Fight Aging!

Today's open access review article is a discussion of the importance of being able to measure biological aging, easily and robustly. Initially, this is an approach to speed the development of rejuvenation therapies; at present one can only efficiently and quickly assess the results of a potential rejuvenation therapy in the context of its ability to reverse a specific age-related disease. There are scores of important age-related conditions to assess, and animal models of these conditions are usually significantly different from the human condition - different enough for a careful consideration of the details to be needed to determine whether or not the model is useful.

If one wants to assess the overall efficacy of a rejuvenation therapy rigorously, it remains the case that life span studies are the only recourse. At minimum, deliver the treatment to old mice and run the study for six months to a year to see how mortality differs between the treatment and control groups. This is painfully expensive, and just doesn't scale to a world in which the research and development community may want to assess hundreds to thousands of variants of potential rejuvenation therapies at any given time. What is desired here is a way to run a quick study in normal aged animals: take a baseline assessment of the state of aging, deliver the intervention, and then within a week or two redo the assessment to see what has changed.

At present a number of different approaches to the measurement of biological aging are under development to one degree or another. The epigenetic clock is one such approach, which looks for epigenetic reactions to the underlying damage of aging. In this case, the challenge is connecting the epigenetic alterations characteristic of aging back to the underlying processes of damage and dysfunction: it is far from clear that the present clocks measure all of aging, versus part of aging. Another approach would be to take the list of cell and tissue damage that causes aging and measure each portion of it. Until rejuvenation therapies based on repairing this damage are developed, however, it will remain unclear as to the relative contribution of each form of damage to the progression of aging. Further, few of these forms of damage can actually be measured in a practical, non-invasive fashion in human patients. There is much work yet needed here.

Measuring biological aging in humans: A quest

Substantial investment is necessary to develop an estimator of biological aging that is robust, precise, reliable, and sensitive to change. Thus, a fair question is whether such a titanic project is worth the effort and cost. The answer is YES, without hesitation. Developing an index of biological aging is perhaps the most critical milestone required to advance the field of aging research and, especially, to bring relieve from the burden of multimorbidity and disability in an expanding aging population. Ideally, these measures would be obtained by running tests using blood samples without performing a biopsy, preferably quickly and at low cost.

An index of biological aging could be used to empirically address the geroscience hypothesis: "Is biological aging is the cause of the global susceptibility to disease with aging." Data collected longitudinally - ideally in a life course epidemiological study - could then be used to test if individuals that accumulate coexisting diseases faster than in the general population also have accelerated biological aging. Similarly, these data could be used to test if individuals who are biologically "older," independent of chronological age, are at a higher risk of developing different medical or functional conditions that do not share physiological mechanisms. Once validated, the fundamental basis of biological aging can be used to probe deeper into questions related to the mechanisms of aging, such as the following: Are there genetic traits that are associated with faster or slower biological aging? Are there "hallmarks" that are better at capturing biological aging at different stages of life?

Developing a proxy measure of biological aging for humans still requires work but is a very dynamic and promising area of investigation with strong potential for translation. Some of the measures - namely mitochondrial function, DNA methylation, and, to a lesser extent, cellular senescence and autophagy - are ready to be implemented based on several epidemiological studies, although refinements are always possible. Measures of telomere length are hampered by noise and wide longitudinal variations that cannot be explained by health events and at this stage are not useful for measuring biological age. New methods are being developed, some of which are focused on detecting the DNA damage response (a typical marker of critical telomere shortening) may yield better results. Senescence has been studied successfully in T lymphocytes, skin, and intramuscular fat, and high-throughput methods will be available soon. In addition, specific patterns of circulating proteins may exist that indirectly estimate the burden of senescence. Similarly, measures of autophagy are routinely used in mammalian studies and should be applicable to humans.

Multiple lines of evidence suggest that the measures listed above are associated with the severity of multimorbidity but, except for the epigenetic clock, this association has not yet been clearly established. Logically, none of the measures described above represent an exhaustive measure of biological aging and, therefore, new aggregate measures are needed that leverage differences and complementarities of the various biomarkers. To accomplish these goals, the hallmarks of aging should be assessed in a group of individuals that is reasonably sized and enough dispersed across the lifespan to represent the variability of biological age in the general population. Initially, it will be important to evaluate the intercorrelation between these measures.

These questions have immense relevance for geriatric medicine. Despite the rising emphasis on prevention, most current medical care is dedicated to diagnosing and managing diseases that are already symptomatic, which does not address the underlying issues related to geriatric health conditions. By understanding the intrinsic mechanisms of biological aging, including damage and resilience, medical professional will be able to best orient and prescribe therapeutic choices.

Progress in research is not linear. Periods characterized by rates of incremental knowledge are interlaced with "eureka" moments as milestone discoveries suddenly open new possibilities that thrust research and knowledge to a higher level. Galileo's use of the telescope to explore the stars, Kary Mullis's description of polymerase chain reaction, and Edwin Hubble's demonstration that the universe is expanding are just few examples of these moments. The field of aging research is living one of those magical moments. Finding a reference metric for the rate of biological aging is key to understanding the molecular nature of the aging process. Defining and validating this metric in humans opens the door to a new kind of medicine that will overcome the limitation of current disease definitions, approaching health in a global perspective and bringing life course preventative measures to the center of attention.