Cardiorespiratory Fitness & Mitochondrial Function

An analysis of a 25-year observational study of the relationship between exercise testing and all-cause mortality was recently published online in the International Journal of Cardiology. Over 120,000 patients were included (at a mean age of 53.3), all having undergone some type of stress testing after being referred to the Cleveland clinic for a variety of reasons. Exercise capacity, considered equivalent to cardiorespiratory fitness (CRF), was quantified by the peak estimated metabolic equivalents of task, or peak METs. A MET approximates the amount of oxygen being consumed at varying activity levels, with 1 MET equal to the amount of oxygen consumed at rest (quietly sitting in a chair). Peak METs refers to the oxygen consumption at a maximum workload, which can also be referred to as VO₂max (note, METs can be converted to VO₂max by multiplying by 3.5, as 1 MET = 3.5 mL O₂ per kg body weight per minute). Essentially, peak METs is a measure of the maximum amount of oxygen an individual is capable of consuming to produce energy and is typically a benchmark for CRF.

There were several important take-aways from this study, including sex differences in both outcomes and testing; women were more often referred for less demanding stress protocols (i.e., non-Bruce protocols) despite a lower rate of established risk factors for coronary artery disease, likely due to an implicit bias regarding perceived exercise capacity, which the authors advocate for correcting. Women were also more likely to live longer, despite having lower CRFs, an important finding that strongly suggests CRFs at all levels are not equivalent between sexes, as they have a different influence on mortality risk. (It’s also important to note that peak METs are protocol dependent.)

But a critical conclusion of this study is the relative impact of CRF on mortality risk as compared to other important risk factors. At all levels and in both genders, a higher CRF was associated with a lower mortality risk; a low CRF in men for example, was associated with a hazard ratio (HR) on overall mortality of over 10 (over 5 after multivariate adjustment) compared to a mid-range CRF, while a high CRF cut the mortality risk in half, again, compared to a mid-range CRF. Table 2c in this article lists the multivariate adjusted risk on mortality of CRF as 0.4; this can be interpreted as a HR of 2.5 for a low CRF. In comparison, the adjusted HR for diabetes was only 1.17, and smoking only 1.32. None of the conditions reported (including hypertension, coronary artery disease, even end-stage renal disease) had an HR as high. Thus, it could be stated that CRF is the most important risk factor, at least among the variables studied, for determining mortality risk.

This is consistent with the results reported in 2018 in JAMA Network Open, also using data from this Cleveland clinic cohort. This study reported no upper limit of benefit for the effect of CRF on mortality, with a remarkable effect on the HR for mortality over the entire spectrum of aerobic fitness. For example, the HR for mortality comparing the highest to the lowest CRF was 5.04, but even comparing the lowest group to the “below average” group had an HR of 1.95. For comparison, diabetes had an HR of 1.4, smoking 1.41, and coronary artery disease 1.29. Thus, while smokers had a 41% higher mortality risk, having low fitness vs. below average had a 95% higher risk, more than double that of smoking; this is a pretty large impact on mortality, one that doesn’t require being an elite athlete. A systematic review and meta-analysis published in June strongly supported the importance of exercise capacity, concluding that CRF is a powerful predictor of mortality of patients with cardiovascular disease. It has also been found to be a strong independent predictor of all-cause, cardiovascular, and cancer mortality in specific populations, including among cancer patients.

Certainly there are many influences on CRF, and improving CRF is likely to extend both the quantity and quality of life, at any given level. For example, a recent systematic review of randomized trials found that high intensity interval training improved not only CRF in older adults, but it also improved muscle strength, cardiac contractile function, and mitochondrial oxidative capacity. Given the large hazard ratios between even low levels of physical fitness compared to well-established risk factors, it’s worth making every effort to improve.

Lastly, the connection between mitochondrial function and CRF also needs to be emphasized, as the ability for our cells to use oxygen largely depends on the functional capacity and overall number of mitochondria. Aging has been associated with a decline in mitochondrial function that tracks with both exercise capacity and insulin sensitivity, with that decline somewhat negated by physical activity. Results from the Baltimore Longitudinal Study of Aging put a spotlight on this connection; mitochondrial respiratory capacity was associated with both VO₂max and muscle strength in older adults. Importantly, although the ability of the mitochondria to produce ATP decreased with age, the actual number of mitochondria did not. This opens the door for maintaining or improving CRF by enhancing/restoring mitochondrial function, a hallmark of aging as well as age-associated disease.