March 12, 2004

Developing Biomarkers For Aging

A couple of days ago Reason at wrote a post entitled "The Meaning of Anti-Aging." In the post Reason mentioned biomarkers:
We need biomarkers for aging: ways of measuring the progression of the aging process in our bodies. Even if we do find aging biomarkers, however, it isn't clear that they will allow accuracy to the point of being able to say "this treatment is giving you an extra two years of healthy life."
When biomarkers are first developed there will be difficulty making measurements as accurate as "you have two extra years." But, like everything else, biomarkers can be improved.

Until biomarkers (imperfect or not) are established, we will have no way of measuring the effectiveness anti-aging treatments. Apart, that is, from running 30-year studies. And there will be no mainstream acceptance of anti-aging treatments until their effectiveness can be measured.

If biomarkers were available the doctor and patient could see how well anti-aging therapy was working. I can imagine a patient being happy that his biomarkers showed an effective age of 45 when he is 65. The doctor could then say that yes, this was good for five years ago, but now we expect people your age to have an effective age no higher than 40.

The first step to establishing biological markers to aging is to establish scientific consensus on those factors that cause aging. The scientific community is not in full agreement on these factors at this time.

Aubrey de Grey has said:
There are really only seven types of, major types of damage that actually accumulate during time, and if we could fix them all we simply wouldn’t age.
For purposes of this post let's assume that Aubrey de Grey's seven factors are correct and complete. These are:
  1. Cell loss

  2. Mutations in our chromosomes

  3. Mitochondrial mutations

  4. Excess cells of unneeded types (senescent cells, fat cells)

  5. Extracellular cross linking (reaction between sugars in the blood stream and long lived proteins that causes, among other problems, hardening of the arteries)

  6. Extra cellular junk, garbage that needs to be brought into the cell to be broken down by the cellular lysosomes

  7. Junk within the cells that the lysosomes are not adapted to break down.
The second step to establishing biological markers is to invent effective tests for each of these seven factors. Measuring cell loss might require a noninvasive scan of the brain and the heart. By measuring the body fat percentage with calipers a doctor could determine the level of unneeded fat cells and the loss of lean muscle mass. Mutations of chromosomes and mitochondrial mutations could perhaps be measured with a blood test. Senescent cells, extracellular cross linking, and junk inside and outside the cells could also be measured with a blood test. A biopsy might be needed in certain cases.

Once these tests are available and are accepted medical practice, a doctor could run these tests on an individual and the results of these tests could then be assigned a score from 0 to 100 (100 being the best, 0 being the worst).

If, for example, a patient had no measurable chromosome mutation, he would score 100 in that category. Once the doctor had a score for each of the seven categories he or she could plug those values into a weighted average formula like this one:
B = (Lp + CMp + MMp + ECp + CLp + XJp + IJp) / 7

B = biomarker score

L = Cell loss

CM = chromosome mutations

MM = mitochondrial mutations

EC = excess cells

CL = extracellular cross linking

XJ = extracellular junk

IJ = intracellular junk

p = the percentage of importance each of the seven factors play in aging.
In order to know the relative importance of each of these seven factors, the tests of the seven factors will have to be run on many individuals of every age. Doctors would probably want test subjects that are in reasonably good health for their age. Once they have average values for each of these tests for all age groups they will have a better understanding how each factor affects aging and how important each factor is in the overall picture of aging (the little p's in the formula). This will be the third and final step toward establishing the first biomarkers for aging.

The biomarker formula will return a score from 0 to 100. This score could be converted into an "effective age" to aid the patient's understanding.

UPDATE: Biomarkers are debated here.

Posted by Stephen Gordon at March 12, 2004 09:26 AM | TrackBack

Aubrey added a good comment to the post on biomarkers a little while ago:

Posted by: Reason at March 12, 2004 12:53 PM

Aubrey de Grey sends this comment via email:

Hi Stephen,

Very good! Change "calipers" to "DEXA" and the biology is basically OK.

The fact that one person at age 50 can be much "older" than another is not a simplification - it's your whole point.

I had said in my email to Aubrey: "I'm sure this is an oversimplification, but the entire concept of using a number to describe age is a simplification - one person at age 50 can be much "older" than another."

And go here for an explanation of DEXA:

Essentially you say what I said in my last paragraph at an hour or so ago. If we can measure the real mediators of age-related decline, the things that causally link being alive to being dead, we're done re biomarkers. The problem is that the biopsies you mention are not as easy as they sound: blood tests, for example, will only pick up mutations in some cell types, which may not be representative. And the problem with existing, easy-to-measure attempts at biomarkers is that they aren't on the causal chain of events from metabolism to pathology -- they're epiphenomena -- which means the fidelity of how well they reflect processes that *are* on that chain is very modest.

You might also note that the percentages in your equation will change as rejuvenation therapies are developed. My point about mitochondrial mutations at fightaging is a simple case - their contribution would fall to zero once we can get the substitute nuclear genes in place.

Cheers, Aubrey

Yes. As individual aging factors are addressed the other factors will represent larger percentages of what is left of the aging problem.

Posted by: Stephen Gordon at March 12, 2004 02:37 PM
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