Actionable autophagy checkpoints in cardiovascular ageing

Human life expectancy has increased across the globe, leading to a drastic shift in the demographic landscape towards an ageing population. As ageing advances, so too does the prevalence and socio-economic impact of non-communicable diseases. Amongst these, cardiovascular disorders stand out as the primary contributors to both morbidity and mortality, exerting major strains on healthcare systems and society at large. While the ageing process inevitably impacts various physiological functions and organ systems, perhaps none are as vulnerable as the circulatory system. By virtue of its function in disseminating essential resources and eliminating waste products, the cardiovascular system must operate under unremitting mechanical pressure and shear stress, let alone the constant exposure to noxious biochemical waste from almost every cell in the body. Remarkably, cardiomyocytes, the major cell type comprising the heart and responsible for its pumping action, are post-mitotic cells with limited, if any, proliferative potential and thus have to endure these conditions for the majority or perhaps even the totality of human lifespan. For all these reasons, age is arguably the strongest risk factor for the development of cardiovascular diseases yet remains largely considered as ‘non-modifiable’ in the absence of interventions that efficiently target the mechanisms driving the process of ageing itself. In this regard, we have recently defined eight molecular hallmarks of cardiovascular ageing, representing potential entry points to counteract the time-dependent decline in cardiovascular health with its concomitant surge in cardiovascular diseases.1 Chief amongst these is the cellular quality control mechanism of macro-autophagy(definition) (herein referred to as autophagy). Autophagy is responsible for the degradation and recycling of dysfunctional, damaged, or simply surplus cytoplasmic components, including, amongst others, cytosolic proteins, lipid droplets, entire organelles, and even invading microbes.2 Through this vital role, autophagy controls the health and lifespan of not only post-mitotic cardiomyocytes but also virtually all cell types comprising the cardiovascular system. Indeed, evidence from mice and humans indicates that autophagy progressively declines with ageing both in the heart and vasculature.1,2 Artificially enforcing this decline in vascular or cardiac cells closely phenocopies the aspects of cardiovascular ageing in mutant mice.1,2 Conversely, genetic manipulations and dietary regimens known to induce autophagy promote cardiovascular health and extend longevity.2 However, human translation of these interventions is challenging, if at all possible. Thus, pharmacological interventions that can safely and effectively promote autophagic activity are needed to promote cardiovascular health and lower residual cardiovascular risk beyond the management of traditional risk factors, like dyslipidaemia and hypertension, which might have reached a glass ceiling. We propose a number of mechanistic nodes potentially amenable to therapeutic stimulation of autophagy in the context of cardiovascular ageing. We refer to these as ‘autophagy checkpoints’, which encompass both intracellular and extracellular molecular targets renowned for their autophagy-suppressing effects (Figure 1). The antagonism of these autophagy checkpoints offers a promising, viable, and conceivably safer strategy for provoking autophagy for cardiovascular benefits compared with the direct activation of autophagy-inducing pathways. Indeed, the pharmacological antagonism of inhibitory targets is known to offer a broader therapeutic window than the administration of agonists, which often entail intricate design complexities to avert adverse effects. Exemplifying this antagonistic approach is the effective heart failure medication, sacubitril/valsartan, which operates by antagonizing angiotensin II receptors and inhibiting neprilysin, an enzyme that catalyses the degradation of natriuretic peptides. Another example is the potent lipid-lowering drug class, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, which act by increasing the numbers of LDL receptors on hepatocytes via suppressing PCSK9-binding and subsequent degradation of LDL receptors. Autophagy checkpoints and residual cardiovascular risk. Schematic representation of intracellular and extracellular autophagy-inhibitory targets, which are referred to as autophagy checkpoints. The scheme also lists examples of pharmacological antagonists or inhibitors of such autophagy checkpoints that may exert anti-ageing effects on the cardiovascular system. (Created with BioRender.com.) Among the most extensively studied intracellular autophagy checkpoints in the context of cardiovascular ageing are the mammalian target of mTOR(definition)-inhibiting drug studied for extending healthspan and lifespan." style="text-decoration:underline dotted; text-underline-offset:2px; cursor:help;">rapamycin(definition) complex 1 (mTORC1) and the acetyltransferase EP300—both of which are pharmacologically targetable. For instance, mTORC1 can be targeted using rapamycin or its analogues, while EP300 can be suppressed using spermidine and aspirin. These pharmacological interventions efficiently induce autophagy and exert major anti-ageing effects on the heart and vasculature. Indeed, rapamycin has been shown to effectively induce autophagy in ageing murine hearts,3 while delaying several cardiac manifestations of ageing.4 Notably, rapamycin appears to transiently promote autophagy,3 eliciting long-lasting cardiac benefits, even after treatment discontinuation.3,4 However, rapamycin is an immunosuppressive compound and may also have other adverse effects due to its mTORC1-independent actions. Irrespectively, aspirin, which is one of the most commonly used drugs in cardiovascular medicine, albeit for its anti-thrombotic action, can induce cardiac autophagy via inhibiting the acetyltransferase EP300.5,6 However, aspirin has failed to prevent primary cardiovascular events in aged, otherwise healthy, individuals.7 This may be attributed to commonly used aspirin dose