Pharmaceutical and nutraceutical activation of FOXO3 for healthy longevity

Life expectancy has increased substantially over the last 150 years. Yet this means that now most people also spend a greater length of time suffering from various age-associated diseases. As such, delaying age-related functional decline and extending healthspan, the period of active older years free from disease and disability, is an overarching objective of current aging research. Geroprotectors, compounds that target pathways that causally influence aging, are increasingly recognized as a means to extend healthspan in the aging population. Meanwhile, FOXO3 has emerged as a geroprotective gene intricately involved in aging and healthspan. FOXO3 genetic variants are linked to human longevity, reduced disease risks, and even self-reported health. Therefore, identification of FOXO3-activating compounds represents one of the most direct candidate approaches to extending healthspan in aging humans. In this work, we review compounds that activate FOXO3, or influence healthspan or lifespan in a FOXO3-dependent manner. These compounds can be classified as pharmaceuticals, including PI3K/AKT inhibitors and AMPK activators, antidepressants and antipsychotics, muscle relaxants, and HDAC inhibitors, or as nutraceuticals, including primary metabolites involved in cell growth and sustenance, and secondary metabolites including extracts, polyphenols, terpenoids, and other purified natural compounds. The compounds documented here provide a basis and resource for further research and development, with the ultimate goal of promoting healthy longevity in humans.

Automated summary

Life expectancy has increased significantly in the past 150 years, but this also means that most people now experience a longer period of suffering from age-related diseases. Delaying age-related decline and extending the period of healthspan has become a major goal in aging research. Geroprotectors, compounds that target aging pathways, are recognized as a way to extend healthspan. FOXO3 has emerged as a gene involved in aging and healthspan, with its variants linked to longevity and reduced disease risks. This study reviews compounds that activate FOXO3 or influence healthspan and lifespan in a FOXO3-dependent manner, providing a basis for further research on promoting healthy longevity in humans.