Lack of exercise is a major cause of chronic diseases

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.

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).

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 10^th 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
10^th–20^th 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.

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

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.

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, 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.

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 (), looking at exercise responses in MZ twins relative to
dizygotic twins (), correlating health
parameters with physical activity or fitness levels in MZ twins (), and looking at the genetic component of physical fitness and
activity parameters (). 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.

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 –, 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.

12.2 Etiology

12.3 Dose-response relationship between sitting time and prediction of premature
death

12.4 Biomarkers of premature death

Low values of functional capacities for maximal aerobic capacity
(VO₂max) and for maximal skeletal muscle mass/strength, each alone, are
biomarkers for death as they are associated with shorter life expectancies.

Sedentary lifestyle speeds secondary aging of VO₂max by 30 yrs
(illustrated by shifting of age-VO2max relationship leftward in shown example)

As previously discussed, VO₂max is a measure of CRF. CRF is a
health-related component of physical fitness defined as the ability of the circulatory,
respiratory, and muscular systems to supply oxygen during sustained physical activity.
While physically active and inactive individuals lose a
VO₂max at a similar rate (slope of the curve) due to
primary aging, the inactive individuals have a leftward shift of the curve. For
instance, 80-yr-old, physically active women had VO₂max’s that were
equivalent to 50-yr-old physically inactive women. () (503).

Best-fit linear lines are shown for aerobic capacities of two cross-sectional groups
(aerobic trained and sedentary) as a function of their increasing chronological age. At
the chronological age of 80 yrs, a horizontal line is extended from the endurance trained
line to the left where it intersects the sedentary line at age 50 yrs. Subjects were women
who had been aerobically trained for at least 2 yrs with road-racing competition (closed
circles) vs. women who were sedentary (open squares) who performed no regular exercise and
had BMI’s <35 kg/m² (aerobic-trained women were matched across the
entire age range for age-adjusted world-best 10-km running times to ensure homogeneity
relative competitiveness). [Reproduced with permission from (503)].

Low VO₂max increases prevalence of death

Convincing evidence exists that lower CRF is associated with increased
mortality in both men and women, independently of other risk factors (79, 96, 277, 312,
313).

An inverse relationship between CRF and death was present with a
cross-sectional comparison between lesser fit men and women with greater fit men and
women showed. When CRF in the second lowest CRF quintile is compared to the lowest
quantile, the risk of all-cause death in the lowest CRF quantile is increased by 39% and
67% in a prospective study of 40,451 men and 12,831 women, respectively (312) ().
Likewise comparing the highest CRF quintile) to the second lowest increased all-cause
death risk by 26% and 28% in men and women, respectively. Thus, comparing the top
quintile to the lowest quintile increased all-cause death risk by 75% and 113% in men
and women, respectively.

Relative risk of death as a function of cardiorespiratory fitness (CRF) or change in CRF.
Relative risks of all-cause mortality by (CRF) quintiles for 12,831 women aged
20–100 years without cardiovascular disease (CVD) or cancer in the Aerobics Center
Longitudinal Study. Relative risks were adjusted for age, year of examination, body mass
index, smoking status, abnormal electrocardiogram, hypertension, diabetes,
hypercholesterolemia, and family history of CVD. [Reproduced with permission from (312)].

Changes in CRF level result in a similar change in mortality risk. Men (n =
9777; aged 20–82 at baseline) had two CRF assessments with an average period of
4.9 years between first and second examinations (44, 312). The men were then followed
an average of 5.1 years for mortality after the second CRF test. Men who were unfit at
both visits had the highest death risk while men who were fit at both visits had the
lowest death risk. Remarkably, men who changed fitness status between the two CRF
assessments had intermediate risk of death between the fit-that-stayed-fit group and
unfit-who-stayed-unfit group. Fit-who-became-unfit between assessments had an increased
risk of death. Unfit-men who-became-fit between CRF assessments decreased their risk of
death. Erikssen et al. (165) found similar trend
and concluded that even small improvements in physical fitness are associated with a
significantly lowered risk of death.

Sedentary lifestyle speeds secondary aging of skeletal muscle power by 24 yrs
(illustrated by shifting of age-power relationship leftward in shown example)

Low muscle strength has been inversely associated with all-cause-mortality in
thirteen studies using subjects > 65 yrs of age (see (451) for refs). While, aging causes a similar rate of loss in power
between 40 and 90 yrs of age, untrained, healthy men generate 35% less average power
than male competitors at a World Masters Weight-Lifting Championships (402) ().
Recreational resistance training results in strength gains ranging from 10%–257%
after 9–52 weeks of 2–3 days/week resistance training in subjects mainly
aged between 60–80 years of age (252),
however a cross-sectional study spanning 20–80 yrs of age in recreational
weight-lifters is not available to our knowledge. (Cross-references: Influence of
exercise on protein and amino acid metabolism; Physical activity and skeletal muscle
size)

Best-fit linear lines are shown for power of two cross-sectional groups (strength trained
and sedentary) as a function of their increasing chronological age. At the chronological
age of 80 yrs, a horizontal line is extended from the power-trained line to the left where
it intersects the sedentary line at age 56 yrs. The cross-sectional strength-trained
subjects are shown in closed circles and sedentary in open circles. [Reproduced with
permission from (402)].

12.5 Mechanisms

14.1 Disease definition

MS is currently defined as a cluster of three of five risk factors for CVD and
type 2 diabetes, which tend to cluster together in the same individual () (6). Four
of the five factors have drug treatments in attempts to normalize them, and include
elevated triglycerides, reduced HDL-cholesterol, elevated blood pressure, and elevated
fasting glucose. The fifth factor, elevated waist circumference (as a marker of elevated
visceral obesity) does not have as an effective drug treatment. Three abnormal findings
out of the five risk factors indicate that an individual has MS. In addition, MS is
associated with increased risk of certain forms of cancer, polycystic ovarian disease,
nonalcoholic fatty liver disease, and neurodegeneration (39).

14.2 Etiology

The total number of U.S. adults who have MS ranges from 77–86 million
(34.3%–38.5% of total age-group) (187). A
Joint Scientific Statement indicates that patients with MS have twice the risk of
developing CVD and type 2 diabetes, respectively, over the next 5 to 10 years, as compared
to individuals without MS (6). Physical inactivity
has been shown to be an important risk factor of MS (38, 186, 296, 560). The proportion of
sedentary time, determined by accelerometry was strongly related to metabolic risk,
independent of physical activity (22).

14.3 Mechanisms

A 2009 Joint Scientific Statement from the American Heart Association states,
“Most persons with the metabolic syndrome have abdominal obesity and insulin
resistance. Both of the latter conditions appear to contribute to the development of
metabolic risk factors, although the mechanisms underlying these contributions are not
fully understood (6).” However, it is
understood that physical inactivity is a primary causal mechanism of every MS risk factor
– dyslipidemia, hypertension, hyperglycemia, visceral obesity, prothrombsis, and
pro-inflammatory events ().

Several risk factors for MS are associated with physical inactivity, including
low-grade inflammation and impaired metabolism (403, 404). Conversely, prevention of
physical inactivity through physical activity improves inflammatory markers by reducing
resting CRP, interleukin-6 (IL-6), and tumour necrosis factor-α concentration
(403). On potential mechanism is highlighted by
Pedersen (404) who has put forth the hypothesis
that the muscle secretome (termed myokines) is involved in mediating some of the health
effects of regular exercise, in particular chronic diseases associated with low-grade
inflammation and impaired metabolism, as well as the brain. For example, contracting
skeletal muscle during exercise produces interleukin-6, which has anti-inflammatory
properties (490). Cross-reference: Muscle as an
endocrine organ)

16.2 Misconception that obesity is independent of physical inactivity

The next sections document historical declines in physical activity, putatively
reflecting increases physical inactivity.

16.3 Caloric expenditure from physical activity has decreased historically

Modern human caloric expenditure is less than free-ranging mammals

Compared to other free-ranging mammals, Hayes et al. (225) calculate that sedentary humans have a significantly lower
level of relative physical activity-induced energy expenditure. However, highly active
humans have relative physical activity-induced energy expenditure that nears that of
other free-ranging mammals ().

Human caloric expenditure for physical activity in non-athletes is much lower than
physically active populations. The y axis is the ratio of Activity Energy Expenditure
(AEE) /Resting Energy Expenditure (REE). AEE = free-living energy expenditure –
(diet-induced energy expenditure + REE). Data are presented for various human groups
(non-athletes living in developed nations, military trainees, individuals from rural areas
engaged in high levels of physical activity, and athletes in training) on the x axis. Each
bar is a single subject. Non-athletes in developed nations have AEE/REE ratio of =
~0.5, which is equivalent to PAL of ~1.67). [Reproduced with permission from
(225)].

16.4 Primary prevention of total-body fat gain by physical activity

It is preferable to avoid, in the first place, the excess weight gain that
leads to overweight and then obesity…A major emphasis on obesity prevention is
needed in the population at large to prevent the development of obesity in those adults
who are still in the normal weight range and in successive generations of children and
adolescents during development. Treatment will continue to be of critical importance,
but treatment alone cannot curb the epidemic…prevention has not been the primary
focus (292).

Mimimal research exists on preventing weight gain.

Primary prevention is demonstrated by one human study. A threshold of
~60 minutes a day of moderate-intensity activity throughout a 13-yr study was
needed to gain <2.3 kg in 34,079 healthy US women consuming a usual diet. In a 3-yr
sub-study, the only group having significantly less weight gain than other groups was
women whom fit all 3 of the next criteria: BMI < 25, moderate-intensity exercise
>60 min/day, and < 64 yrs of age (314).

Primary prevention of further weight gain in already overweight to obese
individuals was accomplished with 8 months of low volume-moderate intensity activity
(caloric equivalent of walking 12 miles/wk at 40–55% of VO₂max), while
high-volume (caloric equivalent of jogging 20 miles/wk at 65–80% of
VO₂max) decreased total fat mass by 4.8 kg (480)

Primary prevention of weight regain was calculated retrospectively, after 12
months in previously obese female, to be 80 min/day of moderate activity, 35 min/day of
vigorous activity, or 0.011 kcal physical expenditure/kg body weight/day (461). Maintenance of a 10% reduced body weight in
humans with BMIs >30 is associated with a significant decrease in total energy
expenditure of ~300–500 kcal/day greater than that predicted by changes in
body mass and composition, which is due predominantly to increased work efficiency of
skeletal muscle at low work intensities (203).

Joyner and Pedersen (260) present
another example. Low prevalence of obesity has been related to poor economic conditions.
Collapse of the Soviet empire in at the end of the 1980s led to decreased food
availability, increased physical activity and ~50% decrease in adult obesity
prevalence in Cuba (441). Upon economic recovery,
obesity rose 50% from 1993 to 1996.

16.5 Preferential decrease in visceral adipose tissue (VAT) by exercise

Primary prevention of VAT obesity by physical activity has been demonstrated in
numerous human studies. Physical training of T2D patients produced a greater loss in VAT
(48%) than subcutaneous adipose tissue (SAT) (18%), did not significantly affect body
weight (360). Ross et al. (447) reported that exercise without weight change in
obese men reduced VAT more than SAT. Likewise, a greater percentage loss in VAT percentage
than in body weight occurred after 12 months in a moderate-intensity exercise intervention
study of sedentary, overweight, postmenopausal women. VAT loss was exercise dose-dependent
(253).

A 6-month study examined the dose-response relationship for exercise volume-VAT
mass in men and women whose BMI’s ranged from 25–35 (479). Low volume-moderate intensity (caloric equivalent of walking 12
miles/wk at 40–55% of VO₂max) was sufficient to prevent any further
gains in VAT mass, while high-volume, high-intensity activity decreased VAT by 6.9% ().

Gain by visceral and abdominal fat depots in non-exercising group while 6 months of
exercise training produced loss in these fat depots. Data are presented as change in A)
visceral abdominal fat, B) subcutaneous abdominal fat, and C) total abdominal fat on the y
axis. Four exercise levels are given on the x axis; they are 1) Control (no exercise); 2)
Low-amount, moderate-intensity exercise (caloric equivalent of walking ~12 miles/wk
at 40–55% of peak oxygen consumption); 3) low-amount, vigorous-intensity exercise
(same amount of exercise as group 2, but at 65–80% of peak oxygen consumption); and
4) high-amount, vigorous-intensity exercise (caloric equivalent of jogging ~20
miles/wk at 65–80% of oxygen consumption). [Reproduced with permission from (479)].

Remarkably, the non-treatment group (no exercise) had an 8.6% increase in VAT.
Extrapolated to 10 years, this would have been a 172% increase in VAT. Kraus et al. (482) later wrote about the non-exercise group,
“current levels of physical activity may be so low that significant metabolic
deterioration occurs in numerous health-related parameters in as little as 6 months of
continued inactivity.” The study provides the evidence that a primary cause of VAT
obesity is lack of exercise and that primary prevention for the expansion of VAT is
physical activity ().

16.6 Primary prevention of inactivity prevents obesity with predisposed obesity
gene

Sedentary lifestyle reveals an obesity phenotype that is primarily prevented by
enhanced physical activity.

16.7 Mechanisms

Physical inactivity, as one of the two components in the caloric balance
equation, is an actual cause of positive caloric balance, i.e., obesity. The most
effective control of obesity is primary prevention of physical inactivity by moderate
levels of physical activity, rather than secondary or tertiary prevention of obesity
associated co-morbidities.

18.2 Insulin sensitivity

How successful blood glucose is lowered by blood insulin

18.3 Insulin resistance

Diminished ability of skeletal muscle and liver cells to respond to the action
of a given dose of insulin by transporting glucose from the bloodstream into these
tissues, or by reducing glucose production, respectively (B to D in )

Insulin secretion is presented as a function of insulin sensitivity. Insulin secretion
rises as insulin sensitivity falls when physically active individual (point A) becomes
sedentary (point B). A failure of insulin secretion to compensate for fall in insulin
sensitivity is noted when both insulin secretion and insulin sensitivity decline from
point B to point C, indicating prediabetes. The upper axis for increased and decreased
levels of physical activity implies bidirectionality of the two arrows for glucose
intolerance and insulin resistance. The leftward enlarging two arrows illustrate
increasing glucose intolerance and insulin resistance with 2–3 days of decreased
physical activity. The clinical significant is that low levels of physical activity
produce a permissive environment for prediabetes. In opposite direction, high levels of
daily physical activity markedly diminish the permission state to develop prediabetes. The
distinction between the two arrows is based upon variability in Masters athlete’s
responses to stopping training as shown in
of ref (443) in which 4 subjects had lesser
increases in blood insulin (insulin resistance arrow) at 30 min into an oral glucose
tolerance test as compared to 10 other subjects (glucose intolerance arrow). A continued
decline in both insulin secretion and insulin sensitivity at point D is where overt type 2
diabetes is present. Reproduced with permission from Bergman’s original figure (ref 36).

A hyperbolic relationship between insulin sensitivity and insulin secretion has
been defined as by Bergman (36). illustrates the progression from normal glucose
tolerance (Point A) to overt clinical T2D (Point D), as described in Harrison’s textbook,

glucose tolerance remains to near-normal (NGT), despite insulin resistance,
because the pancreatic beta cells compensate by increasing insulin output (Points A to
B). As insulin resistance and compensatory hyperinsulinemia progress, the pancreatic
islets in certain individuals are unable to sustain the hyperinsulinemic state.
Impaired glucose tolerance, characterized by elevations in postprandial glucose, then
develops (Points B to C). A further decline in insulin secretion and an increase in
hepatic glucose production lead to overt diabetes with fasting hyperglycemia (Point
D). Ultimately, beta cell failure may ensue (418).

We have further modified Harrisons’ redrawing of Bergman’s original figure to
indicate that Point A is representative of a daily physically active human and point B is
an occasionally active human. Based on a number of studies we propose that increases and
decreases in daily physical activity over a time frame of hours to a few days places
subjects between Points A and B. Thus, daily physical activity prevents the progression to
Point B, making it impossible to continue from Point B, to Point C and Point D, overt
diabetes. Therefore, only if continual physical inactivity is present can the progression
to Point C, impaired glucose tolerance, and eventually into Point D, overt diabetes,
occur. As Zimmet astutely and succinctly wrote, “A large proportion of cases of
type 2 diabetes is preventable” (579).

18.4 Impaired glucose tolerance (IGT) may increase cardiovascular disease (CVD)
risk

After adjusting for age and sex, an increased risk of CVD mortality was
observed in those with postchallenge hyperglycemia (PCH) and fasting glucose ≥7.0
mmol/l, with 2-h glucose ≥7.8 and <11.1 mmol/l and fasting glucose
<7.0 mmol/l, or with PCH and fasting glucose <7.0 mmol/l (459).

18.5 T2D was preventable 35–70 years ago

Diabetes prevalence has risen from 1.4% in 1950 to 7.8% in the U.S. (367) and from 1% in 1975 to 9.7% in 2007–2008
in China (576). Zimmet commented, “In
conjunction with genetic susceptibility, particularly in certain ethnic groups, type 2
diabetes is brought on by environmental and behavioral factors such as a sedentary
lifestyle, overly rich nutrition and obesity” (579). We will propose the notion that proper volumes of physical activity would
essentially primarily prevent most of T2D, as illustrated by maintaining at point A in
.

18.6 Inactivity/exercise rapidly change insulin sensitivity

18.7 Biochemical mechanisms

18.8 mRNA mechanisms

Global mRNA analysis of human vastus lateralis muscle identified 4500
transcripts changing after development of insulin resistance following 9 days of
continuous bed rest in 20 healthy young men (8).
They found that 54% of 162 transcripts in the oxidative phosphorylation pathway decreased.
Vaag and coauthors (8) emphasized that they could
not exclude the possibility that down-regulation of oxidation phosphorylation as well as
other genes may have occurred as a result of – not as a causal factor for –
skeletal muscle insulin resistance during bed rest. Two potential physiological mechanisms
may be decreased capillarization (not determined), as suggested by decreases in both
VEGFα mRNA and PGC1α mRNA, or increased fat accumulation due to decreased
CPT1B mRNA and thus decreased fatty acid oxidation (8). Furthermore, increased reactive-oxygen species generation and endoplasmic
reticulum stress were also identified as potential mechanisms of inactivity induced
insulin resistance (8).

19.1 Etiology

It is estimated that 57 million people have prediabetes in the U.S (88). Prediabetes is a condition in which blood glucose
levels are higher than normal, but not high enough to be classified as T2D. Prediabetics
have an increased risk of developing T2D, and T2D’s-associated comorbidities of heart
disease, and stroke.

20.2 Etiology

Nearly 24 million people in the U.S. are diagnosed with T2D in 2007 (11). Today the number is likely even higher. By 2020
> 50% of Americans could have diabetes or prediabetes, at a cost of $3.35 trillion
based according to new projections by UnitedHealth Group’s Center for Health Reform and
Modernization (533). The estimated lifetime risk
of developing diabetes for babies born in 2000 is 32.8% for males and 38.5% for females,
with Hispanics having the highest estimated lifetime risk (males, 45.4% and females,
52.5%) among ethic groups (366), Remarkably, some
adolescents have been reported to have T2D in the past 5 years, a disease once called
adult-onset diabetes because of its time of onset.

20.3 Primary prevention of T2D – overview

The CDC Website states that progression to diabetes among those with
prediabetes is not inevitable (88). The National
Physical Activity Guidelines Advisory Committee Report (NPAGCR¹) (412) states that usage of
physical activity questionnaires in large prospective cohort and cross-sectional
observational studies all show that increased physical activity levels show associations
with reduced risk for developing T2D. A systemic review of follow-up, case–control
or cross-sectional studies by Fogelholm (185)
concludes for individuals with BMI of 25–35 having high BMI even with high physical
activity were at a greater risk for the incidence of T2D and the prevalence of
cardiovascular and diabetes risk factors, compared with normal BMI with low physical
activity. Nonetheless, in men with a BMI of 25 or more, a history of hypertension, a
positive parental history of diabetes, or any combination of these factors, the incidence
of T2D declined by 41% from the lowest to the highest levels of energy expenditure (234) ().

20.5 Primary prevention of T2D – Exercise clinical trial

Prescribed exercise was associated with a 46% reduction in risk of developing
T2D in 110,000 men and women with impaired glucose tolerance in Da Qing China over a 6-yr
intervention period (398).

20.6 Primary prevention of T2D- Lifestyle clinical trial

Prediabetic individuals who incorporate lifestyle modification including
increases in their physical activity prevent or delay the onset of T2D by returning their
elevated blood glucose levels to normal. During the Finnish Diabetes Prevention Study
(Finnish DPS), T2D risk was reduced in prediabetics by 58% (530). In the U.S. Diabetes Prevention Program (DPP), T2D incidence was
11.0, 7.8, and 4.8 cases per 100 person-years in the placebo, metformin, and diet-exercise
groups, respectively, with reductions, compared to placebo, of 31% and 58% in metformin,
and diet-exercise groups, respectively (276). The
result led Knowler et al. (276) to conclude that
the lifestyle intervention was significantly more effective than metformin. However, the
58% reduction in the diet-exercise group and 31% reduction with metformin in the Finnish
DPS and DPP were both intent-to-treat values. Intent-to-treat values in both studies are
the sum of behavioral and biological mechanisms for 100% of the subjects, providing data
for physicians on effectiveness of prescription. However, intent-to-treat does not
separate behavioral from biological mechanisms. Thus, the biological effectiveness of diet
and exercise, independent of behavior, is underestimated due to lower compliance rates in
the lifestyle versus metformin groups.

20.7 Physical activity can prevent T2D without weight loss

Primary prevention of T2D without weight loss has major public health
importance due to media and medical emphasis on weight loss.

20.8 Mechanisms

A recent review describes available evidence suggesting that exercise primarily
acts to lower hyperglycemia by improving glucose sensitivity and mechanisms that interfere
directly with endothelial metabolism (4). Another
review indicates that it is likely that one of the mechanisms by which physical fitness
and activity reduce health risk associated with high BMI is by decreasing fat-to-lean mass
ratio and also by decreasing visceral-to-subcutaneous fat ratio. The review indicates that
decreasing VAT is particularly important for BMIs between 25 and 30 (185). Physical activity also improves glucose-induced insulin
secretion in pancreatic beta cells, likely through enhanced gastric inhibitory protein
(GIP) secretion (483).

20.9 T2D predisposing genes-environmental interactions

A complex disease such as T2D has, at present, 18 multiple candidate loci that
account for only a small percentage (< 7%) of the total identifiable genetic load.
Snyder at al. wrote,

“Thus, the interpretable genetic contributions that can be
identified are quite minor… Presumably, either many low-frequency alleles at
different loci contribute to the genetic load or perhaps the many phenotypes are
because of other phenomena such as synergistic effects between variants at more than
one locus or between different loci and factors in the environment, recurrent
spontaneous mutations, or epigenetic defects.” (484).

Contemporary hypotheses are that many individual rare gene variants play a much
larger role in the genetic predisposition to T2D (436), but currently there is little data to support this speculation.

21.2 Etiology

NAFLD is recognized as the leading cause of chronic liver disease in adults and
children (518). Prevalence estimates are
~20% of adult Americans have benign fatty liver without inflammation or damage and
2–5% have NASH (164). Prevalence of NAFLD
in a subpopulation of morbidly obese population ranges from 75–92%. The prevalence
of NAFLD in American children is estimated at 13% (472) and has emerged as the leading cause of chronic liver disease in children
and adolescents in the United States (322).

21.3

Church found lower CRF directly associated with higher NAFLD prevalence in
healthy, nonsmoking, nonalcoholic 33–73-yr-old men (101). A second study reported a low level of habitual physical
activity was associated with higher intrahepatic fat content in healthy, nonalcoholic
males and females ages 19–62 (407).

21.4 Interventions/animals

OLETF rats have a spontaneous mutation that inactivates cholecystokinin
receptor 1 protein to signal satiety. Without the satiety signal, hyperphagia leads to
concurrent obesity and NAFLD between the ages of 5 and 8 wks old, which progress to T2D
(429). Sixteen weeks of voluntary running of
4-wk-old OLETF rats totally prevented the development of NAFLD. Morphologically, livers of
runners had both fewer and smaller lipid droplets compared non-runners.

21.5 Cross-sectional

Habitual leisure-time physical activity, especially anaerobic, may play a
protective role in NAFLD by a reduced rate of abdominal obesity in 24–70-yr old
human subjects (578). Further, only the
association with resistance physical activity remained significant with further adjustment
for BMI. Lower VO₂peak was associated with increasing NAFLD activity and with
disease severity by NASH diagnosis (283).

21.6 Intervention

Maintaining or increasing physical activity provides health benefits for
patients with fatty liver, independent of changes in weight (488). An intensive lifestyle intervention program can successfully
produce a 7%–10% weight reduction and significant improvements in liver chemistry
and histological activity in patients with NASH (420). Targeting weight loss by energy restriction alone or in combination with
exercise training has been shown to reduce NAFLD pathology. In patients with and without
NAFLD, nine months of diet and exercise intervention led to three important outcomes: 1)
reduction in liver fat was approximately twice reduction of VAT; 2) subjects who resolved
NAFLD tended to have higher CRF at prior to the intervention; and 3) VO₂max at
baseline was a predictor of change in liver fat, independently of total- and VAT mass
(264). The study indicated that CRF fitness and
liver fat are related to each other.

21.7 Clinical trials

Long-term RCTs examining the effects of exercise, independent of weight loss,
on NAFLD are lacking.

21.8 Mechanisms

Two approaches were tested. The first approach compared OLETF rats with and
without 16 weeks of voluntary running. OLETF rats that underwent the voluntary running had
3-fold higher rates of hepatic fatty acid oxidation (complete palmitate oxidization to
CO₂); lower TG synthesis [70% and 35% lower protein concentrations of fatty
acid synthase and acetyl-coenzyme A carboxylase (ACC), respectively], and higher oxidative
capacity (35% and 30% higher ACC phosphorylation and cytochrome c concentrations,
respectively), as compared to sedentary OLETF rats (429). The second approach was to suddenly cease 16 wks of daily voluntary
running by OLETF rats. The times for hepatic metabolic adaptations to occur with stoppage
of running were: 2 days (malonyl-CoA protein increased while phospho-acetyl-CoA
carboxylase (ACC) decreased) and 7 days (fatty acid synthase increased and cytochrome
oxidase activity and fatty acid oxidation decreased). Thus, reduced physical activity for
less than 7 days initiates biochemical sequences that leads to NAFLD in OLETF rats (428).

22.2 Known and unidentified risk factors

Of the identified CVD risk factors, modest percentage changes occur with
habitual physical activity. Mora and Lee (349)
indicate that changes in individual risk factors with physical activity are on the order
of 5% for blood lipids, 3 to 5 mm Hg for blood pressure, and 1% for hemoglobin A1c, in
contrast to the large (30% to 50%) reductions seen in CVD risk with physical activity.

Mora and Lee (349) presented an
analysis that showed that almost one-half of risk factors by which physical activity
lowers CVDs are not identified. Subjects were 27,000 women compared by >1500
kcal/wk vs. <200 kcal/wk. Differences in “known” risk factors
explained 59.0% of CVD and 36% of coronary heart disease (CHD) of the inverse association
between higher physical activity levels and fewer CVD events (349). Respective contributions of “known” risk factors
for CVD and CHD were inflammatory/hemostatic (33% and 21%), blood pressure/hypertension
(27% and 15%), traditional lipids (19% and 13%), BMI (10% and 7%), HbA1c/diabetes (9% and
5%), and homocysteine (0.7% and 0.3%) (349). Mora
and Lee (349) caution that some or all of the
aforementioned risk factors have interactions, or are acting in concert, since they add up
to more than 59% for CVD and 36% for CHD. The deduction then is 41% and 64% of mechanisms
by which physical activity primary prevents CVD and CHD, respectively remained to be
identified in 2007.

22.3 Unknown pathophysiological mechanisms

Joyner and Green (261) proposed a
global hypothesis that might include some, or all, the unknown ~40% and ~60%
of unidentified risk factors by which physical activity reduces CVD and CHD, respectively.
Their suggestions for additional risk factor candidates that are improved by habitual
physical activity include:

• Enhanced vagal tone via improved peripheral baroreflex function and
  central nervous system cardiovascular regulation. In populations, this will be
  protective and be seen as improved or maintained heart rate variability.

• Enhanced or maintained endothelial function that will both favor
  vasodilatation and contribute to enhanced peripheral baroreflex function by limiting
  age- or risk factor-associated increases in vascular stiffness.

• Positive interactions between enhanced endothelial function and
  sympathetic outflow that limit the effects of high levels of baseline sympathetic
  outflow on blood pressure (261).

24.2 Etiology

CHD caused ~1 of every 6 deaths (~425,000) in the U.S. in 2006.
In 2010, an estimated 785,000 Americans will have a myocardial infarction, and
approximately 470,000 will have a recurrent attack. The American Heart Association
recognized physical inactivity as a risk factor for CHD and CVD in 1992 (183) and the Surgeon General concluded in 1996 that
“regular physical activity or cardiorespiratory fitness (CRF) decreases the risk of
CVD … and CHD” (531).

24.3 Primary prevention of CHD

Each 1-MET decrease in maximal aerobic exercise capacity increases the adjusted
hazard ratio for death by 12% (279). Using those
individuals with 4 MET maximal aerobic exercise capacity as a reference value of 1.0, the
mortality risk was 38% lower for those who achieved 5.1 to 6.0 METs, mortality risk
declining progressively to 61% for those who achieved >9 METs, regardless of age.
Unfit individuals who improved their fitness status with serial testing had a 35% lower
mortality risk compared with those who remained unfit (279). The NPAGCR reports the literature shows a strong inverse relation between
the amount of habitual physical activity performed and CHD morbidity and mortality (412). Sedentary behavior is a major independent risk
factor for CHD as middle aged or older individuals of both genders who have moderate or
higher amounts of physical activity lower their CHD risk 20% and 30%, respectively,
compared to sedentary (412).

24.4 Mechanisms

Positive effects of chronic exercise on primary prevention of CHD could be
explained by several mechanisms including: increased nitric oxide and antioxidants,
decreased pro-inflammatory cytokine levels in blood by decreasing production from multiple
tissues, and increased regenerative capacity of endothelium expressed by an increased
number of circulating endothelial precursor cells, according to a recent comprehensive
review of the topic (433). However, these
mechanisms do not totally explain the primary prevention of CHD.

25.2 Etiology

PAD affects affects 8–12 million people million in the U.S.
(12%–20% > 65 yrs old have PAD). The NPAGCR concludes that a lack of RCT
exercise studies exists to evaluate the effect of exercise training on preventing PAD
(412). However, the Report does find support
that physical inactivity contributes to accelerated disease progression in those who have
PAD. A recent review concludes that the magnitude of effect from a supervised exercise
program exceeds that achieved with any of the pharmacologic agents available to treat PAD
(388).

25.3 Mechanisms

Mechanisms by which physical activity is primary prevention of PAD are
potentially similar to those given for coronary artery disease.

26.2 Etiology

In the United States, >62% of adults have blood pressures above optimal
levels. The NPAGCR concluded that both aerobic and progressive resistance exercise cause
reduced SBP and DBP in adult humans, although aerobic exercise evidence is stronger (412). The influence of exercise intensity on
post-exercise hypotension occurred in dose-response fashion such that for each 10%
increase in relative VO₂peak, SBP decreased 1.5 mmHg and DBP 0.6 mmHg, thus
showing a dose-response relationship for physical activity intensity and lowering of blood
pressure post exercise (post-exercise hypotension) (156).

26.3 Mechanisms

Eicher et al. (157) suggest potential
mechanistic clues for post-exercise hypotension involve the renin-angiotensin system and
sympathetic nervous systems and include modulation by cardiometabolic, inflammatory, and
hemostatic factors.

27.2 Etiology

Each year ~800,000 individuals experience a new (~610,000) or
recurrent (~185,000) stroke with ~185,000 deaths in the U.S. The most
physically active men and women have a 25% to 30% lower risk for stroke incidence and
mortality. Data on ischemic and hemorrhagic stroke subtypes is quite limited according the
NPAGCR (412). Thirteen of 992 articles satisfied
all eligibility criteria to be included in a meta-analysis. Compared with low physical
activity, moderate physical activity caused an 11% reduction in risk of stroke outcome and
high physical activity a 19% reduction. No significant risk reduction associated with
moderate physical activity in women (137). A
meta-analysis of 33 prospective cohort studies and 10 case-control studies found that
physical activity reduces the relative risk of 0.75 for fatal or non-fatal cerebral
infarction, while the corresponding relative risks for cerebral hemorrhage and stroke of
unspecified type are 0.67 and 0.71, respectively. The reduction of risk was only
statistically significant for men (432).

27.3 Mechanisms

Reimers et al. (432) suggest potential
mechanisms of risk reduction by physical activity on stroke. They include:
antihypertensive effect, beneficial effect on lipid metabolism, and improved endothelial
function (increased endothelial NOS activity and extracellular superoxide dismutase
expression). Other mechanisms that may play a role include a lowered blood viscosity, a
tendency toward platelet aggregation, increased fibrinolysis, reduced plasma fibrinogen,
increased activity of plasma tissue plasminogen activator activity, and higher of
HDL-cholesterol.

28.2 Etiology

After 65 yrs of age, ~10 per 1000 individuals have CHF. Hypertension
precedes 75% of CHF cases. RCTs for prevention of congestive heart failure are not
available. Observational data supports the notion that habitual endurance training is
primary prevention against development of CHF.

28.3 Mechanisms

Levine and co-authors (16) have
concluded that prolonged, sustained endurance training preserves ventricular compliance
with aging and may be an important approach to reduce the probability of heart failure
with aging. Preservation of ventricular compliance with endurance training probably
includes preservation of viscoelastic myocardial properties (absence of increased
ventricular stiffening) and eccentric ventricular hypertrophy (a balanced enlargement of
ventricular mass and dimensions) (16). These
adaptations lead to profoundly improved cardiac performance without apparent change in
contractility, which thus is largely explained by enhanced diastolic filling due to low
stiffness (16). Together these are coupled with
endurance training prevention of arterial stiffening with aging result in preserving
ventricular-vascular coupling of compliance, lowering afterload on the left ventricle
(16).

29.2 Atherogenic Dyslipidemia

31.2 Epidemiology of developing better cognition

Research in exercise and prevention of cognitive decline is relatively new and
moving rapidly. Recent reviews exist (239, 341).

31.3 Mechanisms

As a new frontier in inactivity disease, we chose to provide a more extensive
presentation on the inactivity/exercise mechanisms for cognitive function.

32.2 Etiology

Depression is relatively common affecting 8% of women and 4% of men, having a
lifetime prevalence of 16%, and an annual cost of $83 billion dollars in the United States
(208). Anxiety is prevalent in 10% of the
general public, has many similar symptoms and treatments to depression, but can also
include a wide range of phobias. Both depression and anxiety are associated with increased
risks of many other diseases. Genetic, biological, chemical, hormonal, environmental,
psychological, and social factors all likely intersect to contribute to depression in
women (see (369) or details). Some of these same
factors play a role in men. For anxiety, disorders last at least 6 months and commonly
occur along with other mental or physical illnesses, including alcohol or substance
abuse.

Since 1995, more than 100 population-based observational studies have been
completed. Looking at these studies, the 2008 NPAGCR (412) concluded that active people were nearly 45% less likely to have depressive
symptoms than inactive people. Looking at the 28 prospective cohorts allows for
examination of physical activity levels before depression symptoms occur. Nearly 4 years
of physical inactivity increased risk for depression by about 49% without adjustment for
depression risk factors and by 22% after adjusting for known risk factors such as age,
sex, race, education, income, smoking, alcohol use, and chronic health conditions. In 66
of 67 cohort studies, physical inactivity increased the risk of depression. While many of
the studies relied on self-questionnaires, 8 cohort studies contained clinical diagnosis
of depression symptoms, which reported an increase of 40% in the inactive group. Physical
working capacity was found in depressed male patients but not female patients (350). Morgan et al, who noted that both grip strength
inversely related to hospital length stay and lower in depressed patients (351). In Britain, children under the age of 15 had an
8% reduction in depression symptoms for every hour of exercise completed/week (448). Likewise, lower fitness was found in depressed
male patients but not female patients (350).

Treatment of depression with exercise has also been shown to be effective. In
1979, Greist et al (211) found that running and
time-limited/unlimited psychotherapy reduced depression symptoms similarly. Depressed
patients that participated in exercise had less of a need for medication and less relapse
(18), and adhere to exercise (66%) greater than
medication (40%). An exercise dose consistent with public health recommendations in
1998–2001 (about 12 miles/week of walking for 12 weeks) reduced depressive symptoms
47% from baseline while a lower dose exercise (5 miles/week) group did not respond any
better than the exercise placebo control group (150). Other studies have found a relatively quick effect of exercise involving
10 days of walking for 30 min/day resulted in a decrease in the Hamilton Rating Scale for
Depression and self-assessed intensity of symptoms (139).

The NPAGCR (412, 532) concluded that after examining 4 population-based cross-sectional
studies of over 121,000 Americans that regular physical activity decreases the odds of an
anxiety disorder. Specifically, the national Co-Morbidity study found physical inactivity
increased anxiety disorder by 1.75 times in raw odds and 1.38 times once adjusted for
sociodemographic and illness (204). Australians
reporting no activity were 2.1 times more likely to develop anxiety disorders than those
conducting more than 3 hours of vigorous activity a week (30); similar results were found in inactive young Germans (493). In summary of all random controls trials the Committee Report
concluded a strong effect of a moderate (>25minutes/day) amount of physical
activity (both resistance and aerobic) in reducing anxiety symptoms.

32.3 Mechanisms

33.2 Etiology

Among males >50 yrs old, prevalence of osteoporosis and osteopenia was
6% and 47%, respectively; and in females >50 yrs of age, prevalence was 7% and 40%,
respectively (202).

An actual cause: lack of exercise

Bone is lost from the lumbar spine and femoral neck at the rate of ~1%
per year in sedentary pre-and postmenopausal women (). Inactivity, i.e., reduced gravitational loading and muscle contraction
forces on the skeleton, might contribute to aging-associated bone loss as suggested by
the studies described below. (Exercise: the key to bone health through the life
span)

Peak value for bone mineral density (BMD) in third decade of life contributes to the age
in later life at which threshold for osteoporosis is passed. The higher the peak value for
BMD, the later age in life delays age at which BMD reaches the osteoporosis threshold,
below which osteoporosis is diagnosed. The upper line reflects a population that had high
bone-loading physical activities throughout lifespan with genes predisposing to high bone
strength in contrast to the lower line reflecting low lifetime bone loading with genes
predisposing to low bone strength. Adapted from Rizzoli et al. (438) who modified original figure of Hernandez et al. (235). [Reproduced with permission from (438)].

33.3. Primary prevention

Exercise-training programs prevent or reverse almost 1% of bone loss per year
in the lumbar spine and femoral neck in both pre-and postmenopausal women, who were
presumably sedentary, in a meta-analysis (572).
Mixed loading exercise programs combining jogging with other low-impact loading activity
and programs mixing impact activity with high-magnitude resistance exercise were effective
in reducing postmenopausal bone loss at the hip and spine (329). In a first study, a 3-yr program of combined low-volume,
high-resistance strength training, and high-impact aerobics maintained bone mineral
density at the spine, hip, and calcaneus, but not at the forearm (which lost 3%), in early
post-menopausal women (162). Importantly, the
non-trained group bone mineral density decreased 2–8% over the same 3-yr period.
These findings emphasize the clinical importance of avoiding inactivity in the early
post-menopausal period and the specificity of the lack of impact on critical bones with
high fracture rates in later life (162). In a
second study, site-specific increases in bone density by resistance training happened in
50–70 year-old postmenopausal women and men who exercised ~3–4 days
each week for 1 yr (212). As in the first study,
inactive “control” subjects lost bone mass.

Finally, it is important to emphasize the site-specificity of exercise on bone.
Only bones subject to loading will become stronger as adaptations are site-specific.
Further, not all “weight-bearing” exercise is equivalent when it comes to
increasing bone mass/strength, e.g., comparisons of walking (which does relatively little)
< jogging < jumping.

33.4 Physiological mechanisms

Physical inactivity results in reduced mechanical, both gravitational and
muscle contraction, forces which in turn induces catabolism (resorption) by promoting
osteoclastogenesis with concurrent suppression of both bone formation and
osteoblastogenesis. Dynamic exercise alters the balance between bone formation and
resorption to favor anabolism through osteoblast recruitment and activity.

Mechanical loading of bone occurs in response to compressive forces from
gravity during walking or running, or to in response to muscular forces at the bone
attachments during contractions. Physical activity, alone, only increases strain on bone
by ~0.1%. However, strains of 1–10% are needed to activate bone cells. The
implication, then, is that a mechanism must therefore exist to amplify strains from
physical activity (compressive impact forces from striking surfaces and tensile forces
from contracting skeletal muscle at attachment sites to bone) to exceed the threshold
needed to activate bone cells. Ozcivici et al. (394) conclude that mechanical targeting of the bone marrow stem-cell pool might,
therefore, represent a novel, drug-free means of slowing the age-related decline of the
musculoskeletal system.

33.5 Cellular mechanisms

Current thought for how a bone strain of ~0.1% can be amplified to a
1–10% has been suggested based upon 25 years of publications by Riddle and Donahue
(437). Deformation of skeletal tissues induces
pressurization of interstitial fluid, producing a positive pressure gradient from the
matrix to the haversian cannels, allowing bone cells perceive changes in their mechanical
environment (an amplification mechanism) (437). It
is not completely settled whether the conversion of the physical force of fluid flow to a
biochemical signal is by means of integrin/cytoskeletal transduction of forces or
chemotransport ion channels, or both.

34 2 Etiology

The type and duration of physical activity is a key factor determining whether
exercise is beneficial to joint health or not. Buckwalter wrote,

Participation in sports that cause minimal joint impact and torsional
loading by people with normal joints and neuromuscular function may cause osteophyte
(bony projections that form along joints) formation, but it has minimal, if any,
effect on the risk of osteoarthritis. In contrast, participation in sports that
subject joints to high levels of impact and torsional loading increases the risk of
injury-induced joint degeneration. People with abnormal joint anatomy or alignment,
previous joint injury or surgery, osteoarthritis, joint instability, articular surface
incongruity or dysplasia, disturbances of joint or muscle innervation, or inadequate
muscle strength have increased risk of joint damage during participation in
athletics” (71).

The NPAGCR(412) lists sports/activities
associated with an increased prevalence of incident osteoarthritis as being ballet/modern
dance, orienteering, running, track and field, football (American and Australian rules),
team sports (basketball, soccer, and ice hockey), boxing, weight lifting, wrestling,
tennis, and handball. Confirming the specificity of sport/activity is a longitudinal study
that followed 45 long-distance runners and 53 control subjects from age 58 in 1984 until
2002 with a series of knee radiographs to examine the progression of OA (93). In 2002 20% of runners and 32% of controls had
prevalent OA, with 2.2% and 9.4% being severe. The small size of this study prevented this
difference from reaching statistical significance. The NPAGCR(412) concluded that no evidence presently exists to indicate that
regular moderate to vigorous physical activity of 30–60 minutes for general health
benefits increases the risk of developing osteoarthritis in those without pre-existing
major joint injury.

39.2 Randomized control trials

The NPAGCR (412) states that RCTs have
demonstrated effects of physical activity interventions on cancer risk factors, which
further support a role of physical activity in reducing risk for cancer.

39.3 Mechanisms

40.2 Mechanisms

Neilsen (373) suggests that physical
inactivity might increase breast cancer prevalence by any or the following: higher than
normal BMI, androgens, estrogens, lifetime exposure to estrogen, leptin, insulin, insulin
resistance, TNF-α, IL-6, CRP, and inflammation. Lower levels of steroid hormone
binding protein by physical inactivity have been suggested to increase breast cancer risk.
The mechanisms by which long-term physical activity lowers postmenopausal breast cancer
risk, however, remain unclear (373).

Thompson et al.’s comprehensive review provides extensive literature to support
three hypotheses by which physical inactivity could enhance breast cancer’s prevalence
(509). Hypothesis 1 proposes that
inactivity-induced changes in circulating growth factors and hormones activate the
mTOR-signaling network to increase proliferation and decrease apoptosis in breast cells
while stimulating new blood vessel formation. Hypothesis 2 states that inactivity
increases breast cells responsiveness to physiological stresses, potentially through FoxO,
Sirtuin, and/or adipokine/myokine signaling. Hypothesis 3 says that inactivity increases
glucose and glutamine availability in mammary carcinomas, thereby attenuating breast cell
apoptosis and, thus, increasing the accumulation of breast tumor masses.

42.2 Gestational diabetes mellitus (GDM)

42.3 Preeclampsia

42.4 Excessive weight gain during pregnancy

Gavard and Artal (196) conclude that
prospective clinical trials are needed to establish exercise’s effectiveness for lowering
risk of maternal and fetal comorbidities during pregnancies with excessive weight-gain.
Likewise, Shirazian and Raghavan (471) call for
prospective interventional studies to demonstrate the benefits of weight limitation on
pregnancy outcomes.

42.5 Polycystic ovarian syndrome (PCOS)

42.6 Female athlete triad (Triad)

44.2 Occurrence of low-back pain (LBP)

One-quarter of adults have at least 1 day of low back pain in a 3-month period
and most adults suffer low back pain at some point during their lives (192). Well-trained individuals seem to exhibit higher
pain tolerance to skeletal muscle biopsies and to skin suturing, but to our knowledge
clinical trials testing the hypothesis are not available.

44.3 Clinical trials

Limited evidence exists according to a systemic review of 10 RCTs and 5
non-randomized clinical trials for the overall effectiveness of exercise to prevent LBP in
humans (31).

44.4 Mechanisms

Moderate-intensity aerobic exercise reduced cutaneous and deep tissue
hyperalgesia induced by acidic saline and stimulated neurotrophic factor-3 synthesis in
gastrocnemius but not the soleus muscle (469).
Sharma et al. (469) caution that their results are
limited to animal models and cannot be generalized to chronic pain syndromes in
humans.

45.2 Diverticulitis

45.3 Gallbladder disease

46.2 Etiology

Causes of these respiratory diseases are varied and include behavioral
(smoking), environmental (air pollution and occupational hazards), and suppression of the
immune system.

46.3 Physical inactivity

There are no studies to our knowledge showing that physical inactivity is
associated with an increase in most chronic obstructive pulmonary diseases. With sleep
apnea it is difficult to determine whether physical inactivity is a cause or a result of
the sleep apnea resulting in a viscous cycle of less sleep coupled with less activity
(549). With asthma, an interaction of an
increased environmental pollution with physical activity may be the factor for more recent
studies finding higher asthma in athletes. In two cross-sectional studies, asthma was more
prevalent in swimmers [Odds ratio (OR) = 10], long distance runners (OR = 6), and power
athletes (OR = 3–4), than in less active individuals (232, 233). However, in
contrast, an older study of Finnish athletes that died between 1936 and 1985 showed that
they were no more likely to have asthma and about 50% less likely to die of any pulmonary
disease than non-athletes (291). Our suggestion is
that increased environmental pollution interacting with physical inactivity, rather than
physical activity per se, is a major cause for increased asthma rates in
athletes. The conclusion is consistent with an increase in asthma in the general
population as well in the last several decades.

The sum of data suggests that a “J-shaped” curve exists where
physical inactivity and extreme physical activity increase the risk the greatest for
acquiring upper respiratory tract infections (URTI). While some prospective studies
suggest a greater risk for URTI after a competitive event (381, 382), with increasing
amount of training (229, 408), and higher in faster finishers (487) others show no difference after an event (159) and lower UTRI with 6–7 METs/day of any activity (331). A decreased prevalence of UTI existed in two
intervention studies utilizing lower levels of physical activity [one involving elderly
women (380) and the other mildly obese females
(383)] However, many of these studies contain
methodological problems including, failure to report bouts of physical activity, UTRI are
only reported never verified by virus analysis, higher medical awareness during high
intensity training, contact with other infections (large marathon), stress, nutrition,
supplements, and all the studies are focused on exercise not physical inactivity.

46.4 Mechanisms

There are several excellent reviews that the reader is directed to on
immunosuppression following high levels of physical activity (64, 199, 401). The changes in immune function include low levels of lymphocytes
and lymphocyte function (301), impaired
phagocytosis, impaired neutrophilic function with prolonged exercise (401), neutrophil degranulation (400), reduced monocyte function (302), reduced oxidative burst activity, and potentially lower mucosal
immunoglobulin levels (201).

51.2 Obesity in children and adolescents

Between the mid-1960’s and mid-1980’s, childhood and adolescent obesity ranged
between 4%–6% (). About 25 yrs later
(mid-1980’s to 2008), obesity (>95% BMI percentile for children in the 1960’s) in
children (6–11 yrs) had risen 5-fold from ~4% in 1963–1974 to 20% in
2007–2008, and in adolescents (12–19 yrs) rose 3-fold from
~5%–6% in between 1966–1980 to 18% in 2007–2008 () (386,
387). Even with a more liberal cutoff for
overweight and obesity, 36% of children and 34% of adolescents, rather than 15% were above
the 85^th percentile of the 1960’s (386). Higher BMI during childhood is associated with an increased risk of CHD in
adulthood (20).

Rise in childhood and adolescent obesity in U.S. From 1980’s to 2007–2008 obesity
in 2–5, 6–11, and 12–19-yr-old U.S. females increased
3–5-fold. [Tabular data is converted from graphic from (386, 387)]

51.3 Fasting blood glucose

The number of youth with elevated fasting blood sugar increased 87% from
1999–2000 to 2005–2006 (318). The
children with high fasting blood glucose have 49% lower glucose deposition index (504). More importantly, children with elevated fasting
blood glucose were 3.4 and 2.1 times more likely to develop prediabetes and diabetes,
respectively, as adults (378).

51.4 Prediabetes in children and adolescents

The number of US adolescents with elevated fasting glucose reached
~2,769,000 in 1999–2002 (147).
Within this population, adolescents of Mexican Americans decent are overrepresented (15.3%
of all Mexican American adolescents) relative to non-Hispanic whites (11.3%) and
non-Hispanic black adolescents (7.4%).

51.5 Adult-onset diabetes in our adolescents

Once considered a disease of adults, T2D is becoming increasingly common among
adolescents (376) with ~39,005 U.S.
adolescents having T2D in 1999–2002, and now almost as common as T1D in some
pediatric populations (147). Children in whom T2D
develops are at earlier risks for complications as adults from the disease, including
retinopathy, neuropathy, and cardiovascular and renal disease that may require decades of
treatment (188). Primary prevention of T2D is
essential in children and adolescents (327).

The estimated lifetime risk of developing diabetes for children born in 2000 is
32.8% for males and 38.5% for females, about 10–15% higher than current prevalence
(366). This risk is higher for Hispanics, at
45.4% for males and 52.5% for females. In addition to developing complications,
adolescents diagnosed as having diabetes have large reductions in life expectancy. For
example, Narayan et al. (366) estimated that if
diagnosed with T2D at age 20 yrs, males and females would die 17 and 18 years before
normal, with a reduction of 27 and 30 quality-life adjusted years.

51.6 Metabolic syndrome in adolescents

A major problem with identifying the metabolic syndrome in children and
adolescents is that there are no established criteria in this population (315). According to Cook et al., “In obese
adolescents only, the prevalence rates were 44.2% using the definition of Cook/Ford (113), 26.2% using the adult criteria, 14.1% using the
definition of Caprio, and 12.4% using the definition of Cruz” [As different
modifications of adult criteria for the metabolic syndrome were applied, the specific
criteria can be located in of and of (315)]. Children with BMI and waist circumference values greater than normal values
are at increased risk for the adult metabolic syndrome (500). Morrison et al. (356) contend that
evaluating 5- to 19-year-old children for metabolic syndrome and family history of
diabetes could identify children at increased risk of adult metabolic syndrome and T2D,
allowing prospective primary prevention of these outcomes.

51.7 Atherosclerosis

Atherosclerosis is a consequence of lifetime accumulation of vascular lesions
and plaques. Expectedly, Gillman indicates that the extent of coronary lesions in
adolescents is associated with risk factors including lipids, smoking, blood pressure,
obesity, and hyperglycemia (we add inactivity as a risk factor). Reversibility of
childhood metabolic syndrome is rare, thus leading to high risk of adulthood
cardiovascular disease” (197, 548).

51.8 Non-alcoholic fatty liver disease (NAFLD) in children

The prevalence of NAFLD among normal-weight children is 3–10%, rising up
to 40–70% among obese children (32, 33).

51.9 Cognitive function

Children and adolescents who are physically inactive will develop less
cognitive skills than more active cohorts, as discussed in Cognitive Function section.

51.10 Peak lifetime value determines years to reach clinical disease

Increases in bone mineral mass, skeletal muscle mass, and CRF occur throughout
childhood and adolescence peaking and have their greatest lifetime values in the third
decade of life. Thereafter with aging, their respective values progressively decline to
lower values, at some age reaching a threshold past which an overt clinical condition has
an increased probability of existing (osteoporosis, sarcopenia, and endurance
frailty).

Jacob Brown, Marybeth Brown, Pam Hinton, Arthur Kramer, Thomas Meek, Scott Rector, Mike
Roberts, Ron Terjung, John Thyfault, and Ryan Toedebusch for reviewing comments on specific
sections of the article. Howard Wilson for constructing figures. Supported by anonymous
gifts to FB. The article is dedicated to the continuing legacy of Charles M. Tipton and John
O. Holloszy, who directly or indirectly touched the training of the authors.