|
| Extrinsic heart senescence triggers | |
| (i) Hypercholesterolemia | [33, 36–40] |
| (ii) Hypertension |
|
| Intrinsic heart senescence triggers | |
| (i) Leukocyte telomere length shortening | [33, 36–40] |
|
| Upregulated (↑) and downregulated (↓) molecular pathways and functions | |
| (i) ↓ autophagy, mediated by ↑ oxidative stress | |
| (a) Early signs of senescence, accumulation of dysfunctional mitochondria, disorganization of sarcomere structure, and age-related cardiomyopathy in Atg5-deficient mice | [41] |
| (b) ↓ cardiac function and survival in Parkin-deficient mice | [42] |
| (c) Stimulation of mitophagy with spermidine, a natural polyamine, preserves cardiac function in old mice | [43, 44] |
| (d) Inhibition of miR-22 rescues autophagy and improves cardiac function in old mice | [45, 46] |
| (ii) Alterations of the inflammatory, endothelial, and myogenic phenotype of cardiac cells are also observed, with most of changes related to the aging-dependent manifestation of mutations in genes involved in the calcium cycling and signaling (↓ activity of SERCA2 and calsequestrin and Ica) | [47, 48] |
| (iii) ↓ cardiac sympathetic innervation | [49, 50] |
| (a) ↓ catecholamine uptake, ↓ isoproterenol response, ↓ epinephrine reuptake, and ↓ noradrenalin transport in senescent cardiac neuronal cells |
| (iv) Age-dependent hERG mutations | [51] |
| (a) Disorganization of the structure of the sarcomeric structure and myofibrillary proteins |
| (v) ↓ SIRT 3 | [52] |
| (a) Pericyte loss and endothelial dysfunction, further exacerbated in the case of concomitant diabetic condition |
| (vi) ↑ ADAM/TACE overexpression in adipose tissue, mediated by ↓ negative regulation by caveolin-1 | [53] |
| (a) ↑ TNF-α activity |
| (vii) ↑ senescence-associated genetic program in recruited fibroblasts of cardiac ischemia can be considered a protective mechanism from endothelin-1-mediated cardiac fibrosis | [54, 55] |
|
