4. Discussion
cerebral ischemic stress
VASODILATION, CARDIOVASCULAR DISEASES, INFLAMMATION, OXIDATIVE STRESS, ENDOTHELIAL DYSFUNCTION
The main results of our study showed that 30 days of energy restriction, i.e., a 1000 kcal diet, or 500 mg daily resveratrol supplementation similarly increased circulating SIRT1 and decreased plasma noradrenaline. Plasma noradrenaline reduction was correlated with higher baseline circulating SIRT1. After the interventions, circulating SIRT1 was positively correlated with NMD independently of sex and interventions. Furthermore, circulating SIRT1 was independently associated with NMD in the energy restriction group. Regarding SIRT1 gene expression, we did not find any statistically significant differences at the end of the study, but we found a statistically significant association with FMD in men.Dietary energy restriction is the only physiological intervention that increases life expectancy in mammals [Resveratrol increases cell cAMP content, which in turn activates monophosphate-activated protein kinase (AMPK), a protein that acts as an upstream molecule to regulate expression of SIRT1 [SIRT1 has gained attention due to its metabolic regulation effect with concomitant activation of AMPK (adenosine5′-monophosphate (AMP)-activated protein kinase), a key molecule in cellular metabolism. Both proteins induce mitochondrial biogenesis, fatty acids β-oxidation, and gluconeogenesis through the activation of peroxisome proliferator-activated receptor- γ coactivator 1α (PGC1α) [Inflammation and oxidative stress are key factors for nitric oxide (NO) degradation and, subsequently, endothelial dysfunction, which is a critical factor for the development and progression of cardiovascular diseases [Our results showed that baseline SIRT1 gene expression positively correlated with changes in FMD, suggesting that individuals with higher SIRT1 gene expression presented higher FMD. Furthermore, we showed that SIRT1 expression was positively associated with FMD in men. This may be explained by the lower levels of circulating estrogen in men than in women, resulting in lower basal activation of SIRT1 in this group. Laboratory studies showed that, in female rats, estrogen activated the SIRT1/AMPK signaling pathway, increasing protection against cerebral ischemic stress [Regarding endothelium-independent vasodilation, our results showed that circulating SIRT1 was independently associated with NMD in the energy restriction group. Vascular reactivity measured by NMD provides information about the response of vascular smooth muscle cells (VSMCs) to a NO donor, i.e., endothelium-independent vasodilation [Both interventions reduced plasma noradrenaline, indicating a sympatholytic effect of resveratrol and dietary energy restriction. We also found that higher baseline levels of circulating SIRT1 were inversely correlated with plasma noradrenaline, suggesting that SIRT1 regulates plasma noradrenaline. Vascular reactivity is regulated by sympathetic nervous system (SNS) activation, which can be assessed by plasma noradrenaline [Our study has limitations. Firstly, we analyzed a small number of subjects. Our sample size was calculated using circulating SIRT1. Therefore, variations in parameters such as gene expression of SIRT1 and vascular reactivity could be undetected. On the other hand, we used multivariate analysis and correlations to detect change tendencies. Another limitation was that all subjects were at low cardiovascular risk, which could mask alterations in vascular reactivity parameters after interventions. In addition, the applicability of vascular reactivity tests on low cardiovascular risk populations is still debated [As far as we know, this is the first study that associated SIRT1 with well-established markers of vascular function in humans. Our results corroborate a previous laboratory study that showed that SIRT1 improves endothelial function [