As described thoroughly in Unit 2, being physically active is of major importance for maintaining health and normal functioning (Bangsbo et al., 2019; Koehler & Drenowatz, 2019). Nowadays, there is historical recognition that physical inactivity is detrimental to health by causing significant decline in the functional capacity of most organ systems in humans, mammals, and rodents (Booth, Roberts, & Laye, 2012). Physical inactivity is an actual cause of numerous physiological dysfunctions that cause, usually permanent, pathological changes which over time lead to overt chronic diseases, culminating as contributors to premature mortality (Booth, Roberts, Thyfault, Ruegsegger, & Toedebusch, 2017). Studies conducted in the United States indicate that older adults above 60 years of age, who live in community‐based environments, spend approximately 8 to 11 hours per day being sedentary, with their most common pastimes watching television or browsing the internet (Kehler & Theou, 2019). It is important to mention, however, that physical inactivity and activity/exercise are not considered mirror images; there are different mechanisms that govern each state of body activity, and it is important to understand the difference between how inactivity causes disease and how exercise acts as a primary prevention for the same diseases (Booth et al., 2012). According to the 2020 guidelines on physical activity and sedentary behavior by the WHO, physical inactivity is defined as the incapability of an individual to follow current age‐group recommendations regarding weekly levels of physical activity. This practically means 150 to 300 min of moderate‐intensity or 75 to 150 min of vigorous‐intensity exercise per week for people of 18 years and older (Bull et al., 2020). The Physical Activity Guidelines Advisory Committee also recognizes a strong dose‐response relationship between sedentary behavior and cardiovascular disease (CVD) mortality and all‐cause mortality (Chaput et al., 2020). Physical inactivity is an initiating cause of a chronic disease or condition. Figure 11.1 presents a comprehensive view of how low physical activity correlates with all kinds of diseases. Indeed, high levels of physical inactivity, or sedentary behavior, is linked with at least 35 chronic diseases/clinical conditions such as CVD; colon, endometrium, or lung cancer: type 2 diabetes and obesity; and increased overall mortality rates (Thyfault, Du, Kraus, Levine, & Booth, 2015; Ross et al., 2020) (Figures 11.2 and 11.3). Based on the famous reduced stepping studies conducted in the 2000s, an important reduction in even the number of steps taken on daily basis by a healthy adult, could result in a 7% decrease in VO2max, 17% decrease in peripheral insulin sensitivity, and concurrent decreases in the insulin‐stimulated ratio of pAkt‐Thr/total Akt in skeletal muscle (Booth et al., 2012). FIGURE 11.1 Health deficiencies accelerated by decreasing physical activity from higher to lower levels. Source: (Booth et al., 2012 / with permission of John Wiley & Sons). Physical inactivity uses multiple pathways to cause chronic diseases that are not necessarily similar to those through which exercise acts as a primary protector. For example, inactivity and exercise differ in the context of the time courses of structural changes in conduit arteries and change in endothelial function; inactivity leads to immediate negative remodeling of the vessel, while exercise needs up to 6 weeks to enact positive effects (Booth et al., 2012; Thijssen et al., 2010). In addition, the cardio‐protective effects of exercise are due to vasodilation by the nitric oxide pathway while deconditioning activated vasoconstrictor pathways (Figure 11.4). Moreover, an analysis of skeletal‐muscle gene expression before bed rest, immediately after bed rest, and after 4 weeks of post‐bed rest training, indicated a difference in the number of mRNAs produced. A 9‐day period of bed rest altered a total of 4500 mRNAs, while a 4‐week post‐bed training program normalized the expression of only 80% of the original mRNA count. This finding strengthens the hypothesis that even short periods of inactivity (such as 9 days) can severely alter biological pathways relevant to an individual’s health, even at the molecular level. This result agrees with the findings of Stein and Bolster, who investigated the genes that govern muscle catabolism and rebuilding. These researchers hypothesized that if physical activity were the opposite of physical inactivity, then the expected result would be changes in many of the same genes for atrophy and regrowth. However, a comparison of these two gene lists showed virtually no genes appearing on both lists (Booth et al., 2012). Although literature suggests that the mechanisms through which exercise and inactivity impact the physiological functions are directly correlated with aging parameters, studies on the molecular neurobiology for physical inactivity are only in their infancy. FIGURE 11.2 Physical inactivity increases 35 chronic diseases. Source: (Booth et al., 2017). FIGURE 11.3 Physical inactivity is an actual cause of premature death by interacting with other environmental factors to increase risk factors for metabolic syndrome, which, in turn produces two “leading causes” of “premature death” (type 2 diabetes and atherosclerosis). Source: (Booth et al., 2012 / with permission of John Wiley & Sons). Physical activity positively affects many physiological mechanisms related to the aging process. Evidence shows that a person’s rapid/severe turn to inactivity can rapidly decrease cardio‐respiratory fitness (CRF); an individual’s cardiovascular (heart and blood vessels) and respiratory systems capacity to supply oxygen to the rest of the body. Higher CRF correlates with improved insulin sensitivity, lipid and lipoprotein profile, body composition, systematic inflammation, blood pressure, and autonomous nervous system functioning. Low functional capacity values for maximal aerobic capacity (VO2max) are a risk biomarker for death as it correlates with a shorter life expectancy, independent of other risk factors. For example, the Dallas bed‐rest study indicated that when healthy young men were put on a continuous 20‐day bed rest, their VO2max decreased by 27%. Regular physical activity can also, in the long term, reduce systematic inflammation, endothelial dysfunction, and common cardiovascular risks like hypertension (Booth et al., 2012; Gremeaux et al., 2012; Daskalopoulou et al., 2017). Overall, achieving and maintaining an increased CRF (and muscle strength) from young to older stages of life through regular physical exercise can delay the onset of frailty due to primary aging (Booth et al., 2012). FIGURE 11.4 Hypothesized changes in artery function and structure (remodeling) in response to inactivity and exercise training in humans. Studies performed in both animals and humans suggest that rapid changes occur in artery function, including nitric oxide (NO) bioavailability, in response to exercise training and that these changes are superseded by arterial remodeling and normalization of function. Physical inactivity is associated with rapid changes in arterial diameter, with structural remodeling occurring within weeks of, for example, spinal cord injury. There is little evidence for longer term vascular dysfunction in response to inactivity. Changes in artery function and structure occur rapidly in response to activity and inactivity. Source: (Thijssen et al., 2010 / with permission of Springer Nature). Although physical activity during aging helps immune activity, most mechanisms through which exercise exerts these beneficial effects are still unknown (Simpson et al., 2012). Yet, they include multiple neuro‐endocrinological factors that alter exercise‐induced metabolism and metabolic factors. For instance, reductions in plasma glucose or glutamine concentrations influence lymphocyte function through alteration of stress hormone, catecholamine, growth hormone, and other cytokine levels (Pedersen & Hoffman‐Goetz, 2000; Scartoni et al., 2020). Also, exercise contributes to a lower accumulation of autoreactive immune cells in a way that improves programmed cell death (Scartoni et al., 2020). A single bout of exercise in older adults can increase natural killer (NK) cell activity and significantly decrease TNF‐α, IL‐6, and IL‐1β levels. NK and effector‐memory CD8+ T cells are mobilized into the bloodstream with acute exercise, causing a two‐ to threefold increase in the blood lymphocyte count. The same type of cells leave the bloodstream during the early stages of exercise recovery, although the number of cells that extravasate the blood (presumably to recirculate to the peripheral tissues), are usually bigger than the number of cells that were mobilized, which results in short‐term lymphocytopenia. Given that the cell types preferentially mobilized by exercise have high effector functions (NK cells, effector‐memory T cells), one possible mechanism for enhanced immunity through exercise is due to the increased trafficking of cells throughout peripheral tissues and circulation (Simpson et al., 2012). Regular moderate activity over a 2‐month period also reduced the pro‐inflammatory profile of older adults by decreasing TNF‐α, MCP‐1, and nitric oxide synthase mRNA levels in peripheral‐blood mononuclear cells (PBMCs). These results were independent from a reduction in adipose tissue, suggesting that exercise has a direct anti‐inflammatory effect (Simpson et al., 2012; Scartoni et al., 2020). Exercise also moderates immunosenescence and provides anti‐inflammatory properties that act against inflamm‐aging (Simpson et al., 2012). Age‐related accumulation of late‐stage differentiated T cells and/or thymic involution are key contributors to the immunosenescence process, due to induced restrictions in T cell repertoire and stress reduction (Simpson et al., 2012). Moreover, increases in the body’s antioxidant capabilities with regular exercise can prevent cellular DNA and structural damage from ROS, therefore preventing the premature biological aging of specific immune cells (Pedersen & Hoffman‐Goetz, 2000). Physically active older adults, compared to their inactive counterparts, show benefits in terms of physical and cognitive function, depression, quality of life (QOL), and compression of disability (Bangsbo et al., 2019). Physical health (with a focus on aerobic health/fitness), is a crucial factor in improving cognition, memory, and mental health. It is also important for promoting structural and functional plasticity in the brain along the same pathways as pharmacological antidepressants (Panagiotou, Michel, Meijer, & Deboer, 2021). The neuroprotective effect of aerobic exercise was demonstrated in patients with mild cognitive impairment, dementia (Nuzum et al., 2020), and depression (Gujral, Aizenstein, Reynolds, Butters, & Erickson, 2017). Trophic factor production of brain‐derived neurotrophic factor and IGF‐1 is induced after exercise and, along with the increased availability of serotonin and norepinephrine as well as better HPA‐axis activity, may alleviate depression through an increase in hippocampal volume. Physically active older adults, compared to their inactive counterparts, show benefits in terms of physical function, intrinsic capacity, mobility, musculoskeletal pain, and risk of falls and fractures (Booth et al., 2012). A history of falls consistently correlates with the functional capacity and physical activity level of older adults, which implies that strength and balance decline affects their ability to avoid a fall after an unexpected trip or slip (Moreira, Rodacki, Pereira, & Bento, 2018). A higher prevalence of disability, premature death, and reduced QOL among the population is associated with less physical activity (Booth et al., 2012). In these terms, expert groups around the world recommend physical exercise and/or nutritional intervention to prevent and treat sarcopenia, which dramatically deteriorates an older individual’s independence and QOL (as discussed below in this chapter) (Dedeyne et al., 2020).
CHAPTER 11
Physical Activity as a Determinant of Healthy Aging
INTRODUCTION
PHYSICAL INACTIVITY
PHYSICAL ACTIVITY AS A DETERMINANT OF HEALTHY AGING
CARDIOVASCULAR HEALTH
IMMUNE SYSTEM
COGNITIVE FUNCTION
MUSCULOSKELETAL HEALTH
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