Cardiorespiratory fitness related to longevity in middle-aged men without CVD

Midlife cardiorespiratory fitness and the long-term risk of mortality

Literature - Clausen JSR, Marott JL, Holtermann A et al. - JACC 2018; 72(9) DOI: 10.1016/j.jacc.2018.06.045

Introduction and methods

Since the mid-20th century, research has shown that physical activity and cardiorespiratory fitness (CRF) are inversely associated with cardiovascular disease (CVD) and mortality, and even a small increase in CRF is associated with a significantly lower risk of mortality [1-3]. CRF is measured as maximum oxygen (V02max) uptake per minute per kilogram body weight, which can be estimated with non-exercise algorithms and exercise-based tests [4,5]. However, sparse evidence of the association between CRF and CV and all-cause mortality exists [4,6]. Therefore, this sub-analysis of the Copenhagen Male study assessed the relation between CRF and mortality in middle-aged, employed men without CVD.

This analysis of the prospective Copenhagen Male cohort study (1970-1971) included 5,107 men aged 40-59 years who were followed for 46 years. Initial measures included blood pressure, height and weight. CRF (VO2-max adjusted for age) was estimated with Åstrand’s nomogram, by using a standard bicycle ergometer test. Heart rate was measured by using a stethoscope and stopwatch in a working steady state, with 100, 150 and 200 W as workloads, based on the participant’s weight and height or the heart rate in the first minute of the examination. A physician interviewed all subjects at inclusion and a questionnaire was used to assess CV risk factors, and self-reported physical activity (high/moderate/low), smoking (never/former/present) and alcohol (high/moderate/low) consumption, and the occurrence of familial coronary heart disease, hypertension, and diabetes. General health status and previous CVDs were evaluated during the interview. Vital status was extracted from the Danish national Central Person Register and deaths from CVDs were extracted from the Danish Register of Causes of Death. For this analysis, all subjects with self-reported pre-existing CVD at inclusion were excluded.

Because VO2-max decreases with age, the authors developed an age-standardized VO2-max, to be able to categorize participants by CRF levels: below lower limit of normal (BLLN), low normal (LN), high normal (HN) and above upper limit of normal (AULN).The endpoints were all-cause mortality and CV mortality.

Main results

Baseline characteristics

  • Higher CRF was associated with lower prevalence of hypertension, lower BMI and lower alcohol consumption. Participants with higher CRF reported higher physical activity and those were more likely to smoke, compared with participants in the lower CRF categories.

All-cause mortality

  • Higher levels of CRF were associated with increased longevity (P-trend across categories <0.001).
  • After adjustment for age, LN CRF was associated with 3.0 years (95%CI: 1.6-4.3, P<0.001), HN CRF with 4.2 years (95%CI: 2.8-5.6, P<0.001), and AULN CRF with 6.4 years (95%CI: 4.6-8.3, P<0.001) longer life expectancy, compared with participants in the BLLN CRF category.
  • After multivariable adjustment, LN CRF was associated with 2.1 years (95%CI: 0.7-4.4, P<0.002), HN CRF with 2.9 years (95%CI: 1.5-4.2, P<0.001), and AULN CRF with 4.9 years (95%CI: 3.1-6.7, P<0.001) longer life expectancy, compared with participants in the BLLN CRF category. All between-category estimates showed highly significant differences from each other (all P≤0.002).
  • After full adjustment, each 1mL/(kg x min) increase in V02max was associated with a 45-day (95%CI: 30-61, P<0.001) increase in longevity when V02max was considered as a continuous variable.

CV mortality with competing risk

  • CRF was inversely associated with an cumulative incidence of CV mortality.
  • After adjustment for age, LN CRF was associated with a 3.3 years (95%CI: 1.8-4.9, P<0.001), HN CRF with a 4.4 years (95%CI: 2.9-5.9, P<0.001) and AULN CRF with a 6.7 years (95%CI: 4.6-8.9, P<0.001) increase in longevity, compared with participants in the BLLN CRF category.
  • After full adjustment, LN CRF was associated with a 2.2 years (95%CI: 0.7-3.9, P<0.001), HN with a 2.6 years (95%CI: 1.0-4.1, P<0.001) and AULN with a 4.5 years (95%CI: 2.4-6.6, P<0.001) increase in longevity, compared with participants in the BLLN CRF category.
  • After multivariable adjustment, each 1mL/(kg x min) increase in V02max was associated with a 30-day (95%CI: 14-49, P<0.001) increase in life expectancy.
  • In a competing risk model with non-CV mortality as the competing risk, all estimates were non-significant (all P>0.15) and with V02max as continuous model, the estimate coefficient was 0.000 (95%CI: -0.002 to 0.002, P=0.97), suggesting that the relation between CRF and mortality is not specific to CV mortality.

Sensitivity analysis

  • To examine the role of reverse causation, all men who died within the first ten years of follow-up were excluded, which left a study population of 4,728 men.
  • After full adjustment, LN CRF was associated with 1.8 years (95%CI: 0.6-3.1, P-0.003), HN CRF with 2.6 years (95%CI: 1.4-3.9, P<0.001), and AULN CRF with 4.3 years (95%CI: 2.6-5.9, P<0.001) longer life expectancy, compared with participants in the BLLN CRF category.


This prospective study on measured CRF, with the longest follow-up so far, showed a strong and dose-responsive association between increased levels of midlife CRF and longevity in healthy, middle-aged men. The effect on longevity was not specifically related to CV mortality. These findings show that the benefits of higher midlife CRF extend well to later in life, suggesting that health care professionals should recommend fitness-enhancing physical activity to improve public health and to promote healthy aging.

Editorial comment

In their editorial comment [7], Stamatakis et al. discuss the lack of repeated CRF measures in the Clausen et al. study, which might have led to overestimation of the independent associations between CRF and future mortality risk, and the lack of data on physical demands at work and CRF in terms of all-cause mortality risk. Next, they discuss the translation of the results into a public health and clinical practice message, including the positive effects of less vigorous intensity on all-cause and CVD mortality. They conclude: ‘The study by Clausen et al. made excellent use of a historical data resource and contributed important information on the question of whether CRF is associated with long-term mortality risk.’(…) ‘Regardless of whether the identified associations were causal or predictive, the current study supported the use of CRF as a clinical vital sign. Promoting incidental physical activity such as active transportation in the least fit and least physically active segments of the middle-aged adult population is a safe investment that will likely lead to improvements in CRF and will certainly save lives.’


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3. Paffenbarger RS Jr., Blair SN, Lee IM. A history of physical activity, cardiovascular health and longevity: the scientific contributions of Jeremy N. Morris, DSc, DPH, FRCP. Int J Epidemiol 2001;30:1184-92.

4. Kodama S, Saito K, Tanaka S, et al. Cardiorespiratory fitness as quantitative predictor of all-cause mortality and cardiovascular events in healthy men and women: a meta-analysis. JAMA 2009;301:2014-35.

5. Stamatakis E, Hamer M, O’Donovan G, Batty GD, Kivimaki M. A non-exercise testing method for estimating cardiorespiratory fitness: associations with all-cause and cardiovascular mortality in a pooled analysis of eight population-based cohorts. Eur Heart J 2013;34:750-8.

6. Ross R, Blair SN, Arena R, et al. American Heart Association Physical Activity Committee of the Council on Lifestyle and Cardiometabolic Health; Council on Clinical Cardiology; Council on Epidemiology and Prevention; Council on Cardiovascular and Stroke Nursing, Council on Functional Genomics and Translational Biology; Stroke Council. Importance of assessing cardiorespiratory fitness in clinical practice: a case for fitness as a clinical vital sign: a scientific statement from the American Heart Association. Circulation 2016;134:e653-99.

7. Stamatakis E, Koster A and Mork PJ. Cardiorespiratory Fitness and Long-Term Mortality. JACC 2018;72:9

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