Recent Advances on Drug Development and Emerging Therapeutic Agents Through Targeting Cellular Homeostasis for Ageing and Cardiovascular Disease

Abstract

Ageing is a progressive physiological process mediated by changes in biological pathways, resulting in a decline in tissue and cellular function. It is a driving factor in numerous age-related diseases including cardiovascular diseases (CVDs). Cardiomyopathies, hypertension, ischaemic heart disease, and heart failure are some of the age-related CVDs that are the leading causes of death worldwide. Although individual CVDs have distinct clinical and pathophysiological manifestations, a disturbance in cellular homeostasis underlies the majority of diseases which is further compounded with aging. Three key evolutionary conserved signalling pathways, namely, autophagy, mitophagy and the unfolded protein response (UPR) are involved in eliminating damaged and dysfunctional organelle, misfolded proteins, lipids and nucleic acids, together these molecular processes protect and preserve cellular homeostasis. However, amongst the numerous molecular changes during ageing, a decline in the signalling of these key molecular processes occurs. This decline also increases the susceptibility of damage following a stressful insult, promoting the development and pathogenesis of CVDs. In this review, we discuss the role of autophagy, mitophagy and UPR signalling with respect to ageing and cardiac disease. We also highlight potential therapeutic strategies aimed at restoring/rebalancing autophagy and UPR signalling to maintain cellular homeostasis, thus mitigating the pathological effects of ageing and CVDs. Finally, we highlight some limitations that are likely hindering scientific drug research in this field.

Differentially Expressed Genes and Molecular Susceptibility to Human Age-Related Diseases

“…First, we used the PubMed database [ 75 ] and characterized each of the 39 novel PAG-related DEGs of the tame and aggressive rats ( Table 2 ) by answering the question as to how under- or overexpression of their human orthologs can aggravate or alleviate ARDs [ 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 , 136 , ...…”

Mkk7 Protects Against Cardiac Dysfunction in Heart Failure with Preserved Ejection Fraction

“…The UPR consists of three main signalling pathways, that are activated by a transmembrane protein sensor located on the ER membrane; Proteinkinase RNA-like kinase (PERK), Inositol-requiring enzyme 1 (AzamIRE1) and Activating Transcription Factor 6 (ATF6). Together, these branches work in a coordinated manner to initially mitigate ER stress and restore protein homeostasis [8].…”