TABLE 1.

Summary of the interventions targeting endothelial cell metabolism with a potential role in the treatment of age-related diseases.

Pathway/mechanism	Intervention	Experimental model	Outcome(s)	References	Progression to the clinical trial stage
Glycolysis	Genetic inhibition of PFKFB3	Tumor ECs from C57BL/6 mice livers	Tightening of the vascular barrier, decreased expression of cancer cell adhesion molecules in ECs, improved delivery of chemotherapeutic drugs	Cantelmo et al., 2016	Phase 1 NCT02044861
Hypoxia response	MCT1 inhibition	HUVECs, RJ:NMRI mice	Inhibition of HIF-1-dependent angiogenesis	Sonveaux et al., 2012	Phase 1 NCT01791595
	Administration of telomerase activator TA-65	C57BL/6 mice	Enhancement of collateral vascular flow recovery during age-related ischemia	Kokubun et al., 2019	Phase 1 NCT02766790, NCT02531334, NCT01753674, NCT02731807
Aminoacid metabolism	Arginase II knockout	HUVECs, C57BL/6J mice	eNOS recoupling, inhibition of EC SASP	Wu et al., 2015	Phase 1 NCT02009527, NCT02903914, NCT03314935, NCT03361228
		C57BL/6J mice	Extended lifespan via inhibition of p16INK4a, p66Shc, and S6K1 signaling pathways	Xiong et al., 2017
	Glutamine administration	Sprague-Dawley rats	Attenuation of cardiopulmonary bypass-induced inflammatory response via regulation of NOSs activity	Hayashi et al., 2002	Commercially available as food supplement
		STZ diabetic C57BL/6 mice	Enhancement of circulating EPC mobilization via increase of plasma MMP-9, SDF-1, HIF-1 and VEGF levels	Su et al., 2017
	Glutaminase overexpression	HUVECs	Delaying of EC senescence	Unterluggauer et al., 2008	No
	Glutaminase-1 inhibition	HUVECs, HAECs, HMECs	Inhibition of aberrant EC proliferation and migration	Peyton et al., 2018	Phase 1 and 2 (18 trials)
Fatty acid metabolism	Fenofibrate administration	Middle-aged/older men and women	Improvement of endothelium-dependent vasodilation, reduction of plasma oxLDL	Walker et al., 2012	Commercially available for the treatment of dyslipidemia
		HFD C57BL/6J mice	Inhibition of HFD-induced insulin resistance and kidney injury via AMPK activation	Sohn et al., 2017
		MAECs, STZ diabetic C57BL/6 mice	Decreased intracellular O2– levels, improvement of endothelium-dependent relaxation via enhanced eNOS and AMPK phosphorylation	Xin et al., 2019
		STZ diabetic C57BL/6 mice	Amelioration of vascular endothelial dysfunction, reversal of kidney injury	Xu et al., 2019
	Genetic and pharmacological inhibition of CPT1A	HUVECs, C57BL/6 mice	Inhibition of pathological ocular angiogenesis	Schoors et al., 2015	No
	L-carnitine administration	Hypertensive Wistar Kyoto rats	Improvement of endothelial function via enhanced NO and PGI2 bioavailability and upregulation of the antioxidant systems	Bueno et al., 2005; Miguel-Carrasco et al., 2010	Commercially available as food supplement
		HAECs	Stimulation of eNOS activity via AMPK/Src-mediated signaling	Ning and Zhao, 2013
mTOR pathway	Rapamycin administration	B6D2F1 mice	Improvement of age-related endothelium-dependent vasodilation, amelioration of arterial senescence markers	Lesniewski et al., 2017	Commercially available as immunosuppressive drug

HAECs, human aortic endothelial cells; HMECs, human dermal microvascular endothelial cells; MAECs, mouse aortic endothelial cells; HUVECs, human umbilical vein endothelial cells; PGI₂, prostaglandin I₂; STZ, streptozocin; S6K1, ribosomal protein S6 kinase beta-1.