Mitochondrial quality control and age-associated arterial stiffening

Abstract

Stiffening of large elastic arteries with age increases the risk of cardiovascular diseases (CVD), but the underlying mechanisms are incompletely understood. We investigated the role of mitochondrial quality control (QC, i.e., mitophagy and biogenesis) in arterial stiffening with aging. In C57BL6 mice, aging was associated with impaired aortic expression of mitochondrial QC mediators, greater activation of the mitochondrial redox/stress sensor p66shc, elevated superoxide production and increased arterial stiffness—as indicated by ~20% higher aortic pulse wave velocity (aPWV). In old mice, supplementation with trehalose, a nutraceutical reported to enhance mitophagy, normalized mitochondrial QC markers, p66shc activation and superoxide production, and reduced aPWV and aortic collagen I (a structural protein that confers stiffness). In vitro experiments indicated that mitochondrial QC processes were enhanced in aorta from old trehalose-treated mice, and in aortic rings studied ex vivo, both aging and treatment with the mitochondrial stressor rotenone were associated with increases in p66shc activation and intrinsic mechanical stiffness, whereas co-incubation with trehalose prevented these effects. Taken together, these findings suggest that mitochondrial stress/dysfunction as a result of impaired mitochondrial QC contributes to large elastic artery stiffening with age. Enhancing mitochondrial QC with agents such as trehalose may be a novel strategy for reducing age-associated arterial stiffness and CVD.

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“…[100] 13 Trehalose, a neutraceutical that enhances mitophagy, was reported to reverse agerelated arterial stiffening of the aorta and pulse wave velocity when given as a food supplement to old mice. [101] This study inferred and supported the notion that mitochondrial stress/dysfunction during aging underlies age-related aortic stiffening, possibly in the presence of oxidative stress and inflammatory cytokines. Thus, trehalose and similar non-reducing disaccharides, could lower free radical production and pulse wave velocity while normalizing the over-produced aortic collagen I, a key contributor to age-associated arterial stiffness.…”

“…Thus, trehalose and similar non-reducing disaccharides, could lower free radical production and pulse wave velocity while normalizing the over-produced aortic collagen I, a key contributor to age-associated arterial stiffness. [101,102] (Fig. 2) Downstream, trehalose also acts as an antioxidant and free radical scavenger.…”

Voluntary aerobic exercise increases arterial resilience and mitochondrial health with aging in mice

“…Despite relatively low abundance [64] and minimal respiratory activity [10–12], arterial mitochondria play a vital role in maintaining arterial function, presumably via other roles involving intra- and extra-cellular signaling [10–12, 15]. However, arterial mitochondrial health and quality control decline with aging and in disease models of hypertension, NO deficiency, atherosclerosis, diabetes and metabolic syndrome [13–14, 27–29, 41, 44–45]. In the present study we observed age-related declines in PGC-1α and SIRT3, key regulators of mitochondrial biogenesis, health and antioxidant defenses [21–22, 39], as well as a shift in mitochondrial dynamics favoring increased mitochondrial fission (e.g., increased Fis1 and decreased Mfn2), a characteristic of mitochondrial dysfunction [41, 44–46].…”

“…A key source of arterial oxidative stress is excessive production of mitochondrial reactive oxygen species (mtROS). Whereas healthy mitochondria are critical mediators of arterial homeostasis [10–14] and produce physiological levels of mtROS vital for cell signaling [15], declines in mitochondrial health are characterized by excessive mtROS production [10–12, 15–16]. We have recently shown that excess arterial mtROS production is a major contributor to tonic arterial oxidative stress-mediated suppression of EDD with primary aging in mice [13].…”

Nutrition and other lifestyle influences on arterial aging

“…Several naturally occurring nutraceuticals may have the potential to boost autophagy. For example, oral supplementation with trehalose, a disaccharide found in mushrooms and honey, stimulates autophagy and reverses endothelial dysfunction and arterial stiffening in old mice by normalizing oxidative stress and structural proteins, while also ameliorating vascular inflammation (LaRocca et al, 2014; LaRocca et al, 2012). The autophagy enhancer spermidine (a polyamine found in grapefruits and fermented soy products) also enhances arterial autophagy and reverses age-associated endothelial dysfunction and arterial stiffness in mice (LaRocca et al, 2013).…”