Biomarkers of Aging and Aspect of Aging
The term biomarker, which is encountered with increasing frequency in the gerontological literature, is used with a variety of implicit or explicit definitions. In some contexts, a biomarker is expected to predict longevity; in other usages, it is expected to be correlated with physiological age; in still other, it is expected to be descriptive of a fundamental aspect of aging, and so on. This breadth of usage is so great that an argument can be made that the phrase, ‘biomarker of aging’ is simply synonymous with ‘age-related variable’.
When understood in this broad sense the only advantage of the label biomarker over the term ‘variable’ might be the specific emphasis on biology provided by ‘bio’ and the reminder provided by ‘marker’ that the variable in question is a proxy or surrogate variable. In the final analysis, whether it be labeled biomarker or age-related variable, it is being used because one cannot measure biological age or aging directly.
In some contexts, the term biomarker is employed in a more restricted sense to refer specifically to variables being used in a multivariate attempt to define bilogical or functional age. In another, specialized usage, the biomarker label is reserved for outcome variables appropriate to assess the efficacy of an intervention designed to affect some aspect of aging processes. The desirability of a standard reference set of biomarkers of aging in the letter sense has motivated a major program initiative of the National Institute on Aging.
In a recent evaluation of biomarkers, Arking has provided the following paraphrased) list of desiderata, which may be regarded as a representative summary of current thinking in the field. Biomarkers should
1. Change with time at a rate that reflects the rate of aging,
2. Be monitoring some basic, important process,
3. Be non-lethal, and preferable non-invasive and minimally traumatic,
4. Be highly reproducible,
5. Reflect physiological age,
6. Display change over a relatively short period,
7. Be crucial to the maintenance of health,
8. Be measurable in a variety of species,
9. Serve as a predictor of life span, and/or
10. Serve as a retrospective biomarkers of aging.
As a further summary, it might be suggested that the desired attributes of biomarkers fall into three classes: pragmatic, ethical, and methodological. Pragmatically, biomarkers should be simple and inexpensive to measure. Ethically, they should be minimally intrusive, causing the least possible pain and stress. Methodologically, it is desirable that they be non-destructive (permitting longitudinal research); capable of demonstrating change over a relatively short portion of the life span; insensitive to effects of previous measurement; and robust over a large range of laboratory and experimental conditions. Of utmost importance is that they measure aging validly and reliably. The meaning of this last statement engages subtle issues, some of which will be elaborated later.
The Diversity in Biomarkers of Aging
In the broadest usage described above, every attribute measured in a study of aging could reasonable be regarded as a biomarker. The range of applicability is nearly as great when more constrained definitions are used. In a conference reviewing the state of research at the onset of the biomarker initiative of the National Institute on Aging, genetic, molecular, cellular, tissue, and whole-organism variables were discussed. A few years later, the First International Congress on Biomarkers of Aging: Expression and Regulation was convened. Titles from the proceedings of that congress reveal a similarly wide array of measures. A sample of the domains within which putative biomarkers were investigated include neuroendocrine systems, degradation of altered protein molecules, lateral mobility of cell membrane proteins, DNA repair, molecular myocardial changes, membrane cholesterol, blood–brain barrier permeability, immune system alteration, heat shock proteins, activity levels, and cognitive functioning.
In a book on preventive intervention oriented to ward the general reader, Evans and Rosenberg identified the following as pertinent biomarkers: muscle mass, strength, basal metabolic rate, body fat percentage, aerobic capacity, blood sugar tolerance, cholesterol or high-density lipoprotein (HDL) ratio, blood pressure, bone density, and ability to regulate internal temperature.
Obviously, neither a comprehensive review nor an evaluation of the degree to which each of these biomarkers of aging meets the specified criteria is within the scope of the present article. What follows is, therefore, a discussion of some principles that have general applicability.