Table.

Examples of geroprotective agents

	Molecular target	FDA-approved indication	Effect on senescence or immunosenescence
mTOR inhibitors: first generation (allosteric, non-competitive)—sirolimus and everolimus; second generation (active site inhibitors, competitive with ATP)—RTB101 and AZD8055	First generation inhibitors target mTORC1, decrease translation, increase autophagy and alter metabolism; second generation inhibitors target mTORC1 and possibly mTORC2, as above and also affect cytoskeleton	Cancer; immunosuppressant in kidney transplant rejection and some autoimmune conditions (NB doses for these indications are far higher than those that provide geroprotection)	Improve outcomes in many age-related diseases;4 improve response to flu vaccination5 (ACTRN12613001351707); decrease incidence and severity of respiratory tract infections in older adults;6 sirolimus in trials (NCT04341675) for COVID-19 pneumonia; RTB101 in trials for COVID-19 prophylaxis in older people in the community (NCT04584710) or in nursing homes (NCT04409327), geroprotective at 1/120th maximum tolerated dose, well tolerated in older adults
Statins	Pleiotropic: main target is the HMG-CoA reductase pathway; might also target small G protein Rho, affecting the actin cytoskeleton and cell motility	Reduction of low density lipoprotein cholesterol	Increase neutrophil cytokinesis and NETosis; decrease sepsis, organ failure and death in older adults hospitalised with community acquired pneumonia7 (EudraCT 2012-00343-29); currently in many trials for COVID-19 (NCT04407273, NCT04390074, NCT04348695, NCT04426084, NCT04333407, NCT04380402, and NCT04343001) and reported to COVID-19 deaths8
Dasatinib (in combination with plant flavonoid quercetin)	src-family tyrosine kinase inhibitor (also inhibits BCR-ABL kinase)	Cancer	Senolytic—ie, selectively kill senescent cells; improve physiological function in idiopathic pulmonary fibrosis;9 in phase 2 trials in chronic kidney disease (NCT02848131)
Metformin	Pleiotropic: main target is mitochondrial complex I, inhibition of which leads to activation of AMPK, and inhibition of acetyl CoA carboxylase; increases GLP-1 in gut	Type 2 diabetes	Immunomodulatory especially through T helper cell balance, leading to reduced autoantibodies, cytokines, and neutrophil NETosis; retrospective analysis suggests might improve outcomes for female patients with obesity and diabetes who have COVID-1910