Interview with Prof. Slagboom Part 1: Genetic and lifestyle factors in ageing

Nightingale recently interviewed Prof. P. Eline Slagboom (Leiden University Medical Center, The Netherlands) about her pioneering research on biological ageing. In this part 1 of our interview, Eline explains why genetics and lifestyle factors play key roles in age-related diseases. 

Eline, your Ph.D. thesis was on the topic of “Genomic Instability and Ageing.” What was it that attracted you to studying ageing and how did this become a main focus in your career?

I was very interested in repetitive DNA, as this had just been discovered at the time, and I thought that it may be dangerous to have repetitive DNA in the genome. I had a feeling that during ageing there might be this sort of “time bomb” of genetic instability. During the years afterwards, I became interested in ageing because it’s a shared factor in many diseases. 

The diversity of human health-span can range from unhealthy 60-year-olds to healthy centenarians, not to mention displaying considerable gender-influenced differences. Why is this the case?

At one extreme, you have very strong familial components with those families that don’t live very long – as they have a propensity to get diabetes, cancer or other diseases earlier. At the other end of the spectrum though, you have families with a propensity to become long-lived, and do so generation after generation. These very long-lived families have healthy intrinsic capacities in immunology and metabolism, but there’s also a whole range in-between without clear familial aspects. I think that this diversity is mainly due to environmental factors throughout a person’s life course. 

The genetic components of life-expectancy in the population at large are not that significant. It’s about 25%. So that means 75% of your lifespan is really determined by what happens to you throughout your life course. Already, early in development, parental lifestyle factors and environment matter. If you’re exposed to some adverse aspects and accumulate exposures, you will develop age-related diseases at 60 or 70 years of age. I’m convinced that in the second half of life, your own personal life course has a bigger effect than your genetics.  

What have the results of the GARP study told us?

When we were looking into the families with osteoarthritis (let’s say at middle age and younger) we found that the genes involved were related to early development. We became interested in how the genes that play an early role in development of your skeleton might be epigenetically dysregulated in later life. That is how we linked osteoarthritis to more general theories about ageing. 

Why is evidence-based medicine for people over 70 currently so undeveloped?

It’s because of the heterogeneity of ageing. If you go directly to people over 70 then there is such heterogeneity you don’t really know if you’ll get a clear answer as to whether a medication helps or not, and at what dose. I think, even for approved medications, you could already improve the situation by classifying elderly individuals according to their intrinsic capacity and see in which people medications work best. 

How can we improve the monitoring and understanding of treatment responses in the elderly throughout the second half of their lives? 

Since people are so heterogeneous, they respond heterogeneously to treatments. This is partly due to their homeostasis. Knowing that immune, metabolic and inflammation factors are immensely important for healthy ageing and homeostasis, I think that any kind of monitoring marker that combines these aspects of health could be very useful. In an ideal world, you would measure all metabolites and immune responses in blood as a generic read-out of the health status of tissues. I became interested in Nightingale’s NMR platform because it detects a relevant fraction of this. I would hope that if you look at generic factors, in the end you would be able to make estimates of the biological age of individuals (e.g. “one third of 75 years olds are at risk of developing adverse responses to a specific course of treatment because of their vulnerable physiology, their older biological age”). 

Your novel combination of twin studies with molecular (telomere) genetics in the nineties has had significant impact on ageing research. Twin studies have shown that longevity has low heritability (20–30%). What do you think has the greatest molecular impact on human ageing? 

I think factors that affect your immune system and metabolism have the greatest impact, for example the accumulation of damaged proteins and DNA, senescent cells, blood-borne factors. Such factors are to great extent influenced by exercise, lifestyle, nutrition, sleep patterns, stress and your intrinsic capacity (due to your genetic background). We know that what happens very early in life (even prenatally), really affects the regulation of the genome. In monozygous twins, you see that they start to diverge more and more in the second half of life in molecular and physical terms. For example, not only the weight gain in the second half of life but also in the way your fat is distributed changes. 

I think the most important thing is to make people understand that when they’re at risk, they can really do something about it. That said, you can’t say to a 70-year-old who has never exercised whatsoever, “start exercising now.” People overdo it, they damage their tissues because their homeostasis wasn’t all that good in the first place.

I’m convinced that a lot of the things that happen to you in ageing are actually modifiable. Animal studies have shown that you can break down aspects of ageing into a handful of cellular problems. If you change the physical exercise or food intake, or by certain compounds for example those that remove old (senescent) cells from tissues, you really can make ageing effects reversible. We always thought that “wear and tear” meant the body gets more and more damaged and you can’t repair it again. We know now for animals that’s not really the case and the first trials to modify the presence of senescent cells in tissues of osteoarthritis and glaucoma patients are now underway. In humans we also see that lifestyle interventions beneficially influence health and the capacity to restore age changes in tissues.   

In the second part of this interview, Eline discusses healthy ageing and "age-predictors." 

Extra reading

Find out more about how metabolomics is helping researchers to unravel the complex biological mechanisms underpinning ageing in our article, Measuring Youth.