Sirtuins (SIRTs) are proteins that regulate many cellular processes including mitochondrial function and genome integrity. In mammals, SIRT1-SIRT7 have been discovered, amongst which SIRT1 is probably the most extensively studied.

Although many studies have reported the association of SIRT1 with protection against cardiometabolic diseases, there may be a scarcity of evidence regarding how this protein contributes to human vascular function. A recent Nutrients study investigates the results of SIRT1 activation by resveratrol and energy restriction on vascular reactivity in adult men and ladies.

Study: Sirtuin 1 and Vascular Function in Healthy Women and Men: A Randomized Clinical Trial Comparing the Effects of Energy Restriction and Resveratrol. Image Credit: lianleonte / Shutterstock.com

Background

The endothelium regulates vascular homeostasis by acting as a barrier and lively regulator. Many studies have linked endothelial dysfunction with risk aspects for atherosclerosis.

Vascular reactivity parameters are used to evaluate endothelial function. For instance, nitroglycerin-mediated vasodilation (NMD) and flow-mediated dilation (FMD) are non-invasive techniques based on vascular reactivity parameters which might be extremely useful for predicting cardiometabolic events in high-risk populations.

Oxidative stress has been identified to be a key factor for endothelial dysfunction. During oxidative stress, nitric oxide (NO) production, activation, and bioavailability decrease.

FMD, an endothelium-dependent process, indicates the comfort of an artery in high stress conditions during post-occlusive reactive hyperemia. FMD is inversely linked with cardiovascular events and risk aspects, reminiscent of blood lipids, body mass index (BMI), and smoking. In high-risk individuals, low FMD can be correlated with impaired endothelium-dependent rest of coronary arteries.

Sympathetic nervous system (SNS) activation by alpha1- and beta2-adrenoreceptor signaling regulates vascular reactivity through the induction of vasoconstriction and vasodilation. Impaired beta-adrenergic signaling is often related to aging, hypertension, heart failure, obesity, metabolic syndrome, and diabetes. This impaired condition results in increased noradrenaline release and a chronic vasoconstrictive state.

Animal studies have shown that SIRT is related to longevity. SIRT1 is an nicotinamide adenine dinucleotide NAD+-dependent protein deacetylase that possesses antioxidant and anti inflammatory activity. In vitro experimental studies have demonstrated sympatholytic effects of SIRT1, together with improved cardiovascular function.

In animals, dietary energy restriction is a typical activator of SIRT1 that facilitates longevity-increasing effects. Nonetheless, the long-term maintenance of energy restriction conditions could possibly be difficult.

Notably, several foods and compounds have shown SIRT1 activation ability. Resveratrol, for instance, is a non-flavonoid polyphenolic compound that is of course present in lots of foods including berries, grapes, and peanuts. Previous studies have shown that this compound improves cardiometabolic parameters, reminiscent of the lowering of blood lipids, glucose homeostasis, and blood pressure.

In regards to the study

A randomized trial was conducted to find out the effect of SIRT1 activation by resveratrol supplementation and energy restriction on vascular reactivity in healthy female and male adults.

On this trial, 48 healthy individuals were recruited to investigate the results of 500 mg/day resveratrol supplementation and energy restriction of 1,000 kcal/day for 30 days on vascular reactivity parameters and SIRT1.

This cohort comprised 24 postmenopausal women  and 24 men between 55 and 65 years of age. Not one of the participants had a history of cardiovascular conditions or any non-communicable diseases.

Participants were subjected to a 15-day washout period, during which no medications or supplements were provided. Each participant was randomly assigned to either caloric restriction or resveratrol groups in a 1:1 ratio based on gender.

Biochemical parameters including triglycerides, high-density lipoprotein cholesterol (HDL-c), total cholesterol, apolipoprotein A-I (apoA-I), low-density lipoprotein cholesterol (LDL-c), apolipoprotein B (apoB), non-esterified fatty acids (NEFA), lipoprotein (a) (Lp(a)), glucose, insulin, gene expression of SIRT1, high-sensitivity C-reactive protein (hsCRP), noradrenaline (NA) and serum levels, were measured. Moreover, vascular reactivity parameters reminiscent of endothelium-independent vasodilation and endothelium-dependent were estimated.

Study findings

The present study revealed that 30 days of energy restriction and 500 mg/day of resveratrol supplementation increased circulating SIRT1 and reduced plasma NA levels.

At baseline, plasma NA reduction was robustly related to higher circulating SIRT1. After 30 days of interventions, circulating SIRT1 was positively correlated with NMD, independent of sex and interventions.

Circulating SIRT1 was also independently related to NMD within the energy restriction group. Although no statistically significant difference was observed regarding SIRT1 gene expression, a statistically significant association with FMD in men was observed.

Mechanistically, SIRT1 activation by energy restriction occurs resulting from declining glycolytic rates that aids respiratory metabolism. This results in SIRT1 activation through NAD+ replenishment and NADH reduction. Increased pyrazine-amidase and nicotine-amidase 1 (PNC1) and nicotinamide phosphoribosyl-transferase (Nampt) expression also occurs resulting from energy restriction.

Conclusions

The present study demonstrated that 500 mg/day of resveratrol supplementation increased circulating SIRT1 just like that of a severe energy restriction food regimen.

Baseline SIRT1 gene expression was positively correlated with changes in FMD, thus suggesting that individuals with higher SIRT1 gene expression present higher FMD. SIRT1 expression was also positively linked with FMD in men.

These findings indicate that energy restriction may improve FMD in men by increasing circulating SIRT1 levels and lowering of BMI. Future studies must use more biomarkers of SIRT1 biochemical pathways to higher understand its vascular and metabolism functions.