microbiota from ellagitannins and ellagic acid, which are abundant in pomegranates, berries, and nuts. Urolithin A has been shown to improve mitochondrial function, exert anti-inflammatory and antioxidant effects, and potentially delay aging-related diseases. However, its specific mechanisms in counteracting muscle aging remain incompletely understood, warranting a systematic review of the current evidence.