Physical Frailty As a Clinical Marker of Biological Age and Aging

To the Editor: We read with interest the article by Inglés and colleagues,1 published in the July 2014 issue of the Journal of the American Geriatrics Society, and we commend the authors for their work. We believe the authors underrated the importance of their study and that their findings have implications for the study of aging beyond those discussed in the original paper. The main result of that study was that high levels of markers of oxidative stress were associated with the phenotype of physical frailty but not with age. The authors' interpretation of that finding was that it provided evidence against the free radical theory of aging. Although this is certainly one possible interpretation, we would like to call attention to another, probably more interesting, viewpoint. Our perspective is that, if we start thinking about aging more consistently in terms of biological age and aging instead of simple chronological age and aging, the findings of that study will be in perfect agreement not only with the free radical theory of aging, but also with more-integrative frameworks of biological aging like one previously proposed.2 “The disconnect between chronological age and lifespan” within and across species have led biogerontologists to conclude that “the passage of time is not the best measure of the rate of aging”3 and hence to start looking for biomarkers of aging more than 30 years ago. Before the development and popularization of the concept of physical frailty in the study of aging in humans, the marked heterogeneity that characterized populations of older people was conceptualized mostly in terms of burden of comorbidities and degrees of dependency versus independence. The emergence of the notion of physical frailty advanced the understanding of that heterogeneity by calling attention to the multitude of subclinical physiological changes that diminished the ability of individuals to maintain homeostasis when facing different stressors. Recently, it was proposed that physical frailty should be considered a clinical marker of biological aging.4 That argument makes almost mathematical sense (Figure 1) when one considers that biological aging has been described as the progressive deterioration of physiological systems in an organism over time3 and that physical frailty has been defined as a “medical syndrome with multiple causes and contributors that is characterized by diminished strength, endurance, and physiologic function that increases an individual's vulnerability for developing increased dependency and/or death.”5 That viewpoint of frailty as a clinical marker of biological aging leads to a different interpretation of the finding of Inglés and colleagues. Oxidative stress was associated not with chronological age but with frailty because physical frailty is a better indicator of biological age than the simple passage of time. That perspective has several interesting implications for the study of aging and the care of older and even younger individuals. First, it helps us to shift the commonsense view of biological aging into a dynamic process. Instead of aging steadily minute after minute, individuals can really age “1 year within a week” as every geriatrician can testify about the effects of acute medical illness and hospitalization on their patients. Likewise, it seems that individuals can “rejuvenate” at least to some extent if they change some elements of their lifestyle such as by exercising, eating a healthy diet, and dedicating some time to meditation. It was recently shown that, by engaging in a program of comprehensive lifestyle change, individuals can shorten their telomeres—the best biomarker of biological age to date—as if rewinding their biological clock a little bit.6 Even though more evidence is needed to support that argument, it has the potential to be instrumental in helping people change their lifestyles for better. Second, researchers should start including physical frailty more frequently as an important covariate, both as confounder and interaction variable, when modeling outcomes in studies of aging. Third, it points the way forward for new research venues examining longitudinally the relationship between frailty and other biomarkers of aging such as telomere length and telomerase activity. Finally, we would like to ask the authors not only to share their opinion of our interpretation of their findings, but also to present some important pieces of data that they were not able to include in the published article because of space restrictions. In particular, we would be interested in having more information about the variables included in the multivariate linear regression model they used to analyze the relation between oxidative stress and frailty. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: EIOV conceived and drafted the first version of the manuscript. All authors revised the manuscript critically and approved its final version. Sponsor's Role: None.