Prof Ilaria Bellantuono seeks to build faster, better clinical trials for age-related disease with a focus on frailty.

Multimorbidity – an individual suffering two or more chronic conditions – is a key factor leading to increased mortality rates and healthcare utilisation among the older population.

In the spring of last year, the Healthy Lifespan Institute was launched at the UK’s University of Sheffield, with the goal of tackling the “global epidemic“ of multimorbidity. Bringing together more than 120 researchers from a wide range of disciplines, the institute aims to achieve a step-change in understanding of the biological and social underpinnings of the common processes that lead to age-related diseases.

Longevity.Technology: The co-director of the Healthy Lifespan Institute is Professor Ilaria Bellantuono, one of the speakers on Tuesday 28 April at the Longevity2020 online conference (remember, all presentation content is free, so do please join us):

“If you look at the numbers, you’ll see that over 60% of those over 65 have at least two diseases,” she says. “And if you look at the over 80s, which is really the group that has that is growing the fastest at the moment, you can see that 25% to 50% have frailty, which is really an undefined accumulation of deficits, which makes older people less resilient to an adverse event.”

Bellantuono previously headed up MouseAGE, a European initiative for preclinical testing of interventions in mouse models of age and age-related diseases, and the Healthy Lifespan Institute builds on that body of work.

“… because we now know a lot about how aging happens, we can actually offer a solution that decelerates the aging process.”

“Our work is based on the fact that we treat aging as a risk factor for disease – in the same way that we treat smoking for lung cancer,” she says. “So if you have the opportunity to decelerate aging at the biological level, then you have less chances of developing multimorbidity. And, because we now know a lot about how aging happens, we can actually offer a solution that decelerates the aging process.”
The institute’s work is based on three key pillars:

• Mechanisms of aging and disease;
• Interventions;
• Knowledge exchange.

“At the moment you have the group working on these fabulous drugs that decelerate aging and everybody thinks that that is going to be the magic bullet and someone else looking at behavioural changes, and they think that the opposite is true,” says Bellantuono. “So what we are suggesting at the institute is that we need to integrate different interventions and to do that across the life course. And that is where our pillars come in.”

When it comes to the mechanisms of aging, the institute looks at things like senescence and inflammation, and how they apply to the different diseases. But it also approaches the subject from another angle, looking at health data records, patterns and clusters of multimorbidity, in order to identify subgroups that have a causal relationship with all of the diseases.

“We need to do this because we need to understand multimorbidity a lot better before we can actually intervene,” says Bellantuono.

The institute focuses on drug-based interventions and geroprotectors, as well as non-drug based interventions like diet, exercise and behavioural components.

“We go from screening of molecules to testing in models, from Drosophila to zebrafish to mice, and then the clinical translation – we have good cohorts of patients where these can be tested,” says Bellantuono. “We are dedicating quite a bit of work to devising clinical trials where these drugs can be beneficial.”

“We should work very closely with industry and get the bits that are too risky for them over the edge.”

The Healthy Lifespan Institute works in partnership with commercial organisations and Bellantuono likes that partnership aspect. “My view is that academics should de-risk for industry,” she says. “We should work very closely with industry and get the bits that are too risky for them over the edge.”

Bellantuono uses geroprotectors as an example. “They are very risky for many companies to take on because the route to market is very shaky,” she says. “The clinical trials are difficult to perform because the patients with multimorbidity and frailty that we are trying to target are usually excluded from clinical trials. The usual paradigm of one disease, one drug and choosing patients 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.”

“… 70% of the drugs are used for patients with multimorbidity and yet they’re never tested in this group of patients.”

Designing trials is a primary focus for the institute, and Bellantuono wants them to be as short as possible – ideally three to six months in length. This is in sharp contrast to other aging studies, such as TAME, which has a 10 year proposed timeframe.

“We really want to look at resilience in older people – their ability to overcome adverse events,” she says. “This allows you to have trials that are not very long and manageable in terms of cost.”

The drug or compound to be tested isn’t as important to Bellantuono as the set up of the trial itself – everything from patient selection to measurement of outcomes. And frailty has emerged as a key measure.

“… there is not even an agreed a definition of what frailty is. I think this is because it probably brings together different diseases with overlapping phenotypes and I think we need to biologically understand it better – study it more in depth.”

“People that have little resilience to adverse events are usually frail, so what you really want to look at is how their frailty improves or doesn’t improve,” she says. “And so we are thinking about a variety of approaches to measuring this – from using computational models to looking at new biomarkers of frailty.”

Bellantuono feels that frailty is it not well understood at all, the problem being that we don’t understand the biology of it.

“I think this is because it’s always been looked at from a social point of view – and that the best intervention for frailty is exercise,” she says. “But there is very little else and there is not even an agreed a definition of what frailty is. I think this is because it probably brings together different diseases with overlapping phenotypes and I think we need to biologically understand it better – study it more in depth.”

Bellantuono points out that trial outcomes also have to be aligned with things that regulators will understand.

“Longevity and lifespan is not going to be one of them,” she says. “So we need to come up with something more realistic and also something on which we can do some health economics – you need to really to understand where a drug has an economic benefit.”

Image credit: Healthy Lifespan Institute