Reviewing Present Biomarkers of Aging
Today's open access paper, with more than 120 contributing authors, is a tour of the broad topic of biomarkers of aging, an attempt to say at least something about every aspect of cellular biochemistry and functional capacity that is either used or proposed to be used to measure biological age, from grip strength to epigenetic clocks. Biological age is in one sense an aspirational concept, a way to measure the progression of aging that will accurately reflect mortality and disease risk. In another sense, biological age is self-evidently real. Different people age at different rates, and exhibit very different risk levels for age-related disease at a given chronological age. In this sense, biological age is a very complicated state of a very complicated system, a state that we cannot measure comprehensively, even setting aside the presently incomplete understanding of cellular biology and the systems of the body.
Thus scientists search for shortcuts, measurements that are practical and attainable, but nonetheless do a fair job of reflecting the highly complex state of aging. These options are what is usually meant by biomarkers of aging. The challenge with all such approaches is that we'd like to use them to assess the performance of potential rejuvenation therapies. A given rejuvenation therapy will only influence a subset of the important mechanisms that drive degenerative aging, usually a narrow subset. That in turn means that any given biomarker of aging will likely place too little weight or too much weight on specific mechanisms of aging, and it is rarely clear in advance as to which of these is likely to be the case. This makes it hard to use biomarkers of aging as we would like to use them, and suggests that a great deal of work will be needed to make any given set of biomarkers useful in this way.
Do we truly know how old we are biologically, that is, more accurately describing the status of our body than our chronological ages? Are some people at higher risk of certain types of age-related diseases, i.e., cardiovascular disorders or neurodegenerative diseases, and how can they be identified? Or how do we know if any of the claimed geroprotective treatments are effective? To answer these questions, we need to establish biomarkers for aging. In a broad aspect, these biomarkers are defined as scientifically measured parameters of the physiological aging process, to measure age-related changes and to predict the transition into a pathological status.
As a biological measurement to qualify aging, a biomarker must be specific, systemic, and serviceable. (i) Specific: aging is such a heterogeneous process that it proceeds at different rates in different individuals and varies in different organs, even in the same individual. Therefore, it is impossible to have one biomarker for the entire organism but different ones or even different sets of biomarkers for different organs for evaluation; vice versa, each biomarker should be able to capture a unique aging signal of the relevant organ. Moreover, aging biomarkers should be predictive of the risk of disease development, which requires a specific threshold for the transition from physiological aging to pathological disorder. (ii) Systemic: aging involves almost very organ system, comprising numerous interconnected biological processes. Moreover, changes in one organ may elicit compensatory mechanisms or systemic feedback across the body. Therefore, biomarkers should be able to reflect such systemic changes with age, and a collection of biomarkers from multiple dimensions is required for this aspect. (iii) Serviceable: biomarkers collected through non-invasive or minimally invasive methods are particularly suited for translation into clinical practice. As aging is a gradually deteriorating process over time, longitudinal studies are needed, and again, non-invasive measurements are preferred. In larger cohort studies, cost and convenience should be considered when choosing biomarkers. In all, being specific, systemic, and serviceable are as critical to the broad spectrum of aging biomarkers as the three primary colors.
Over the years, various data types and modeling techniques have been used to develop a broad spectrum of aging biomarkers. Based on the nature of these parameters used for aging biomarkers, the collection of alterations with age can be categorized into 6 classes, or 6 pillars, although biomarkers in different categories are often interconnected with each other. There are higher-order types of changes that reflect physiological and functional changes, such as physiological characteristics, imaging traits, and histological features. Additionally, there are more causal or mechanistic driver types of biomarkers, such as cellular alterations and molecular changes. Finally, there are biomarkers serving in between, such as hormones and secretory factors that are detectable in body fluids, such as blood, urine, saliva, and cerebrospinal fluid (CSF), among which those act in a paracrine manner are of particular interest. The latter three types, as they may also serve as hallmarks or drivers of aging, may be targeted to intervene in the aging process.
Aging biomarkers are critical to answer the three major questions in the field of aging: how old are we? Why do we get old? And how can we age slower? In this comprehensive review, we provided an encyclopedia summary of aging biomarkers covering a hierarchy of dimensions at cellular, organ, organismal, and populational aging levels, along with associated ethical and social implications. We hope this re- view serves as a resource for readers in academia, industry and medical practice, broadening our understanding of not only what biomarkers can be used to monitor aging, but also how to use them to assess novel therapies to slow, modify or even reverse aging. As such, we can accelerate the journey of basic science discoveries in the aging field from bench to bedside.