Effects of aging and exercise training on apoptosis in the heart

Abstract

Aging is characterized by a progressive decline in cardiac function. A critical contributor to the age-related impairment in cardiac function is the loss of cardiac myocytes through "apoptosis", or programmed cell death. Structural remodeling in the heart with advancing age includes (a) loss of cardiomyocytes, (b) reactive hypertrophy of the remaining cardiomyocytes, and (c) increased connective tissue and altered geometry. The loss of cardiomyocytes with aging occurs through apoptosis. Particularly, mitochondrial-mediated apoptotic pathway is the best characterized and believed critical in regulating apoptosis with aging, suggesting that mitochondria are very important sites of programmed cell death. It has been also reported that mitochondrial dysfunction, oxidative stress, and impaired stress response contribute to age-induced mechanical remodeling as well as apoptosis. In contrast, exercise training not only improves cardiac function, but also reduces the risk of heart disease. We recently found that aging increased mitochondrial-mediated apoptotic signaling and apoptosis in the left ventricle, while chronic exercise training was effective in diminishing mitochondrial-mediated apoptotic signaling pathways in the aging heart, as indicated by lower DNA fragmentation, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive staining, and caspase-3 cleavage, when compared with left ventricles from the age-matched sedentary group. In this review, we will provide a comprehensive update regarding the effects of aging and exercise training on apoptosis in the heart.

Keywords: Aging; Apoptosis; Heart; Mitochondria; Myocytes.

Fig. 1

Apoptotic signaling pathways. Schematic overview of three major caspases-dependent apoptotic signaling pathways including (a) cytokines/Fas-mediated caspase-8 pathways, (b) mitochondrial-mediated caspase-9 pathways, and (c) endoplasmic reticulum (ER)/Ca²⁺-mediated caspase-12 pathways. Alternatively, mitochondria can release AIF and EndoG, which perform apoptosis independent of caspases activation.

Fig. 2

Effects of aging and exercise training on apoptosis in the heart. (A) Cleaved capase-3 protein levels and (B) DNA fragmentation through quantification of mono and oligonucleosomes via ELISA of left ventricles in young control (YC), young exercise trained (YE), old control (OC), and old exercise trained (OT) (Kwak et al., 2006).

Fig. 3

Exercise protection model against apoptosis in the heart. An integrative model of exercise protection against apoptosis in the heart whereby exercise can potentially upregulate stress proteins such as MnSOD, ERK, IGF-1/Akt, HSPs, and NF-kB.