All Cause Mortality
Today, the average life expectancy of a person living in the United States is among the lowest in high-income countries. Overall, Japan has the highest life expectancy at birth (82.6 years), while the United
States ranks only 38th (78.2 years) (United Nations
2007). As indicated in Table 4.1
, the highest average life expectancy at birth belongs to men in Iceland (80.2 years) and women in Japan (86.1 years), while in the
United States, life expectancy is 75.6 years for men and 80.8 years for women. (see Table 4.1, p.78)

All Cause Mortality
In 2006, 2.4 million men and women in the United States died (Heron 2010). Table 4.2 shows that the three leading causes of death overall were heart disease, cancer, and cerebrovascular disease, accounting for more than half of all the deaths occurring.
Heart disease and cancer also were the two leading causes of death in men and in women looked at separately. Among men, the third leading cause of death was accidents; in women, it was cerebrovascular disease.

All Cause Mortality
In a review by the 2008 Physical Activity
Guidelines Advisory Committee
(an expert panel appointed by the federal government) of the cumulative evidence from
73 studies published after 1996, the committee reported that 67 studies found a significant
relation between physical activity and all-cause mortality rates.
The median relative risk (RR), comparing most active with least-active subjects, was 0.69 across all studies, indicating a 31% risk reduction with physical activity.

All Cause Mortality
A subsequent meta-analysis of 38 studies published in
2009 reported essentially similar findings, observing that highly active men had a 22%
(RR: 0.78; 95% confidence interval, CI:
0.72-0.84) lower risk of all-cause mortality compared with lowactive men, while highly active women had a 31% lower risk
(RR: 0.69; 95% CI: 0.53-0.90)
Moderately active men and women had 19% and 24% lower risks, respectively, indicative of an inverse dose – response relation.

Physical Activity and All-Cause Mortality

Studies Cited
(mostly prospective and leisure time studies)
US Railroad Workers (occupational study)
Men and Women in Eastern Finland Workers (occupational study)
Harvard Alumni Health Study (leisure time study)
The Seventh Day Adventist Study (leisure time study)
Iowa Women’s Study
(leisure time study)
Cardiovascular Health Study (leisure time study)
Honolulu Heart Program (leisure time study)
The Finnish Twin Study (leisure time study / genetic factors)
Canada Fitness Survey Cohort (leisure time study)
Nurses’ Health Study
(leisure time study)
Health, Aging, and Body Composition Study (leisure time study)
Swedish Twin Registry Study (leisure time study / genetic factors)

Physical Activity and All-Cause Mortality

Studies Cited
(mostly prospective and leisure time studies)
Aerobics Center Longitudinal Study (fitness level study)
Veterans Study (fitness level study)
St. James Women Take Heart Project and Economics of
Noninvasive Diagnosis Study (fitness level study)
Veterans Affairs Health Care System Study (fitness level study)
Harvard Alumni Health Study (changes in fitness level)
Study of Osteoporotic Fractures (changes in fitness level)
Aerobics Center Longitudinal Study (changes in fitness level)
Norwegian Men Study (changes in fitness level)

Physical Activity and All-Cause Mortality

Research in All Cause Mortality is important because it helps us to determine.
Is there a protective factor in occupational positions that require a greater amount of energy expenditure?
Is there a protective factor in expending calories in leisure-time activities?
What are the relative risks of sedentary behavior that is practiced over a long period of time?
What are the protective (negative risk) benefits of engaging in physical activity, and does the level of physical fitness matter?
Does a change in physical fitness increase or decrease risk over time?

Physical Activity and All-Cause Mortality
US Railroad Workers (occupational study)
•
•
•
Men who had worked in the U.S. railroad industry for at least 10 years by 1951, and who were employed in 1954, were classified by level of occupational activity as sedentary (clerks) or active
(switchmen or section men, the most active)
The age-adjusted death rates (per 1000) were 11.7 for clerks,
10.3 for switchmen, and 7.6 for section men.
Although the mortality rate was significantly lower among the most active men, the results should be interpreted cautiously because data on potential confounding factors, such as smoking, body mass index (BMI), blood pressure, and cholesterol, were not available and thus the analysis did not adjust for them

Physical Activity and All-Cause Mortality
Men and Women in Eastern Finland Workers
(occupational study)
•
•
•
Men / women aged 30 to 59 years from two counties in eastern
Finland for seven years.
Questionnaire used measured occupational physical activity.
This information was then dichotomized into low or high physical activity at work.
The relative risk of all-cause mortality associated with low, compared with high, occupational physical activity adjusted for age, BMI, cigarette smoking, diastolic blood pressure, and serum cholesterol was 1.9 (95% CI: 1.5-2.5) in men and 2.2 (95% CI:
1.5-3.3) in women. (Investigators also examined leisure-time physical activity, using a single item on a questionnaire, and observed findings similar to those for occupational activity.)

Physical Activity and All-Cause Mortality
Harvard Alumni Health Study
(leisure time study)
• cohort study of the predictors of chronic disease in men who entered Harvard University as undergraduates between 1916 and 1950.
• 17,000 men, who were aged 35 to 74 years in 1962 or 1966 and who were free of heart disease, for 12 to 16 years until
1978 for mortality, during which 1413 men died.
• assessed physical activity on questionnaires by asking men about the number of flights of stairs climbed daily, the number of city blocks walked daily, and the types of sports and recreational activities they engaged in, and the duration
(hours per week) spent on these activities
• self-reports were then used to estimate energy expenditure in kilocalories per week.
• There was a steady decline in all-cause death rates across weekly energy expenditure categories from 500 kcal/week to through expending ≥2000 kcal/week (Figure 4.2 Next Slide).

Physical Activity and All-Cause Mortality
Harvard Alumni Health Study (leisure time study)
M en were classified as active, expending 2000 kcal/week or more, or inactive, expending
<500 kcal/week. Overall, after adjustment for differences in age, smoking, BMI, blood pressure, and age of parental death, active men could expect to live 2.15 years longer up to age 80, compared with inactive men
Figure 4.2 - Age-adjusted death rates according to physical activity. Harvard
Alumni Health Study

Physical Activity and All-Cause Mortality
Harvard Alumni Health Study
(leisure time study)
• Follow-up research - Harvard alumni were categorized according to groups of energy expenditure from light- (<4
METs), moderate- (4-<6 METs), and vigorous-intensity physical activity greater than 6 METS.
• Investigators concluded there was a benefit of vigorousintensity activities while providing some support for moderate- intensity activities in lowering all-cause mortality rates
• Investigators observed that light-intensity activities were not associated with all-cause mortality rates

Physical Activity and All-Cause Mortality
The Seventh Day Adventist Study
(leisure time study)
• The associations of work and leisure-time physical activity with all-cause and disease-specific mortality rates were examined among nearly 9500 Seventh Day Adventist men aged 30 years or older in 1958
• Questionnaires assessed physical activity
• All-cause death by age 50 was reduced among men with moderate activity, compared to inactive men (RR = 0.61;
95% CI: 0.50-0.74), and for men with heavy activity (RR =
0.66; 95% CI: 0.50-0.87)
• Moderate physical activity remained associated with reduced mortality rates up to age 80; but neither moderate nor heavy activity was significantly associated with lower mortality rates at age 90 (Narrowing gap to genetic lifespan?)

Physical Activity and All-Cause Mortality
Iowa W omen’s Health Study
(leisure time study)
• Investigators observed an inverse relation between physical activity and all-cause mortality rates in women
• Postmenopausal Women, aged 55 to 69 years, were sent a questionnaire on health habits and personal medical history.
• Physical activity was assessed through questions about whether the women participated in regular physical activity, as well as about their participation in moderate- and vigorous-intensity activities.
• After adjusting for possible confounding factors the relative risks of all-cause mortality associated with moderate and high physical activity, compared with low, were 0.77 (95% CI:
0.69-0.86) and 0.68 (0.60-0.77) (p, trend <0.001), respectively. (lower relative risk with higher activity level)

Physical Activity and All-Cause Mortality
Cardiovascular Health Study
(leisure time study)
• The Cardiovascular Health Study is a prospective cohort study designed to determine the extent to which subclinical disease, functional health, and personal characteristics jointly predict mortality among older adults aged ≥65 years
• Physical activity was assessed by interview which evaluated the frequency and duration of participation in 15 leisure-time activities. Using this information, the energy expended in kilocalories per week was estimated, and subjects were categorized into quintiles.
• Men and women who expended >980 to 1890 kcal/week had about a 30% lower risk of mortality during follow-up (RR =
0.72; 95% CI: 0.550.93), and those expending >1890 kcal/week had about one half the risk (RR = 0.56; 95% CI:
0.43-0.75), compared to those expending <68 kcal/week
• There also was a significant inverse dose –response relation across quintiles of energy expenditure

Physical Activity and All-Cause Mortality
Honolulu Heart Program (leisure time study)
• Japanese men living in Hawaii, who were aged 61 to 81 years and who were physically capable, were followed over
12 years
• Men were asked to report the distance they walked per day.
• The relative risks for all-cause mortality associated with walking 1 to 2 miles and 2.1 to 8 miles per day were 0.7
(95% CI: 0.5-0.9) and 0.6 (0.4-0.8), respectively, compared with walking <1 mile/day

Physical Activity and All-Cause Mortality
The Finnish Twin Study (leisure time study / genetic factors)
• The Finnish Twin Study was designed to determine whether genetic factors or family health habits during childhood could explain part of the protective effects of physical activity against premature death.
• A cohort of 7925 healthy men and 7977 healthy women aged
25 to 64 years, who were members of twin pairs
• Responded to questionnaire - Leisure-time physical activity was assessed through questions about the frequency, duration, and intensity of exercise sessions.
• The relative risk for all cause mortality was 0.80 (95% CI:
0.69-0.91) among occasional exercisers and 0.76 (0.59-0.98) among conditioning exercisers, compared with sedentary subjects. (continued on next slide)

Physical Activity and All-Cause Mortality
The Finnish Twin Study (leisure time study / genetic factors )…continued..
• The results suggest that the inverse relation between physical activity and mortality rates is likely to be causal and is unlikely to be due to genetic factors.
• The results would have been more persuasive if only monozygotic twin pairs (identical twins) had been analyzed, since they share genetic information more completely than dizygotic twins (non-identical twins).
• In a study from the Swedish Twin Registry, (see later slide), investigators were able to examine dizygotic and monozygotic twins separately and observed results that support those from the Finnish Twin Study.

Physical Activity and All-Cause Mortality
Canada Fitness Survey Cohort (leisure time study)
• More than 6000 men and 8,000 women, aged 20 to 69 years, who participated in the Canada Fitness Survey
• Subjects were categorized into five groups of energy expended on leisure-time activities. (0 to <0.5, 0.5 to <1.5,
1.5 to <3.0, 3.0 to <0.5, and ≥0.5 kcal · kg−1 · day−1 of energy expended on leisure-time activities)
• No significant risk reduction found in men; significant reduction found in women when accounting for ADL in household chores (ie. Total energy expenditure)
• Women were categorized into quartiles of total energy expenditure; in age-adjusted analyses, higher levels of total physical activity were significantly related to lower mortality rates. (Sitting time increases risk)
• The relative risks for all-cause mortality associated with total activity quartiles (lowest to highest) were 1.0 (referent), 0.66
(95% CI: 0.50-0.87), 0.68 (0.51-0.89), and 0.71 (0.50-0.87), respectively

Physical Activity and All-Cause Mortality
Nurses’ Health Study (leisure time study)
• Female registered nurses 30 to 55 years of age residing in
11 large U.S. states completed a mailed questionnaire regarding their medical history and lifestyle, including physical activity.
• Women were asked to report their usual walking pace outdoors and the number of flights of stairs climbed daily.
Additionally, they were asked about the average time per week spent on each of several specified leisure-time activities
• Lower mortality rates found among women with higher physical activity levels with a tapering of the reduction in risk occurring after about 2 h/week of physical activity.
• Physical inactivity and obesity increased the risk of mortality, with women having no risk factors at lowest risk, those with either risk factor at intermediate risk, and those with both risk factors at highest risk.

Physical Activity and All-Cause Mortality
Health, Aging, and Body Composition Study
(leisure time study)
• The only study to date that has used an objective assessment of physical activity to examine its association with all-cause mortality (302 high functioning adults, aged 70 to 82 years)
• Total energy expenditure was assessed over a two-week period using doubly labeled water
• Subjects were divided into thirds of free-living energy expenditure: <521, 521 to 770, and >770 kcal/day.
• Survival curves indicated that the most active participants survived at the highest rate, the least-active participants at the lowest rate.
• The relative risks for all-cause mortality in the three activity groups as defined earlier were 1.00 (referent), 0.65 (0.33-
1.28), and 0.33 (0.15-0.74), respectively

Physical Activity and All-Cause Mortality
Swedish Twin Registry Study (leisure time study / genetic factors)
• Like the Finnish Twin Study, the aim of the Swedish Twin
Registry Study was to investigate whether genetic factors could explain the inverse relation between physical activity and all-cause mortality rates
• Physical activity was assessed on questionnaires using a single question about average leisure-time physical activity over the past year
• Among 3112 monozygotic twins (1556 pairs), the odds ratio, adjusted for age and smoking, associated with a higher physical activity level was 0.80 (0.65-0.99); that is, even among persons sharing much genetic data in common, the more active twin was 20% less likely to die during follow-up, supporting a causal relation between physical activity and lower all-cause mortality rates

Physical Fitness and All-Cause Mortality
• In the studies already discussed, physical activity was primarily assessed using self-reports, likely resulting in imprecise measures and possible underestimation of the true magnitude of the association between physical activity and all-cause mortality.
• Physical fitness, tends to be objectively measured in epidemiologic studies (e.g., with use of a maximal treadmill exercise test), which may potentially yield stronger associations with all-cause mortality.
Thus, individual fitness studies may show greater reductions in risk when compared to physical activity studies. In general, both types of studies (when examined as aggregate data) show similar relative reduction in risk (approximately 1/3 risk reduction)

Physical Activity and All-Cause Mortality
Aerobics Center Longitudinal Study
(fitness level study)
• The Aerobics Center Longitudinal Study is an observational cohort study of over 25,000 men and
7000 women who received preventive medical examinations at the Cooper Institute in Dallas,
Texas
• Reported on the relationship between maximal treadmill time and mortality rates. Separated groups in quintiles
• Least fit men approx. 3.5x , women 4.5x mortality rate compared to most fit counterparts
• Largest change in risk reduction from lowest group to second lowest fit group
• Regardless of the BMI of subjects, lower fitness (bottom 20% of distribution) was associated with higher all cause mortality rates (Fit vs. Fat ??)

Physical Fitness and All-Cause Mortality


The Aerobics Center Longitudinal Study suggested that higher levels of cardiorespiratory fitness could remove the excess risk of mortality associated with being overweight or obese.
A research review examining the “fit versus fat” hypothesis agreed that findings related to all-cause mortality were mixed - being physically inactive or being overweight or obese is associated with increased risk of premature mortality, of approximately equal magnitude, and that possessing both risk factors increases risk yet further.

Physical Fitness and All-Cause Mortality
Veterans Study (fitness level study)
• Assessed cardiorespiratory fitness and all-cause mortality in men, 6213 consecutive male veterans who were referred for treadmill exercise testing from 1987 onward.
• For each 1-MET higher peak exercise capacity, the ageadjusted relative risk of all-cause mortality was 0.84 (0.79-
0.89).
• Cardiorespiratory fitness was inversely associated with mortality in men both with and without a history of CVD.
• When men were divided into quintiles of fitness, the least-fit quintile had more than four times the risk of dying during follow up compared with the most fit quintile.

Physical Fitness and All-Cause Mortality
St. James Women Take Heart Project and
Economics of Noninvasive Diagnosis Study
(fitness level study)
• A total of 5721 asymptomatic women from the Chicago metropolitan area with mean age 52 years who were participating in the St. James Women Take Heart Project underwent a treadmill test in 1992 to assess cardiorespiratory fitness. Another 4471 women with cardiovascular symptoms and mean age 61 years who were participating in the Economics of Noninvasive Diagnosis
Study underwent a treadmill test between 1990 and 1995.
• Both asymptomatic and symptomatic women had approximately 2x the risk of all cause mortality if their exercise capacity was less than 85% of their age-predicted value

Physical Fitness and All-Cause Mortality
Veterans Affairs Health Care System Study
(fitness level study)
• Investigated the association between cardiorespiratory fitness and all-cause mortality specifically in black men .
• These men received a symptom-limited exercise tolerance test, either for routine evaluation or for evaluation of exerciseinduced
• For each 1-MET increase in peak exercise capacity, the relative risk of dying during follow-up decreased by 18% (RR:
0.82; 95% CI: 0.81-0.83). ischemia.
• Findings are similar for both black and white men.
• Approx 1/3 to ¼ RR in groups with highest peak exercise vs. lowest peak exercise group regardless of race.
• Investigators concluded that the inverse relation between cardiorespiratory fitness and all-cause mortality, previously observed primarily in white subjects, also extended to African
Americans.

Physical Fitness and All-Cause
Mortality
Harvard Alumni Health Study (changes in fitness level)
• This was the first investigation of the association of changes in physical activity with all-cause mortality rates, as well as estimated years of life gained by changing from low to high levels of physical activity
• Men were dichotomized into two groups at each time: not participating in moderateintensity recreational activities (≥4.5
METs), deemed “inactive,” or participating in such activities, deemed “active.”
• Men who changed from being inactive to active had a significant 23% lower all-cause mortality rate
• Men who changed from being active to inactive were as badly off as those who had remained inactive, with a relative risk of 1.15

Physical Fitness and All-Cause
Mortality
Study of Osteoporotic Fractures (changes in fitness level)
• Women aged 65 years and older were enrolled , physical activity was assessed using a modified version of the
Harvard Alumni Health Study questionnaire.
• Women in the lowest 40% of distribution and expending <595 kcal/week were classified as sedentary, and the remaining
60% were classified as active.
• Women who were sedentary at both times or who changed from being active to sedentary were most likely to die during follow-up.
• Those who changed from being sedentary to active had a relative risk for all-cause mortality of 0.52 (95% CI: 0.40-0.69)
• Those who changed from being active to sedentary had a relative risk of 0.92 (0.77-1.09), not significantly different from that of the women who had remained sedentary.

Physical Fitness and All-Cause
Mortality
Aerobics Center Longitudinal Study (changes in fitness level)
• The Aerobics Center Longitudinal Study was the first study to examine the association of changes in physical fitness (men) with all-cause mortality.
• Physical fitness was assessed at baseline and follow-up by time on a treadmill in a maximal exercise protocol, and subjects were classified by investigators as unfit (lowest 20% of distribution of cardiorespiratory fitness for age) or fit (the remaining 80%).
• Men who changed fitness category from unfit to fit had a relative risk of 0.52 . For each minute of increased treadmill time (equivalent to about 1-MET increase in fitness) between the first and second examination, mortality risk was reduced by 7.9%.

Physical Fitness and All-Cause
Mortality
Norwegian Study (changes in fitness level)
• A cohort of 1428 healthy Norwegian men aged 50 to 70 years underwent a clinical examination during 1972 through
1975 that included an exercise test on a bicycle. A second identical examination was given in 1980 through 1982, after which men were followed for mortality through 1994.
• There was a significant relation between increasing physical fitness from examination 1 to examination 2 and lower allcause mortality rates (RR = 0.70; 95% CI: 0.62-0.79) per 1unit standard deviation of increase.

Physical Fitness and All-Cause Mortality -
?
A first step toward determining that the observed association is causal, we have to ensure that the observed associations are valid and not the result of some other factor such as chance, bias, or confounding.
Almost all of the studies discussed in the preceding slides did show statistically significant results, indicating that chance is an unlikely explanation.
Bias is a possibility; however, this chapter has presented findings primarily from prospective cohort studies in which selection bias is less of a possibility since the outcome has not yet occurred at the start of the study
( Read / Review Text : pp.89 for bias and confounding factors
–
1) Loss of follow-up, 2) Reverse causation, 3) Misclassification, and p. 90 for confounding factors)

Physical Fitness and All-Cause Mortality –
?

Only well-designed and well-conducted randomized controlled trials can provide data supportive of a causal relationship.

To date, there have been no data from randomized controlled trials of physical activity and mortality among persons at usual risk. Thus, the available observational data cannot prove that there is a causal relation between higher levels of physical activity (or fitness) and lower mortality rates.

While no randomized clinical trials have been conducted among persons at usual risk, such trials have been conducted among persons who have coronary heart disease.
(continued on next slide)

Physical Fitness and All-Cause Mortality –
?

A meta-analysis of 48 randomized clinical trials involving 8940 patients with myocardial infarction or coronary artery revascularization procedures found an odds ratio for total mortality of 0.80 (95% CI: 0.68-0.93) among patients assigned to cardiac rehabilitation that included exercise as compared with usual care

Additionally, we can apply several criteria to observational epidemiologic data to judge whether the observed associations are likely to be causal
(see chapter 2 slides - Mills Cannons): temporal sequence, strength of association, consistency of results, biological plausibility, and dose response.

Physical Fitness and All-Cause Mortality
–



If an association were causal, the exposure —in this case, physical activity or fitness —would have to precede the outcome, mortality.
All of the studies reviewed in Chapter 4 were prospective cohort studies, in which the appropriate temporal sequence occurred.
Prospective cohort studies have demonstrated consistent associations of higher activity or fitness levels with lower mortality rates

Physical Fitness and All-Cause Mortality
–

The magnitude of the inverse association between physical activity or fitness and all-cause mortality, based on observational epidemiologic studies, is moderate.

In the meta-analysis by Lollgen and colleagues (2009), the most active subjects had a 31% risk reduction compared with the least active.

For physical fitness, the meta-analysis by Kodama and colleagues (2009) showed a risk reduction of 36% for the most fit compared with the least-fit subjects.

The strength of association related to beneficial changes in activity or fitness is comparable to that seen for beneficial changes in other cardiovascular risk factors such as BMI, blood pressure, cholesterol, and smoking.

Physical Fitness and All-Cause Mortality
–

Data on the association of physical activity or fitness with allcause mortality have been consistently reported across many studies, and in men and women.

The studies, conducted at different times using different methodologies and subjects from different countries, have yielded overall similar results, supporting a causal association.

Physical Fitness and All-Cause Mortality
–

The leading causes of death in the United States are heart disease, cancer, and cerebrovascular disease, accounting for more than half of all deaths.

There is an inverse relation between physical activity or fitness and each of these major causes of mortality

Many plausible biological mechanisms exist to explain why physically active or fit men and women should have lower rates of these diseases, and thus all-cause mortality.

Physical Fitness and All-Cause Mortality
–

The available data do support an inverse, curvilinear relationship between physical activity and mortality.

In the 2009 meta-analysis of leisure-time physical activity (for which the most data are available) and all-cause mortality previously discussed, the relative risks for low-active, moderately active, and highly active men were 1.00, 0.81, and 0.78, respectively, and among women, they were 1.00, 0.76, and 0.69, respectively. (Lollgen, Bockenhoff, and Knapp 2009).


In the 2009 meta-analysis of cardiorespiratory fitness and all-cause mortality by Kodama and colleagues, the relative risks for low, intermediate, and high fitness categories were 1.00, 0.68, and 0.64, respectively
Thus, these data indicate a larger magnitude of risk reduction between low and intermediate categories, and a smaller magnitude of risk reduction between intermediate and high categories, indicating a curvilinear dose –response relationship.

Physical Fitness and All-Cause Mortality

The question of “how much” can refer to the total volume of energy expended on physical activity, the intensity, the duration, or the frequency of physical activity.
1.
The equivalent of 2 to 2.5 h per week of moderate-intensity physical activity is sufficient to significantly decrease all-cause mortality rates.
2.
Moderate- or vigorous-intensity physical activity is associated with lower allcause mortality rates
3.
However, it is unclear whether vigorous-intensity physical activity is associated with additional risk reduction in mortality rates, compared with lower-intensity activities, beyond its contribution to the total energy expended. That is, for the same volume of energy expended, does vigorous intensity activity confer additional benefits compared to moderate- or light-intensity activity?
4.
A few studies, providing limited data, suggest that higher intensities of physical activity are associated with additional risk reductions for all-cause mortality beyond their contribution to greater total volume of energy expended
(continued on next slide)

Physical Fitness and All-Cause Mortality
5.
With regard to the duration and frequency of physical activity required, there are no data on these dimensions that are independent of their contributions to the total volume of energy expended.
6.
Stated in another way, it is unknown whether multiple short bouts of physical activity versus a single long bout that expends the same energy are differentially associated with all-cause mortality rates.