Aging Rate Indicators as Speedometers for Aging Research

Is it possible to measure the pace of aging at any given moment? Are there biomarkers that reveal not the biological age of the individual, but rather how fast that biological age is changing? The field is presently focused on developing measures of biological age, such as the extensive work on epigenetic clocks. Some information about pace of aging might be inferred from whether biological age is higher or lower than chronological age, assuming a biological age measurement that is actually accurate, something that still a topic for contention. But that doesn't say anything about the momentary pace of aging at any given time. That information would certainly prove useful in the context of testing interventions that adjust the pace at which aging proceeds. It isn't all that interesting in the context of interventions that reverse aging, such as by repairing the underlying cell and tissue damage that causes aging. In that case, pace of aging becomes irrelevant. The desire to measure the pace of aging reflects a bias towards merely slowing aging rather than achieving rejuvenation, and that is certainly the character of much of the field, sad to say.

Researchers interested in the biology of aging, and its potential modification by antiaging drugs, have devoted a substantial amount of community effort to the search for possible biomarkers of aging, conceived as quantifiable traits that can reveal the biological age of an individual animal. The central framework here is that such biomarkers might change monotonically through some relevant portion of adult life, might discriminate younger from older adults, might predict mortality risk at some useful distance from ultimate date of death, and, crucially, might serve, individually or collectively, as surrogate endpoints for studies of putative antiaging diets, drugs, or polymorphic alleles. Like an odometer in a car, biomarkers or weighted combinations of biomarkers might in principle reveal how far along the aging trajectory an individual organism has already proceeded. Odometers do not reveal the speed at which a car is currently traveling. A low-mileage or high-mileage car might be going quickly or slowly. Speed and distance traveled are independent and unconnected measures of a vehicle's state.

This essay presents the concept of aging rate indicators (ARIs) as speedometers for aging research. In principle, an ARI is a quantitative trait or measurement, an endpoint, which discriminates slow-aging mice from normal mice; it measures how quickly the aging process is proceeding in an individual organism. (The definition carefully takes no position on whether ARIs might also discriminate fast-aging animals from normal ones, a topic that will be deferred for another occasion). An ideal ARI would make this discrimination regardless of the age at which it is measured, at least within the portion of adult life where serious diseases are rare and mortality risk is minimal. The critical feature of an idealized ARI, the critical test of a candidate ARI, is that it should be modulated, in the same direction, by antiaging perturbations, whether the slowed aging and extended lifespan are caused by genetic factors, by dietary intervention, or by lifespan-increasing drugs.

It is helpful to consider the differences between ARIs and the more familiar biomarkers of aging. If a measurement - an estimate of collagen cross-linking, a score of visual acuity, or reflex speed, an index combining levels of DNA methylation at several sites, a T cell subset ratio, and so on - is proposed as a biomarker of aging, it is expected to show age-related change in adults, that is, to distinguish young, middle-aged, and older adults. Evaluation of an endpoint as a candidate ARI involves an entirely different set of criteria. Evidence that a candidate ARI changes with age is quite beside the point, because ARIs are taken to be measures of the pace or speed at which aging is currently occurring, and not as indices of how much a given subject has already aged, in the past. In such a framework, estimates of ARIs made in young adults are expected to be highly informative, because these individuals may actually be aging at different rates; for example, one might be on a calorie-restricted (CR) diet, or carry a mutant growth hormone receptor (GHR) allele, or be in a rapamycin treatment cohort. The key criterion for a putative ARI is that it should be modified, in a consistent direction, by most or all genes, diets, and drugs that are known, on independent evidence, to slow the signs of aging, postpone late-life illnesses, and increase lifespan.