Cardiovascular disease (CVD) affects one in three adults and remains the leading cause of death in America Advancing age is a major risk factor for CVD Recent plateaus in CVD-related mortality ra

Mitochondrial contributions to vascular endothelial dysfunction, arterial stiffness, and cardiovascular diseases.

The human sirtuins are a group of NAD+-dependent protein deacylases. They "erase" acyl modifications from lysine residues in various cellular targets including histones, transcription factors, and metabolic enzymes. Through these far-reaching activities, sirtuins regulate a diverse array of biological processes ranging from gene transcription to energy metabolism. Human sirtuins have been intensely pursued by both academia and industry as therapeutic targets for a broad spectrum of diseases such as cancer, neurodegenerative diseases, and metabolic disorders. The last two decades have witnessed a flood of small molecule sirtuin regulators. However, there remain relatively few compounds targeting human sirtuins in clinical development. This reflects the inherent issues concerning the development of isoform-selective and potent molecules with good drug-like properties. In this article, small molecule sirtuin regulators that have advanced into clinical trials will be discussed in details as "successful" examples for future drug development. Special attention is given to the discovery of these compounds, the mechanism of action, pharmacokinetics analysis, formulation, as well as the clinical outcomes observed in the trials.

/pdf/human-sirtuin-regulators-the-success-stories-k8f6h741wc.pdf

Human Sirtuin Regulators: The "Success" Stories.

In recent years, many efforts have been made to identify micronutrients or nutritional strategies capable of preventing, or at least, attenuating, exercise-induced muscle damage and oxidative stress, and improving athlete performance. The reason is that most exercises induce various changes in mitochondria and cellular cytosol that lead to the generation of reactive species and free radicals whose accumulation can be harmful to human health. Among them, supplementation with phenolic compounds seems to be a promising approach since their chemical structure, composed of catechol, pyrogallol, and methoxy groups, gives them remarkable health-promoting properties, such as the ability to suppress inflammatory processes, counteract oxidative damage, boost the immune system, and thus, reduce muscle soreness and accelerate recovery. Phenolic compounds have also already been shown to be effective in improving temporal performance and reducing psychological stress and fatigue. Therefore, the aim of this review is to summarize and discuss the current knowledge on the effects of dietary phenolics on physical performance and recovery in athletes and sports practitioners. Overall, the reports show that phenolics exert important benefits on exercise-induced muscle damage as well as play a biological/physiological role in improving physical performance.

/pdf/effects-of-functional-phenolics-dietary-supplementation-on-1sab29sl.pdf

Effects of Functional Phenolics Dietary Supplementation on Athletes’ Performance and Recovery: A Review

Vascular aging, featuring endothelial dysfunction and large elastic artery stiffening, is a major risk factor for the development of age-associated cardiovascular diseases (CVDs). Vascular aging is largely mediated by an excessive production of reactive oxygen species (ROS) and increased inflammation leading to reduced bioavailability of the vasodilatory molecule nitric oxide and remodeling of the arterial wall. Other cellular mechanisms (i.e., mitochondrial dysfunction, impaired stress response, deregulated nutrient sensing, cellular senescence), termed “hallmarks” or “pillars” of aging, may also contribute to vascular aging. Gonadal aging, which largely impacts women but also impacts some men, modulates the vascular aging process. Regular physical activity, including both aerobic and resistance exercise, is a first-line strategy for reducing CVD risk with aging. Although exercise is an effective intervention to counter vascular aging, there is considerable variation in the vascular response to exercise training with aging. Aerobic exercise improves large elastic artery stiffening in both middle-aged/older men and women and enhances endothelial function in middle-aged/older men by reducing oxidative stress and inflammation and preserving nitric oxide bioavailability; however, similar aerobic exercise training improvements are not consistently observed in estrogen-deficient postmenopausal women. Sex differences in adaptations to exercise may be related to gonadal aging and declines in estrogen in women that influence cellular-molecular mechanisms, disconnecting favorable signaling in the vasculature induced by exercise training. The present review will summarize the current state of knowledge on vascular adaptations to regular aerobic and resistance exercise with aging, the underlying mechanisms involved, and the moderating role of biological sex. 

Effects of Regular Exercise on Vascular Function with Aging: Does Sex Matter?

Significance: The vasculature responds to the respiratory needs of tissue by modulating luminal diameter through smooth muscle constriction or relaxation. Coronary perfusion, diastolic function, and coronary flow reserve are drastically reduced with aging. This loss of blood flow contributes to and exacerbates pathological processes such as angina pectoris, atherosclerosis, and coronary artery and microvascular disease. Recent Advances: Increased attention has recently been given to defining mechanisms behind aging-mediated loss of vascular function and development of therapeutic strategies to restore youthful vascular responsiveness. The ultimate goal aims at providing new avenues for symptom management, reversal of tissue damage, and preventing or delaying of aging-induced vascular damage and dysfunction in the first place. Critical Issues: Our major objective is to describe how aging-associated mitochondrial dysfunction contributes to endothelial and smooth muscle dysfunction via dysregulated reactive oxygen species production, the clinical impact of this phenomenon, and to discuss emerging therapeutic strategies. Pathological changes in regulation of mitochondrial oxidative and nitrosative balance (Section 1) and mitochondrial dynamics of fission/fusion (Section 2) have widespread effects on the mechanisms underlying the ability of the vasculature to relax, leading to hyperconstriction with aging. We will focus on flow-mediated dilation, endothelial hyperpolarizing factors (Sections 3 and 4), and adrenergic receptors (Section 5), as outlined in Figure 1. The clinical implications of these changes on major adverse cardiac events and mortality are described (Section 6). Future Directions: We discuss antioxidative therapeutic strategies currently in development to restore mitochondrial redox homeostasis and subsequently vascular function and evaluate their potential clinical impact (Section 7). Antioxid. Redox Signal. 35, 974-1015.

Aging-Induced Impairment of Vascular Function: Mitochondrial Redox Contributions and Physiological/Clinical Implications.

The benefits of endurance exercise training on endothelial function are diminished in estrogen-deficient postmenopausal women, but estradiol treatment appears to restore improvements in endothelial...

https://journals.physiology.org/doi/pdf/10.1152/japplphysiol.00488.2019

Effects of resveratrol or estradiol on postexercise endothelial function in estrogen-deficient postmenopausal women.

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Effects of resveratrol or estradiol on postexercise endothelial function in estrogen-deficient postmenopausal women.