Reviewing the State of Biomarkers of Aging

By way of following up on a brace of papers on biomarkers of aging that arrived over the past few weeks, here is an open access review on the topic. It is an important topic, it has to be said. The development of therapies to treat the causes of aging – and thereby significantly extend healthy life spans – is made expensive and slow by the lack of efficient ways to assess outcomes. It is easy enough to see whether a given therapy achieves what it intended to achieve in the short term, that genes are suppressed or unwanted cells are removed, for example, but at present the only way to then link that to increased long-term health and life span is to wait and see. Waiting to see carries a million dollar price tag and several years of effort for studies in mice, and the equivalent situation in humans is obviously impractical. The research community needs a generally agreed upon, robust, low-cost assessment of biological age, an assay that can run immediately before and immediately after a potential rejuvenation therapy to assess its effect on the state of aging in the patient, and does so in a way that is independent of the mechanism of the therapy itself.

Chronological age is a major risk factor for functional impairments, chronic diseases and mortality. However, there is still great heterogeneity in the health outcomes of older individuals. Some individuals appear frail and require assistance in daily routines already in their 70s whereas others remain independent of assistance and seem to escape major physiological deterioration until very extreme ages. In keeping with the unprecedented growth rate of the world’s aging population, there is a clear need for a better understanding of the biological aging process and the determinants of healthy aging. Towards this aim, a quest for (biological) markers that track the state of biophysiological aging and ideally lend insights to the underlying mechanisms has been embarked upon.

During the past decades, extensive effort has been made to identify such aging biomarkers that, according to the stage-setting definition, are “biological parameters of an organism that either alone or in some multivariate composite will, in the absence of disease, better predict functional capability at some late age, than will chronological age”. Later on, the American Federation for Aging Research (AFAR) formulated the criteria for aging biomarkers as follows: (1) It must predict the rate of aging. In other words, it would tell exactly where a person is in their total life span. It must be a better predictor of life span than chronological age. (2) It must monitor a basic process that underlies the aging process, not the effects of disease. (3) It must be able to be tested repeatedly without harming the person. For example, a blood test or an imaging technique. (4) It must be something that works in humans and in laboratory animals, such as mice. This is so that it can be tested in lab animals before being validated in humans.

However, to date, no such marker or marker combination has emerged. Moreover, the existence of such markers has been questioned, because the effects of many chronic diseases are inseparable from normal aging. The rate of biological aging can also vary across different tissues, and hence it may not be feasible to assume a measurable overall rate. Recently, however, several new biomarkers for biological aging have come into play. They can be separated into molecular (based on DNA, RNA, etc.) or phenotypic biomarkers of aging (clinical measures such as blood pressure, grip strength, lipids, etc.), although we include both types. The focus of this review is on novel biological age predictors, and we define them as markers that predict chronological age, or at least can separate “young” from “old”. They should also be associated with a normal aging phenotype or a non-communicable age-related disease independent of chronological age in humans. Promising developments consider multiple combinations of these various types of predictors, which may shed light on the aging process and provide further understanding of what contributes to healthy aging. Thus far, the most promising new biological age predictor is the epigenetic clock; however its true value as a biomarker of aging requires longitudinal confirmation.




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