Healthspan - Exercise Benefits in Promoting Cardiovascular Function
This is the second in the blog series on Promoting Healthspan & Healthy Aging Through Exercise. We’ll focus on the benefits of exercise with the promotion of increased Cardiovascular Function
Cardiovascular diseases are the leading cause of all mortalities around the world, with sedentary lifestyle being one of the biggest risk factors [28,29]. The most direct clinical indicators of cardiorespiratory fitness are cardiac output and VO2max, both are major parameters that decline with aging, potentially a determining factor for healthspan [30].
Cardiac output is defined as the amount of oxygenated blood pumped by the left ventricle per minute and calculated as the product of stroke volume and heart rate. In a healthy individual, rigorous exercise may increase cardiac output by 4-fold; in trained elite athletes, this increase may be up to 6–8 fold [17].
VO2max is the maximal amount of oxygen that is utilized by the all the organ systems during exercise. Since the 1980s, it has been well categorized that VO2max increases with endurance exercise training regardless of age, sex or exercise mode, and is a critical measurement of risk factors of aging-related diseases [31]. A thorough analysis by Gries et al. showed that enhanced VO2max by exercise training during adulthood can even be kept up to the eighth decades in athletes [32].
One of the mechanisms proposed for exercise-mediated promotion of cardiovascular fitness is via physiological hypertrophy, i.e., an increase in heart muscle mass along with enhanced contractile function, as opposed to pathological hypertrophy along with pathological changes such as fibrosis that may lead to heart failure. Physiological hypertrophy occurs in response to increased wall stress and other signaling events during exercise training. A series of studies discovered that the insulin and insulin-like growth factor 1 (IGF1) pathways including insulin receptor substrate 1/2 (Akt1/2), IGF receptor and phosphoinositide 3-kinase (PI3K) are important in exercise-mediated physiological hypertrophy in mice [33,34,35,36,37]. In addition to hypertrophy, many other adaptations including contractile apparatus remodeling, mitochondrial remodeling, change in metabolism and angiogenesis along with altered gene expression also occur during exercise training [33,38,39]. Other pathways that are pertinent to physiological heart growth in response to exercise training remain to be fully explored. Therefore, future studies that focus on a more thorough investigation of the mechanisms behind exercise-induced physiological hypertrophy and enhanced cardiac function will provide new insights into healthspan benefits of exercise.
Exercise Benefits in Ameliorating Cardiovascular Diseases (CVD)
Endurance exercise has also been demonstrated to have both preventative and therapeutic effects on myocardial infarction [40,41,42,43,44], atherosclerosis [45,46], and hypertension [47,48,49], which are among the biggest risk factors that shorten our healthspan. Substantial amount of evidence have shown that long-term endurance exercise can delay aging-associated decline of both cardiac output and VO2max, contributing to disease prevention and promotion of quality of life [50,51,52,53,54]. In the past decade, the notion of “exercise as medicine” has gained tremendous popularity, which has prompted a number of clinical studies focusing on exercise regimens and methodologies to tackle cardiovascular challenges in patients [55,56,57,58]. Overall, it is recommended to prescribe moderate to low intensity (<60% maximal HR) endurance exercise at a frequency of 3–5 times per week to patients with cardiovascular diseases [55]. Significant effort has been committed in the past 50 years to unravel the molecular mechanisms behind exercise-mediated protection against CVD and promotion of recovery from cardiac injuries like ischemia-reperfusion (I/R); however, our understanding is still incomplete.
Heart failure is one of the top leading causes of death worldwide. Exercise is the best intervention for prevention and even treatment of heart failure without causing further cardiac injuries [59,60,61,62,63]. An early study in exercise intervention in human chronic heart failure patients in 1999 showed that one year of moderate intensity cycling (60% VO2max) led to better cardiac outcomes and quality of life improvements [64]. The mechanisms of exercise benefits on heart failure are multifaceted, without clear understanding of the exact molecular targets. Potential aspects that exercise may positively impact on preventing heart failure include enhanced energy metabolism [39,65], mitigated oxidative stress [66], improved mitochondrial function [64,67]; a clear understanding of the molecular mechanisms is yet to be investigated.
Atherosclerosis
Atherosclerosis is a prevalent, chronic vascular disease that affects millions of people worldwide. The pathology of atherosclerosis is complicated and multifaceted, with inflammatory factors and endothelial activation being early contributors; eventually, arterial wall lesions form, and cholesterol-rich lipids form blockades in the vessels, causing detrimental damage. Exercise has been discovered to (1) enhance endothelial function, and (2) exhibit anti-inflammatory and antioxidant effects as ways to help prevent the onset of atherosclerosis [68,69,70,71,72,73,74,75,76].
Overall, molecular mechanisms underlying exercise benefits in CVD is multi-faceted and incompletely understood. First and foremost, physiological stress signaling induced by exercise may be key. The most studied stress signaling kinase in exercise is 5′ AMP-activated kinase (AMPK) since it is activated during energetic stress, i.e., increased AMP/ADP concentration [77]. Studies over the years have found it to be a critical signaling molecule in CVD like ischemia/reperfusion (I/R), fibrosis and vascular dysfunction [78,79,80,81,82]. AMPK is a heterotrimeric complex with a catalytic α domain, a non-catalytic β domain and a regulatory, AMP/APD-binding γ domain. Each subunit has different isoforms that are encoded by separate genes, which determines AMPK expression of different tissues (α1, α2, β1, β2, γ1, γ2, and γ3). In heart, α2-, β2- and γ1-subunit are most commonly expressed [83]. Acute exercise causes energetic stress and signaling events that are sensed by AMPK and activates AMPK, leading to a series of phosphorylation cascades to regulate downstream signaling. Recent evidence also suggested that subcellular localization of AMPK may also be of importance, e.g., exercise may specifically activate mitochondria-associated AMPK [84]. Future studies on subcellular AMPK pools will improve the understanding in how AMPK regulates exercise benefits.
Mitochondria may also be a key player in exercise-mediated protection from CVD due to its central role in CVD progression [85,86]. Exercise training can potentially both improve mitochondrial content (biogenesis) and dynamics (fission, fusion and mitophagy). It has been well-established that increases in transcription and abundance of peroxisome proliferator-activated receptor co-activator (PGC-1α), a master transcriptional co-activator for mitochondrial and oxidative metabolism, is responsible for increased mitochondrial biogenesis after exercise [87,88,89]. In addition, recent evidence suggests that the improved quality of mitochondria, alongside with increase in quantity, may also be a key factor in protecting the heart from CVD [67,90,91,92]. Mitochondrial quality is usually measured with O2 consumption, membrane integrity and morphology, which can all be enhanced by regular exercise [93,94,95,96,97,98]. A 2019 study found that mitophagy, more than macroautophagy, is critical in maintaining cardiac function in diabetic cardiomyopathy [99]. Although the necessity of exercise-induced mitophagy is not explored in this model, it has been suspected that, in other cardiac injury models, exercise may help maintain cardiac function through upregulating mitophagy [100,101,102].
Last but not least, skeletal muscle-derived humoral factors by endurance exercise may provide protection against pathological development of heart failure under disease conditions. For example, extracellular superoxide dismutase (EcSOD) is a superoxide scavenger that is upregulated in skeletal muscle upon exercise and travels to the peripheral tissues/organs, including the heart through the circulation, which has been shown to prevent diabetic cardiomyopathy [103,104].
If you want longevity and an increased healthspan the benefits of cardiovascular exercise cannot be understated. Physical activity has many health benefits. These benefits apply to people of all ages, races and ethnicities, and sexes. Physical activity helps you maintain a healthy weight and makes it easier to do daily tasks, such as playing your your kids (and grand children), climbing stairs and shopping. All of which are vital for your health span and prolonged independent living.
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