**5. Targeting endothelial SIRT1 for the prevention of arterial aging**

Slowing down the vascular aging requires early intervention, lifelong treatment, and sitespecific approaches. To reduce arterial stiffness, pharmacological agents, including angiotensinconverting enzyme inhibitors, angiotensin II type 1 blockers, aldosterone antagonists, and statins, are currently available and in clinical use [35]. The evident vasoprotective effects of SIRT1 definitely pose great opportunities and challenges for drug discovery targeting endothelial dysfunction. So far, a few natural and synthetic substances have been demonstrated as SIRT1 activators to promote vascular health. The first potent activator of SIRT1 is resveratrol, a small polyphenol discovered in red wine, which could protect ECs against inflammation, apoptosis, and oxidative stress [72]. It was found to dramatically lower the incidence of cardiovascular diseases in spite of high saturated fat diet, which was termed as "French paradox" [73]. Several natural ingredients extracted from various traditional Chinese herbs were also found to activate SIRT1. Tetramethylpyrazine is proved to reverse high-glucoseinduced endothelial dysfunction via SIRT1 [74]. Polydatin can attenuate hemorrhagic shock by upregulating SIRT1 [75]. Quercetin is capable of inhibiting oxidized LDL-induced EC damage by SIRT1 activation [76]. Some other natural polyphenols including fisetin and butein can also activate SIRT1 [77]. Vitamin D protects ECs from irradiation-induced senescence and apoptosis by modulating MAPK/SirT1 axis [78]. On the other hand, a series of SIRT1 activators like SRT2183, SRT1460, SRT1720, SRT2379, SRT501, SRT2104, SRT3025, and BMT0-512 have been synthesized and developed as potential drugs to protect against vascular aging [77, 79].

Despite the fact that SIRT1 is as an optimal therapeutical target for cardiovascular diseases, the dosage of upregulation of SIRT1 should be considered seriously and titrated cautiously in clinical practice. It was reported that 2.5- to 7-fold overexpression of SIRT1 prevented heart from oxidative stress via SIRT1/FOXO, while 12.5-fold overexpression of SIRT1 increased apoptosis and hypertrophy and decreased cardiac function, suggesting that only low to moderate doses of SIRT1 can exert beneficial effects [80]. The aforementioned findings call for more careful evaluation of dosage and possible adverse effects in drug development targeting endothelial SIRT1.

In light of all the above studies, there have already been several potential drugs to target the anti-vascular aging effects of endothelial SIRT1. The entry of SIRT1 activators into human trials is exciting but also highlights the necessity to better understand the SIRT1 specificity, clinical effects, and side effects of these promising activators in vivo.
