Antiaging Properties of a Grape-Derived Antioxidant Are Regulated by Mitochondrial Balance of Fusion and Fission Leading to Mitophagy Triggered by a Signaling Network of Sirt1-Sirt3-Foxo3-PINK1-PARKIN

Abstract

It was proposed that resveratrol, a polyphenolic antioxidant and a calorie restriction mimetic could promote longevity but subsequent studies could not prove this. The original proposal was based on the fact that a grape-derived antioxidant could activate the antiaging gene Sirt1. Most studies agree that indeed grape activates Sirt1, but a question remains whether Sirt1 is the cause or consequence of resveratrol treatment. Subsequently, mitochondrial Sirt3 was found to be activated. The present study on ischemic reperfusion (I/R) in rat hearts demonstrates that Foxo3a is activated subsequent to Sirt3 activation, which then activates PINK1. PINK1 potentiates activation of PARKIN leading to the activation of mitochondrial fission and mitophagy. Confocal microscopy conclusively shows the coexistence of Sirt3 with Foxo3a and Foxo3a with PINK1 and PARKIN. Mitophagy was demonstrated both by confocal microscopy and transmission electron microscopy. Western blot analyses data are consistent with the results of confocal microscopy. It appears that the grape-derived antioxidant modifies the intracellular environment by changing the oxidizing milieu into a reducing milieu and upregulating intracellular glutathione, potentiates a signal transduction cascade consisting of Sirt1/Sirt3-Foxo3a-PINK1-PARKIN-mitochondrial fusion fission-mitophagy that leads to cardioprotection, and paves the way to an anti-aging environment.

Losartan Protects the Heart Against Ischemia Reperfusion Injury: Sirtuin3 Involvement

“…Mukherjee et al have demonstrated that longevinex (modified SIRT1 activator) improves cardiac performance and decreases infarct size in hearts subjected to 30 min of ischemia followed by 2 h reperfusion while increases survival factors expression and theses effects were accompanied by enhanced SIRT3 expression (30). In another study resveratrol, SIRT1 activator, protected the heart against ischemia reperfusion injury via activation of Foxo3a subsequent to SIRT3 activation which increased intracellular concentration of glutathione in the heart (31).…”

Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3‐dependent regulation of oxidative stress and apoptosis

“…Accumulating evidence confirms that a tight relationship exists between SIRT1 and SIRT3. Resveratrol, a polyphenolic antioxidant and a calorie restriction mimetic, exerts its anti‐aging effects by potentiating a signal transduction cascade consisting of SIRT1/SIRT3‐FOXO3a‐PINK1‐PARKIN . Liu et al.…”

Curcumin Enhanced Cholesterol Efflux by Upregulating ABCA1 Expression Through AMPK-SIRT1-LXRα Signaling in THP-1 Macrophage-Derived Foam Cells

“…FOXO3a, a transcription factor, is an important target of SIRT1. SIRT1 deacetylates FOXO3a, triggers transcription of FOXO3a-dependent stress resistance genes, and contributes to increased longevity (Das et al, 2014). However, recent research has found that curcumin reduces macrophage lipid accumulation in LDL receptor knockout mice fed a high-fat diet for 4 months through the SIRT1-FOXO3a axis.…”