Challenging the one drug/one disease model

A new paper supports the targeting of aging processes, rather than just one disease, to improve Longevity outcomes.

Multimorbidity is a challenge for Longevity; defined as suffering two or more long-term health conditions, it affects two-thirds of people aged 65 or over [1] and is an enormous obstacle both in terms of extending life and improving the quality of that life.

Now a new paper delves into the challenges of polypharmacy, looking at recent clinical trial success with repurposed drugs and at how targeting specific aging processes with new drugs could affect more precise interventions.

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Longevity.Technology: Like whack-a-mole, common risk factors often make more than one disease pop-up and age is a massive risk factor. Not only does suffering from multimorbidity affect quality of life and lead to poorer health outcomes, but it is responsible for disproportionate healthcare workload and costs.

Professor Chris Whitty, Chief Medical Officer for England has reiterated the importance of multimorbidity as a research priority [2] and the UK’s National Institute for Health Research launched an initiative last year with the strategic objective of improving prevention, management and treatment of multimorbidity. The key to treating multimorbidity and promoting Longevity lies in targeting the underlying age mechanisms.

“We suggest that it is vital that we move away from the one drug/one disease model for therapeutic interventions …”

The population is aging – aging well and staying healthy, or aging chronologically, but not biologically, are what Longevity is all about … but the challenges of multimorbidity will only increase in the coming years unless their causes are addressed. This is especially pertinent as many healthcare systems are focused on treating single diseases as they pop up, rather than treating aging as the disease it is.

A team based at the Institute of Inflammation & Ageing at the University of Birmingham and the University of Dundee in the UK has published a paper in Drug Discovery Today that highlights the drug discovery challenges presented by multimorbidity.

When a range of drugs is given to treat a range of conditions, not only do the drugs become less effective, but this polypharmacy can have serious adverse consequences [3]. The paper argues that we must move away from treating diseases individually as this can result in fragmented and conflicted therapies, rather than tackling the core reason for the conditions – aging itself.

The authors say: “There is an urgent need for a novel approach to age-related multimorbidity, and we suggest that this requires a drug development and testing paradigm that focuses on the core processes driving multimorbidity rather than on its individual disease components. We suggest that it is vital that we move away from the one drug/one disease model for therapeutic interventions and drug discovery in multimorbidity towards a more holistic approach that brings its underlying causes into greater consideration [4].”

When we spoke to Professor Ilaria Bellantuono earlier this year, she made this point as well: “…we need to understand multimorbidity a lot better before we can actually intervene … The usual paradigm of one disease, one drug and choosing patients [for clinical trial] that only have that disease does not correspond to reality and I think this is something that we’ll have to change because 70% of the drugs are used for patients with multimorbidity and yet they’re never tested in this group of patients.”

“… an exciting opportunity to treat the generic drivers of multimorbidity to extend human healthspan …”

The paper authors argue that basing therapy on a biogerontological understanding of aging, and targeting the nine hallmarks of aging when treating and preventing age-related disease and multimorbidity, will “not only provide a potential route to understanding the complex process of ageing and age-related diseases, but also offer an exciting opportunity to treat the generic drivers of multimorbidity to extend human healthspan [5].”

As well as repurposed drugs (metformin, rapamycin, dasatinib, quercetin, navitoclax, &c) there are promising results from novel senolytic therapies, including selective Bcl-xL inhibitors, fisetin, heat-shock protein 90 (HSP90) inhibitors and cardiac glycosides.

With progress in AI-led drug discovery and the application of Big Data, we would expect to see an ever-growing raft of possible therapies; however these need to be tested in an effective way, mapping effectively to humans from animals and tackling the specific aging process, rather than the resulting disease for maximum effect.

The paper concludes that geroscience-guided clinical trials are the route to Longevity success, and that biomarkers will be vital in understanding and combating aging: “Any progress in preventing multimorbidity and late-life poor health will inevitably come from better predictors of their occurrence and the ability to intervene and monitor therapeutic responses in individuals at greatest risk of developing multimorbidity,” the authors write.

“The use of surrogate biological measures, biomarkers, to detect individual variability in the progress of ageing as a risk indicator (i.e., accelerated ageing) and to monitor responses to interventions will be vital in testing the geroscience hypothesis [6].”
We agree.

[5] & [6] Ibid

Editorial image credit: Logan Bush /