Table 3.

Summary of studies investigating the effects of candidate Gerotherapeutic drugs on healthspan and mortality in human. (Adapted from Kulkarni et al., 2022)

Gerotherapeutics	References	Primary outcome(s)
SGTL-2 inhibitors	Packer et al.78	A composite of cardiovascular death or hospitalization for worsening heart failure.
SGTL-2 inhibitors	Perkovic et al.79	A composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes.
SGTL-2 inhibitors	Heerspink et al.80	A composite of a sustained decline in the estimated glomerular filtration rate (GFR) of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.
SGTL-2 inhibitors	Neal et al.81	A composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
SGTL-2 inhibitors	Zinman et al.82	A composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke.
SGTL-2 inhibitors	McMurray et al.83	A composite of worsening heart failure (hospitalization or an urgent visit resulting in intravenous therapy for heart failure) or cardiovascular death.
Metformin	Knowler et al.84	Diagnosis of diabetes.
Metformin	UKPDS Group85	Any diabetes-related clinical endpoint (sudden death, death from hyperglycemia or hypoglycemia, fatal or non-fatal myocardial infarction, angina, heart failure, stroke, renal failure, amputation [of at least one digit], vitreous hemorrhage, retinopathy requiring photocoagulation, blindness in one eye, or cataract extraction); diabetes-related death (death from myocardial infarction, stroke, peripheral vascular disease, renal disease, hypoglycemia, or hyperglycemia, and sudden death); and all-cause mortality.
Metformin	Hong et al.86	A composite of cardiovascular events, death from a cardiovascular cause, and death from any cause.
Metformin	Luchsinger et al.87	The co-primary clinical outcomes were changes from baseline to 12 months in total recall of the Selective Reminding Test (SRT) and the score of the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). The secondary outcome was change in relative glucose uptake in the posterior cingulate-precuneus in brain fluorodeoxyglucose positron emission tomography.
Metformin	Cryer et al.88	The primary end point was the incidence of serious adverse events (SAEs), death, and hospitalization.
Acarbose	Holman et al.89	To assess whether acarbose could reduce the frequency of cardiovascular events in Chinese patients with established coronary heart disease and impaired glucose tolerance, and whether the incidence of type 2 diabetes could be reduced.
Acarbose	Chiasson et al.90	The primary endpoint was development of diabetes on the basis of a yearly oral glucose tolerance test (OGTT).
Acarbose	Chiasson et al.91	To evaluate the effect of decreasing postprandial hyperglycemia with acarbose, an alpha-glucosidase inhibitor, on the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance (IGT).
Rapamycin/Rapalogs	Mannick et al.92	To evaluate whether the mammalian target of rapamycin (mTOR) inhibitor RAD001 ameliorated immunosenescence (the decline in immune function during aging) in elderly volunteers, as assessed by their response to influenza vaccination.
Rapamycin/Rapalogs	Mannick et al.93	To determine whether low-dose mTOR inhibitor therapy enhanced immune function and decreased infection rates in 264 elderly subjects given the study drugs for 6 weeks.
Rapamycin/Rapalogs	Kraig et al.94	To determine the safety and tolerability of RAPA in older human subjects.
Methylene Blue	Wishick et al.95	The primary outcome was change on the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) at 24 weeks relative to baseline severity.
Angiotensin-converting enzyme inhibitor and angiotensin receptor blocker (ACEi/ARB)	NAVIGATOR study group96	Three coprimary outcomes: the development of diabetes; an extended composite outcome of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, hospitalization for heart failure, arterial revascularization, or hospitalization for unstable angina; and a core composite outcome that excluded unstable angina and revascularization.
ACEi/ARB	Lithell et al.97	The primary outcome measure was major cardiovascular events, a composite of cardiovascular death, non-fatal stroke and non-fatal myocardial infarction.
ACEi/ARB	Ravid et al.98	To evaluate the effect of prolonged ACE inhibition on renal function and albuminuria in patients with type 2 diabetes.
ACEi/ARB	Onder et al.99	The aim was to see whether ACE inhibitors also prevent reduction in physical performance and in muscle strength in older women who do not have congestive heart failure (CHF).
ACEi/ARB	Lithell et al.100	Primary: major cardiovascular events (cardiovascular mortality, non-fatal stroke or non-fatal myocardial infarction).
Dasatinib + Quercetin	Justice et al.46	The primary endpoints were retention rates and completion rates for planned clinical assessments. Secondary endpoints were safety and change in functional and reported health measures. Associations with the senescence-associated secretory phenotype (SASP) were explored.
Dasatinib + Quercetin	Hickson et al.47	Senescent cell and macrophage/Langerhans cell markers and circulating SASP factors.
Dasatinib + Quercetin	Martyanov et al.101	Primary objectives were safety and pharmacokinetics. Secondary outcomes included clinical assessments, quantitative high-resolution computed tomography (HRCT) of the chest, serum biomarker assays and skin biopsy-based gene expression subset assignments. Clinical response was defined as decrease of >5 or >20% from baseline in the modified Rodnan Skin Score (MRSS).