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Published 5 March 2009, doi:10.1136/bmj.b688
Cite this as: BMJ 2009;338:b688
Liisa Byberg, researcher 1, Håkan Melhus, professor 2, Rolf Gedeborg, researcher 3, Johan Sundström, researcher 4, Anders Ahlbom, professor 5, Björn Zethelius, researcher 6, Lars G Berglund, statistician 7, Alicja Wolk, professor 8, Karl Michaëlsson, senior lecturer 1
1 Department of Surgical Sciences, Section of Orthopaedics, and Uppsala Clinical Research Centre, Uppsala University, SE-75185 Uppsala, Sweden, 2 Department of Medical Sciences, Section of Clinical Pharmacology, Uppsala University, Uppsala, 3 Department of Surgical Sciences, Section of Anaesthesiology and Intensive Care, and Uppsala Clinical Research Centre, Uppsala University, Uppsala, 4 Department of Medical Sciences, Section of Acute and Internal Medicine, Uppsala University, Uppsala, 5 Department of Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, SE-17177 Stockholm, Sweden, 6 Department of Public Health and Caring Sciences, Section of Geriatrics, Uppsala University, Uppsala, 7 Uppsala Clinical Research Centre, Uppsala University, Uppsala, 8 Department of Nutritional Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Stockholm
Correspondence to: L Byberg liisa.byberg{at}surgsci.uu.se
Design Population based cohort study with follow-up over 35 years.
Setting Municipality of Uppsala, Sweden.
Participants 2205 men aged 50 in 1970-3 who were re-examined at ages 60, 70, 77, and 82 years.
Main outcome measure Total (all cause) mortality.
Results The absolute mortality rate was 27.1, 23.6, and 18.4 per 1000 person years in the groups with low, medium, and high physical activity, respectively. The relative rate reduction attributable to high physical activity was 32% for low and 22% for medium physical activity. Men who increased their physical activity level between the ages of 50 and 60 continued to have a higher mortality rate during the first five years of follow-up (adjusted hazard ratio 2.64, 95% confidence interval 1.32 to 5.27, compared with unchanged high physical activity). After 10 years of follow-up their increased physical activity was associated with reduced mortality to the level of men with unchanged high physical activity (1.10, 0.87 to 1.38). The reduction in mortality associated with increased physical activity (0.51, 0.26 to 0.97, compared with unchanged low physical activity) was similar to that associated with smoking cessation (0.64, 0.53 to 0.78, compared with continued smoking).
Conclusions Increased physical activity in middle age is eventually followed by a reduction in mortality to the same level as seen among men with constantly high physical activity. This reduction is comparable with that associated with smoking cessation.
In prospective studies that have examined changes in leisure time physical activity level in relation to mortality,9 10 11 12 13 14 15 few have considered the possibility of additional changes in physical activity behaviours during follow-up.13 14 15 Furthermore, the impact on mortality in relation to age at the time of the activity changes and the time elapsed since the changes occurred have not been established.
We investigated the impact of physical activity on total (all cause) mortality from middle to old age, taking into account changes in activity during follow-up. We studied this in a population based cohort of men aged 50 at baseline who were followed up for more than 35 years and investigated on five occasions. We also compared the effect of an increased level of physical activity on the mortality rate with that achieved by cessation of smoking.
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We considered the two highest activity categories, questions 3 and 4, together as only 5% of the participants reported hard physical training. Participants answering yes to question 1 were categorised as low activity; 2 as medium; and 3 and 4 as high. The questionnaire has been used and validated in other studies and has also been shown to have a high reliability over time.17 18 19 20
Changes in the physical activity level between the first and second survey were considered in four categories: unchanged low (low or medium activity at both surveys), unchanged high (high activity at both surveys), decreased (high in survey 1, low or medium in survey 2), and increased (low or medium in survey 1, high in survey 2).
Based on job titles retrieved from the national censuses from 1970 and 1980, we categorised occupational physical activity as sedentary, light, medium, high, unknown, and none (unemployed).21
Height and weight were measured at each survey and body mass index (BMI, weight (kg)/height (m)2) calculated. Obesity was defined as BMI
30. Systolic and diastolic blood pressure in the supine position was measured by standard procedures. Information on antihypertensive medication was retrieved by questionnaire, as was information on smoking habits. Smoking status was categorised as current smoker, former smoker, or never smoker. Changes in smoking status between two surveys were categorised as continued smoking, smoking cessation, and never smoking. Total fasting serum cholesterol concentration was measured with enzymatic techniques. The presence or absence of diabetes mellitus was determined at each survey according to the guidelines current at that time. Information on perceived health (classified as not good or good) and alcohol use at surveys 2 and 4 (classified according to the Michigan alcoholism screening test as abstainer, normal, suspected alcohol dependence22) was retrieved from the questionnaires. The census from 1970 provided information on educational level. Socioeconomic group at survey 1 was interview based and categorised as low, medium, and high.23 By linkage to the national hospital discharge register, we collected information on any musculoskeletal, neurological, or psychiatric disorder. The prevalence of each of these disorders and of diabetes was <1.2% at baseline.
Using the individual 10 digit personal identification number given to all Swedish citizens,24 we traced the entire cohort in the continuously updated Swedish National Population Register until the date of death or 31 December 2006. Our main outcome was total (all cause) mortality. There was no loss to follow-up.
Statistical analyses
We used Coxs proportional hazards regression with delayed entry to estimate hazard ratios with 95% confidence intervals and survival curves for the association between physical activity and mortality. The values of physical activity, as well as covariate information, were updated by data from each subsequent visit. The last observed value carried forward technique was used for missing data. The non-response frequencies for physical activity were 130, 89, 68, and 0 at surveys 2-5, respectively. Table 1 shows details of the sensitivity analyses.
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We assessed the relative excess risk due to interaction, a measure of biological interaction,25 from a Coxs proportional hazards model as described previously.26 27
Remaining life expectancy was calculated as the area under the survival curve using the trapezoidal rule approximation for the integral between the start of the study and the end of follow-up. We calculated differences in remaining life expectancy between exposure levels with 95% confidence intervals for the differences using the bootstrap centile method with 10 000 replications.
In analyses of changes in physical activity level between the ages of 50 and 60, we partitioned follow-up time from date of examination in the second survey into five year intervals to account for non-proportional hazards.
Statistical analyses were performed with Stata/SE 10.1 (StataCorp, College Station, TX), SAS 9.1 (SAS Institute, Cary, NC, USA), and R (R Foundation for Statistical Computing, Vienna, Austria, 2007).
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We converted the differences in death rates into differences in remaining life expectancies from age 50. Men who reported high levels of physical activity were expected to live 3.8 (95% confidence interval 2.7 to 4.8) years longer than sedentary men and 1.8 (1.3 to 2.2) years longer than men who reported medium levels of physical activity. After adjustment for potential confounding variables the corresponding remaining life expectancies were 2.3 (1.3 to 3.3) and 1.1 (0.6 to 1.6) years, respectively.
Changes in physical activity level
We investigated the influence on mortality of changes in physical activity between the ages of 50 and 60 in the 1759 men who participated in the first and second survey. From the date of examination in survey 2, we studied 34 020 person years and 998 men died. At the age of 60 about 27% (n=474) still reported high physical activity, 11% (n=194) had increased and 24% (n=414) had reduced levels, and 38% (n=677) reported unchanged low activity. Men who changed their physical activity level could not be distinguished from men with unchanged activity based on baseline clinical characteristics (not shown).
Changes in physical activity between the ages of 50 and 60 were associated with mortality (fig 3)
. After 10 years of follow-up the mortality rate did not differ between men who had increased their physical activity and men who were at an unchanged high level (table 4).
This is also illustrated by the parallel failure curves after about age 70 (fig 3).
During the first five years of follow-up, however, the mortality rate was 2.6 times higher in men who had increased their level of physical activity compared with men whose physical activity was high but unchanged (table 3).
Adjustment for smoking, obesity, and other covariates attenuated the estimates but did not change the interpretation of the results.
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We studied men who increased their physical activity level in more detail. The mortality rate after more than 10 years of follow-up was halved in men who had increased their physical activity to a high level both from a medium (adjusted hazard ratio 0.58, 0.39 to 0.87) and a low (0.51, 0.26 to 0.97) level. There was no evident reduction in mortality rate among men who increased their physical activity from low to medium (0.81, 0.51 to 1.31). As a comparison, smoking cessation was associated with a 40% lower mortality rate after more than 10 years of follow-up compared with current smoking (0.64, 0.53 to 0.78). Men who had never smoked had a 60% lower mortality rate than current smokers (0.42, 0.33 to 0.52).
There was no evidence of biological interaction between increased physical activity and smoking cessation in their effects on mortality; the relative excess risk due to interaction was –0.40 (–1.30 to 0.50).
Strengths and weaknesses of the study
The main strengths of our study include the population based design, the long follow-up from a time before the men reached ages with a high mortality rate, the repeated measurements, and the objective and complete information on mortality. Our analyses also took into account changes over time in potential confounders including smoking, obesity, self perceived health, and morbidity and in classic risk factors for mortality including hypertension and total cholesterol concentration. We also adjusted our estimates for socioeconomic group and educational level.
The main limitation of our study is its restriction to men and the crude assessment of physical activity by questionnaire, with risk of misclassification possibly leading to underestimation of the results.28 There is, however, no ideal test to measure physical activity,29 either by questionnaire or by more objective assessments. We used a questionnaire created in collaboration with the Swedish National Institute of Public Health that estimates physical activity over the life cycle.30 Although our categories indexing physical activity should be regarded as reflecting common perceptions or patterns of physical activity rather than precise measures of levels, the levels estimated from these four simple questions are positively associated with physiological measurements of fitness,16 17 skeletal muscle capillary density,31 and pedometer results,32 indicating that these levels do represent physical activity. Simple questionnaires are well suited for the study of changed behaviour in large epidemiological studies,28 and the repetition of identical questions at each survey is one of the main strengths of our study.
The last observed value carried forward technique could introduce bias, despite being the preferred imputation method.33 As results from sensitivity analysis were consistent with the main results, it seems unlikely that this imputation method introduced bias. In our multivariable models, the adjustment for variables that can be regarded not only as confounders but also as intermediates on the causal pathway—such as perceived health, body weight, and diabetes—might also have conservatively biased our estimates.
Strengths and weaknesses in relation to other studies
Many previous studies have used baseline data and changes in activity to examine whether physical activity influences mortality, without applying a time dependent approach in their analyses.9 10 11 12 34 35 Our associations between baseline data on physical activity and mortality rates were generally weaker than when we took into account changes within individuals in the level of physical activity during follow-up, further emphasising the importance of using time updated variables when behaviour such as physical activity is studied in relation to clinical outcomes.36 Time dependent life table analysis for estimation of remaining life expectancy among 50 year old men in the Framingham Heart Study showed 3.9-4.1 years longer life expectancy for men reporting high physical activity and 1.6-1.8 years longer life expectancy for men reporting medium physical activity, compared with the sedentary group.13 14 We obtained estimates of similar magnitude.
Total mortality was substantially influenced by the length of time since the change in physical activity took place. One recent study that used time dependent analysis to investigate change in physical activity in relation to mortality in men and women aged 19 to over 90 years found an association between change in physical activity and mortality in men under the age of 70.15 In that study, however, the direction of change, the age when the change in physical activity occurred, and the time that had elapsed since the change remained unclear.
A change in physical activity in the lower activity range might reflect a change in sedentary behaviour rather than in actual physical activity. Recent research showed that sedentary behaviour and physical activity were independently associated with obesity.37 Future research should aim to separate these two effects.
As measurement of physical activity is crude and difficult to compare between studies, we wanted to compare the effect of physical activity on mortality with the effect of smoking. Self reported smoking has a high validity,38 and smoking is probably the most well established modifiable behavioural risk factor for premature death.39 The graded inverse association between physical activity level and mortality was independent of and present in each category of smoking status. The impact of increased physical activity on mortality was on par with the effect of smoking cessation. A recent study in women found a comparable reduction in mortality after smoking cessation.40
Our observational results might differ from those from meta-analyses of clinical trials because such trials tend to be conducted in high risk populations and are designed so that the exposure has a low measurement error and that the probability of confounding is reduced. The effect we observed after increased physical activity, however, is larger than the effect of a 1 mmol/l reduction in cholesterol concentration (18% reduction of total mortality)41 and the effect of treatment with any antihypertensive drug (10% reduction of total mortality).42
Possible explanations
We previously showed that an increase in the level of physical activity in the present cohort was associated with beneficial changes in the metabolic profile, including a decrease in body weight and in blood concentrations of insulin, proinsulin, glucose, and lipids.43 An improved metabolic profile reduces the prevalence of metabolic syndrome, obesity, and cardiovascular disease. This is one suggested pathway whereby physical activity is thought to reduce mortality.13 34 The effect of hypertension and high total cholesterol concentration on mortality is well established, but in our analysis the association between physical activity and mortality was independent of these. Other suggested mechanisms for the effect of physical activity on mortality include changes in inflammatory and hormonal responses and gut mobility44 and effects on the nervous systems, which influence neuromuscular and brain function.45 All these mechanisms might be important for the progression of many diseases and general wellbeing. In older people physical activity is also important for maintaining muscle strength, postural balance,46 47 functional independence, and health related quality of life.48 The effect of physical activity on the risk of premature death might be modulated by genetic differences.49 Recent results in Swedish twins, however, argue against genetics as a cause of the association between physical activity and mortality.50 In addition, inactive twins have been reported to have shorter telomere lengths corresponding to higher biological age by up to 10 years compared with their more active co-twin.51
Implications, unanswered questions, and future research
Within the first five years after the investigation at the age of 60 we observed an increased risk associated with increased physical activity compared with men with unchanged high activity. Given the small numbers of deaths we are reluctant to place a strong emphasis on this increased risk, especially as mortality was not higher than mortality in men who continued to be sedentary. Although there might not be a true increase in mortality soon after increased physical activity, there is nonetheless no immediate benefit. This has also been observed in a community based cluster randomised trial in older people in whom participation in an exercise programme had no effect on mortality during the two year follow-up.52 There was, however, a much larger than expected improvement in health related quality of life after the intervention, suggesting that increased activity might have early health benefits that are collectively too small to have an impact on total mortality.
Our results could have important implications in the planning of clinical trials as these would need to be long enough to extend beyond the period of no benefit and to take into consideration the ethical implications of a possible increase in short term risk. Different follow-up times might also yield different results in observational studies.
It is difficult to quantify the least amount of physical activity needed for a beneficial effect on mortality in our study. Our dose-response relations suggest that the more activity the better, but on the basis of our data it is not possible to determine whether the recommended minimum amount of physical activity was achieved or not.5 6 7
We could not identify any characteristics distinguishing those who died shortly after taking up physical activity. A healthy survivor effect cannot be excluded as survival until age 60 was necessary for this analysis. Further research should investigate whether and to what extent increased physical activity affects mortality in the period soon after the change. In addition, the effects in other age groups and in women need to be studied. Mechanisms and reasons for an active choice to change physical activity are not fully understood.
Conclusion
In conclusion, we have shown a graded reduction in total mortality risk with increasing physical activity level in men. Increased physical activity in middle age increases longevity after an induction period of up to 10 years of no benefit. An increase in physical activity has the same impact on lowering mortality rate in the long term as smoking cessation. Thus, efforts for promotion of physical activity, even among middle aged and older men, are important.
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Cite this as: BMJ 2009;338:b688
Funding: The study was funded by the Swedish Research Council. The funder had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of data; the writing of the manuscript; or the decision to submit the manuscript for publication.
Competing interests: None declared.
Ethical approval: The study was approved by the ethics committee at the Faculty of Medicine, Uppsala University, Sweden, and all participants gave written informed consent.
© Byberg et al 2009
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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