Obesity and lack of exercise cause a variety of problems in both the adult and child populations of the United States. From increased risk of diseases, impact on the economy, overall poor health and psychological issues, the consequences of obesity and a sedentary lifestyle are complex and far reaching. Learning the effects of obesity and lack of exercise may encourage you to stay healthy and active.
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Increased health care costs to obese, sedentary individuals and to the health-care system in general is an economic effect of the obesity crisis. A 2009 study funded by the Centers for Disease Control and Prevention, found that obesity-related costs may be as high as $147 billion a year. If a person suffers from obesity and lives an inactive lifestyle, he spends more than 40 percent more in health care expenses than a person of normal weight. The increased need for medical attention boosts the overall cost of health care, as insurance companies may raise rates to offset the increased cost of care.
Obesity and a lack of exercise often go hand in hand. The more weight a person carries, the more difficult it can be to move and exercise. The health consequences and effects of obesity and lack of exercise are dire. According to the 2010 publication “The Surgeon General’s Vision for a Healthy and Fit Nation,” more than 112,000 Americans die unnecessarily each year from preventable diseases directly related to obesity. Lack of exercise often leads to obesity, which in turn raises the risk of increased levels of bad cholesterol, heart diseases, cancers of the breast and prostate, stroke and type 2 diabetes.
Obese children who do not exercise experience the effects of obesity on many levels. Psychologically, an obese child may be teased by her peers and feel left out when she is unable to keep up with her faster playmates during recess or organized sports. The teasing may make her more likely to eat, stay sedentary and continue struggling with weight for years. Additionally, obese children often show increased risk factors for diseases most often seen in adults, such as increased blood pressure, a tendency toward type 2 diabetes and high cholesterol.
In addition to serious health consequences of obesity and a lack of exercise, adults also experience emotional stress and trauma because of their obesity. Right or wrong, the media often portrays an ideal body shape as one that is slim and fit. This portrayal can cause a person who struggles with obesity to feel isolated. Isolation can make a person feel anxious and depressed, and these feelings may contribute to a cycle of emotional overeating. An obese, sedentary person may be less likely to join a gym or exercise class for fear of feeling uncomfortable or being unable to perform the exercises adequately.
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Chronic diseases are major killers in the modern era. Physical inactivity is a primary cause of most chronic diseases. The initial third of the article considers: activity and prevention definitions; historical evidence showing physical inactivity is detrimental to health and normal organ functional capacities; cause vs. treatment; physical activity and inactivity mechanisms differ; gene-environment interaction [including aerobic training adaptations, personalized medicine, and co-twin physical activity]; and specificity of adaptations to type of training. Next, physical activity/exercise is examined as primary prevention against 35 chronic conditions [Accelerated biological aging/premature death, low cardiorespiratory fitness (VO2max), sarcopenia, metabolic syndrome, obesity, insulin resistance, prediabetes, type 2 diabetes, non-alcoholic fatty liver disease, coronary heart disease, peripheral artery disease, hypertension, stroke, congestive heart failure, endothelial dysfunction, arterial dyslipidemia, hemostasis, deep vein thrombosis, cognitive dysfunction, depression and anxiety, osteoporosis, osteoarthritis, balance, bone fracture/falls, rheumatoid arthritis, colon cancer, breast cancer, endometrial cancer, gestational diabetes, preeclampsia, polycystic ovary syndrome, erectile dysfunction, pain, diverticulitis, constipation, and gallbladder diseases]. The article ends with consideration of deterioration of risk factors in longer-term sedentary groups; clinical consequences of inactive childhood/adolescence; and public policy. In summary, the body rapidly maladapts to insufficient physical activity, and if continued, results in substantial decreases in both total and quality years of life. Taken together, conclusive evidence exists that physical inactivity is one important cause of most chronic diseases. In addition, physical activity primarily prevents, or delays, chronic diseases, implying that chronic disease need not be an inevitable outcome during life.
1. Organization of article
1.1 Entire article
An underappreciated primary cause of most chronic conditions is the lack of sufficient daily physical activity (“physical inactivity”). Overwhelming evidence proves the notion that reductions in daily physical activity are primary causes of chronic diseases/conditions and that physical activity/exercise is rehabilitative treatment (therapy) from the inactivity-caused dysfunctions. The general strategy of presentation divides the article into three major sections: 1) Conceptual information forming the foundation to understand the remaining article; 2) Primary literature supporting physical inactivity as a primary cause to a myriad of chronic conditions/diseases, and 3) additional considerations. The aim of the entire article is to bring better understanding and insight into the observation that a lack of physical activity at ancestral levels initiates 35 pathological and clinical conditions.
1.2 First third of article
Conceptual information is presented in five parts in the first third of the article. 1) Definitions of forms of physical activity, functional capacity, types of fitness, chronic diseases, types of prevention so that the reader understands how the article employs these words; 2) A brief chronology of the three-millennia history that recognizes that physical inactivity reduces functional capacity and health; 3) Cause vs. treatment are discussed to emphasize that physical inactivity is a primary cause of chronic conditions/diseases; 4) Growing evidence that mechanisms by which inactivity causes disease differ from mechanisms by which physical activity is a therapy/treatment to act as a primary preventer of disease; and 5) Gene-environment interactions have varying degrees of gene involvement in the magnitude of change to physical activity.
1.3 Center portion of article
Physical inactivity is a primary cause initiating 35 separate pathological and clinical conditions. Many of the 35 conditions are subdivided under major categories, such as loss of functional capacities with chronological aging; metabolic syndrome, obesity, insulin resistance, prediabetes/type 2 diabetes, non-alcoholic liver disease, cardiovascular diseases, cognitive functions and diseases, bone and connective tissue disorders, cancer, reproductive diseases, and diseases of digestive tract, pulmonary, and kidney.
1.4 Final portion of article
The article ends with considerations of clinical significance, increasing risk factors during long-term sedentarism, the developmental and clinical consequences of inactive childhood/adolescence, and policy.
2.1 CDC definitions of forms of physical activity
Verbatim definitions for exercise and health are from the US Centers for Disease Control and Prevention (CDC) are used where possible due to the authority they carry (90). US governmental definitions were selected for the article to provide the framework for this article's discussions of how 1) exercise/physical activity prevents chronic diseases and 2) lack of physical activity is a primary event that causes chronic diseases.
“A subcategory of physical activity that is planned, structured, repetitive, and purposive in the sense that the improvement or maintenance of one or more components of physical fitness is the objective”, as defined by CDC (90).
“Physical activity performed during leisure time with the primary purpose of improving or maintaining physical fitness, physical performance, or health”, as defined by CDC (90).
“Any bodily movement produced by the contraction of skeletal muscle that increases energy expenditure above a basal level. Physical activity generally refers to the subset of physical activity that enhances health”, as defined by CDC (90).
“A human condition with physical, social and psychological dimensions, each characterized on a continuum with positive and negative poles”, as defined by CDC (90).
Health-enhancing physical activity
“Activity that, when added to baseline activity, produces health benefits. Brisk walking, jumping rope, dancing, playing tennis or soccer, lifting weights, climbing on playground equipment at recess, and doing yoga are all examples of health-enhancing physical activity”, as defined by CDC (90).
As previously stated, this article will concentrate on the use of physical activity to prevent physical inactivity, and, thus, prevent many chronic diseases.
2.2 Definition of physical inactivity
CDC definitions for exercise do not include a definition of “physical inactivity”. We define physical inactivity as “physical activity levels less than those required for optimal health and prevention of premature death”. Further consideration of the definition is given in section entitled, “Prevention of death by primary prevention of physical inactivity”.
2.3 Definition of functional capacity
We define “functional capacity” as the ability of a cell, organ, system, or body to maintain homeostasis within their narrow limits of survival in response to a specified stress. If an external stress disrupts homeostasis beyond an organism's functional capacity, life may not be sustained. Diminished ability to adapt to stressors increases the likelihood of death. Functional capacity is pliable; declining rapidly with extreme physical inactivity or more slowly with aging, while preventing inactivity can increase functional capacity (considered in specific detail in the aging section). Importantly, a direct relationship between functional capacity and survival is a cornerstone of general medicine theory. A major predictor of functional capacity is maximal aerobic capacity (VO2max), which while directly testing cardiovascular fitness and integrity also represents a combination of other physiologic components. For instance, VO2max also depends on pulmonary and muscle function, health status of other organ systems, nutritional status, medications, orthopedic limitations, and others (352). An aerobic functional capacity in patients under 4-metabolic equivalents (METs), a typical demand during normal daily activities, increases postoperative (time from admission to discharge from surgery) cardiac and long-term risks (155). In another study, patients were grouped by MET capacity in relationship to complication prevalence after they underwent angiographically verified coronary artery disease and subsequent open abdominal nonvascular surgery. (265). Those from the group < 4 METs had cardiologic complications in 64% of cases, the 4–7 METs group had 29%, and the 7–10 METs group had 8%. These remarkable findings can be extrapolated to other stresses where the probability of complications, and even survival, is dependent upon the functional capacity needed to maintain homeostasis.
2.4 Physical fitness vs. physical activity
Some people incorrectly use physical fitness and physical activity interchangeably. The CDC defines physical fitness as “The ability to carry out daily tasks with vigor and alertness, without undue fatigue, and with ample energy to enjoy leisure-time pursuits and respond to emergencies. Physical fitness includes a number of components consisting of cardiorespiratory endurance (aerobic power), skeletal muscle endurance, skeletal muscle strength, skeletal muscle power, flexibility, balance, speed of movement, reaction time, and body composition”. The CDC defines physical activity as “Any bodily movement produced by the contraction of skeletal muscle that increases energy expenditure above a basal level” (90)..
Inherited genes and their interaction with physical activity levels determine physical fitness. However, chronic physical activity levels themselves modulate fitness. Further, the levels of physical activity, themselves, modulate whether fitness improves. For example, Sisson et al. (478) concluded that the most important finding of their study was that greater volumes of exercise were associated with a lower probability of being a nonresponder. The percentage of non-responders at a given level of training progressively decreased as the exercise volume increased.
2.5 Cardiorespiratory fitness (CRF)
We define CRF as the capacity of the cardiovascular (heart and blood vessels) and respiratory (lungs) systems to supply oxygen-rich blood to the working skeletal muscles and the capacity of the muscles to use oxygen to produce energy for movement. The gold standard to determine CRF is the aforementioned VO2max, or maximum aerobic fitness. However in large clinical human studies, an acceptable surrogate for VO2max is the length of time running or cycling in standardized test, assuming appropriate physiological/biochemical/psychological proof of exhaustion is obtained (65, 263).
The majority of data about fitness and physical activity is focused on aerobic fitness. Data indicates that rapid, severe physical inactivity can rapidly decrease CRF. For instance, in the Dallas Bed Rest study, healthy, young males' VO2max decreased 27% after 20 days of continuous bed rest (454) and another study in Denmark 2 weeks of reducing daily step number from 10,501 to 1344 VO2max decreased 7% (389).
2.6 Strength fitness
We define strength fitness as the capacity of the skeletal muscle to move an external load. Strength is highly dependent upon skeletal muscle mass, which contains a major genetic component (Discussed later in Twin studies-Modulation of twin health by physical activity), and is sensitive to decreased mechanical loading resulting in skeletal muscle atrophy regardless of endowed muscle mass (49, 508).
2.7 Balance and flexibility fitness
We define balance fitness as the ability to control the body's position throughout movement,and flexibility fitness as the ability to achieve an extended range of motion. Both have components of genetic inheritability and are also trainable (Discussed later in Twin studies-Modulation of twin health by physical activity).
2.8 Definition of chronic diseases and their prevalence
We define chronic disease as a disease slow in its progress (decades) and long in its continuance, as opposed to acute disease, which is characterized by a swift onset and short course.
Medicine, public health, pharmaceutical industry, and educational systems have reduced infectious diseases and early life mortality resulting in record average life spans for much of the human population. In place of infectious diseases most people in the US now die of chronic diseases.
The CDC Website states, “Chronic diseases—such as heart disease, cancer, and diabetes—are the leading causes of death and disability in the United States. Chronic diseases account for 70% of all deaths in the U.S., which is 1.7 million each year (85). These diseases also cause major limitations in daily living for almost 1 out of 10 Americans or about 25 million people (85), The CDC further wrote, “Chronic diseases – such as heart disease, stroke, cancer, diabetes, and arthritis – are among the most common, costly, and preventable of all health problems in the U.S.” (86). In addition to the CDC, former US Secretary of Health and Human Services, the Honorable Michael O. Leavitt in the 2008 Physical Activity Guidelines for Americans, wrote,
Along with President Bush, I believe that physical activity should be an essential component of any comprehensive disease prevention and health promotion strategy for Americans. We know that sedentary behavior contributes to a host of chronic diseases, and regular physical activity is an important component of an overall healthy lifestyle. There is strong evidence that physically active people have better health-related physical fitness and are at lower risk of developing many disabling medical conditions than inactive people (532).
2.9 Definitions of types of prevention
For the purposes of this article, physical activity is presented as primary prevention of physical inactivity. The CDC defines physical inactivity as an actual cause of chronic conditions (213, 345). Physical activity, itself, rarely causes chronic conditions, e.g., participation in specific sports improves general health, but can increase the risk of osteoarthritis in specific populations (71); discussed later in section “Osteoarthritis”. The next definitions are taken from a commissioned paper by the U.S. Institute of Medicine (267).
Prevent implies taking advanced measures against something possible or probable. Prevention in medicine has been divided into three progressive stages – primary, secondary, and tertiary (267).
“Primary prevention refers to health promotion, which fosters wellness in general and thus reduces the likelihood of disease, disability, and premature death in a nonspecific manner, as well as specific protection against the inception of disease” (267).
“Secondary prevention refers to the detection and management of pre-symptomatic disease, and the prevention of its progression to symptomatic disease. Screening is the dominant practice…The margins between primary and secondary prevention can at times blur (268).”…For example, `”If hypertension is defined as a disease, its treatment is secondary prevention; if defined as a risk factor for coronary disease that does not yet exist, it is primary prevention” (267).
“Tertiary prevention refers to the treatment of symptomatic disease in an effort to slow its further progression to disability, or premature death…there is a legitimate focus on prevention even after disease develops, such as the prevention of early cancer from metastasizing, or the prevention of coronary disease from inducing a myocardial infarction or heart failure. This domain also encompasses rehabilitation, the purpose of which is to preserve or restore functional ability, and thus prevent its degeneration” (267).
2.11 Application of exercise to prevention categories
Examples for our view that exercise is a primary, secondary, and tertiary preventer of disease are as follows: 1) Primary prevention (direct treatment of cause to prevent disease occurrence) is voluntary avoidance of physical inactivity or treatment of physical inactivity with physical activity; 2) Secondary treatment [eliminating one cause (physical inactivity) of existing hypertension by eliminating physical inactivity] is treatment of existing hypertension with physical activity; and 3) Tertiary prevention with physical activity is cardiac rehabilitation where exercise benefits do not reverse the anatomical pathology from myocardial infarction. We propose that the greatest health benefit of physical activity is primary prevention of 35 chronic diseases/conditions to become clinically overt. This article is largely restricted to consideration of primary prevention of inactivity as an actual cause of chronic conditions.
3. Overview for next three sections
While, concerns that physical inactivity is detrimental to health have been documented for over three millennia, much remains unknown, e.g., a) how to change the sedentary behavior of the 92% of U.S. adolescents and > 95% of adults who do not met the U.S. Department of Health and Human Services guidelines for physical activity (527), b) how to have health care professionals provide effective individualized exercise prescriptions, and c) what are the molecular links between inactivity and chronic disease that will provide a policy tool in the same way as the molecular link between the carcinogen in tobacco and lung cancer did (129).
4. Summary of daily step reductions from antiquity
Historical evidence shows that physical inactivity is prevalent in today's society relative to historical levels (385). Estimated daily step numbers have declined ~50% to ~70% since the introduction of powered machinery. (Table 1).
Estimated historical reductions in daily steps by humans.
5. History of inactivity's compromising effects on function and health
Three millennia of evidence exist to indicate historical recognition that physical inactivity is detrimental to health by reducing the functional capacity of most organ systems in humans, mammals, and rodents.
5.1 Ancient India (~1500–600 BC)
A historical review by Tipton (519) described the tridosa doctrine in India, which contended that the three humors regulated all functions of the body. When humors were in equilibrium, good health was present. However, sedentary living and lack of exercise could displace one or more of the humors, impairing health and potentially leading to illness and death. Susruta (600 BC) was convinced a sedentary lifestyle elevate the kapha humor to a level that could disrupt humoral equilibrium resulting in a disease state and potential death. He included exercise in his recommendations to prevent the occurrence of diseases.
5.2 Hippocrates (~450 BC)
Quotations attributed to Hippocrates promote the primary prevention of disease by physical activity.
“If we could give every individual the right amount of nourishment and exercise, not too little and not too much, we would have found the safest way to health” (240).
“If there is any deficiency in food and exercise the body will fall sick” (477).
“Walking is man's best medicine” (240).
“All parts of the body, if used in moderation and exercised in labors to which each is accustomed, become thereby healthy and well developed and age slowly; but if they are unused and left idle, they become liable to disease, defective in growth and age quickly” (278).
5.3 Bed rest (1945–1955)
Three days of physical inactivity produces glucose intolerance (47). Paul Dudley White, one of Dwight Eisenhower's cardiologists after the President's heart attack on September 24, 1955, prescribed physical activity to President Eisenhower long before the end of the standard treatment of 6-months bed rest for a heart attack. The medical community followed White's practice of substituting physical activity for bed rest in management of acute coronary syndromes, with bed durations progressively decreasing to 2 weeks in 1980 in 2005 (340). A 2011 meta-analysis concludes that exercise training has greatest beneficial effects on left ventricular remodeling in clinically stable post-MI patients when training starts one week following the MI (227).
5.4 Initial epidemiology (1949–1953)
Jeremiah Morris is recognized as the person who first used physical activity in epidemiology (his history is available (43). In 1953, Morris and co-workers compared bus drivers, who are sedentary in their occupation, with the physically active bus conductors, who were constantly moving up and down double-decker buses to collect fares in London. Physically active conductors had a 30% lower incidence rate of coronary heart disease (CHD) than the physically inactive bus drivers (353). Furthermore, even the physically active conductors who did develop CHD with age were better off, presenting with less severe disease and lower fatality rates than the inactive bus drivers (353). However, while VO2max was not determined in Morris' report, others have since shown that workers in physically active occupations have higher aerobic capacity than their inactive peers (220). Morris' 1953 report (353) is a milestone as the initial publication documenting daily physical inactivity is associated with increased morbidity and mortality (43).
In his 10th decade of Morris' life, he wrote, “We in the West are the first generation in human history in which the mass of the population has to deliberately exercise to be healthy. How can society's collective adaptations match?” (43, 354).
5.5 Primary prevention: Human space flight (1957–1961)
The Space Race for national security began in earnest in 1954 leading to the successful launch and orbit of Sputnik from the USSR on October 4, 1957. Four years later on April 12, 1961 Yuri Gagarin became the first human in outer space and the first to orbit the Earth. The Space Race hastened physiological exploration that the microgravity experienced in space reduced human functional capacities. As an outcome, NASA researched countermeasures to the microgravity-induced functional loss during spaceflight that relied on experimental bed rest on Earth, an extreme form of inactivity. However, interest in the primary mechanisms of inactivity was a lower priority.
Today over 6500 publications arise from a PubMed search for the terms spaceflight and physiology. Inspection of this body of literature led Vernikos and Schneider (540) to contend that spaceflight results in losses of functional capacities in multiple organ systems, similar to an accelerated model mimicking aging. For example, they conclude that bone atrophy occurs 10-times faster in spaceflight than with aging. Similarly, reductions in immune function, sensitivity of arterial baroreflex, maximal stroke volume, maximal cardiac output, and VO2max also occur more rapidly in spaceflight than in aging (540, 561). (Cross-reference: Importance of exercise in microgravity)
5.6 Bed rest book (1965)
The preface of Browse's book “The Physiology and Pathology of Bed Rest”, published in 1965 states that the principle purpose of the book,
…is to lay bare our ignorance of the whole subject, to stimulate research…The dangers of bed rest are so many, and in some cases so final, that we should always be striving to discard it from our therapeutic armamentarium…and to emphasize the absurdity of using a non-specific treatment for specific diseases without reason or proven value (68).
The book carefully documents the widespread systemic deterioration of the body when continuous bed rest occurs. Some of the pathologies documented are: postural hypotension, tachycardia, kidney stones (renal calculi), loss of skeletal muscle mass, weakness in antigravity muscles, pressure ulcers, osteoporosis, constipation, deep vein thrombosis, pulmonary embolism, pneumonia, and difficulty with micturition.
5.7 Dallas Bed Rest Study (1960's)
Saltin, et al. (454) studied five healthy college-age males during 20 days of continuous bed rest. During acute exercise following bed rest reductions of 28%, 11%, 26%, and 29% in VO2max, ventricular volume (ml), maximal cardiac output, and maximal stroke volume occurred, without a change in maximal A-VO2 difference. Further detrimental changes with bed rest were increased heart rate at a submaximal workload of 600 kpm/min from 129 to 154 beats/min and total peripheral resistance (TPR) increasing from 449 to 520 TPR units. From the 10th–20th day of bed rest day resting heart rate increased from 47 to 51 beats/min.. (Cross-reference: Cardiac Function; Cardiac output during exercise: contribution of the cardiac, circulatory and respiratory systems)
5.8 Sitting studies (2000's)
A perspective was proposed as to whether too much sitting is distinct from too little exercise (218, 317, 392, 393). Owen et al.'s 2010 review states,
Further evidence from prospective studies, intervention trials, and population-based behavioral studies is required…many scientific questions remain to be answered before it can be concluded with a high degree of certainty that these adverse health consequences are uniquely caused by too much sitting, or if what has been observed so far can be accounted for by too little light, moderate, and/or vigorous activity (392).
A 2010 review co-authored from multiple research sites concluded from an examination of 43 papers, “Limited evidence was found to support a positive relationship between occupational sitting and health risks. The heterogeneity of study designs, measures, and findings makes it difficult to draw definitive conclusions at this time” (537). The concept of intermittency of lack of weight bearing by sitting is supported by older basic science research. In rats cycling 4 times/day through periods of weight bearing and non-weight bearing (hindlimb suspension), soleus muscle atrophy was prevented by 4 × 15-min periods of ground support during 12 hrs of the day (118).
5.9 Animal wheel lock studies (2000's)
In order to optimize primary prevention by physical activity, mechanisms by which physical inactivity initiates risk factors for chronic diseases must be elucidated for the optimal science-based physical activity prescription. One animal model used young male rats that underwent 3 weeks of voluntary running and then had their wheels locked (WL) for 5 hrs (WL5), 29 hrs (WL29), or 53 hrs (WL53). Within 53 hrs two major changes in functional capacities were observed, decreased submaximal insulin sensitivity and enhanced storage of TG in visceral adipose tissue. (For the purposes of this article, visceral and intra-abdominal adipose tissues are considered similar and the term visceral is used). Specifically, submaximal insulin-stimulated 2-deoxyglucose uptake, insulin binding, insulin receptor ß-subunit (IRß) protein level, submaximal insulin-stimulated IRß tyrosine phosphorylation, glucose transporter-4 protein level, and Akt/protein kinase B Ser473 phosphorylation (an index of proximal insulin signaling) in the epitrochlearis muscle, returned to sedentary levels at WL53 (293). Further, the epididymal adipose tissue mass at WL53 weighed 25% more than at WL5 in the same rats as studied for insulin sensitivity above.
5.10 Translation studies - Reduced stepping studies in humans (2000's)
While continuous bed rest is a model examining the absence of physical activity, a novel human reduced-activity model was designed to test the effects of reduced, rather than lack of, physical activity on metabolic health. Step numbers were reduced by taking elevators instead of stairs and riding in cars instead of walking or bicycling within a free-living environment by young, healthy male adults who were not undertaking >2 hrs/wk exercise at the start of the study. After reducing daily step number form 6203 to 1394 for 3 weeks, areas under the curve (AUC) for plasma insulin during an oral glucose tolerance test (OGTT) progressively increased 53%, 61%, and 79% after 1, 2, and 3 weeks, respectively (389).
In a second study, subjects reduced daily steps from 10,501 to 1,344 (where there are ~2000 steps in a mile). After 2 weeks, VO2max decreased 7%, peripheral insulin sensitivity decreased by 17% with concurrent decreases in insulin-stimulated ratio of pAkt-Thr308/total Akt in skeletal muscle. Body composition was also significantly altered by 2 weeks of reduced stepping with visceral adipose tissue mass increased 7%, total fat-free mass decreased by 1.2 kg, 0.5 kg of it in the legs, while total-body fat mass and BMI were unchanged (286, 389). Thus, an inverse relationship existed between gain of visceral adipose tissue and loss of lean mass, indicative of body composition repartitioning. Similar observations have been made in a rat WL model. In a different WL experiment visceral adipose tissue mass, but not lean mass increased independent of food intake after 173 hours of WL followed 6 weeks of voluntary running (310). Thus, both human and rat models of reduced daily steps increased visceral adipose tissue while diminishing lean mass, independent of caloric increases.
5.11 Clinical significance
Short-term reductions in daily step number (producing less daily physical activity) cause decreased CRF, loss of insulin sensitivity, reduced lean mass and increased visceral adipose tissue. These functional decrements help explain the link between reduced physical activity and the risks that have been associated with the progression of chronic disorders and premature mortality (389). Using physical activity prescriptions to prevent physical inactivity would help maintain functional capacities.
5.12 Summary: Inactivity causes loss of functional capacities
Taken together, the historical work provides overwhelming evidence that physical inactivity cause decreases in capacities of functional systems, leading to premature deterioration of health in humans. The Copenhagen study of reduced stepping, while low in subject number, is particularly relevant to everyday living because the reduced physical activity level is similar to the step numbers performed in a free-living environment by billions of humans worldwide in both developed and developing countries.
6. Cause vs. treatment
A sedentary lifestyle over several years is associated with increased risk for type 2 diabetes, cardiovascular disease, and premature mortality. What is much less appreciated is the high cost of physical inactivity even in the short term. Booth et al. have been drawing attention for years to the societal and individual burden of inactivity-related chronic diseases. They remind us that while exercise is a treatment to prevent many chronic diseases, it is the lack of regular exercise or physical inactivity that is one of the actual causes of many of these diseases” (481).
Convincing proof that physical inactivity causes primary deterioration of function is provided from extensive historical and scientific evidence. Thus, physical activity can prevent physical inactivity-induced chronic diseases (left panel of Fig 1). In contrast (right panel of Fig 1), physical activity can treat against lung cancer-induced dyspnea, a common side effect 1 to 6 years after lung cancer resection (179) (Right panel Fig. 1). Thus, in the left panel physical activity addresses the cause of the disease, while in the right panel physical activity only acts as a treatment against a disease in which it cannot prevent. We will focus on the disease processes of the left panel in this article.
Physical activity produces primary and tertiary preventive health benefits for chronic diseases. Left panel. Physical inactivity is an actual initiating cause of a chronic disease/condition. Restoration of physical activity (primary prevention) removes...
7. Mechanisms of physical inactivity and activity differ
Mechanisms of physical inactivity are considered anti-parallel, rather than in series (continuum) to physical activity (210, 570). Physical activity and inactivity reside in different mechanistic planes, and are not merely mirror images of each other as is commonly considered (discussed below). Optimal therapies and preventive strategies require knowledge of causal mechanisms. Thus, it is important to understand that some of the mechanisms by which inactivity causes chronic diseases differ from mechanisms by which exercise acts as primary prevention of same diseases.
One example is that inactivity and exercise differ with regards to time courses of structural changes in conduit arteries and changes in endothelial function. This difference is summarized nicely in a review where Thijssen et al. state: “However, the nature and impact of inactivity and exercise on vascular structure and function suggest that inactivity and exercise are not simply the opposite ends of a linear spectrum of physiological adaptation” (506). In our figure 2, distinct mechanisms by which inactivity and/or exercise alter conduit size and endothelial function are outlined. For instance inactivity results in immediate negative remodeling of the vessel, while activity requires 4–6 weeks to positively remodel the vessel.
Changes in artery function and structure (remodeling) show differential time courses in response to increasing or decreasing human physical activity as hypothesized by Thijssen et al. (506). Exercise training (right side) produces early, rapid increases...
A second example that inactivity and exercise are not mirror images of one another is found from global analysis of skeletal muscle gene expression, before bed rest, immediately after bed rest, and after 4 weeks of post-bed rest training. Compared to pre-bed rest levels, 9 days of bed rest altered 4500 mRNAs. If physical activity were merely the reverse of inactivity then all 4500 would be hypothesized to return to pre-bed rest levels following 4 weeks of training. However, a normalization of expression failed to occur in 20% of the 4500 genes that changed with bed rest. This observation led Vaag and co-workers (8) to speculate that rather severe and long lasting adverse alterations in mRNA levels may develop in important biological pathways relevant to their general health after 9 days of bed rest.
A third example is by Stein and Bolster (491) who compared muscle atrophy (311) to skeletal muscle regrowth from atrophy (184), and reiterated by Greenhaff and Hargreaves (210). Again, if physical activity were the opposite of physical inactivity, then the expected result would be many of the same genes changes would be similar for atrophy and regrowth. However, comparison of these two gene lists showed virtually no common gene names on both lists. These examples illustrate a fundamental principle of biochemistry, which Stein and Bolster concisely state, “This is a common finding in biochemistry. Anabolic and catabolic pathways are usually separate” (491)”, or put another way, opposite processes work through entirely different mechanisms rather than altering the level of one pathway. Further biochemical examples include; irreversible steps in glycolysis and glycogen synthesis, protein synthesis and degradation, lipolysis and lipogenesis, and mitochondrial biogenesis and mitophagy, all of which support the idea that exercise and inactivity are not merely opposites of each other. Thus, a single molecular paradigm to explain adaptations to exercise and inactivity does not exist.
8. Gene-Exercise/physical inactivity interactions
Physical fitness and physical activity/inactivity interact with genes. While many fitness examples of gene-environment could be chosen, VO2max will be used because it is well studied and integrates the function of multiple organs at multiple levels (i.e. tissue, cell, protein, and gene). (Cross-reference: Genetics: environment and their interaction)
8.1 Genetic Component Alone
Phenotype responsiveness variability to aerobic training
Using untrained pairs of monozygotic twins, dizygotic twins, and brothers approximately 40–50% of VO2max was estimated to be due to genetics (57). Similarly, pairs of identical twins had significantly more similar increases in VO2max than unrelated twin pairs after aerobic training in three papers in the mid-1980s (217, 421, 474). The papers led to the milestone paper reporting that some individuals experiencing little or no gain in VO2max, whereas others gained >1.0 L/min in 481 sedentary subjects (55). A 2.5-times greater variance existed between families than within families in the VO2max response variance.
8.2 Higher VO2max associates with better health
The 1996 US Surgeon General's Report (531) concluded that high CRF decreases the risk of cardiovascular disease (CVD) mortality. High VO2max is associated with “positive health”; low VO2max is associated with “negative health.” Remarkably, low CRF was a stronger predictor of death than clinical variables or established risk factors, such as hypertension, smoking, and diabetes, as well as other exercise-test variables, including ST-segment depression, the peak heart rate, or the development of arrhythmias during exercise in both healthy subjects and those with CVD (363). Specifically, subjects aged 60 and older with low CRF had notably higher mortality risk from all causes than those with high CRF (499). Maintaining the highest possible VO2max is a primary preventer of morbidity and mortality from low VO2max (discussed later). Further information on the role of genes, physical activity, VO2max (CRF), and health is presented next.
8.3 Using VO2max to identify “health” genes
Theoretic selection of specific genes to optimize functional capacities
In 1979, Bennett and Ruben elegantly described a basis for natural selection of genes by physical activity to maximize inherited potential VO2max,
“We believe that this increased stamina and sustainable activity were important selective factors from the outset… The selective advantages of increased activity capacity are not subtle but rather are central to survival and reproduction. An animal with greater stamina has an advantage that is readily comprehensible in selective terms. It can sustain greater levels of pursuit or flight in gathering food or avoiding becoming food. It will be superior in territorial defense or invasion. It will be more successful in courtship and mating” (34).
The quotation hints that some genes were selected during evolution to support high levels of physical activity and the ability to adapt to physical activity. However, recent observations that a small portion of the population is low responders for VO2max suggest a greater biological complexity than known in 1979.
Genes associated with plasticity of VO2max
In 1998, Bouchard and co-investigators published, “Maximal heritability estimates were at least 50%, a value inflated to an undetermined degree by inclusion of nongenetic shared factors” (56). Timmons employed a novel approach to improve the examination of complex physiological variables in human models. To identify genes responsible for variance of VO2max plasticity, Timmons et al. (517) used a novel approach by first conducting mRNA expression microarray profiling, which were then used to produce molecular predictors to locate or rank a discrete number of genes that correlate with the change in VO2max following endurance training. Follow up studies allowed for subsequent targeted genotyping and, hence, discovery of key genetic variants responsible for the variance of VO2max plasticity. A signature of 29 mRNAs and of 11 single nucleotide polymorphisms (SNPs) were identified that predicted ~50% and ~23%, respectively, of the estimated variance for VO2max plasticity following aerobic training in humans (517). Timmons et al. (517) noted two remarkable characteristics in their identified 29 predictor mRNAs: 1) pretraining levels were greater in high than low responders for VO2max; and 2) >90% of the 29 mRNAs did not change with aerobic training. They suggested that individuals with a low responder predictor gene profile would require alternative exercise intervention paradigms or more intensive pharmacological and dietary protocols to help compensate for their genomic profile. Timmons and co-authors further examined the same subjects after 6 weeks of endurance training at 70% of maximal VO2max (517). They observed that low-responders did not switch on their proangiogenic network genes effectively (269). (Cross-references: Molecular mechanisms and muscle plasticity with acute and chronic exercise; Muscle plasticity: energy demand and supply processes; Regulation of gene expression in skeletal muscle by contractile activity).
Timmons et al.'s (517) development and validation of mRNA predictors to hunt for genetic markers have many advantages over existing approaches of SNP. Each SNP seems to contribute only weakly for chronic complex human diseases. For example, after genome-wide association analysis in type 2 diabetes (T2D) patients, 18 robust SNPs explain <7% of the total disease variance (484). As to generalization of a low responder to all of tens of health benefits from exercise training from VO2max alone, Timmons cautions, “No systematic analysis allows us to be certain that a `nonresponder' for one trait does not cluster with a poor response for another” (516). Thus, additional research is needed to determine whether low responders for gain in VO2max with endurance training respond to other “positive health” benefits of physical activity, such as improved cognitive function, bone density, skeletal muscle strength, visceral adipose tissue quantity and quality, and the tens of other “positive health” benefits detailed later in this article (52). Blair, Church, and co-workers (478) reported that non-responders to for increase in VO2max comprised a total of 44.9%, 23.8%, and 19.3% of the 4-, the 8-, and the 12-kcal/kg/wk treatment groups, respectively. They concluded that greater volumes of exercise were associated with a lower probability of being a nonresponder. In summary then, additional research is needed to determine if low responders to aerobic exercise are low or high responders to high-intensity interval training, to resistance training, balance, or flexibility training.
Proof due to experimental selection of physical aerobic-fitness genes in animals
Britton and Koch's experimental selection, based upon a single volitional/behavioral forced running test to exhaustion, provided experimental evidence that natural selection for high aerobic capacity during evolution is a feasible concept (569). Selection of rats on the basis of the longest or shortest running distances during a single exercise test resulted in selection of a 58% higher aerobic capacity in the high-distance line than the short-distance line over 11 generations. Rats with high VO2max had healthier cardiovascular systems (12% lower mean 24-hr blood pressures and 48% better acetylcholine-induced vasorelaxation), and healthier metabolic risk factors (16% less fasting plasma glucose, 39% less visceral adipose tissue, 63% lower plasma triglyceride levels, and greater mitochondrial protein concentrations). These data provides evidence of a genetic role in inter-animal variation in VO2max that is correlated with better health outcomes.
8.4 Phenotype responsiveness variability to resistance training (RT)
In addition to VO2max variance among subjects in response to aerobic training, RT also has a tremendous amount of variability in adaptive responsiveness. In 585 subjects undergoing 12 weeks of RT, changes from 2 to +59%, 0 to +250%, and −32 to +149% occurred in cross sectional area, one repetition max, and maximal isometric contraction, respectively (250). The variability in muscle mass may, in part, be related (but not limited) to inter-individual differences in genome code (as with IGF2 in the aforementioned porcine model) (377), the individual's ability to activate intramuscular mTORC1 signaling within skeletal muscle in response to exercise (333), and/or different responses of microRNA (miRNA) to RT(120). Successful RT-induced hypertrophy in human skeletal muscle was associated with specific differences in miRNA expression to RT in high- and low- responders, respectively, which Davidsen et al. (120) suggest means that miRNAs may play a role in regulating the translation of key gene networks responsible for human skeletal muscle growth. One possible pathway is the PI3K/Akt/mTOR pathway, which is up-regulated during skeletal muscle hypertrophy in humans, and related to the ability for satellite cells to proliferate and/or differentiate (411).
8.5 Pharmacogenetics interactions with exercise
The efficacy of drugs is affected by physical fitness/activity status (104, 328) in addition to genetic disposition. For instance, in patients with abnormal left ventricular (LV) relaxation and preserved LV ejection fraction, exercise and weight loss plus drug reduced the LV relaxation dysfunction that was not reduced by the drug alone (104). Martin et al. (328) speculate that drugs with good efficacy in sedentary overfed (overweight) animal models may be less effective in active normal weight animals.
8.6 The future of personalized human medicine
The findings of the previous sections have led Timmons et al. (517) to predict that they could apply gene data for changes in VO2max in personalized medicine to tailor exercise prescription. Medicine will continue to become more personalized with the looming question of how to optimize how it is applied to ensure the greatest patient benefit. Carl Sagan wrote, “It is the tension between creativity and skepticism that has produced the stunning and unexpected findings of science” (452). It is the spirit of Sagan's quotation that we now raise issues about which we are skeptical. We are skeptical that exercise experts will be used to inform health care professionals on how to make personalized exercise prescriptions based on science. The fear is that a patient will be informed that they have low-responder genes for VO2max, which may lead to failure of the patient to exercise or lack of compliance to alternative exercise prescriptions. We hope that solutions, such as encouraging low responders to aerobic exercise or to engage in resistance exercise, can lead to striking improvements in personalized health.
8.7 Clinical significance
In a statement in Science, NIH Director Francis Collins wrote,
However, the best opportunity to reduce risk in genetically susceptible people for the foreseeable future will not be to re-engineer their genes, but to modify their environment. We need to understand how genetic factors and environmental exposures interact in individuals to alter normal biological function and to affect the risk of disease development (464).
The clinical significance of low- and high-responders for a given dosage and type of exercise, implies that individualized medicine, if exclusively restricted to viewing genetic background in vacuum, will result in less than optimal prescriptive therapy. Rather, individualized medicine for primary prevention of disease and premature death must also be based on individualized variation of inherited genes for: a) disease susceptibility, b) responsiveness to exercise training and type of exercise, and c) drug-exercise interactions, if appropriate. Thus, fully capturing personalized gene-environment interactions.
Kujala et al. (289) wrote, “When tailoring clinical physical activity interventions, we must remember that not all individuals are suited to the same guidelines for exercise intensity, because the ability to exercise seems to vary not only by training background but also by genetic predisposition.”
9. Twin studies - Modulation of twin phenotype by physical activity
Claude Bouchard has extensively used the experimental approach of MZ twins to minimize genetic variability for estimating the percentage contribution of environmental (physical activity) interventions since the mid-1980s. In addition to studies where twins were subjected to exquisitely controlled exercise protocols, a number of studies used overfeeding protocols to look at the effect of excess calories (not included in the following tables). The twin approaches have been critical to our ability to separate genetic from environmental effects related to health and chronic disease in humans. Future, twin-activity studies will contribute to prescription of exercise types and of dose-response thresholds for primary prevention of chronic diseases.
9.1 Comprehensive presentation of twin-activity (gene-environment) studies
In this section, we take the approach of searching the literature for all articles (that we could find) that have examined a variety of health outcomes in monozygotic twins (MZ) to attempt to control for genetic variation.
9.2 MZ twin-activity comparisons show high mortality component
To summarize the most important health outcome, mortality, Table 2 is presented to show the mortality outcome in MZ twins discordant for physical activity in a large cohort of Swedish twins (77). The higher physically active MZ had a 36%–66% lower mortality than their inactive MZ pair.
Tendency for dose-response between higher physical activity level and lower mortality in Swedish monozygotic twins [modified from (77)].
9.3 MZ twin activity comparisons show variable chronic disease component
These studies have taken the approach of either a priori separating pairs of MZ that are discordant for physical activity (Table 3), looking at exercise responses in MZ twins relative to dizygotic twins (Table 4), correlating health parameters with physical activity or fitness levels in MZ twins (Table 5), and looking at the genetic component of physical fitness and activity parameters (Table 6). By evaluating this approach, we can obtain an idea about which factors are controlled mainly by genetics and which are most modifiable for physical activity levels. However, it should be noted that many of these studies have methodological limitations including a wide range of physical activity levels and outcomes that differ from classical exercise physiology adaptations.
Studies with Twin Discordant for Physical Activity Levels.
Studies with Twin Response to Exercise
Studies with Twin Correlations that are corrected for PA levels or Unique Environmental Effects (twins may not be discordant for PA).
Genetic Influence on Physical Activity, Exercise Levels, and Exercise Capacity. B = both; DZ= dizygotic; F = female; H = heredity effect; M = male; monozygotic; N.D. = not determined; n = number of subjects; Y = young
As expected many of the tested health parameters had both genetic and environmental components. In many studies, questionnaires were used to evaluate physical activity levels, a less than optimal method to collect such data. Thus, while the design of the studies analyzed was not optimized for elucidating the effects of physical activity independent of genotype, some cautious conclusions may be made from Tables 2–6, presented next.
9.4 Important physical activity component to activity adaptation
The data indicate that inactivity increases both visceral and total fat masses independent of genetic disposition. Additionally, Alzheimer's and dementia both have a large physical inactivity component. However, changes in muscle morphology (length, shortening velocity, of ventricular diameter) do not exhibit compelling genetic components. Genotype is apparently not a major determinant of the changes in insulin levels and sensitivity brought about by negative energy balance with exercise (390) (see insulin resistance later in article).
9.5 Important gene component to activity adaptation
In these studies, while physical activity levels themselves exhibit a large genetic component; it varies tremendously between countries and cultures. In addition to activity levels, a major genetic component is found for both measures of strength fitness (muscle strength and power) and in endurance fitness as well as responses (lactate levels, blood pressure) to exercise. More surprisingly is the minor effect of physical activity on overall “well-being”, which is in contrast to a number of cross-sectional studies suggesting that physical activity is strongly negatively correlated with depression and anxiety. Another surprisingly result is that twins discordant for physical activity do not differ in generalized bone mass or spinal cord bone mass (542), despite the well-known effects of bed rest and inactivity on increasing bone loss. These contradictory results may simply be due to the lack of specific measures of bone mass in the active limbs, or to the variation in types of load-bearing physical activity, and thus bone health, in the physically active group.
9.6 Clinical significance
Taken together, data in Tables 2–6 provide conclusive evidence that physical inactivity alone is sufficient to increase chronic diseases and death. “Together, the 80 monozygotic publications unequivocally show that co-twins with lower physical activity levels exhibit increased risks for chronic diseases regardless of genotype. Such data, therefore, empowers physicians and other health care providers to prescribe physical activity as primary preventative medicine”
10. Variety of training types to primarily prevent disease
Specificity of training (i.e., adaptation to training is specific to the class of exercise (aerobic vs. resistance) is dogma. For example in 1976, one of us wrote that the nature of the exercise stimulus determines the type of adaptation (243). One type of adaptation involves hypertrophy of the muscle cells with an increase in strength; it is exemplified in its most extreme form by the muscles of weight lifters and body builders. The second type of adaptation involves an increase in the capacity of muscle for aerobic metabolism with an increase in endurance and is found in its most highly developed form in the muscles of competitive middle- and long-distance runners, long-distance cross-country skiers, bicyclists, and swimmers. Further, hypertrophied muscles of weight lifters did not have the increased mitochondria of aerobic training and that prolonged daily run training increases mitochondria, but does not hypertrophy the muscles. Application of the information to elderly individuals is that they must perform both types of exercise to prevent physical (endurance and strength) frailty.
Recent information expands and emphasizes the specificity dogma. High-intensity interval training (HIT) (near peak performance for short bursts alternating with longer periods of low-intensity aerobic activity) has been said to “prove more benefit than traditional continuous exercise programs in several metabolic, muscular, and cardiovascular parameters” (278). For example, HIT-walking resulted in greater increases in VO2peak and thigh muscle strength and a greater reduction in SBP than moderate-intensity continuous walking in older men and women (375). In contrast, one HIT report indicates that HIT by untrained men produced greater (VO2max), the same (improvements in oral glucose tolerance), and less (resting bradycardia, total-body fat percentage, and reducing ratio between total and HDL plasma cholesterol.) adaptations than in a second group performing continuous training (384).
11. Diseasome of physical inactivity (35 diseases/conditions)
The term “diseasome of physical inactivity” was presented by Pedersen (403) to describe a clustering of diseases. Our article enlarges Pedersen's cluster to include over 35 diseases/conditions and death, which constitute most of the remaining article (Fig. 3). (Cross-reference: Muscle as an endocrine organ) Joyner and Pedersen (260) contend that it is a failure of regulation at multiple levels that causes many common diseases. They further argue that a lack of fluency to use key physiological concepts (like homeostasis, regulated systems and redundancy) as major intellectual tools to understand at multiple levels how whole animals adapt to exercise and maladapt to physical inactivity.
Health deficiencies accelerated by decreasing physical activity from higher to lower levels. Gheorghe Constantinescu generously made original drawing. [Reproduced with permission from (53)].
12. Inactivity accelerates loss of functional capacities with years of life
Inevitable deterioration of cellular structure and function, independent of disease (241)
Maximum amount of time one member of a species has been observed to survive between birth and death
Aging processes which result from disease, bodily abuse, and/or disuse and which are often preventable
Average lifespan of a population
Absolute maximal value of a function
Relative functional capacity Relative age of functional capacity of an organ system, an organ, or cell to its lifetime highest value at a given calendar age
The next quotation is impactful because of its source, a report from top exercise scientists that was accepted by the top official of the U.S. Department of Health and Human Services.
The data very strongly support an inverse association between physical activity and all-cause mortality. Active individuals — both men and women — have approximately a 30% lower risk of dying during follow-up, compared with inactive individuals. This inverse association has been observed among persons residing in the United States, as well as in other countries, older persons (aged 65 years and older), and persons of different race/ethnic groups. In one study of persons with impaired mobility (unable to walk 2 km and climb 1 flight with no difficulty), physical activity also appeared to be associated with lower all-cause mortality rates. (412)
Less physical activity shortens years of life relative to average lifespan
Healthy behavioral choices in Californian Adventists extend life expectancy by several years, even as much as a decade, (190). Various reports estimate that higher physical activity levels may extend life expectancy relative to average lifespan by 2.1 (405), 2.5 (395), 5.1 (men)(181), and 5.7 (women)(181) yrs for the physically active population.
Another example of lifetime physical activity shortening years lived is the increased risk of chronic diseases such as type 2 diabetes (See type 2 diabetes later in article). Diagnosis of type 2 diabetes at the age of 20 yrs is associated with 17.2 and 17.9 yrs of life lost in males and females, respectively (366).
Less physical activity increases percentage of population that is disabled
At the same age for death, the high physical activity group spent less time disabled than the overall population of men (2.5 vs. 3.0 years), while the low physical activity group actually spends more time disabled than all men (2.6 vs. 1.4 years)(181). Thus, less lifetime physical activity shortens years of life. (Cross-reference: Implications of aging and athletics)
12.3 Dose-response relationship between sitting time and prediction of premature death
Katzmarzyk et al. (268) reported a dose-response association existed between sitting time and mortality from all causes and CVD, but not for cancer, independent of leisure time physical activity in 17,000 Canadians, such that hazard ratio was 1.54 for the greatest sitting time. Dunstan et al. (151) found that each 1-hour increase in TV viewing time was associated with 11% and 18% increased risks of all-cause and CVD mortality, respectively, in 20,000 Australian men and women. Further, all-cause and CVD mortalities increased 46% and 80%, respectively for TV viewing time >4hr/day as compared to <2 hrs/day, which were independent of smoking, blood pressure, cholesterol, diet, waist circumference, and leisure-time exercise.
While light physical activity is associated with rather low-intensity muscle contractions, it still has favorable improvements on plasma glucose in glucose tolerance tests (228), and differs substantially from the absence of muscle activity while sitting The detrimental effects of sitting have been hypothesized by Stamatakis et al. (489