Few things in aging research are ever straightforward, and today’s topic is no exception, as two researchers enjoy some back and forth regarding whether and how the World Health Organization (WHO) should recognize the aging processes as a disease.
Proposing a new framework to facilitate development of rejuvenation therapies
Back in November 2019, an international group of researchers published a paper proposing a new healthcare framework in the journal Science in order to help older people stay healthier for longer by improving the development of therapies that target age-related diseases .
The proposal encouraged WHO, governments, and the medical science community to work together to develop a classification and staging system that uses a new framework as the foundation for the diagnosis and treatment of age-related diseases.
The publication came as a response to the fact that many age-related diseases currently lack sufficient diagnostic criteria and clinical-severity staging. This then presents a considerable barrier to the development of therapies that aim to address those diseases.
Currently, the classification and severity staging of age-related diseases is limited in effectiveness due to it being inconsistent, incomplete, and non-systematic. For example, some diseases can develop in several organs but are only classified in a single organ. This is the case for intrinsic organ aging, which can affect multiple organs.
In order to solve this problem, the researchers, including bench scientists and medical practitioners guided by Dr. Stuart Calimport and Dr. João Pedro de Magalhães, created a position statement to serve as the foundation for properly and comprehensively classifying and staging the severity of age-related diseases. The statement includes aging at both the tissue and organ level, organ atrophy, the pathological remodeling and calcification of tissues, and age-related systemic and metabolic diseases.
The aim of this publication is for WHO to adopt its suggested framework, which would potentially speed up the development of therapies that target the aging processes directly.
A drug development researcher begs to differ
As is the norm in academia, there is often a great deal of back and forth between researchers, and this is especially true with a project of this kind. There has been considerable discussion around this proposal, including a response letter from Dr. Alexander Zhavoronkov of Insilico Medicine, published in the journal Science in response to this original publication.
One of Dr. Zhavoronkov’s concerns is the timing, and as a year has passed since the latest version of the International Classification of Diseases (ICD), which included sarcopenia (age-related muscle wastage) in its codes, the proposal might seem a bit late to the game.
ICD-10, the previous version, was first endorsed by the World Health Assembly in 1990, and it was first used by member states in 1994, which offers some idea on how infrequently major updates occur.
Changing the ICD between these periodic updates is, of course, possible, but it would require considerable effort, including a comprehensive review of the literature by medical researchers from multiple countries. The next revision of the ICD is anticipated to be in 2028 or later, and there is a lot of basic research on aging to be done before then.
Dr. Zhavoronkov suggests that the proposal also overestimates our understanding of aging in the context of classifying age-related diseases. There is evidence that the detrimental effects of aging begin from a very early age, making the staging of most aging processes a massive undertaking requiring large-scale longitudinal studies in humans and animals.
Also, the concept of staging is not consistent with the current ICD code system, which is designed to provide a standardized system for disease reports and cause of death. Implementing a staging system as proposed into the ICD would require some serious levels of retooling that would need a huge international effort.
Dr. Zhavoronkov believes that we are still in the early days for aging research in the pharmaceutical drug discovery field. Indeed, the majority of the industry is still currently focused on the common biological pathways linking aging and age-related diseases and are doing it within the current healthcare model; in other words, they are mostly treating symptoms and not the root causes of aging.
He suggests that in order to change the focus of drug discovery as a whole, we must now demonstrate that basic research on aging can provide us with useful therapeutic targets that can deliver demonstrable results in treating or preventing age-related diseases.
This is a good point, and, really, until there is some very clear demonstrable evidence that anti-aging is plausible in humans, things will not change. Let us hope that human trials for senolytics and other approaches that directly target aging will change things in the near future and that the pharmaceutical drug discovery industry will put its full weight behind developing drugs that seek to restore youthful function.
Finally, he also points out that there is still yet to be a consensus on which biomarkers of aging are optimal for measuring senescence. This is true and something that we have written about many times here at Lifespan.io: there is not only an urgent need to develop a range of accurate biomarkers of aging but also a need to agree, as a scientific community, which biomarkers together best constitute a panel able to measure changes to biological age resulting from therapeutic interventions. If we cannot measure those changes accurately, then we cannot demonstrate a therapy works and get it approved for human use.
An author’s response
One of the original authors, Dr. Stuart Calimport, also responded to these concerns in the same edition of Science.
Dr. Calimport argues that while indeed the major updates of the ICD are infrequent, WHO does accept submissions and proposed updates on an ongoing basis. Given that the ICD sees regular revision, Dr. Calimport believes that this would not be a major barrier.
Regarding the concern of our current knowledge of aging and the processes of senescence being barriers to their addition to the ICD, Calimport suggests otherwise. He counters that classification and staging consensus are things that the ICD would benefit from now. He also suggests that as senescence at the level of our organs is already in the ICD, in the case of “intrinsic aging of the skin” and “photo-aging of the skin”; with a corresponding staging scale, it should be equally valid to apply that to all organs and tissues of the body in the same manner as well as to age-related diseases.
The author accepts that there is indeed still much to learn about age-related diseases; however, he counters that there are also diseases currently defined in the ICD which are not fully understood either, and yet they have codes. In the case of skin aging, for example, the level of knowledge grew following its classification in the ICD. He also uses the example of Alzheimer’s disease and its inclusion in the ICD-9; prior to its classification, it was not acknowledged as a leading cause of age-related death. Essentially, Dr. Calimport argues that if a disease or a disorder can be identified, is distinct enough to be recognized, and has sufficient supporting research behind it, then it should be included.
He also begs to differ for the case for staging in the context of senescence in the ICD. He argues that it is quite common for diseases to be classified and included in the ICD before they have clinically accepted biomarkers.
Dr. Calimport suggests that macroscopic and histologic measures, similar to the Glogau scale used for skin, could be used to determine the staging of organismal senescence, at least initially. Longitudinal studies in animals and humans could then be used to further develop and refine staging of organismal senescence in tissues and organs and be used in the context of clinical endpoints and personalized medicine.
The author also accepts that senescence does begin from an early point in life but suggests that the ICD classification would be able to distinguish between this early stage of aging and the harmful changes and decline aging causes later in life.
Dr. Calimport also welcomes the development of effective aging biomarkers and a comprehensive staging system that would support the creation of interventions against the aging processes and thus against age-related diseases.
Considering aging as a disease in its own right, and how it could be included in a way that supports the development of effective therapies, is currently a hotly debated topic. The exchange described above is fairly typical of such discussions surrounding this topic, and hopefully sooner, rather than later, a solution that satisfies the majority of the academic community will be found.
 Calimport, S. R., Bentley, B. L., Stewart, C. E., Pawelec, G., Scuteri, A., Vinciguerra, M., … & Fleming, G. A. (2019). To help aging populations, classify organismal senescence. Science, 366(6465), 576-578.