TABLE 4.

Senomorphics: effects in vascular cells and clinical trials for vascular diseases. COPD: chronic obstructive pulmonary disease.

Compound	Mechanism of action	Outcomes			References
		In vitro	In vivo	Clinical trials (study phase, identifier)
Rapamycin/sirolimus	mTORC1 inhibitor	mTOR inhibition by low-dose rapamycin prevented cell senescence and inhibited the SASP in cultured cells derived from patients with COPD	Significant reduction in atherosclerotic lesions area and improved neurovascular measures in mice	Immune, Cognitive, and Functional Consequences of mTOR inhibition in the elderly (including assessment of cardiac function) (Phase 2, NCT04742777) (Phase 2, NCT02874924) Angiofibromas in Tuberous sclerosis (Phase 2, NCT01526356) Alzheimer’s and Cognitive Health (Phase 2, NCT04629495)	Houssaini et al. (2018), Jahrling et al. (2018)
Metformin	Numerous cellular targets. Some related to SASP inhibition are: IKK inhibition, upregulation of Nrf2-mediated glutathione peroxidase 7 (GPx7), or downregulation of the STAT3 pathway	Metformin decreased the secretion of SASP factors and adhesion molecules, as well as LPS-triggered hyper-inflammation, in doxorubicin-induced senescent ECs	Metformin reduced pro-inflammatory markers such as CCL2 and also improved oxidative stress, nitric oxide bioavailability, and endothelial dysfunction in general in a murine model of non-obese type 2 diabetes	Treatment of frailty in obese seniors (Phase 3, NCT04221750) Peripheral Arterial Calcification in Type 1 Diabetes (Phase 3, NCT04583462) Peripheral artery disease (Phase 3, NCT05132439)	Sena et al. (2011), Abdelgawad et al. (2023)
Aspirin	Unknown	Inhibition of astrocyte-driven inflammation by targeting cGAS in a brain organoid model of ataxia-telangiectasia	Normalization of vascular remodeling of renal and carotid arteries, and reversion of the increment in systolic blood pressure on a model of metabolic syndrome	Cerebral Small Vessel Disease (Phase 4, NCT01932203) Primary prevention of cardiovascular events in the elderly (Phase 4, NCT00225849) Secondary prevention of CVD in the elderly (Phase 3, NCT02596126)	Renna et al. (2009), Aguado et al. (2021)
Statins	HMG-CoA reductase inhibitor	Atorvastatin, pravastatin, and pitavastatin inhibited senescence in a cell line of senescent HUVECs, by targeting the Akt pathway	-	-	Ota et al. (2010)
Ruxolitinib	JAK 1/2 inhibitor	Reduction of the levels of some key SASP components in senescent HUVECs, including IL-6, IL-8, and MCP-1	Reduction of systemic inflammation in aged mice	-	Xu et al. (2015)
Oridonin	p38 and NF-κB inhibitor	Inhibition of the secretion of IL-8 and IL-6 in a cell line of human senescent fibroblasts	-	-	Yasuda et al. (2022)
Curcumin	Unknown, probably by downregulation of Nrf2 and NF-kB pathways	Senescent HUVECs induced to exert a pro-inflammatory response significantly reduced the expression of pro-inflammatory markers such as MCP-1	-	Chronic Kidney Disease (recruiting, NCT04413266)	Matacchione et al. (2022)
Resveratrol	SIRT-1 and AMPK activator	Prevention of the onset of senescence in cultured endothelial progenitor cells, and also an increase of the proliferation and migration of these cells	Protective effects against arterial aging by reducing the aorta media thickness, inflammation, fibrosis, and oxidative stress and reduction of the number of senescent VSMCs in mice	Cardiovascular Health in the Elderly (Phase 2, NCT01842399)	Xia et al. (2008), Kim et al. (2018)
	Inhibitor of the NF-kB pathway			Vascular system and lipid metabolism disorders in Women and Men Aged 55–65 Years (NCT01668836)
Apigenin	IRAK1/IkBa/NF-kB inhibition	Reduction of the levels of SASP factors (IL-1α, IL-1β, IL-6, IL-8, GM-CSF, CXCL1, MCP-2 and MMP-3) detected in a cell line of senescent fibroblasts	The same outcomes in the kidneys of aged rats	Improvement of Organ Function by Apigenin in Elderly Patients with Sepsis (Phase 2, NCT05999682)	Lim et al. (2015)