Unanswered questions in ageing: an interview with Dr Joris Deelen

I am a Research Group Leader at the Max Planck Institute for Biology of Ageing, working on the genetics of longevity and biomarkers of healthy ageing. The key questions my research tries to answer are two-fold; first, we aim to identify variations in the DNA of people who live to a very old age that protect them against age-related diseases. By using experiments in cellular models and mice, we subsequently determine how these variations influence ageing, with the ultimate goal to mimic these effects with pharmacological or lifestyle interventions that can be applied to the population at large. Second, we aim to identify substances in the blood that predict the development of several age-related diseases at once. We subsequently plan to use these so-called biomarkers to identify the vulnerable individuals in the population so that we can provide them with targeted interventions before the onset of these age-related diseases.

I have been fascinated with research on ageing since the start of my Bachelor of Biomedical Sciences in Leiden, the Netherlands. I therefore decided to do my master thesis in the group of Prof. Dr. Eline Slagboom and to continue my work there as a PhD student. From the start of my master thesis internship, I worked on both the genetics of longevity and biomarkers of healthy ageing and have continued that ever since. I think this research is of utmost importance since we are on the brink of the ‘Silver tsunami’, which means a massive increase in the number of people over the age of 65, which will have major economic and societal consequences, including increased healthcare costs. By identifying and then targeting the mechanisms underlying ageing, we will hopefully be able to decrease this burden on our society by having more people ageing healthily.

Ageing is often defined as a progressive loss of physiological integrity leading to functional impairment and consequently an increased likelihood of dying. Healthy ageing is therefore defined as the maintenance of functional ability to enable well-being in older age. There is a lot of discussion in the field about the classification of ageing as a disease. In my view, we should classify it as a process and not a disease (otherwise everyone would be sick), but we should treat it in a similar way as we treat diseases. Although some groups in the field are aiming to stop or even reverse ageing, the societal advantages would already be massive if we would be able to just slow it down and thereby compress the time that people are suffering from age-related diseases, that is, increase healthy ageing. We know that this should be possible, since some individuals who live to very high ages also show such compression or even absence of age-related diseases.

Our group, in collaboration with many other groups around the world, has performed large genetic studies on people who live to a very old age to see if they have any genetic variants that are commonly enriched or depleted in them. However, only two genetic variants in the apolipoprotein E protein have consistently been found. The first variant, ApoE ɛ4, has a lower prevalence in long-lived individuals. This variant is also associated with an increased risk for cardiovascular disease and Alzheimer’s disease. The other variant, ApoE ɛ2, shows the opposite effect, that is, it is enriched in long-lived individuals and associated with a decreased risk of disease. More recent efforts looking at the genetics of healthy ageing and longevity have shifted towards approaches focussing on families with multiple long-lived individuals, given that the genetic contribution to longevity in such families is expected to be larger. The first findings on this will be published in the next years.

My work on biomarkers has mainly focused on metabolites in the blood. These are substances that are made or used by the body when breaking down foods or chemicals, such as glucose and amino acids (the building blocks of proteins). We previously identified a set of 14 of such metabolites that are indicative of a person’s remaining lifespan and combined them into a score, which we called MetaboHealth. We were able to show that this score is also predicting the onset of many different age-related diseases and that lifestyle interventions can help to improve this score. As a next step, we are testing the MetaboHealth score in more clinical studies (i.e., in patients visiting the hospital or general practitioner) to see how well it performs there. The ultimate goal is to implement the MetaboHealth score in the population at large to identify people at risk for age-related diseases before they occur so that they can be treated.

In my group, we use a combination of bioinformatic tools and laboratory techniques. Moreover, we make use of data and material from humans, mice, and cultured cells. The laboratory techniques we use are a combination of standard biochemical methods to measure the effects on specific genes, proteins, or processes and so-called omics-based methods, which aim to measure effects on many genes or proteins at once. We also use more advanced methods, such as genome editing, to be able to create cell lines and mice carrying the genetic variants we identified in our long-lived individuals. The effects of the genetic variants on our mice are subsequently measured with a battery of functional tests, such as grip strength and motor coordination. Most of the work in my group would not be possible without the state-of-the-art core facilities within our institute, which support us with both instrumentation and expertise.

One of the main challenges we face in my research is that we are limited by the genetic data we can work with, especially from people of non-European descent. The number of people who live to a very old age is relatively small, especially when looking for families where several individuals meet this criterium. Moreover, we expect that longevity is a complex trait, which means that there are likely many genetic variants, each only present in a limited number of long-lived individuals, that work in concert. Hence, it has been very difficult to identify genetic variants that are commonly shared among long-lived individuals. I have, therefore, decided to shift the focus of my work to genetic variants that are uniquely identified in families with multiple long-lived individuals. We subsequently study these genetic variants in cellular models and mice to gather enough evidence to link them to the longevity of their carriers.

There are still many unanswered questions in the field of ageing, both from an evolutionary and mechanistic perspective. For example, people have proposed many evolutionary theories for ageing, but almost none of them have been experimentally validated. Moreover, from a mechanistic point of view, it is still unclear how much of the processes identified to contribute to lifespan in model organisms also contribute to human ageing. It has proven to be very hard to translate the findings coming from model organisms, especially when it comes to interventions targeting ageing. The big question is, if these interventions would add anything on top of lifestyle interventions, such as eating a healthier diet and increased exercise, and may thus be able to radically extend our lifespan. At the moment, there is no evidence that this is the case, but we should anyway rather aim to extend the healthy lifespan of the population at large, which is challenging enough by itself.