Pro-Senescence and Anti-Senescence Mechanisms of Cardiovascular Aging: Cardiac MicroRNA Regulation of Longevity Drug-Induced Autophagy

Abstract

Chronological aging as well as biological aging accelerated by various pathologies such as diabetes and obesity contribute to cardiovascular aging, and structural and functional tissue damage of the heart and vasculature. Cardiovascular aging in humans is characterized by structural pathologic remodeling including cardiac and vascular fibrosis, hypertrophy, stiffness, micro-and macro-circulatory impairment, left ventricular diastolic dysfunction precipitating heart failure with either reduced or preserved ejection fraction, and cardiovascular cell death. Cellular senescence, an important hallmark of aging, is a critical factor that impairs repair and regeneration of damaged cells in cardiovascular tissues whereas autophagy, an intracellular catabolic process is an essential inherent mechanism that removes senescent cells throughout life time in all tissues. Several recent reviews have highlighted the fact that all longevity treatment paradigms to mitigate progression of aging-related pathologies converge in induction of autophagy, activation of AMP kinase (AMPK) and Sirtuin pathway, and inhibition of mechanistic target of rapamycin (mTOR). These longevity treatments include health style changes such as caloric restriction, and drug treatments using rapamycin, the first FDA-approved longevity drug, as well as other experimental longevity drugs such as metformin, rapamycin, aspirin, and resveratrol. However, in the heart tissue, autophagy induction has to be tightly regulated since evidence show excessive autophagy results in cardiomyopathy and heart failure. Here we discuss emerging evidence for microRNAmediated tight regulation of autophagy in the heart in response to treatment with rapamycin, and novel approaches to monitor autophagy progression in a temporal manner to diagnose and regulate autophagy induction by longevity treatments.

Targeting Long Non-coding RNA to Therapeutically Regulate Gene Expression in Cancer

“… 64 In a hypoxic environment, HIF-1 will be located in the nucleus, on the promoter of its target gene, and activate the transcription of the target gene. 65 The target gene of HIF-1 is related to the occurrence and development of tumors, such as glycolysis, energy metabolism, and cell migration, among others. 66 lncHIFCAR (long non-coding HIF-1α-coactivating RNA) seems to reveal the mechanism of HIF-1 in activating downstream genes.…”

The Effects of Resveratrol on Telomeres and Post Myocardial Infarction Remodeling

“…They concluded that senescent cells significantly influence the outcome of cardiac diseases, therefore novel therapies targeting clearance of senescent cells and reversing the senescent phenotype should be explored [ 16 ]. According to Pulakat et al aging is accelerated by obesity and diabetes and induces cardiovascular changes characterized by pathological remodeling associated with myocardial and vascular fibrosis, stiffness and hypertrophy, macro and microcirculatory impairment, left ventricular diastolic dysfunction leading to heart failure, and ultimately cardiovascular cell death [ 17 ]. They noted that many longevity treatments are related to the induction of autophagy, activation of the Sirtuin pathway, AMPK Activation, inhibition of mTOR (mechanistic target of rapamycin) [ 17 ].…”

“…According to Pulakat et al aging is accelerated by obesity and diabetes and induces cardiovascular changes characterized by pathological remodeling associated with myocardial and vascular fibrosis, stiffness and hypertrophy, macro and microcirculatory impairment, left ventricular diastolic dysfunction leading to heart failure, and ultimately cardiovascular cell death [ 17 ]. They noted that many longevity treatments are related to the induction of autophagy, activation of the Sirtuin pathway, AMPK Activation, inhibition of mTOR (mechanistic target of rapamycin) [ 17 ]. Such treatments focus on calorie restriction and drugs like resveratrol, metformin, rapamycin, aspirin [ 17 ].…”

“…They noted that many longevity treatments are related to the induction of autophagy, activation of the Sirtuin pathway, AMPK Activation, inhibition of mTOR (mechanistic target of rapamycin) [ 17 ]. Such treatments focus on calorie restriction and drugs like resveratrol, metformin, rapamycin, aspirin [ 17 ]. Autophagy is highly regulated in cardiac tissue; excessive autophagy may cause cardiomyopathy and heart failure; they concluded that regulation of autophagy is important for preventing myocardial aging [ 17 ].…”

“…Such treatments focus on calorie restriction and drugs like resveratrol, metformin, rapamycin, aspirin [ 17 ]. Autophagy is highly regulated in cardiac tissue; excessive autophagy may cause cardiomyopathy and heart failure; they concluded that regulation of autophagy is important for preventing myocardial aging [ 17 ]. According to Shimizu et al senescent cells are pro-inflammatory and cause chronic sterile inflammation [ 18 ].…”