. 2023 Jan 4;55(1):1–12. doi: 10.1038/s12276-022-00906-w

Table 1.

Summary of senotherapeutics and their in vitro and in vivo evidence in endothelial cells or cardiovascular diseases.

	Target mechanism	In vitro anti-senescence evidence	In vivo anti-senescence evidence	Clinical trial stage	Trial
Senolytics
Quercetin	Inhibits PI3K/AKT, BCL-2 and Serpine activity	Induced apoptosis in IR-induced senescent HUVECs¹⁴⁶	Reversed bleomycin-induced pulmonary fibrosis and reduced SASP marker levels in aged mice¹⁴⁹ and Wistar rats¹⁵⁰	Phase 2 in patients with Alzheimer’s disease	NCT04063124
				Phase 2 in patients with Alzheimer’s disease	NCT04685590
				Phase 2 in patients with coronary artery disease	NCT04907253
Dasatinib	Inhibits tyrosine kinase activity	Induced apoptosis in IR-induced senescent human preadipocytes, and was much less effective on senescent HUVECs¹⁴⁶	Exerted antidiabetic effects on older patients with type 2 diabetes mellitus in a retrospective cohort study¹⁵¹	Phase 2 with healthy participants	NCT04313634
Quercetin + Dasatinib		Induced apoptosis in IR-induced senescent HUVECs and preadipocytes¹⁵³	1. Improved cardiac function and carotid vascular reactivity in old mice¹⁴⁶ 2. Reduced hepatic steatosis in old mice¹⁴⁸	Phase 2 with patients with chronic kidney disease	NCT02848131
Quercetin + Dasatinib				Phase 1 with patients with idiopathic pulmonary fibrosis	NCT02874989
Fisetin	Inhibits BCL-2 and PI3K/AKT	Selectively induced apoptosis in IR-induced senescent HUVEC¹⁵³	Reduced senescence marker levels in multiple tissues in progeroid and old mice and restored tissue homeostasis, reduced age-related pathology and extended the lifespan of wild-type mice¹⁵⁵	Phase 2 with patients with knee osteoarthritis	NCT04210986
				Phase 2 with patients with knee osteoarthritis	NCT04815902
				Phase 2 with patients with frailty	NCT03675724
					NCT03430037
					NCT04733534
A1331852, A1155463	Inhibits BCL-XL	A1331852 and AB1155463 selectively induced apoptosis in IR-induced senescent HUVECs and IMR90 cells¹⁵³	Cleared senescent cholangiocytes and reduced SASP factor levels and attenuated liver fibrosis in mice¹⁵⁶
ABT263 (Navitoclax; UBX0101)	Inhibits BCL-2, BCL-XL and BCL-W	Induced apoptosis in IR-induced senescent HUVEC and IMR90c cells¹⁵⁴	1.Cleared senescent cells in irradiated mice and normally aged mice¹⁵⁷ 2. Cleared senescent cells and reduced atherogenesis in murine model of atherosclerosis¹⁵⁸
SSK1 (gemcitabine with an acetyl group and β-gal-responsive moiety)	Activates the p38 MAPK pathway	Selectively induced apoptosis in HUVECs¹⁴³	Eliminated SA-β-gal-positive cells and senescence markers, attenuated lung fibrosis and reduced SASP factors in aged mice¹⁴³
BPTES	Inhibits glutaminase 1		Reduced the expression of p16^Ink4A, KGA, and IL-6 mRNA and the KGA protein and ameliorated symptoms of diabetes, arteriosclerosis, and NASH in mice¹⁵⁹
ABH	Inhibits arginase 1	Reduced the number of senescent cells in bovine retinal endothelial cells¹⁶⁰	Reduced senescence-associated diabetes-induced alterations (p16^Ink4A, p21^WAF1, p53, and IGFBP3) in diabetic mice¹⁶⁰
Senomorphics
Rapamycin	Inhibits mTOR	Inhibited SASP acquisition in senescent pulmonary vascular endothelial cells from patients with chronic obstructive pulmonary disease¹⁷⁷	1. Reduced cardiac inflammation and improved cardiovascular function in mice¹⁷⁸ 2. Reversed age-related vascular dysfunction and improved arterial function in 30-month-old mice¹⁷⁹
Metformin	Inhibits IKK/NF-ƙB, activates AMPK	Reduced hyperglycemia-induced senescence and apoptosis in mouse microvascular endothelial cells¹⁷²	Restored endothelial function and reduced inflammation in diabetic rats¹⁷⁶	Phase 3 with people at high risk of developing diabetes	NCT00004992
Metformin	Inhibits IKK/NF-ƙB, activates AMPK			Phase 3 with people at high risk of developing diabetes	NCT00038727
Resveratrol	Inhibits NF-ƙB (an IĸB-kinase inhibitor), activates AMPK and SIRT1	1. Delayed the onset of senescence in human endothelial progenitor cells by increasing telomerase activity¹⁷⁰ 2. Reduced oxidative reaction and inhibited senescence in endothelial progenitor cells¹⁷¹	1. Exerted cardioprotective effects on old senescence-accelerated mice¹⁷⁴ 2. Reduced aorta media thickness inflammation, fibrosis and oxidative stress and inhibited arterial aging in mice¹⁷⁵
Ruxolitinib	Inhibits JAK1/2	Suppressed SASP acquisition in IR-induced senescent human preadipocytes and HUVECs and decreased inflammation in senescent cells¹⁷³	Decreased SASP factor levels and enhanced physical activity in aged mice¹⁷³
FGF21	Activates SIRT1	Delayed replicative senescence and attenuated senescent phenotypes in HUVECs³⁵	1. Protected against immunosenescence in mice¹⁸⁰ 2. 2. Extended lifespan in transgenic mice with high levels of FGF21¹⁸¹

IR irradiation, HUVEC human umbilical vein endothelial cell, SASP senescence-associated secretory phenotype, SIRT1 sirtuin-1, AMPK AMP-activated protein kinase, NASH nonalcoholic steatohepatitis.