Searching for a Biomarker of Aging in Gene Expression Patterns

A reliable biomarker for biological age would be some measure that reflects the level of cell and tissue damage present in an individual. The existence of such a biomarker would greatly speed up work on treatments for aging, allowing at least preliminary evaluation of the effectiveness of potential rejuvenation therapies based on damage repair very soon after their application in a test subject. The only presently available option is to run life span studies, to take the wait and see approach, which is very expensive and time-consuming, even in mice.

Researchers have made inroads towards a biomarker for aging by looking at DNA methylation patterns, and here is news of an analogous project that analyzes changes in gene expression levels. By the sound of it this new methodology only captures a slice of the wide-ranging cellular responses to accumulating damage, missing some of the important changes related to, for example, deterioration of the cardiovascular system:

Researchers used a process called RNA-profiling to measure and compare gene expression in thousands of human tissue samples. Rather than looking for genes associated with disease or extreme longevity, the researchers discovered that the "activation" of 150 genes in the blood, brain and muscle tissue were a hallmark of good health at 65 years of age. The researchers were then able to create a reproducible formula for "healthy ageing," and use this to tell how well a person is ageing when compared to others born the same year.

The researchers found an extensive range in "biological age" scores of people born at the same time indicating that a person's biological age is separate and distinct to his or her chronological age. Importantly, a low score was found to correlate with cognitive decline, implying that the molecular test could translate into a simple blood test to predict those most at risk of Alzheimer's disease or other dementias and suitable for taking part in prevention trials. A person's score was not, however, found to correlate with common lifestyle-associated conditions, such as heart disease and diabetes, and is therefore likely to represent a unique rate of ageing largely independent of a person's lifestyle choices.

However, the study does not provide insight into how to improve a person's score and thus alter their "biological age." While a low score could be considered as "accelerated ageing," an important aspect of the work suggests that ageing does not now need to be defined only by the appearance of disease. "Given the biological complexity of the ageing process, until now there has been no reliable way to measure how well a person is ageing compared with their peers. Physical capacity such as strength or onset of disease is often used to assess healthy ageing in the elderly but in contrast, we can now measure ageing before symptoms of decline or illness occur. We now need to find out more about why these vast differences in ageing occur, with the hope that the test could be used to reduce the risk of developing diseases associated with age."



"The existence of such a biomarker would greatly speed up work on treatments for aging, allowing at least preliminary evaluation of the effectiveness of potential rejuvenation therapies based on damage repair"

If you've actually repaired any damage, you won't need a biomarker to tell you that you did, or you'll create your own biomarker that pertains to the specific form of damage you're trying to fix.

An overall biomarker is useless, Reason, in fact it may be worse than useless. It does not lead to effective therapies. It treats "aging" as this magical whole-body variable, which it is not; in so doing, it encourages less experienced researchers to go after a specific biomarker instead of actual forms of damage, effectively teaching to the test. If drugs are developed with this biomarker in mind, they may or may not help along some small aspects of metabolism for some small amount of time, but they will not replenish cells. They may or may not temporarily restore or preserve some function in a damaged system. They will not bring any tissue, organ, or system back to a youthful state. Even the people developing this biomarker talked about it being for "healthy ageing" and we know that's a waste of time.

Looking for simple scores to evaluate complex, interdependent systems is a symptom of autism. Your mechanic doesn't give you a "car-marker" while fixing your car. Your dentist doesn't create a "tooth-marker" while fixing your teeth (that score is known as the bill...) Do you think, say, the Conboy lab needs an overall biomarker to evaluate the signaling environment? What about the people developing senolytics; do you think they need some overall score to tell them about the presence of senescent cells?

These researchers are creating one variable based on a hundred and fifty others-- how can that possibly benefit anyone?

Nothing can be gained from trying to view a complicated system as a whole. If you want to work on something, you have to take it apart.

Posted by: Slicer at September 10th, 2015 10:13 AM

@Slicer: Indeed. I see these hypothetical biomarkers as more useful for things like sirtuins research than for damage repair research. If you found a drug for, say, eliminating transthyretin amyloid, then measure TTR amyloid itself or heart pumping capacity or something like that, not a global biomarker of aging.

Posted by: Antonio at September 10th, 2015 10:39 AM

Slicer, Antonio: I suspect from the nature of your (Slicer's) critique that you're thinking of the notion of "biomarkers of aging," meaning single (or composite) assays that could give a simple, unitary readout of the "rate of aging" of the entire organism. Despite the quite sensible theoretical challenge you lay out, there's actually some pretty good empirical support for the validity of composite "biomarkers of aging" based on panels of physiological functional deficits: see many papers by Rockwood and Mitnitski. But I share your skepticism of their importance for use in clinical trials or medical practice.

In any case, however, I'm pretty sure that Reason was not thinking of such global "biomarkers of aging," but rather of noninvasive assays for levels of particular forms of cellular and molecular aging damage and/or of their clearance. Many of these do exist, and more will doubtless be forthcoming — and their availability will be critical to demonstrating the efficacy of rejuvenation biotechnologies, as laid out in a "Question of the Month" in a recent issue of the SENS Research Foundation Newsletter: "What is the role of novel diagnostics in rejuvenation biotechnologies?"

Posted by: Michael at September 11th, 2015 3:01 PM

Michael, the link discusses a single, overall biomarker measuring "biological age", not assays or other tests for specific things that can be measured to judge the effectiveness of specific rejuvenative therapies. Like we're all saying, those individual tests and their related therapies obviously go hand in hand.

Posted by: Slicer at September 11th, 2015 5:13 PM
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