# Sirtuin 1 and Hormonal Regulations in Aging
## 4 Natural Activators of SIRT1 and Their Use in the Prevention of Aging  
### Resveratrol  
Resveratrol is a naturally occurring polyphenic compound found in various plants, such as grapes (mainly in red grapes and wines, where the concentration of more stable trans-resveratrol ranges from 1.9 mg/L to 14.3 mg/L [63]), mulberries, raspberries, blueberries, peanuts, and many others, i.e., from 34 families comprising at least 100 species, some of which have been used for centuries in Chinese and other traditional medicines [64]. The amount of resveratrol in these numerous sources ranges from 8.7 g/kg in the seeds of _Paeonia suffruticosa_ Andr. var. _papaveraceae_ (Andrews) [PERSON] to less than 1 mg/kg for the roots of _Smilax scobinicaulis_ and _Caragana sinica_ and the seeds of _Vigna umbellata_ (Thunb.) [PERSON] [64]. Resveratrol exists in cis and trans isoforms, the latter being more stable and potent [61]. Resveratrol is recognized as a potent activator of SIRT1, which has anticancer, anti-inflammatory, neuroprotective, antifungal, antimicrobial, and gut-microbiota-protective effects, effects related to metabolic and non-metabolic diseases, and anti-aging effects, all of which are associated with the activation of sirtuins, primarily by SIRT1 [65]. Resveratrol increases the expression and activity of SIRT1 in various organs, including the liver, adipose tissue, brain, and heart, thereby exerting protective effects against age-related diseases [8]. Thus, activated SIRT1 signaling increases the expression of antioxidant enzymes such as SOD and catalase, further protecting cells from oxidative damage as observed in mouse primary astrocytes obtained from newborn C57 BL/6J mice [66] and in many tissues [5]. Studies have shown that resveratrol can extend lifespan and delay the onset of age-related diseases in a variety of model organisms, including yeast, worms, and flies [67]. In rodent studies, resveratrol supplementation has been shown to improve insulin sensitivity, reduce adiposity, and improve glucose metabolism, thereby reducing the risk of age-related metabolic disorders such as type 2 diabetes [68]. Moreover, the neuroprotective effects of resveratrol mediated through SIRT1 activation have been associated with improved cognitive function and reduced neuronal damage in mice models of Alzheimer's and Parkinson's diseases [69]. Clinical trials in humans have also reported promising outcomes. For instance, a double-blind, randomized study of type 2 diabetes patients showed that 1 g/day of resveratrol for 12 weeks improved insulin sensitivity, reduced HbA1c levels, and decreased oxidative stress markers [70]. In another clinical trial, resveratrol supplementation at doses of 150 mg/day for 90 days improved cognitive performance and cerebral blood flow in older adults, suggesting its neuroprotective benefits [71]. However, other trials have reported limited efficacy, particularly in metabolic outcomes, indicating the need for further research [72]. Moreover, the neuroprotective effects of resveratrol mediated through SIRT1 activation have been associated with improved cognitive function and reduced neuronal damage in mice models of Alzheimer's and Parkinson's diseases [69]. In addition to its direct effects on SIRT1, resveratrol also modulates other signaling pathways associated with aging, such as the AMP-activated protein kinase (AMPK) pathway. Activation of AMPK in combination with SIRT1 promotes autophagy, a critical process for the removal of damaged cellular components, thereby contributing to cellular rejuvenation and longevity of yeast, nematodes, and flies [73]. The ability of resveratrol to activate SIRT1 and AMPK simultaneously highlights its potential as a comprehensive anti-aging agent. Resveratrol is generally recognized as safe for humans, but its overdose can turn its effects from antioxidant and protective to prooxidant and harmful [74].