What does ‘ageing’ mean when it comes
to drug development?  

One of the great triumphs of modern medicine is the fact that people are living longer. As of 2020, people aged over 60 outnumber children under five. And by 2050 the number of over-60s will hit two billion globally (up from 900 million in 2015). There will also be more very elderly people than ever before.

Many of these people can expect to maintain good health for years to come. However, for others, a longer lifespan means a longer period of poor health and dependency. The implications for healthcare systems remain to be seen, but they certainly need to be prepared.

Unfortunately, our understanding of age-related diseases is far from complete. This becomes apparent when you look at the World Health Organization’s (WHO’s) most recent International Classification of Diseases (ICD-11), which was released in 2018 and comes into effect in 2022. Containing around 55,000 unique codes for injuries and diseases, the ICD-11 is an invaluable shared resource for healthcare professionals and researchers around the world.

Although the document does list ‘old age’ under the ‘general symptoms’ classification, it doesn’t delve into the issue very deeply. Ageing is commonly classed as a condition only in relation to skin ageing, leaving the rest of the body unaccounted for.

In November, an international group of experts released a position statement that would fundamentally shake up this approach. Published in the journal Science, the statement is a ‘call to action’ to the WHO, governments and the broader scientific and medical community.

It lays out a framework for classifying age-related diseases, including their level of severity. Importantly, it extends this classification to the tissue and organ level. This means ageing in the liver, for instance, would be given its own stage and classification code. As the researchers see it, ageing is less a single disease than a series of diseases, each with its own pathology.

Dr Stuart Calimpole, honorary fellow at the University of Liverpool, led the multidisciplinary research team, comprised of participants from 36 institutions across six countries. Speaking to Pharma Technology Focus, he explained how the new system might work and what its benefits might be. While he didn’t want to be quoted directly, he was happy for us to detail the thinking behind the framework.

As he explained, there would be a few key reasons to class ageing as a condition in its own right. For one thing, it would help us assess whether populations are ‘ageing well’, and learn which organs and types of damage are causing the most problems. This would lead to more targeted healthcare spending – which is particularly important in countries with fewer resources.

It would also give us a clearer insight into conditions like arthritis, dementia and cardiovascular disease. We know that cellular senescence (a process in which cells stop dividing) plays a role in many of these conditions. With proper classifications of ageing, it might be possible to halt these diseases at an earlier stage, as well as getting the green light for more ageing-related research.

Under the suggested framework, ageing would be tackled at the appropriate functional level. This means that, if two parts of an organ aged at different speeds, the two parts would be classified separately. Cellular senescence would be classed in stages ranging from zero (no damage) to five (life-threatening damage), while other signs of ageing, like atrophy and metabolic dysfunction, would be staged from zero to ten.

This would give health professionals a common language to talk about ageing. It would pave the way for new types of clinical trial, with more indications and clinical endpoints to aid drug development. And within a field like Alzheimer’s disease, it would help clarify the different stages of ‘normal’ and pathological brain ageing.

To understand why the ICD lacks these measures currently, it helps to look at how it was developed. Rather than having a single guiding manifesto, the document has been assembled over decades via a bottom-up, patchwork approach. Teams of specialists, focusing on a specific organ, supply their own insights, while new submissions are added on a case-by-case basis. (The one exception would be cancer, which has been classified by a special WHO body.)

This means its approach to ageing has been inconsistent and incomplete. Calimpole believes that smoothing out these inconsistencies would require top-down change.

This in turn might require ‘buy in’ from many different sources – not just the WHO, but also the UN, academic societies, pharma companies and governments. Given the magnitude of the issue, a piecemeal approach (individual scientists making individual submissions) might simply take too long, and oncology could be a better template to follow.

While the WHO has now rejected the majority of the researchers’ initial classifications, this could be due to the fact they were submitted late in the classification cycle. The researchers will be looking to review the WHO’s decisions, and will submit their revised suggestions at a later stage.

In the meantime, they will work with governments, academic researchers and the WHO itself to ensure their system is as accurate as possible. The next edition of the ICD won’t be for while, meaning strictly speaking the next chance to make a difference won’t be till 2030. However, it might come sooner if pressure starts to mount internationally – for instance, if governments declared a ‘global ageing crisis’.

His co-author at the University of Liverpool, Dr Joao Pedro de Magalhaes, said: “Ageing is the greatest biomedical challenge of the 21^st century. As such, this framework will increase our ability to develop longevity drugs and interventions that target diseases related to the ageing process.”

Professor Judith Campisi from the Buck Institute for Research on Ageing, added: “Bringing WHO and other governments into the effort to identify and classify ageing as a condition is the only way we are going to be able to address the unmet needs of ageing populations around the world.”