J Appl Physiol 111: 1497–1504, 2011.
First published August 11, 2011; doi:10.1152/japplphysiol.00420.2011.
HIGHLIGHTED TOPIC
Review
Physiology and Pathophysiology of Physical Inactivity
Lifetime sedentary living accelerates some aspects of secondary aging
Frank W. Booth,1,2,3,4 Matthew J. Laye,5 and Michael D. Roberts1
Departments of 1Biomedical Sciences, 2Medical Pharmacology and Physiology, and 3Nutrition and Exercise Physiology,
4
Dalton Cardiovascular Institute, University of Missouri, Columbia, Missouri; and 5The Centre of Inflammation and
Metabolism at the Department of Infectious Diseases, Rigshospitalet, Faculty of Health Sciences, University
of Copenhagen, Denmark
Submitted 5 April 2011; accepted in final form 29 July 2011
exercise; mortality; fitness; dysfunction; inactivity
DEFINITIONS OF PRIMARY AND SECONDARY AGING
PRIMARY AGING has been defined by Holloszy (21) as an
inevitable deterioration of cellular structure and function, independent of disease and environment. Maximum life span is
a measure of the maximum amount of time one or more
members of a group has been observed to survive between
birth and death. Slowing of primary aging, as by caloric
restriction, results in an increase in maximal life span in many
species, albeit no therapy has yet been able to slow or reverse
primary aging in humans (15, 18, 21, 24). It should be noted
that no evidence to our knowledge exists for lifetime exercise
increasing maximal life span in rats or other species (22–23, 25).
Secondary aging, as defined by Holloszy, is “caused by
diseases and environmental factors, such as smoking and
exposure to ultraviolet radiation” and are physiological
changes that are not inevitable (21). Secondary aging alters life
expectancy (average length of life in a population), but not
maximum life span. The current review builds from Holloszy
and Kohrt’s statement (24), “A major purpose was to distinguish between the effects of primary aging and those of
exercise deficiency, with particular emphasis on those components of the deterioration in structure and function that are
preventable and reversible consequences of physical inactiv-
Address for reprint requests and other correspondence: F. Booth, Dept. of
Biomedical Sciences, Univ. of Missouri, 1600 East Rollins St., Columbia MO
65203 (e-mail: [email protected]).
http://www.jap.org
ity.” Two themes of this review are that the physical inactivity
contributes more to the secondary aging of some physiological
functions than others and that the reduction in physiological
function due to physical inactivity ultimately reduces the average life expectancy for the lifetime physically inactive population.
PHYSICAL INACTIVITY IS ASSOCIATED WITH SHORTER
AVERAGE LIFE SPAN
Data published by the Centers for Disease Control (CDC; Ref.
17) have determined that “no regular exercise” accounted for 23%
of deaths in the US in 1986 (256,686 of 1.1. million), with these
deaths being attributable to nine chronic diseases. A second CDC
(32) study reported that “poor diet and physical inactivity” were
the second leading cause of preventable deaths from 1980 –2002.
Finally, the US Department of Health and Human Services (52a)
has concluded that “the data very strongly support an inverse
association between lifetime physical activity and all-cause mortality” with lifetime inactive individuals having an ⬃30% higher
risk of dying compared with lifetime active individuals. Thus
multiple epidemiological reports suggest that lifetime physical
inactivity decreases average life expectancy.
VARIABLE EFFECTS OF LACK OF EXERCISE ON
SECONDARY AGING OF FUNCTIONS
We propose a paradigm whereby lifetime physical inactivity
accelerates secondary aging for a variety of physiological func-
8750-7587/11 Copyright © 2011 the American Physiological Society
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Booth FW, Laye MJ, Roberts MD. Lifetime sedentary living accelerates some
aspects of secondary aging. J Appl Physiol 111: 1497–1504, 2011. First published
August 11, 2011; doi:10.1152/japplphysiol.00420.2011.—Lifetime physical inactivity interacts with secondary aging (i.e., aging caused by diseases and environmental factors) in three patterns of response. First, lifetime physical inactivity
confers no apparent effects on a given set of physiological functions. Second,
lifetime physical inactivity accelerates secondary aging (e.g., speeding the reduction in bone mineral density, maximal oxygen consumption, and skeletal muscle
strength and power), but does not alter the primary aging of these systems. Third,
a lifetime of physical activity to the age of ⬃60 –70 yr old totally prevents
decrements in some age-associated risk factors for major chronic diseases, such as
endothelial dysfunction and insulin resistance. The present review provides ample
and compelling evidence that physical inactivity has a large impact in shortening
average life expectancy. In summary, physical inactivity plays a major role in the
secondary aging of many essential physiological functions, and this aging can be
prevented through a lifetime of physical activity.
Review
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LIFETIME INACTIVITY REDUCES FUNCTIONAL CAPACITIES
tions linked to mortality risk. This review is organized into three
categories. The first category is physiological functions in which
lifetime physical inactivity confers no apparent effects on primary
or secondary aging (Table 1). The second category is physiological functions, such as bone mineral density, V̇O2max, and skeletal
muscle strength, in which lifetime physical inactivity accelerates
secondary aging but does not alter the primary aging of these
systems. The third category contains functions, such as endothelial vasodilation and insulin sensitivity that are preventable up
until the age of 60 –70 yr with lifetime physical activity and
protect against premature death due to atherosclerosis or Type 2
diabetes (T2D).
PHYSIOLOGICAL FUNCTIONS IN WHICH LIFETIME
PHYSICAL INACTIVITY CONFERS NO APPARENT EFFECTS
PHYSIOLOGICAL FUNCTIONS IN WHICH LIFETIME
PHYSICAL INACTIVITY ACCELERATES SECONDARY AGING
BUT DOES NOT ALTER THE PRIMARY AGING OF
THESE SYSTEMS
Inactivity effects on bone mineral density. The example of
lifetime peak bone mass, or the highest value of bone mass
during the life span, is influenced by both genetic and
environmental factors. The National Institutes of Health
(NIH; Ref. 34) has stated, “Up to 90 percent of peak bone
mass is acquired by age 18 in girls and by age 20 in boys,
which makes youth the best time to ‘invest’ in one’s bone
health,” and at 30 years of age bones have “reached their
INACTIVITY EFFECTS ON V̇O2max
V̇O2max is also known as maximal aerobic power and is a
biomarker of cardiorespiratory fitness (CRF). To establish the
importance of maintaining as high as possible V̇O2max throughout the life span, the relationships of V̇O2max, lifetime physical
activity/inactivity, and average life expectancy are discussed
next.
Table 1. Approximate percentage contributions of gene-physical interactions contributing to biological aging
Function
References
Physiological functions in which lifetime physical inactivity confers no apparent effects
Maximal heart rate
Ventricular relaxation
Senses (vision, hearing, smell, taste)
Physiological functions in which regular physical inactivity accelerates secondary aging, but does not
alter the primary aging of these systems
Bone mineral density
Maximal aerobic capacity
Maximal skeletal muscle strength/power
Arterial stiffness
Selected mitochondrial proteins
Total prevention of decrements in physiological functions by regular physical activity at least to the
age of ⬃ 60–70 yr of age
Insulin sensitivity
Endothelial function
Ventricular stiffness
Left ventricular mass and stroke volume
34
48
35
49, 53
30
10, 45
13
4
4
Most studies cited use subjects no older than 65–70 ys, with a very few extending to 80 yr of age. Therefore, data are too sparse to extend conclusions to
individuals ⬎80 yr of age.
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Examples of primary aging are the declines in maximal
exercise heart rate and various senses (vision, hearing, smell,
taste). No differences in rates of decline during aging exist
between lifetime physically inactive populations and lifetime
physically active populations on these functions. Lack of an
inactivity effect on some functions during aging can be considered as advantageous to interpretations because it suggests
that lifetime physical activity on other changes in secondary
aging by physical inactivity may affect function through specific mechanisms, i.e., the effects of physical inactivity are not
global on every bodily function.
maximum strength and density, known as peak bone mass.”
Likewise, the NIH has stated that “Given the knowledge that
high peak bone density reduces osteoporosis risk later in
life, it makes sense to pay more attention to those factors
that affect peak bone mass.” Rizzoli et al. (41) indicate that
by the end of bone’s maturation process, ⬃40% of peak
bone mass is influenced by environmental factors (e.g.,
adequate dietary intake of calcium and proteins and vitamin
D, as well as regular weight-bearing physical activity),
whereas genes determine the remaining ⬃60% of peak bone
mass. A key concept presented herein is that inherited genes
interact with environmental factors to produce lifetime peak
bone mass sometime in the third decade of life. Similarly,
lifetime peak V̇O2max and skeletal muscle power are determined by the interaction between genetic and environmental
factors, such as lifetime physical activity. Thus regular
aerobic and resistance exercise during maturation contribute
to higher lifetime peak V̇O2max and peak skeletal muscle
power, respectively. Importantly, increased lifetime peaks
for V̇O2max and skeletal muscle power provide a higher
functional point from which declines due to primary aging
are initiated.
The higher lifetime peak has clinical consequences, delaying
the condition of physical frailty, the quality or state of lacking
skeletal muscle strength or vigor (low V̇O2max). The delay in
the onset of physical frailty increases the likelihood of dying at
a later age. A clinical example is in a study published by
Rockwood et al. (42) in which a higher Frailty Index was
associated with higher mortality and use of health care service
at all ages for the analyzed 14,000 Canadians.
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LIFETIME INACTIVITY REDUCES FUNCTIONAL CAPACITIES
Fig. 2. Relative risk of death is expressed as a function of the maintenance of,
or the change in, cardiorespiratory fitness (CRF) level occurring between two
CRF determinations that were made years apart. Deaths were recorded for 5 or
8 yr following the second test. Results for maintenance or change in CRF are
divided into four groups, including 1) stayed unfit, 2) became fit after being
unfit, 3) became unfit after being fit, and 4) stayed fit. Three sets of data using
this experimental strategy were obtained from two publications. The publications by Blair et al. (7, 31) provided data sets for all-cause mortality (shown in
rectangles) and cardiovascular disease (shown in hexagons) for men. The
publication by Kokkonis and Myers (29) had a male data set (shown in ovals).
Note the essential similarity of data sets. Data were replotted with permission.
not absolutely fixed at the age of 70 – 82 yr. Men who transitioned from a low CRF to a high CRF lowered their mortality
risk by ⬃50%, whereas the subjects who transitioned from a
high CRF to a low CRF increased their mortality risk by ⬃50%
(7, 29, 31). These data are clinically significant because they
show slowing and speeding of mortality is still possible at the
age of 70 yr in men who manage to increase or decrease CRF
(7, 29, 31).
EFFECTS OF PHYSICAL ACTIVITY PATTERNS ON V̇O2max
DURING FIRST, MIDDLE, AND LAST THIRD STAGES OF LIFE
Fig. 1. Relative risk of death is a function of estimated maximal METs. A MET
is an index of aerobic exercise capacity whereby 1 MET unit is resting
metabolic rate and maximal METs are multiples of resting metabolic rate. Risk
of death for each MET unit is replotted from two separate publications. The
first set of data is male and female data replotted for METs ⱖ6 (shown within
ovals) from Fig. 4 of Blair et al. (8) and is rescaled data for relative death risk
relative maximal MET values. The second study of Kokkinos and Myers (28)
replots male data for maximal METs ranging from ⬍2 to ⬎14 (shown in
rectangles). Note in the second study the present of a dose-response relationship from 4 to 9 –10 METs and the lack of dose-response for METs ⬍4 and
⬎9 –10. Also note the essential overlap of data from both studies between 6
and 14 METs. Our suggested lifetime strategy is to minimize risk of death by
maintaining the highest possible maximum METs at each stage of life (see
V̇O2max and mortality for greater details). Data were replotted with permission.
J Appl Physiol • VOL
V̇O2max increases during puberty and is enhanced with regular physical training. Body growth during puberty, independent of physical activity levels, increases V̇O2max with annual
increases ranging from 14 and 22% in V̇O2max until lifetime
maximal values are reached; these being data reported in seven
publications (references to these studies found in Ref. 12). A
monozygotic twin study shows that aerobic training during
puberty increases relative V̇O2max [ml O2·kg lean body mass⫺1
(LBM)·min⫺1] more than in inactive cotwins (12). Briefly, one
cotwin in nine previously untrained monozygotic twin pairs,
aged 11–14 yr, underwent aerobic and anaerobic training for 6
mo while the other did not train. The trained cotwins had 9.0%
greater relative V̇O2max after 6 mo training compared with the
untrained cotwin. Remarkably, the increased absolute V̇O2max
(LO2/min) was similar in trained and untrained cotwins.
Hence, the increases in relative V̇O2max values in the trained vs.
untrained cotwins were attributable to 1) smaller gains in total
body mass in the training cotwins, 2) equivalent gains in lean
body mass in the training cotwins, and 3) relative reductions in
fat mass in the training cotwins (12). A conclusion made by the
authors was that pubertal growth is a critical period during
which higher rates of increase in values for relative V̇O2max
results in a significantly greater adult values (12). The findings
are reminiscent of the concept for environmental enhancements
of peak bone mass prior to 20 yr of age, as discussed earlier.
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V̇O2max and mortality. CRF is inversely related to mortality
as shown by data which we replotted from two different studies
(8, 28) in Fig. 1.
In the first study, Kokkinos and Myers (28) report a doseresponse relationship for V̇O2max and mortality risk that is
somewhat similar to a sigmoidal drug dose-response curve
(Fig. 1). Men with maximal CRF ⬎10 METs (⬃36
ml·kg⫺1·min⫺1 in 70 kg) or maximal METs of ⬍4 METS had
unchanging mortality risks. A MET is an index of aerobic
exercise capacity whereby one MET unit is resting metabolic
rate and maximal METs are multiples of resting metabolic rate.
However, morality risk was three times higher for maximal
METS ⬍4 METS than for ⬍10 maximal METS. A second
study, a decade earlier by Blair et al. (8), similarly observed
that women whose maximal MET values fell from 9 (⬃38
ml·kg⫺1·min⫺1 in 60 kg) to 6 METS had increasing mortality
risks with unchanging risks for ⬎9 METS (Fig. 1).
Modulation of V̇O2max and mortality risk with exercise. It is
our contention that the slowing/accelerating of secondary aging
by lifetime physical activity/inactivity, respectively, can alter
mortality risk and thus life expectancy. In support of this
hypothesis are data clearly demonstrating that improvements in
maximal CRF favorably alter mortality risk in humans up to at
least the age of 70 yr (Fig. 2).
Figure 2 presents data from two independent laboratories.
Blair and colleagues (7, 31) determined mortality risk in 9,777
men, aged 20 – 82 yr old, after the second of two visits where
the interval for the determination of CRF was separated by 5 yr
(Fig. 2). In a second similar study, Kokkinos et al. (29)
examined the association between change in CRF and the
resultant change in mortality for 867 men who had their second
exercise evaluation at least 6 mo (median time 8 yr) after the
initial test at the age of ⬃70 yr old. Importantly, CRF thus is
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similar rate of decline with age in relative V̇O2max as those who
maintained the highest level of aerobic training for competitive
competition (HT in Fig. 3B). However, younger, unfit nonexercising (23– 45 yr old; UT) as one group and older men
(47– 68 yr old; FO in Fig. 3B) that maintained a highly trained
status (FO) as a second group exhibited a greater rate of decline
in their relative V̇O2max levels compared with the group of the
younger aerobically trained men. A potential explanation for
the increased rate of decline in relative V̇O2max in FO is that at
ages ⬎65 yr of age, training volume and intensity declines,
leading to increased rate of decline in relative V̇O2max (39, 51)
and a negative cycling. In the second study by Pollack et al.
(39), 20-yr alterations in relative V̇O2max values were determined. High- and moderate-aerobic training groups had similar
rates of declines in relative V̇O2max with age. In contrast, the
low-intensity group had accelerated secondary aging so that
relative V̇O2max reached the sedentary group at the end of the
20-yr study when the low-intensity group transitioned from
jogging (moderate intensity) to walking [low intensity; Fig.
3C; note walking is often now defined as moderate intensity,
whereas two decades ago walking was low-intensity physical
activity (1)].
CLINICAL CONSEQUENCES OF LIFETIME PHYSICAL
INACTIVITY
Six clinical consequences consequently arising from the
accelerated decline in V̇O2max due to a lifetime of physical
inactivity are 1) increased mortality so death occurs at an
earlier age, as discussed above; 2) younger age for the onset
of physical frailty; 3) fewer years of high quality of life;
4) lowered cardiorespiratory reserve so that stresses, such as
major surgery, are insufficient to maintain homeostasis
within bounds of life; 5) and increased risk of chronic
diseases. Most of the consequences are discussed next.
Fig. 3. Decline in V̇O2max (ml·kg⫺1·min⫺1) as a function of ages for two levels of habitual physical activity. Panels are drawn from three different publications.
One cross-sectional data set from Heath et al. (20) is shown in all three panels. A: the top line is identified as “Heath’s Athletic” and the bottom line is “Heath’s
Sedentary,” representing Masters athletes and untrained men, respectively. Note the slopes of V̇O2max (ml·kg⫺1·min⫺1) vs. age for both lines have similar negative
slopes. Also note the same V̇O2max of ⬃41 ml·kg⫺1·min⫺1 for 80-yr-old Heath’s Athletic (point X at interception of vertical line from 80 yr and Heath’s Athletic
line) and at point Y for the interception of the vertical line from the Heath’s Sedentary line to the age of 37 yr. B: the original longitudinal data, collected over
a mean period of 22 yr was overlaid on the Heath et al. data (20) by Trappe et al. (52), with our slight modification of the identification of the two Heath lines.
The four groups overlaid on the Heath data are highly trained (HT), fitness trained (FT), untrained (UT), and fit older (FT). Note that lines for the more highly
aerobically active groups (HT and FT) tend to parallel to the Heath’s Athletic line over a mean period of 22 yr, whereas the more inactive groups (UT and FO)
have greater negative slopes. C: the original longitudinal data as overlaid on the Heath et al. are shown as published by Pollack et al. (39). Two-subject groups
(high and moderate intensity) tend to parallel the Heath’s Athletic line over a 20-yr period, while the low-intensity group declines to the Heath Sedentary group
line. Slight modifications to the original figure include identification of groups. Figures are reproduced with permission.
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Regular physical activity during puberty will result in a higher
lifetime peak value of relative V̇O2max. Conversely, sedentary
adolescents will have lower lifetime peak relative V̇O2max prior
to the initiation of its primary aging-induced decline in the
third decade of life. Therefore, we posit that an investment in
high aerobic activity during puberty contributes to higher
lifetime peak relative V̇O2max, which, if an adequate amount of
physical activity is maintained throughout a lifetime, would
delay aerobic frailty until an older age.
Primary aging causes the inevitable decline in relative
V̇O2max during the third decade of life, even in the lifetime of
most physically active individuals. At any age between 25 and
75 yr, slopes for the percentage decline in relative V̇O2max are
essentially parallel between lifetime-untrained and lifetimetrained endurance athletes (designated as “Heath sedentary”
and “Heath athletic” in Fig. 3A). Taken together, primary aging
is inevitable for the long-term inescapable decline of relative
V̇O2max after the age of 20 –30 yr old, but secondary aging of
relative V̇O2max can be slowed or accelerated by aerobically
active or sedentary lifestyles, respectively, as discussed earlier.
Other important findings from Fig. 3A are that the difference
of ⬃25–30 ml·kg⫺1·min⫺1 for V̇O2max·kg⫺1·min⫺1 between
lifetime endurance-trained and lifetime sedentary groups is
maintained between the ages of 25 and 65 yr old, as long as
endurance training is continued.
Moderate exercise intensity needed to prevent the accelerated decline in CRF associated with secondary aging. Two
landmark longitudinal studies were published in the mid-1990s
to show the modulatory effects of aerobic activity on relative
V̇O2max’s (V̇O2max·kg BW⫺1·min⫺1) decline. Trappe et al. (52)
in the first publication investigated how differing aerobic
training patterns over ⬃20 yr affected the rate of decline in
relative V̇O2max values. Four groups began the study as highly
trained and possessed a high resting relative V̇O2max. Men
(26 – 49 yr old), who trained for aerobic fitness (FT), had a
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LIFETIME INACTIVITY REDUCES FUNCTIONAL CAPACITIES
INACTIVITY’S ACCELERATION OF FACTORS THAT
CONTRIBUTE TO V̇O2max
Decreases in maximal cardiac output and maximal oxygen
uptake at the skeletal muscle lead to decreased V̇O2max with
aging (reviewed by Tanaka and Seals, Ref. 50). Hagberg et al.
(16) found equal decreases in maximal stroke volume and
maximal arterial-venous O2 difference at skeletal muscle accounted for the 47% lower V̇O2max in older sedentary subjects
compared with age-matched Master athletes. Potential mechanisms for physical inactivity’s lowering of V̇O2max include
increases in left ventricular stiffness (4), arterial stiffness (44),
and losses in left ventricular mass index (40). Together, such
cardiovascular changes may lead to lower maximal cardiac
output with compensatory pathological cardiac right ventricle
hypertrophy. On the other hand, lowering of maximal oxygen
extraction by skeletal muscle may be due to the declines in
skeletal muscle mitochondrial density (26) and mass (discussed
in CLINICAL RELEVANCE OF SKELETAL MUSCLE STRENGTH), which are
accelerated by a lifetime of inactivity.
INTERIM SUMMARY
Lifetime peak V̇O2max per kilogram per minute is set by
aerobic physical activity patterns during puberty and likely
throughout adolescence as well as by inherited genes (Fig. 4).
Primary and secondary aging of V̇O2max become evident in
the third decade of life. Lifetime physical activity levels do not
alter primary aging of relative V̇O2max, although they do delay
the secondary aging of this physiological variable. Maintenance of lifetime endurance activity intensities greater than or
equal to moderate intensities will retain relative V̇O2max values
above sedentary levels so that reaching the aerobic frailty
threshold is delayed by decades (Fig. 3A and Fig. 4).
TWO STRATEGIES TO DELAY MORTALITY
One strategy to delay mortality is to obtain as high a lifetime
peak maximal V̇O2max as possible at the age of 20 yr through
being aerobically active as an adolescent, and a second is to
maintain a lifetime of aerobic activity as long as possible to
delay the age at which maximal METs fall below 9 –10 and 4,
which are the thresholds for increases in mortality and aerobic
frailty, respectively. The latter strategy would shift the frailty
prevalence curve toward older ages and thus increase quality of
life years. This proposed strategy is illustrated in Fig. 1B in
Rockwood et al. (42) where frailty prevalence has an upward
exponential curve that gradually begins about the age of 40 yr
with an upward inflection point at ⬃65 yr of age and reaches
⬃50% of the remaining population at the age of 90 yr.
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Fig. 4. V̇O2max·kg⫺1·min⫺1 is shown as a function age for hypothesized
interactions between inherited genes and lifetime aerobic activity. V̇O2max is
shown to rise from 10 to 20 yr of age, rising less rapidly in sedentary (SED)
than aerobically active (ACT). Negative slopes of lines after the age of 20 yr
indicate the primary aging for those maintaining an unchanged level of
physical activity throughout their life span. The influence of inherited genes is
schematically drawn for extreme examples for the human with the lowest
inherited V̇O2max genetic potential (Low CRF) and from the human who
inherited the highest V̇O2max genetic potential (High CRF). Arrows A and B
show secondary aging effects, where V̇O2max·kg⫺1·min⫺1 changes to a lower or
higher family of declining V̇O2max slopes, depending on whether physical
activity is chronically decreased (A) or increased (B).
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A lifetime of endurance training theoretically slows secondary aging of relative V̇O2max by three or four decades if
moderate-intensity levels of physical activity were to be constantly maintained until the age of 65–70 yr [Fig. 3, A–C, and
other published figures (20, 38 –39, 48, 52)]. An alternative
means of stating the concept is that the value of V̇O2max of a
lifetime sedentary 30-yr-old individual has already secondarily
aged to the V̇O2max value found in a 60- to 70-yr-old lifetime
endurance-trained individual. Sedentary individuals thus reach
aerobic physical frailty (ⱕ18 ml·kg⫺1·min⫺1) at an earlier age
relative to lifetime physically active individuals. The delay in
reaching aerobic physical frailty is associated with a decreased
incidence of assisted care living or nursing home residence (5).
Holloszy (21) has suitably commented, “Whether an individual
who lives to 95 years spends the last 10 years in bed in a
nursing home or leads an active, enjoyable life is obviously of
key importance.” The aforementioned quotation supports the
notion that a higher relative V̇O2max in later life is associated
with higher quality of life based on the ability to be more
regularly physically active.
In addition to directly shortening average life expectancy
and causing aerobic frailty earlier in life, a low V̇O2max means
that if functional reserve falls below a threshold value needed
to survive a moderate stress level, homeostasis may not be
maintained and death may ensue. In direct support of this
notion, Struthers et al. (47) stated “Major surgery produces a
systemic inflammatory response associated with a marked
increase in oxygen consumption in the immediate postoperative period. In patients with poor cardiorespiratory reserve, the
inability to meet this increased demand may lead to avoidable
morbidity and mortality.”
Studies show that CRF is not inevitably fixed up to 70 – 82
yr of age. CRF can be increased by becoming more aerobically
fit with conversion from sedentary to chronic aerobic types of
physical activity and that the decline of CRF with primary
aging can be sped more rapidly by discontinuation of physical
activities.
Low values of maximal METs (absolute V̇O2max) increases
prevalence of one or multiple chronic diseases, which themselves shorten life expectancy (9, 52a). For example, diagnosis
of T2D at the age of 30 yr is associated with 14.5/16.5
life-years lost and 23.1/26.1 quality-adjusted life-years lost
among men/women, respectively (33).
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CLINICAL RELEVANCE OF SKELETAL MUSCLE STRENGTH
AND POWER AS WELL AS INFLUENCES OF LIFETIME
ACTIVITY ON THESE VARIABLES
CLINICAL SIGNIFICANCE OF V̇O2max AND SKELETAL
MUSCLE STRENGTH, ALONE AND TOGETHER, ON LIFE
EXPECTANCY
Vanhoutte (54) stated, “Endothelial dysfunction is probably
a fundamental initial step in the progression of atherosclerosis.” Likewise it is our contention that an initial step toward
T2D is the loss of insulin sensitivity, which is extremely
sensitive to changes in physical activity. Key points to be made
are 1) only days of inactivity are required for normal endothelial function and insulin sensitivity to enter a dysfunctional
state, 2) lifelong physical activity, at least to the ages of
⬃60 –70 yr old, will maintain normal endothelial function and
insulin sensitivity in individuals living healthy lifestyles, and
3) lifelong physical inactivity increases mortality by increasing
atherosclerosis and T2D.
ENDOTHELIAL DYSFUNCTION ASSOCIATION WITH AGING
AND INACTIVITY
Aerobically trained men (50 –76 yrs old) do not demonstrate
an age-related decline in endothelium-dependent vasodilation
(EDD) as their values are similar to younger (22–35 yr old)
men (13). Likewise, the addition of aerobic exercise restores
the loss of EDD in 56-yr-old previously sedentary men (13).
Maintenance of CRF or the adoption of a 24-wk endurancetraining program prevents or reverses the decline in flowmediated dilation in 59-yr-old women (6). However, a shorter
8-wk program of essentially daily brisk walking did not improve mean brachial artery flow-mediated dilation in previously sedentary, 55- to 79-yr-old post-menopausal women
(37), suggesting that longer-term training may be necessary to
reverse endothelial function in this subject group.
The clinical significance of inactivity-induced endothelial
dysfunction is that when coronary risk factors are present, the
endothelium may adopt a phenotype that facilitates inflammation, thrombosis, vasoconstriction, and atherosclerotic lesion
formation (55). Lack of exercise precedes coronary risk factors
(9). Importantly, Vita and Keaney (55) conclude that a maladaptive endothelial phenotype occurs prior to the development of atherosclerosis. Thus shorter-term physical inactivity
increases endothelial dysfunction, which speeds secondary
aging through the initiation of the chronic disease atherosclerosis.
LOSS OF INSULIN SENSITIVITY WITH AGING
AND INACTIVITY
Both low V̇O2max and low handgrip strength independently
predict an increased risk of impending death. Together, low
values of these two variables synergistically increase mortality
risk more than either alone. For instance, men that had both
low CRF and muscle strength had death rates that were 60%
higher than the death rate in the group of high cardiorespiratory
fit men with the highest levels of muscular strength (43). Fleg
and Lakatta (14) suggest that a large portion of the ageJ Appl Physiol • VOL
TOTAL PREVENTION OF DECREMENTS IN PHYSIOLOGICAL
FUNCTIONS, SUCH AS INSULIN RESISTANCE AND
ENDOTHELIAL DYSFUNCTION, BY LIFETIME PHYSICAL
ACTIVITY AT LEAST TO THE AGE OF ⬃60 –70 YR OF AGE
Seals et al. (45) in 1984 observed that 1) glucose tolerance
and insulin sensitivity were similar in 60-yr-old Masters athletes and 26-yr-old athletes who had virtually identical plasma
glucose and insulin levels during glucose tolerance tests that
were 15–18 h after their last exercise bout and 2) the Masters
athletes cleared a glucose load as rapidly as the young, untrained subjects with 50% lower plasma insulin levels. The
authors concluded that a deterioration of glucose tolerance and
insulin sensitivity is not an inevitable process during aging and
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Skeletal muscle power is the rate at which a group of
muscles can shorten against a load (27). Skeletal muscle
strength is the capability for a group of muscles to generate a
maximal amount of force, and whole body strength is typically
represented by grip-strength measurements in epidemiological
studies (46). It is important to distinguish these two variables
due to the fact that runners or cyclists may possess a high
power-generating potential with his/her legs but may be relatively weaker (or possess less strength) compared with a
conventional weightlifter. There are clinical consequences of
possessing low skeletal muscle strength. For instance strength
is inversely and independently associated with death from all
causes and from cancer in 20- to 80-yr-old men, even after
adjusting for CRF and other potential confounders (see Ref.
43). A meta-analysis of 53,476 older individuals determined
that at least one of the specified measures of skeletal muscle
strength or power (grip strength, walking speed, or chair rises)
predicted all-cause mortality (11). Mortality risk increased by
67% from highest to lowest quartiles of grip strengths after
adjustments for age, sex, and body size in 53,000 subjects (11).
Likewise, mortality risk increased by 187% from highest to
lowest quartiles of walking speed after similar covariate adjustments in 14,000 subjects (11).
Only one study, to our knowledge, has examined peak
skeletal muscle power using a cross-sectional design. Master
level weightlifters were compared with sedentary age-matched
individuals (35). Outcomes of the study were reminiscent of
lifetime effects of physical activity on relative V̇O2max in that
lifetime peak power in sedentary humans was ⬃35% lower
than Master level weightlifters at age 40 yr. Interestingly, the
rate of decline in absolute peak power was greater for Master
level weightlifters relative to sedentary individuals, this being
a similar finding with relative V̇O2max in endurance-trained
subjects vs. sedentary counterparts (20, 38, 48). Nonetheless,
the peak skeletal muscle power of 40-yr-old lifetime sedentary individual is that of a 69-yr-old Master weightlifter.
Thus the secondary aging of peak power is apparently sped
in lifetime sedentary individuals. To date, however, the loss
of muscle fibers past the age of 50 yr has not been shown to
be reversible by resistance training (21), which suggests that
the primary aging of skeletal muscle mass (and presumably
strength and power) is not completely preventable. In summary, the literature seems to suggest that older individuals with
greater skeletal muscle strength and/or power exhibit a dampened all-cause mortality risk.
associated decline in relative V̇O2max in non-endurance-trained
individuals is likely due to a loss of skeletal muscle mass. Their
contention suggests that primary aging of relative V̇O2max is in
part linked to sarcopenia.
Review
LIFETIME INACTIVITY REDUCES FUNCTIONAL CAPACITIES
SUMMARY
Lack of lifetime physical activity plays a major role for
initiators of cardiometabolic diseases, including insulin resistance and endothelial dysfunction. Although not discussed here
due to length restrictions, inactivity causes numerous other
specific dysfunctions, pathologies, and chronic diseases, which
are discussed in more detail by us elsewhere.
CONCLUSION
Although death is inevitable and partially explained by
inherited genes that produce primary aging, healthy aging is
within the discretion of each individual. Sedentary lifestyles
accelerate the secondary aging by increasing risks of chronic
diseases, decreasing quality-adjusted years of life, and reducing the average life expectancy. However, studies examining
the lack of exercise as a major contributor to the secondary
aging of various physiological systems remain warranted. The
present review provides ample and compelling evidence proving that increasing lifetime physical activity can have a large
impact at lengthening the average life expectancy.
ACKNOWLEDGMENTS
Thanks to Joe Company, Jaume Padilla, and Grant Simmons for helpful
comments on the review. Howard Wilson and Donald Connor assisted in figure
production.
GRANTS
This work was supported by anonymous gifts (to F. Booth). Funds from
Scivation were received during the course of this review (to F. Booth and M.
Roberts).
J Appl Physiol • VOL
DISCLOSURES
Scivation is providing M. Roberts’ salary to study nutraceuticals on skeletal
muscle mass.
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