At the Helm of the Biological Revolution

What inspired you to study DNA damage and aging?

DNA keeps all instructions for life and it is of key importance to keep DNA in optimal condition. Therefore damage to this molecule must have major implications. When I got a chance to enter the field of DNA damage and repair in 1981 I knew I would be working on something relevant. Indeed, it was known that DNA repair defects could pre-dispose to cancer, but I always believed there was a relation to aging too, which could have links to a range of diseases – Alzheimer’s disease (AD), cancer, diabetes, cardiovascular disease – all of these major killers are age-related. With the average lifespan gaining over two years with every decade since 1840, age is now the most dominant health problem in developed countries.

So during my studies I began to uncover these connections between DNA damage, aging and disease. Many people in the research community were skeptical, but I believe they are becoming increasingly convinced – out of everything I have done in my career, there is nothing I would consider as groundbreaking as my current work.

Why is age-related disease research so challenging?

The lack of suitable animal models for the study of many aging-associated disorders is a huge hindrance. For instance, mouse models for AD and other neurological diseases aren’t actually very useful – mice don’t develop cognitive disease as they age. People have converted the mouse into a model for AD through forced, transgenic overexpression of mutated human genes responsible for the formation of plaques and tangles, but even so, these mice with human plaques and tangles show very few clear features of loss of cognition. So unfortunately, little progress has come from this.

A problem specifically with AD research today is that it concentrates on plaques and tangles in the brain. However, the most important risk factor for AD and other dementia’s is age, which has hardly been addressed in experimental AD research because it takes a long time and is difficult to approach. However, to get a more complete picture we need to take aging into account. Right now, despite at least 500 clinical trials and billions of dollars spent on research, we are nowhere near a drug or an intervention for AD – so it’s clear there’s still a long way to go.

How does your approach differ?

We have focused on DNA damage in order to bring important aging processes into the spotlight – our work shows that accelerated aging can be induced by interfering with DNA damage repair, and this process is of extreme importance for not only understanding aging, but learning to manipulate, delay or modify it. Over time, DNA damage in our cells can lead to mutations and in turn cancer, or can accumulate and interfere with DNA replication and transcription, and therefore gene expression. This can either cause cells to die early, or to attain senescence (the cells stop dividing but do not die), both of which contribute in a major way to aging and onset of aging-related pathologies. These are the processes we want to target.

I also have great hopes for the mouse models we have developed, as they are strikingly similar to human patients who have an inborn DNA repair defect that causes accelerated but bona fide aging –we are able to dramatically accelerate all aspects of aging from years down to weeks, or we can target particular organs and tissues (such as the brain) for accelerated aging using a simple genetic switch. These improved models should mean our results have more clinical relevance, facilitate research to understand the molecular basis of aging, identify biomarkers of aging and find ways to intervene in the aging process.

Importantly, this acceleration also means our studies take less time. If you wish to study lifespan extension, even in mice, it’s time consuming – the average laboratory mouse can live two or three years, so it could be four years before one experiment is finished. With a rapidly aging model, you can get results in weeks with much lower numbers and much reduced costs.

The results we have so far provide concrete evidence for connections I have studied for a long time, and the link between aging and DNA repair is even greater than I could have ever imaged – it has been a dream come true for me.

What do you hope to achieve?

We have yet to publish, but I’m very excited by our recent findings. I believe that in five to 10 years, we could be directly influencing the processes of aging.

Primarily, we have been looking into the relationship between DNA damage, aging and nutrition – which foods are helpful and which are harmful? Besides the air we breathe, food is the only thing which enters our body and our cells, and can remain there for a long time. It is a major external influence, and conditions like AD, Parkinson’s and other dementias are very sensitive to lifestyle factors, so I have high expectations for this link.

Perhaps paradoxically, it appears that dietary restriction (reduced food intake without malnutrition) may help in delaying aging, because the body responds to, for example, 30 percent less food by redirecting energy from investing into growth to investing into maintenance systems of the body. For instance, stress-resistance, immune response and anti-oxidant systems. This improves the chances of surviving the period of starvation. Continuous dietary restriction extends lifespan by delaying aging and reducing cancer. Our repair-deficient premature aging mice respond in an unprecedented manner to dietary restriction: lifespan is extended by more than 100 percent and neurodegeneration is strongly retarded. However, dietary restriction may not be easy to introduce – people don’t like to go hungry – but another potential angle is a pharmacological intervention that could trigger the same response.

So right now, our lab is looking at both the lifespan-extending effect of dietary restriction, and possible ways to implement these nutritional interventions, either through diet or potentially drugs, and I have no doubt that this approach will also prove effective in humans. As for AD research, we hope our mouse models can contribute to the study of that most important factor, aging; and that in some way we will be able to help find ways to prevent, delay or even (although I’m still not certain it is possible) treat AD.

Where is neurological research going?

I have never been as enthusiastic and optimistic as I am now – the biological revolution is only just beginning. Epigenetics is set to have a big impact in the future. DNA can only tell us part of the story. Chromatin is very dynamic and versatile, and the number of modifications that can take place make it extremely complicated, so I don’t know how easy it will be to address experimentally. But I think it will become very important for understanding the more subtle differences between individuals.

Stem cell research is another growing area, but at the moment I find it difficult to see the applications for neuroscience. For tissues with high cell renewal, sure, but important parts of the neuronal system have little or indeed no cell renewal – so although I think stem cells will have an enormous impact on research, it’s still not clear what they can do for neurodegeneration.

Study of genotype/phenotype connections in neuroscience should also become a greater research focus. For instance, the genetic and physiological basis of intelligence, memory and emotion. Our brain is what distinguishes us, and understanding how it functions is crucial to understanding our evolution as a species – both where we’ve been, and where we’re going.

And in the area of protein and metabolites research, new technology, such as mass spec, is revolutionizing this field. Modelling system biology, even though it is a buzz word, I hope in the future will certainly be something that is extremely useful – it provides invaluable insight into complicated responses in biological systems. Synthetic biology is another area that maybe very important as well; it allows the re-design or design of new properties or organisms. The field of molecular biology is so exciting!

As the population continues to grow older, my greatest hope is that neuroscience will present ways to promote healthy, active aging so people can retain neurocognitive function, remain independent, and enjoy a high quality of life for as long as possible. My hope is to leave a world that’s better than the one I entered, at least for a very small part, because of my own contributions.