Molecular therapies delaying cardiovascular aging: disease- or health-oriented approaches

Abstract

Regenerative medicine is a new therapeutic modality that aims to mend tissue damage by encouraging the reconstitution of physiological integrity. It represents an advancement over conventional therapies that allow reducing the damage but result in disease chronicization. Age-related decline in spontaneous capacity of repair, especially in organs like the heart that have very limited proliferative capacity, contributes in reducing the benefit of conventional therapy. ncRNAs are emerging as key epigenetic regulators of cardiovascular regeneration. Inhibition or replacement of miRNAs may offer reparative solutions to cardiovascular disease. The first part of this review article is devoted to illustrating novel therapies emerging from research on miRNAs. In the second part, we develop new therapeutic concepts emerging from genetics of longevity. Prolonged survival, as in supercentenarians, denotes an exceptional capacity to repair and cope with risk factors and diseases. These characteristics are shared with offspring, suggesting that the regenerative phenotype is heritable. New evidence indicates that genetic traits responsible for prolongation of health span in humans can be passed to and benefit the outcomes of animal models of cardiovascular disease. Genetic studies have also focused on determinants of accelerated senescence and related druggable targets. Evolutionary genetics assessing the genetic basis of adaptation and comparing successful and unsuccessful genetic changes in response to selection within populations represent a powerful basis to develop novel therapies aiming to prolong cardiovascular and whole organism health.

Accelerated Cardiac Aging in Patients With Congenital Heart Disease

“…Moreover, longevity genes and proteins could have a significant impact in delaying age-related cardiac dysfunction ( 187 ). In this respect, we discovered that a genetic polymorphism of the BPIFB4 gene is associated with exceptional longevity.…”

miR‑141 impairs mitochondrial function in cardiomyocytes subjected to hypoxia/reoxygenation by targeting Sirt1 and MFN2

“…At the transcriptional level, ROS can transactivate genes encoding enzymatic and non-enzymatic antioxidants (4,5). At the translational level, an additional layer of regulation is achieved by microRNAs (miRNAs/miRs) (9)(10)(11). miRNAs are non-coding RNAs that miR-141 impairs mitochondrial function in cardiomyocytes subjected to hypoxia/reoxygenation by targeting Sirt1 and MFN2 can modulate genetic output of antioxidants, primarily by transcriptional silencing.…”

“…Members of the miR-200 family (miR-200a, miR-200b, miR-200c, miR-141 and miR-429) can respond to and regulate cellular ROS levels ( 9 , 10 ). Two members of this family, miR-200c and miR-141, have been implicated in various pathologies associated with excessive oxidant stress and mitochondrial dysfunction within the heart, including aging and diabetes ( 11 , 12 ). While an increase in miR-200c driving cardiac I/R or H/R injury has been supported by previous studies ( 1 , 2 ), the role of miR-141 is rather ambiguous ( 13 , 14 ).…”

The mechanisms of vascular aging

“…The proportion of aged population is increasing in the world. According to the World Population Prospects, by 2050, it has been estimated that the number of people aged 65 or over will almost double from 2019% to 16%; and the proportion of persons aged 80 years or over is predicted to triple 2 . The demographic change has enormous influence on society.…”

“…According to the World Population Prospects, by 2050, it has been estimated that the number of people aged 65 or over will almost double from 2019% to 16%; and the proportion of persons aged 80 years or over is predicted to triple. 2 The demographic change has enormous influence on society. Cardiovascular disease is a primary cause of death worldwide, 3 leading to a public health burden for patients and society.…”