Targeting Autophagy in Aging and Aging-Related Cardiovascular Diseases

Abstract

Aging, an irreversible biological process, serves as an independent risk factor for chronic disease including cancer, pulmonary, neurodegenerative, and cardiovascular diseases. In particular, high morbidity and mortality have been associated with cardiovascular aging, but effective clinical therapeutic remedies are suboptimal for the ever-rising aging population. Recent evidence suggests a unique role for aberrant aggregate clearance and the protein quality control machinery - the process of autophagy - in shortened lifespan, compromised healthspan, and the onset and development of aging-associated cardiovascular diseases. Autophagy degrades and removes long-lived or damaged cellular organelles and proteins, the functions of which decline with advanced aging. Induction of autophagy using rapamycin, resveratrol, nicotinamide derivatives, metformin, urolithin A, or spermidine delays aging, prolongs lifespan, and improves cardiovascular function in aging. Given the ever-rising human lifespan and aging population as well as the prevalence of cardiovascular disease provoked by increased age, it is pertinent to understand the contribution and underlying mechanisms of autophagy and organelle-selective autophagy (e.g., mitophagy) in the regulation of lifespan, healthspan, and cardiovascular aging. Here we dissect the mechanism of action for autophagy failure in aging and discuss the potential rationale of targeting autophagy using pharmacological agents as new avenues in the combating of biological and cardiovascular aging.

Keywords: autophagy; biology of aging; cardiovascular; lifespan; mitophagy.

Fig. 1:

Schematic diagram depicting dysregulation of autophagy in advanced aging and how various pharmacological interventions may intervene the autophagy signaling process. Aging is commonly associated with impaired autophagy and mitophagy. Two main regulatory signaling machineries involved in dysregulated autophagy are suppressed AMPK activation and elevated class I PI-3K/Akt signaling, resulting in overactivated mTOR signaling, autophagy failure and changes in longevity and cardiac homeostasis. Improved lifespan and cardiac function in aging may be achieved through activation of AMPK directly or NAD⁺-dependent sirtuins indirectly. Sirtuins in turn promote longevity through FOXO-dependent induction of stress response and autophagy. Some pharmacological anti-agents such as resveratrol may benefit longevity and cardiac aging through autophagy-independent mechanism such as cAMP accumulation, leading to phospholipase C (PLC)-mediated activation of CamKKβ. Rapamycin, spermidine and N-acetyl glucosamine are considered autophagy inducers to directly act on mTOR. Free radical accumulation and oxidative stress such as AGEs turn on multiple oxido-reductase enzymes in aging commonly known as plasma membrane redox system (PMRS) that regulates cellular redox homeostasis and mitochondrial integrity. Bottom panel displays the essential steps in autophagy including nucleation and elongation, completion, fusion between autophagosomes and lysosomes as well as lysosomal degradation. Abbreviations PMRS: plasma membrane redox system, IGF-1: insulin like growth factor-1, FOXO: Forkhead O transcriptional factor; IRS: Insulin receptor substrate; EPac1: exchange protein directly activated by cAMP; OPN: osteopontin; CamKKβ: Ca²⁺/calmodulin-dependent protein kinase kinase β; mTOR: mammalian target of Rapamycin, PI3K: Phosphatidylinositol 3-kinase.