Distinct roles of urolithin A and spermidine in mitophagy and autophagy: implications for dietary supplementation

The increasing focus on longevity and cellular health has brought into the spotlight two key compounds, urolithin A (UroA) and spermidine, for their promising roles in autophagy and mitophagy. Urolithin A, a natural metabolite derived from ellagitannins, stimulates mitophagy through pathways such as PTEN induced kinase 1 (PINK1)/Parkin RBR E3 ubiquitin protein ligase (PRKN), leading to improved mitochondrial health and enhanced muscle function. However, spermidine, a polyamine found in various food sources, induces autophagy by regulating key signaling pathways such as 5′ AMP-activated protein kinase (AMPK) and sirtuin 1, thus mitigating age-related cellular decline and promoting cardiovascular and cognitive health. While both UroA and spermidine target cellular maintenance, they affect overlapping as well as distinct signalling pathways. Thus, they do not have completely identical effects, although they overlap in many ways, and offer varying benefits in terms of metabolic function, oxidative stress reduction and longevity. This review article aims to describe the mechanisms of action of UroA and spermidine not only on the maintenance of cellular health, which is mediated by the induction and maintenance of autophagy and mitophagy, but also on their potential clinical relevance. The analysis presented here suggests that although both compounds are safe and offer substantial health benefits and are involved in both autophagy and mitophagy, the role of UroA in mitophagy places it as a targeted intervention for mitochondrial health, whereas the broader influence of spermidine on autophagy and metabolic regulation may provide more comprehensive anti-ageing effects.