Molecular mechanisms in cognitive frailty: potential therapeutic targets for oxygen-ozone treatment

•Cognitive frailty is characterized by complex and multifactorial aetiology and challenges regarding treatments efficacy and costs persist.•Oxygen-ozone (O2-O3) therapy is a non-invasive, non-pharmacological and no-side effect procedure based on regenerative capacity of O3.•A plethora of scientific evidence support omni various properties of O3 in physiopathological processes.•Nrf2-ARE, NF-κB, NFAT, AP-1, HIFα are the principal signalling on which O3 exercises its effects, involved in cognitive frailty.•This review provides a consistent rationale to implement future clinical studies to test the O2-O3 treatment to cognitive frailty. In the last decade, cognitive frailty has gained great attention from the scientific community. It is characterized by high inflammation and oxidant state, endocrine and metabolic alterations, mitochondria dysfunctions and slowdown in regenerative processes and immune system, with a complex and multifactorial aetiology. Although several treatments are available, challenges regarding the efficacy and the costs persist. Here, we proposed an alternative non-pharmacological, non-side-effect, low cost therapy based on anti-inflammation, antioxidant, regenerative and anti-pathogens properties of ozone, through the activation of several molecular mechanisms (Nrf2-ARE, NF-κB, NFAT, AP-1, HIFα). We highlighted how these specific processes could be implicated in cognitive frailty to identify putative therapeutic targets for its treatment. The oxigen-ozone (O2-O3) therapy has never been tested for cognitive frailty. This work provides thus wide scientific background to build a consistent rationale for testing for the first time this therapy, that could modulate the immune, inflammatory, oxidant, metabolic, endocrine, microbiota and regenerative processes impaired in cognitive frailty. Although insights are needed, the O2-O3 therapy could represent a faster, easier, inexpensive monodomain intervention working in absence of side effects for cognitive frailty.