The impact of aging on cardiac repair and regeneration

Abstract

In contrast to neonates and lower organisms, the adult mammalian heart lacks any capacity to regenerate following injury. The vast majority of our understanding of cardiac regeneration is based on research in young animals. Research in aged individuals is rare. This is unfortunate as aging induces many changes in the heart. The first part of this review covers the main technologies being pursued in the cardiac regeneration field and how they are impacted by the aging processes. The second part of the review covers the significant amount of aging-related research that could be used to aid cardiac regeneration. Finally, a perspective is provided to suggest how cardiac regenerative technologies can be improved by addressing aging-related effects.

Keywords: aging; cardiac; cardiomyocyte; fibroblast; heart; mitochondria; regeneration.

Figure 1

Mechanisms in mammalian cardiac regeneration.A, VEGF therapies for revascularization are undergoing clinical evaluation for safety. The molecular mechanism involves the indicated kinases. B, triggers for fibrosis include ROS, proinflammatory cytokines such as IL6, and growth factors including TGFβ. TGFβ inhibitors are showing promise in preclinical animal models. C, cellular reprogramming refers to the process, whereby scar fibroblasts are converted in situ into new cardiomyocytes. Ostensibly, reprogramming factors work by modulating the activity/function of activators and inhibitors. Inhibitor pathways are mainly epigenetic, such as H3K27me3 and H2AK11ub. These epigenetic motifs are regulated by the indicated proteins. These proteins are direct targets for reprogramming factors. Less is known about TGFβ inhibition. Various activator pathways have been reported including immunity (Rig1, TLR3, and IFNβ), autophagy (Atg5), and growth factor signaling (Akt). D, cardiomyocyte proliferation is nonexistent in the adult mammalian heart. Proliferation can be induced through certain growth factors or the overexpression of various CDKs and their cognate cyclins. Another approach is targeting cardiomyocyte cell cycle inhibitors. Manipulation of various kinase signaling pathways has also proven fruitful. Interestingly, these kinase pathways appear to augment each other’s activity. CDK, cyclin-dependent kinase; ROS, reactive oxygen species; TLR, toll-like receptor; VEGF, vascular endothelial growth factor.

Figure 2

Molecular pathways in cardiac aging. Aging is associated with reduced cardiac function. As the heart ages, mitochondria become dysfunctional and cells become senescent. The net result is an increase in ROS levels and the production of proinflammatory proteins respectively. ROS and proinflammatory proteins set up a positive feedback loop which increases cellular senescence and impairs regenerative capacity. ROS, reactive oxygen species.