Targeting Oxidative Stress to Provoke Greater Tissue Maintenance and Regeneration in the Aging Heart

The heart is one of the least regenerative organs, and what limited ability it has to recover from injury is further diminished by age. This is of particular concern in the context of recovery from a heart attack, which leaves regions of scar tissue rather than functional tissue, weakening the heart. The best approach to this problem is to prevent heart attacks from occurring in the first place, which would have to be achieved by in some way halting and reversing the underlying processes of atherosclerosis and the growth of fatty lesions in the vasculature. There is enthusiasm for this goal in academia and industry, at least in principle, but very little concrete progress in departing from the futile focus on lowering LDL-cholesterol in the bloodstream, which can only modestly slow the progression of atherosclerosis, not reverse it.

Thus, a sizable fraction of the regenerative medicine community is interested in finding ways to provoke greater regeneration in heart tissue, largely with the primary goal of helping heart attack survivors to regain at least some lost function. Today's open access paper is a discussion of the role of oxidative stress and cellular senescence in the age-related loss of regenerative capacity in heart tissue, with particular attention given to the function of progenitor cells in the heart responsible for regeneration. Researchers are looking for ways to reprogram the behavior of these cells, to reduce the impact of senescence, and it may be that oxidative signaling is a place to start.

Targeting the redox system for cardiovascular regeneration in aging

Lifespan has nearly doubled over the recent seven decades, but the final years of life come often with aging-associated diseases, most prominently cardiovascular disease (CVD) featured by progressive deterioration of cardiovascular structure and function. Aging imposes extensive changes on cardiovascular tissues that lead them toward a pathological state including hypertrophy, left ventricular dysfunction, arterial stiffness, and vascular dysfunction. Extrinsic factors, such as environment and lifestyle, and intrinsic processes, such as oxidative stress and inflammation, exacerbate DNA damage response, metabolic remodeling, and epigenetic drift, and thereby promote cellular aging in the cardiovascular system. These irreversible changes progressively impair the ability of cells to proliferate, which is critical to replace damaged cells that naturally accumulate in aged cardiac and vascular tissues.

During the recent decade, it is increasingly understood that the accumulation of the non-proliferating cells, so-called "senescent cells," declines mammalian tissues and organ function. According to the emerging "adult stem cell senescence theory of aging," stem cells and/or progenitor cells harboring in the heart and blood vessels or circulating progenitor cells, which replenish either preexisting senescent stem cells or specialized cardiomyocytes (CMs) and endothelial cells (ECs), become exhausted and lose their stemness during aging. The aging/senescence milieu suppresses endogenous regenerative and reparative mechanisms in the adult stem cells and progenitor cells, and also limits the success of cell-based regenerative therapies that aimed at repairing injured and dysfunctional tissues and restoring a youthful phenotype in the cardiovascular system. In a middle-size human study involving 119 humans with cardiovascular disease (32-86 years), more than 50% of tissue-specific cardiac progenitor cells (CPCs) exhibited the senescence phenotype.

Reactive oxygen species (ROS) have been viewed as pathological molecules that undermine normal cellular pathways by increasing oxidative stress. The cardiovascular system is principally vulnerable to reactive oxygen species (ROS) induced oxidative damage due to its high metabolic demand and low antioxidant defense capacity in aging. Single-cell RNA-Seq analysis of mouse aged cardiovascular ECs reveals transcriptomic reprogramming, including upregulation of ROS metabolic process in these cells. Not only in aged arterial ECs, single-nucleus RNA-Seq verify that oxidative responses are enriched in aged CMs in both primate and human hearts. These studies and beyond have demonstrated that these aged cardiac and arterial tissues exhibit a higher level of senescence-associated β-galactosidase staining and expression of pro-senescence genes including IL1β, IL17, and Type-I interferon (IFN-α). The relentless ROS production can also cause oxidative stress in cellular components, leading to cardiovascular stem/progenitor cell senescence and impaired proliferation and differentiation.

A mounting body of evidence underscores the significance of targeting redox machinery to restore stem cell self-renewal and enhance their differentiation potential into youthful cardiovascular lineages. Hence, the redox machinery holds promise as a target for optimizing cardiovascular regenerative therapies. In this context, we delve into the current understanding of redox homeostasis in regulating stem cell function and reprogramming processes that impact the regenerative potential of the cardiovascular system. Furthermore, we offer insights into the recent translational and clinical implications of redox-targeting compounds aimed at enhancing current regenerative therapies for aging cardiovascular tissues.

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