Summary: Biomarkers of aging would be a breakthrough that slashes the time and cost it currently takes to develop lifespan-extension drugs. [Author: Brady Hartman. This article first appeared on the LongevityFacts.com website. ]
Biomarkers of aging would revolutionize the development of lifespan-extension drugs, helping to bring them out of the laboratory and into the clinic in a fraction of the time and at a fraction of the cost. The first scientist to come up with an effective biomarker of aging would produce a true breakthrough in the field of life extension.
Imagine that geroscientists have just developed a miraculous compound called Regulus that promises to extend human lifespans by a significant amount. Unfortunately, the researchers would not have an easy time testing Regulus because humans live a long time. Testing Regulus in mice, would help, but researchers would still have to test the drug’s lifespan-extending effects in humans. Before anti-aging physicians could prescribe Regulus, it would need to undergo an expensive and lengthy clinical trial.
A biomarker of aging would allow us to test Regulus and compounds like it in a fraction of the time. And while Regulus is a fictional substance, there are plenty of potential compounds like it waiting to be tested. Effective biomarkers of aging would revolutionize the field of geroscience.
In Dire Need of Biomarkers of Aging
Felipe Sierra, Ph.D. the Director of the Division of Aging Biology at the National Institute on Aging (NIA) wants these biomarkers. Writing in “The Main Pillars of Research On Aging Biology,” Dr. Sierra tells of the pressing need for biomarkers of aging, saying,
“we are still in dire need of markers that can be used for research purposes, independently of whether they are drivers or not.”
Biomarkers of aging are markers that give the true “biological age,” which may be different from the chronological age. Said in another way, biomarkers predict what a person’s functional capacity will be at later age better than chronological age.
Dr. Sierra gives the reason that no biomarkers of aging exist as of yet, saying,
“The [geroscience] field has traditionally shied away from looking at biomarkers under the assumption that markers of aging might be too elusive. However, new techniques, including a large set of -omics technologies, now open new possibilities that need to be explored; in the absence of such markers, progress in the field remains hindered.”
Moreover, the NIA Director calls for the development of other biomarkers that act very much like the biomarkers of aging, saying,
“In addition to markers that can be used to test the effects of interventions, there is a need to define mechanistic drivers that can be targeted for these interventions, thus paving the way for possible therapeutics that might delay aging and concomitantly delay the onset and/or severity of multiple chronic diseases and conditions that affect primarily the older population.”
Hunting for Biomarkers of Aging
It’s not like the NIA hasn’t been trying. Researchers have been looking for these biomarkers since the NIA organized its first conference on the subject in 1981. In fact, from 1988 to 1998, the NIA turned up the pressure and sponsored a 10-year initiative encouraging research into biomarkers of aging. Scientists searching for biomarkers of aging have looked for changes in genes, cells, hormones, and even behaviors to find a predictor of the rate of aging. Although scientists explored many attractive biomarker candidates and contributed to the body of knowledge on aging, none of the researchers were able to identify and validate a single biomarker successfully.
Moreover, some scientists have questioned the existence of such biomarkers, because the effects of many chronic diseases are inseparable from those of healthy aging. The rate of biological aging can also vary between different tissues, and therefore it may not be feasible to assume a measurable overall rate.
Some researchers believe that as people age, damaging physiological processes can occur that may lead to Alzheimer’s disease, cancer, heart disease, or other conditions. These processes can overlap, but there is no single, underlying biological process driving them all. Despite these criticisms, many scientists still believe aging takes place at a measurable overall rate. The goal for these researchers is to find reliable biomarkers of aging and convince the doubters.
Benefits of Biomarkers of Aging
Biomarkers of aging would make it easy for a scientist to quickly see whether a given therapy achieves what it intended to. At present, the only way for a geroscientist to link a treatment under consideration to increased long-term health and lifespan is to wait and see. When using mice as a test subject, ‘waiting to see’ carries a million dollar price tag and several years of effort and the equivalent situation for human test subjects could cost billions of dollars and take decades. The geroscience community needs lab tests that researchers can run both before and soon after administering a prospective rejuvenation therapy to assess its effect on the patient’s state of aging. Moreover, the biomarker of aging must not interfere with the action of the therapy.
What are Biomarkers of Aging?
Biomarkers of aging need to be simple, relatively inexpensive and should cause little or no pain and stress while accurately measuring aging. The American Federation for Aging Research (AFAR) has formulated the following three criteria for biomarkers of aging, saying
“A true biomarker of aging must meet certain criteria in order to be both accurate and useful:
 It must predict a person’s physiological, cognitive, and physical function in an age-related way. In other words, it must predict the future onset of age-related conditions and diseases, and do so independently of chronological age.
 It must be testable and not harmful to test subjects. For example, it could be a blood test or an imaging technique. It must also be technically simple so that most clinical laboratories could perform the test accurately and reproducibly without the need for specialized equipment or techniques.
 It should work in laboratory animals as well as humans, since preliminary testing is always done in non-human subjects.”
Promising Biomarkers of Aging
Despite the challenges, promising biomarkers of aging are under development, including those based on senescent cells, the epigenetic clock, transcriptomic aging, as well as blood biochemistry and cell counts.
While the epigenetic clock gets the most attention, researchers have shown that basic blood biochemistry and cell counts can also be used to predict chronological age. Scientists have also shown it is possible to predict the chronological age of humans using transcriptomic aging clocks. Measuring the build-up of senescent cells is another promising avenue.
Lacking the Luxury of Time
Before it can be used, a biomarker of aging must be validated, and this is where the trouble begins. Ideally, a clock-maker would validate his biomarker of aging by observing it in a population of humans throughout their lifespan in a longitudinal study. Given that humans are a long-lived species, such longitudinal studies are impractical in that they would take far too much time.
Steve Horvath overcame this time problem by using ‘big data‘ analysis methods to develop his epigenetic clock. Horvath spent over 4 years developing his clock, collecting 8,000 DNA methylation samples, and using statistical methods to create his age estimator.
Biomarkers of Aging in Development
While the outlook for such biomarkers appears dim, one ray of light comes from a group of Swedish researchers who published a review of potential biomarkers of aging in the middle of last year. The researchers, Juulia Jylhävä, Nancy L. Pedersen, Sara Hägg with Department of Medical Epidemiology and Biostatistics, Karolinska Institutet say,
“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.” adding “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.”
Senescent Cells as a Biomarker of Aging
According to AFAR, the level of senescent cells may be a potential biomarker of aging. As we age, old or damaged cells may become senescent, a condition in which they remain alive but cease to reproduce. This is the body’s defense against cancerous tumors. The older an individual becomes, the more senescent cells he or she accumulates. Because senescent cells have been implicated in aging, scientists are testing the use of senolytic compounds to remove them from the body. Researchers have suggested several markers of senescence as biomarkers of aging.
Epigenetic Clock as a Biomarker of Aging
The most famous biomarker of aging is the epigenetic clock; however, it is not quite ready for primetime. Researchers have known for some time that human aging is associated with DNA methylation (DNAm) changes. These findings are based on the Horvath epigenetic clock, developed by Steve Horvath in 2013. Unfortunately, the Horvath clock isn’t accurate enough to be used as a biomarker of aging as it has a median error of 3.6 years across a wide spectrum of tissues and cell types.
As a December 2017 report on the lifespan extension field shows, many potential lifespan-extending compounds sit on the shelf, waiting for sufficient funds to conduct clinical trials. Effective biomarkers of aging would enable the lifespan extension field to vet scores of prospective anti-aging compounds and produce ‘anti-aging’ drugs.
The hunt continues for biomarkers of aging. For example, scientists just announced they can predict a person’s biological age using urine, by detecting RNA and DNA metabolites found in the bodily fluid. Moreover, a company called Insilico Medicine just released an AI-based aging clock that is easy for consumers to use because it is based on common blood tests.
As last year’s report by Jylhävä, Pedersen, Hägg shows, scientists continue to develop improved aging clocks.
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References / Additional Reading
Cover Photo: Yaroslav Astakhov / iStock / Getty Images.
- Sierra, Felipe. “Geroscience.” Elsevier, Inc. 2017. ISBN: 978-0-7020-6185-1
- George T. Baker, III and Richard L. Sprott. “Biomarkers of aging”. EXPERIMENTAL GERONTOLOGY. 23 (4-5): 223–239. (1988) doi:10.1016/0531-5565(88)90025-3.
- Steve Horvath. “DNA methylation age of human tissues and cell types”. Genome Biology. 14 (10): R115. (2013). doi:10.1186/gb-2013-14-10-r115.
- A Zhavoronkov. “Deep biomarkers of human aging: Application of deep neural networks to biomarker development”. Aging 8 (5): 1021. (2016) doi:10.18632/aging.100968.
- Marjolein J. Peters et al. “The transcriptional landscape of age in human peripheral blood”. Nature Communications 6, Article number: 8570 (2015)
- Jylhävä, Juulia et al. “Biological Age Predictors.” EBioMedicine, July 2017, volume 21, Pages 29–36. Link.
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