Open preprint reviews by Ilia Stambler

Classifying Aging as a Disease in the context of ICD-11

Alex Zhavoronkov, Bhupinder Bhullar

Excellent article.

Completely agree with your point that the main problem is the deficit (or even absence) of scientifically grounded or clinically applicable “diagnosis of aging”.

As you write “there is no universal set of biomarkers and guidelines for measuring aging as a system" and “to successfully evaluate the effect of any drug that influences aging, it is essential have a measureable endpoint, such as biomarkers”.

It seems that even biomarkers as such are not enough; there is a need to precisely define measurable *clinical* end points. Without their definition, it seems unlikely that aging can be recognized as a treatable medical condition (or disease). This seems to be a recognized problem for Alzheimer’s disease. Treatments may seem to work on biomarkers (e.g. clear amyloid), but seem to give no clear clinical benefits – and billions of dollars are gone.. But at least in Alzheimer’s there is a more or less clear clinical definition – unlike aging, apparently... As one author writes about Alzheimer’s disease:

«Regulatory agencies are unlikely to provide accelerated approval for a presymptomatic treatment based solely on biomarker (i.e., surrogate marker) endpoints without additional evidence to show that a treatment’s biomarker effects are “reasonably likely” to predict a clinical benefit.»

It seems this is largely a problem of scientific, clinical and even mathematical definition of aging – perhaps even less of its “socially constructed” perception (as in the case of mental illnesses or obesity). In the article "Estimation of Heterogeneity in Diagnostic Parameters of Age-related Diseases" we explored the question of some possible formal mathematical, yet clinically applicable, definition (p. 223)

Also generally, the methods of determining risk factors for mortality (including the factor of aging) appear problematic. For example, even in the authoritative Global Burden of Disease (GBD) study, it appears that the risk of death from various factors can exceed hundreds percents (when in fact it should be no more than 100% ...). And of course, in GBD, aging is not even considered anywhere close to a risk factor (though there are factors like “injuries by pedal cycle vehicles”...)

In the article “Information-theoretical analysis of aging as a risk factor for heart disease" we explored the question of a correct definition of risk factors and their combinations (p. 204)

Indeed, "senility" is already a part of ICD classification – as recognized by some GBD statisticians.

Yet, it is unlikely to affect policy makers, as it is considered a “garbage code” – when there is no clear clinical or biological definition. So in order to successfully use this code, it seems there is again the need to develop the evidential basis of biomarkers and clinical end points.

Here is, for example, how the same article about the Global Burden of Disease speaks about that “garbage code” (pp. 2099-2100).

«Murray and Lopez introduced the notion of “garbage codes” in the GBD and proposed methods to redistribute deaths assigned to garbage codes to probable underlying causes of death. Garbage codes are causes of death that should not be identified as underlying causes of death but have been entered as the underlying cause of death on death certificates. Classic examples of garbage codes include senility or cardiopulmonary arrest. In the GBD 1990, major garbage codes were identified and simple algorithms proposed to redistribute these proportionately to various causes (called “target codes”) that were the likely underlying causes of death. A similar approach was applied for the GBD 2000 and subsequent WHO updates».

And another consideration that seems very important – a treatment may improve the biomarkers and even clinical or functional end points of aging – but shorten the lifespan!!! (as in the case of some stimulants) It seems there is a need for long term analysis (ideally establishing the effect on the actual lifespan, or at least long term effects on mortality). Yet it seems this kind of research may not be very popular with investors or politicians. But without it, our “cures against aging” may shorten people’s lives…

Thank you

Ilia Stambler, PhD

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