Abstract
Sirtuin 1 (SIRT1) enzyme plays a pivotal role in the regulation of many physiological functions. In particular, it is implicated in ageing-related diseases, such as cardiac hypertrophy, myocardial infarct, and endothelial dysfunction; moreover, its expression decreases with age. Therefore, an effective strategy to extend the lifespan and improve cardiovascular function is the enhancement of the expression/activity of SIRT1 with exogenous agents. The Citrus flavonoid naringenin (NAR) presents structural similarity with the natural SIRT1 activator resveratrol. In this study, we demonstrate through in vitro assays that NAR significantly activates SIRT1 enzyme and shows antisenescence effects. The binding mode of NAR into SIRT1 was detailed investigated through in silico studies. Moreover, chronic administration (for six months) of NAR (100 mg/kg/day) to 6-month-old mice leads to an enhancement of SIRT1 expression and a marked reduction of reactive oxygen species production in myocardial tissue. Furthermore, at the end of the treatment, the plasma levels of two well-known markers of cardiovascular inflammation, TNF-α and IL6, are significantly reduced in 12-month-old mice treated with NAR, as well as the cardiovascular risk (total cholesterol/HDL ratio) compared to control mice. Finally, the age-associated fibrotic remodeling, which is well detected through a Mallory trichrome staining in the vehicle-treated 12-month-old mice, is significantly reduced by the chronic treatment with NAR. Moreover, an improvement of myocardium functionality is highlighted by the enhancement of citrate synthase activity and stabilization of the mitochondrial membrane potential after NAR treatment. Taken together, these results suggest that a nutraceutical approach with NAR may have positive impacts on many critical hallmarks of myocardial senescence, contributing to improve the cardiac performance in aged subjects.
Highlights
Ageing is a physiological process associated with a progressive impairment of homeostasis at cellular, tissue, and systemic level that increases the susceptibility to several ageingrelated diseases
We demonstrate that NAR, at least in part via, modulation of Sirtuin 1 (SIRT1) enzyme, can slow down the myocardial degradative processes associated with senescence; and taken together, these results suggest that a chronic treatment with the Citrus flavonoid NAR could guarantee beneficial effects at the myocardial level in humans
A limitation of this study is represented by the inability to correlate with absolute certainty the antiageing effects observed in vivo with the presence of NAR at systemic level
Summary
Ageing is a physiological process associated with a progressive impairment of homeostasis at cellular, tissue, and systemic level that increases the susceptibility to several ageingrelated diseases In this context, the heart is one of the main organs at risk; myocardial remodeling, accompanied by collagen fiber deposition, is considered the gateway to severe cardiac diseases, such as fibrosis and myocardial hypertrophy and heart failure [1]. An age-related lowgrade chronic inflammation, defined inflammaging, has been described [3] In this regard, macrophages are a key source of proinflammatory molecules, such as tumor necrosis factor- (TNF-) α, interleukin (IL) 6, and matrix metalloproteinases (MMPs), responsible in turn for the persistence of the basal inflammatory response [4]
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