Linda Partridge, Institute of Healthy Ageing at UCL, Tom Misteli, National Cancer Institute in Maryland, Jan van Deursen, Mayo Clinic in Rochester, Minnesota
Understanding age and age related diseases involves research at every level Ė from populations through individuals, their organs and separate cells, and even down to the molecular domain. These approaches were brought together recently for conference on Ageing and Bioscience, hosted by the Babraham Institute just outside Cambridge. And despite their different scientific backgrounds, researchers of age and age-related diseases appreciate that itís not a purely academic problem they face.
Linda - I'm Linda Partridge and I'm Director of the Institute of Healthy Ageing at UCL. A very practical problem, I think, is the one that many of us are trying to address, which is how to keep people healthy as they get older. The economic impact of the ageing population on health services is just becoming completely unmanageable. There have been a lot of headlines recently about the National Health Service and the very complex presentations that are coming in with a lot of old people and really, the inability of the system to cope. And of course, the major burden of ill-health is falling on older people now, so thatís where we should be focusing our attention to try and help people.
Ginny - Some people, of course, live longer than others. In some cases, much longer. So can we just look to them to understand how to live long healthy lives?
Linda - One of the most interesting facts is that people who live to be over 100 (centenarians) are terribly average in the way that they behave. They're no less likely to smoke than other people. In fact, the world lifespan record holder was a French lady called Jeanne Louise Calment and she gave up smoking when she was 119. So clearly, these people must be very resistant to the effects. They're no more likely to take exercise, they're no less likely to be podgy than other people. They're a bit of a mystery really, but they do seem to have some genetic characteristics, which interestingly are similar to the ones that made laboratory animals long-lived. So, thatís a rather nice ray of light that suggests that we really can use simpler animals that donít live as long as humans and where we can do experiments to try and understand the mechanisms of human ageing.
Ginny - Genes of people who live long healthy lives can only tell us a part of the story. For Tom Misteli, Associate Director at the National Cancer Institute in Maryland, the answers lie in a set of rare diseases.
Tom - One tool, one way to study human ageing is by looking at premature ageing diseases. So, these are very rare diseases, most of them, where people age prematurely very, very rapidly. There's about 6 or 7 of those that we know of and interestingly, all of those have something to do with DNA damage and DNA repair. The advantage that we have with these premature ageing patients is these are all genetic diseases, so we actually know exactly what is wrong at the DNA level in those patients. So for example, we work on a particularly rare disease, which is called Hutchinson-Gilford Progeria Syndrome. This disease is caused by a single mutation in the genome. We know exactly what the mutation does at the level of DNA, at the level of protein, and then we begin to study what happens at the level of cells. So, this particular mutation, for example, causes a defect in the cell nucleus, in the structure, in the architecture of the cell nucleus, and that influences the organisation of the genome and actually leads to DNA damage and subsequently to that then to the ageing defect.
Ginny - But can disordered ageing conditions really tell us about normal, healthy ageing?
Tom - I think the answer for all of these premature ageing diseases is, yes and no. So, there will be certain aspects of the disease which are also found in normal ageing and then other aspects are missing. So for example in our favourite disease, this HGPS disease, we see many, many of the phenotypes at the cellular level that we see in patients. We also see those in healthy, normally-aged individuals. The patients for example, they all die of cardiovascular defects, heart attacks, and stroke, and the pathology of those cardiovascular defects looks very, very similar to what you see in a normally-aged person. On the other hand, the patients that weíre looking at for example, they never develop tumours. We actually find that interesting. We actually use that now to ask, ďWhat are the mechanisms that prevent tumours or promote tumours in aged individuals?Ē
Ginny - The link between age and tumour growth prompted Jan van Deursen from the Mayo Clinic in Rochester, Minnesota to approach ageing from a perspective of cell biology...
Jan - Around the age of 45-50, chances of getting cancer increase exponentially. Cancer is considered to be a disease of gene mutations. They donít necessarily increase dramatically around that age and so, that doesnít really explain that acceleration. I think that weíre missing something. We have a missing link. Perhaps that missing link is the changes in tissues that happen in general during the ageing process that become much more permissive for cancer cells or pre-cancerous lesions that we are all carrying to turn into tumours. So for instance, as we age, we accumulate more and more so-called senescent cells, which are aged cells. What these aged cells do is they secrete growth factors that stimulate tumour growth and then proteases that kind of chew up the tissue structure so that itís easier for cancer cells, once they are forming in a tissue to actually escape the tissue, and form a metastatic tumour which is usually whatís killing people. So, thatís the kind of hypothesis that is finding some traction right now.
Ginny - Senescent, or aged cells, create a tissue environment that encourages the growth of tumours and these cells are also known to cluster around the sites of damage in age-related diseases. So, could removing them slow ageing?
Jan - We have shown that if you clear senescent cells in an animal thatís ageing - as they are formed, you get rid of them - you can attenuate a series of age-related pathologies. And so, the idea is, if you can find a drug that can mimic what we did through a genetic trick in the mouse that you might have benefits in the health span, so health span is the period of your life in which you're free of major chronic diseases. You know, we always talk about longevity, but nobody wants to live long if you're not healthy.
Ginny - Weíre beginning to develop an understanding of the genetic and cellular underpinnings of age and age-related diseases. But if we are to come up with a formula for a long and healthy life, we need to know more about our lifestyles and the environment in which we age. Linda Partridgeís work at the Institute of Healthy Ageing is shedding some light on the role of diet and nutrition.
Linda - One of the obvious features of these pathways that can seemingly ameliorate the ageing process is that they're the ones that respond to diet, they detect nutrients, and they determine what the animal does in response. Can it afford to reproduce, mount an immune response, grow, that kind of thing. So, given that they are rather central control systems for matching food to activity, knocking down their activity can have quite a lot of side-effects and not desirable side-effects like impaired wound healing for instance. So I think the name of the game at the moment is trying to understand how these pathways can improve health during ageing and whether that can be triaged away from these undesirable side-effects that seem to come along with it. So, drilling down into these pathways, trying to find out what genes show altered activity, can we separate them out into groups that are controlled by different mechanisms, and just target the ones that improve health? I think the jury is out on that at the moment. We donít know if itís going to be possible, but there's every hope I think that it will be.
Ginny - Linda Partridge from UCL and before her, Jan van Deursen from Mayo Clinic and Tom Misteli from the National Cancer Institute.