Healthy lifestyle-based approaches for successful vascular aging

Abstract

This review summarizes a presentation given at the 2016 Gerontological Society of America Annual Meeting as part of the Vascular Aging Workshop. The development of age-related vascular dysfunction increases the risk of cardiovascular disease as well as other chronic age-associated disorders, including chronic kidney disease and Alzheimer's disease. Healthy lifestyle behaviors, most notably regular aerobic exercise and certain dietary patterns, are considered "first-line" strategies for the prevention and/or treatment of vascular dysfunction with aging. Despite the well-established benefits of these strategies, however, many older adults do not meet the recommended guidelines for exercise or consume a healthy diet. Therefore, it is important to establish alternative and/or complementary evidence-based approaches to prevent or reverse age-related vascular dysfunction. Time-efficient forms of exercise training, hormetic exposure to mild environmental stress, fasting "mimicking" dietary paradigms, and nutraceutical/pharmaceutical approaches to favorably modulate cellular and molecular pathways activated by exercise and healthy dietary patterns may hold promise as such alternative approaches. Determining the efficacy of these novel strategies is important to provide alternatives for adults with low adherence to conventional healthy lifestyle practices for healthy vascular aging.

Keywords: caloric restriction; energy sensing; inflammation; nitric oxide; oxidative stress.

Fig. 1.

Primary mechanisms of age-related vascular dysfunction. Vascular dysfunction is a key intermediary event linking aging to increased cardiovascular disease risk. Endothelial dysfunction (bottom left) is characterized by reduced bioavailability of nitric oxide (NO) as a result of excess reactive oxygen (ROS) production by dysfunctional mitochondria, increased NADPH oxidase activity, and uncoupling of endothelial NO synthase (eNOS). Increased proinflammatory cytokine production and an upregulation of the proinflammatory mediator NF-κB also contribute. Arterial stiffening (bottom right) occurs with age as a consequence of increased collagen deposition, loss/fragmentation of elastin, and formation of advanced glycation end products (AGEs). These processes are driven, at least in part, by age-associated increases in oxidative stress and inflammation.

Fig. 2.

Aerobic exercise and “exercise-inspired” approaches for preventing and reversing vascular aging. Continuous moderate-intensity aerobic exercise is one of the most evidence-based strategies for ameliorating vascular aging. The beneficial effects of aerobic exercise are mediated by reduced inflammation and oxidative stress and increased nitric oxide (NO) bioavailability. Aerobic exercise also exerts favorable effects on the composition of the arterial wall (i.e., reduces collagen deposition and advanced glycation end product formation). The efficacy of novel, potentially more adherable forms of exercise and/or “exercise-inspired” approaches such as high-intensity interval training, high-intensity inspiratory muscle strength training, and passive heat therapy for healthy vascular aging remains to be established.

Fig. 3.

Calorie restriction and “calorie restriction-inspired” approaches for preventing and reversing vascular aging. Caloric restriction (i.e., energy intake restriction without malnutrition) prevents or reverses vascular aging, primarily by inducing a low-cellular energy state and modulating key energy-sensing pathways such as AMP-activated protein kinase (AMPK), the deacetylase sirtuin-1 (SIRT-1), mammalian target of rapamycin (mTOR), and autophagy. However, chronic caloric restriction is not practical in older adults. As a result, there is considerable interest in determining the safety, efficacy, and adherence of alternative, caloric restriction-inspired approaches for healthy vascular aging. One such caloric restriction-inspired approach presently under investigation is time-restricted feeding, which entails consuming all daily calories within a shorter time period (e.g., 8 h) than normal and fasting for the remainder of the day.

Fig. 4.

Nutraceutical compounds selected to activate signaling pathways of aerobic exercise, caloric restriction, and a healthy diet. Certain nutraceuticals targeting the signaling pathways modulated by exercise, caloric restriction, and/or a healthy diet hold promise for preventing or treating vascular aging. Examples include nitric oxide (NO)-boosting strategies through increased intake of nitrates or nitrites, which are naturally found in high concentrations in beets, compounds to modulate energy-sensing pathways by increasing levels of the sirtuin-1 substrate NAD⁺ or activation of autophagy via trehalose (found in mushrooms) or spermidine (found in grapefruit) supplementation, anti-inflammatory therapies such as curcumin, and mitochondria-targeted antioxidants to reduce reactive oxygen species (ROS).