Translational evidence that impaired autophagy contributes to arterial ageing

Abstract

Key points• Advancing age is the major risk factor for the development of cardiovascular diseases.• Arterial endothelial dysfunction, characterized by impaired endothelium-dependent dilatation (EDD), is a key antecedent to age-associated clinical cardiovascular disease.• We tested the hypothesis that changes in autophagy, the process by which cells recycle damaged biomolecules, may be an underlying cause of the age-related reduction in EDD.• We show that autophagy is impaired in arteries of older humans and mice with reduced EDD, and that enhancing autophagy restores EDD by reducing superoxide-dependent oxidative stress and inflammation, and increasing nitric oxide bioavailability.• Our results identify impaired autophagy as a potential cause of age-related arterial dysfunction and suggest that boosting autophagy may be a novel strategy for the treatment of arterial endothelial dysfunction and prevention of cardiovascular diseases with ageing.Abstract Ageing causes arterial endothelial dysfunction that increases the risk of cardiovascular diseases (CVD), but the underlying mechanisms are incompletely understood. The aim of the present study was to determine the role of autophagy, the cellular process of recycling damaged biomolecules, in endothelial dysfunction with ageing. In older humans, expression of autophagy markers in arterial endothelial cells was impaired by ∼50% (P < 0.05) and was associated with an ∼30% (P < 0.05) reduction in arterial endothelium-dependent dilatation (EDD). Similarly, in C57BL/6 control mice ageing was associated with an ∼40% decrease (P < 0.05) in arterial markers of autophagy and an ∼25% reduction (P < 0.05) in EDD. In both humans and mice, impaired EDD was mediated by reduced nitric oxide (NO) bioavailability and was associated with increased oxidative stress and inflammation (P < 0.05).In old mice, treatment with the autophagy-enhancing agent trehalose restored expression of autophagy markers, rescued NO-mediated EDD by reducing oxidative stress, and normalized inflammatory cytokine expression. In cultured endothelial cells, inhibition of autophagy increased oxidative stress and reduced NO production, whereas trehalose enhanced NO production via an autophagy-dependent mechanism. These results provide the first evidence that autophagy is impaired with ageing in vascular tissues. Our findings also suggest that autophagy preserves arterial endothelial function by reducing oxidative stress and inflammation and increasing

Autophagy and human diseases

“…Many drugs and compounds that modulate autophagy are currently receiving considerable attention [11,89,108]. These include, for example, autophagy inducers such as the mTORC1 inhibitor rapamycin [109] and its analogues (e.g., CCI-779 [109], RAD001 [110,111], and AP23573 [112]), mTOR kinase inhibitors (e.g., Torin 1 [113], and PP242 [114]), trehalose [115,116], carbamazepine [117], and the newly identified autophagy-inducing peptide Tatbeclin 1 [118]; autophagy inhibitors such as chloroquine [119,120] and hydroxychloroquine [121], Lys05 [122], 3-methyladenine [123] and its derivatives [124], PIK3C3 inhibitors [125], ATG4B inhibitors [126,127], and ATG7 inhibitors [128,129]. Autophagy-modulating drugs that are currently used in clinical trials are summarized in Table 2.…”

The effects of resveratrol on aging vessels

“…Further, failure to remove aldehyde-modified proteins by inhibiting autophagy accelerates aging and cell death (Hill et al, 2008;LaRocca et al, 2012). The importance of autophagy is indicated in these studies by a robust increase of microtubule-associated protein 1 light chain 3 II (LC3II) and significant vacuolization, formation of pinocytic bodies, crescent-shaped phagophores and multilamellar vesicles, all morphological characteristics of autophagy.…”

The Impact of Autophagy on Cardiovascular Senescence and Diseases

“…78) Recently, several studies reported that age-related impairment of autophagy was related to vascular aging, potentially contributing to endothelial dysfunction, arterial stiffness, and vascular pathologies, such as atherosclerosis and calcification. 79,80) Aging properties may be affected by increasing reactive oxygen species (ROS) levels in vasculature. 6,81) Because autophagy clearly modulates oxidation-reduction deficiency, this process can cause worsening of cardiovascular disease, which is exacerbated by oxidative stress.…”

“…82) Endothelial cells of old mice have lower Beclin1 levels and higher SQSTM1/p62 levels than those of young mice, suggesting that age-related changes in the vasculature reduce autophagic flux. 79) Administration of trehalose or spermidine induces autophagy and reverses age-related arterial stiffening. 79,80) Similarly, a recent study indicated that resveratrol, known to activate endothelial autophagy, reduces the development of arterial aging in rhesus monkeys.…”

“…79) Administration of trehalose or spermidine induces autophagy and reverses age-related arterial stiffening. 79,80) Similarly, a recent study indicated that resveratrol, known to activate endothelial autophagy, reduces the development of arterial aging in rhesus monkeys. 83) Autophagy in atherosclerosis: Atherosclerosis is a chronic inflammatory disease of the arteries that progresses with age in accordance with risk factors, including hypertension, diabetes mellitus, hypercholesterolemia, obesity, and cigarette smoking.…”