Move beyond free radical theory of aging

Aging is a gradual pathophysiological process with the loss of functional integrity and gain of disease vulnerability. Mitochondrial DNA is one essential regulatory factor of aging. The canonical free radical theory attributes aging to oxidative damage of mitochondrial DNA caused by free radicals. However, the general validity of this theory has been challenged by incremental evidences, including some seemingly paradoxical reports, which motivates us to substantiate this theory with our current understandings on free radicals and aging. After reviewing this canonical theory and its adapted models, we provided updated insights by emphasizing the dosage-dependent dual roles of free radicals played during aging and characterizing adenosine 5'-monophosphate-activated protein kinase as the nexus between mitochondrial health and free radicals. For practical use, we provided detailed recommendations regarding the dosages of reactive species feasible for treating different health concerns. Additionally, we proposed cold atmospheric plasma (CAP), which is composed of a cocktail of free radicals, as an innovative redox modulatory tool for anti-aging if used appropriately, alone or in combination with other interventions. Our view not only centers mitochondrial redox disequilibrium in the progression of aging, but also underpins the essential value of the fourth state of matter as represented by CAP in keeping redox homeostasis for the sake of human health that should be appropriately harnessed.