What happens to our genes as we age?

What does ageing do to genes, and is there anything we can do ourselves to slow that process? The University of Exeter’s Luke Pilling…

Luke - So DNA is very stable itself, but it undergoes a lot of insults as we go through our lives. Environmental and part of the metabolism even in our bodies. So they can pick up damage as we go. And so some of these will manifest as actual breakages of the DNA, but that's quite uncommon. But what is most interesting, I think from an ageing perspective, is where the damage occurs to the DNA and this results in a mutation, a change to the genetic sequence. And that can change how the gene or the protein is expressed and change the function of the cell. And as our cells and tissues as we go through our lives, there's more of these mutations that we call somatic mutations, as opposed to mutations that we inherit from our parents. These somatic mutations build up in our different tissues and that can quite profoundly impact the cell's ability to function, the tissue's ability to function and can even result in cancer.

Will - Do we know how these mutations occur? Do we know what drives them?

Luke - So there's all sorts of things. For example, the cells in your skin are exposed to a lot of UV radiation from the sun and that can cause damage to the DNA and result in these somatic mutations as I was mentioning earlier. There's part of the metabolism and it goes on in the cells that can produce what are called reactive oxygen species, and these can damage the DNA. And some of it's just chance, they might, whilst they're replicating and cells are dividing, for example, there might be errors introduced. We've got a lot of DNA repair mechanisms that are very good at correcting these errors when they're spotted. But inevitably some are passed on to the next generation of cells in our body as they divide.

Will - So correct me if I'm wrong here, ageing itself isn't necessarily what causes the damage, it's just the amount of time increases the chances that you encounter something that damages you.

Luke - Yeah, I think that's a good way to think about it. We do know as well though that people age at different rates. And so there's this really interesting concept called biological age, that we look at in some of the work that we're doing, where two individuals of the same chronological age, the number of times we've been around the sun might have a different biological age. So someone might be more ill for example, more frail compared to someone else who's still quite fit and healthy. And what we're very interested in is how or why or what results in people reaching older age free of disease and free of frailty. A related term is health span. We do a lot of work looking at how long people live and sometimes people think that we want to make people live forever, but really what we're interested in is the person's health span, the proportion of their lives that they live free of disease. And we know that there are genetic variants, inherited genetic variants in people, that promote health span. So I'm very interested in what drives these differences in ageing rates in different people.

Will - Is that all that happens to DNA as we grow older though? Because if DNA is this thing that almost endlessly replicates, surely that has an effect on the DNA itself.

Luke - Yeah, so telomeres are these bits on the ends of the chromosomes that protect the DNA during cell division because the process isn't perfect as the chromosomes are replicated and a bit is lost on the end each time. And so these telomeres are just repetitive sequences of DNA that essentially get shorter and shorter as the cells divide unless an enzyme is expressed called telomerase to lengthen them again. And in most cells in our body we don't express telomerase because this is actually a protection so that cells don't divide endlessly. But interestingly for some of the work we've done on telomere length, although yes it's true that people predisposed to having shorter telomeres are protected from cancer, it seems that they're at higher risk of other non-cancer chronic diseases. Things like cardiovascular disease. And this might be because people with shorter telomeres, their cells undergo fewer rounds of division before ceasing to divide stoppin., When the telomeres get too short and they, to this state called senescence, there's a lot of work going on cellular senescence in the field of aging and geroscience to try and understand how these cells that are still in your tissues, but they're no longer dividing and they're not necessarily as functional how they're impacting ageing as we get older.

Will - And you've alluded to it throughout this entire piece, but the buildup of small errors and mutations in the DNA as we get older, the errors that build up means it's probably not good news for the body.

Luke - Absolutely, yes. The somatic mutations will definitely result in lower functioning cells. A lot of the work that I do tends to focus on the inherited variation and how this can push people towards different sorts of phenotypes of ageing. And there's a few different ways that we look at this. Some of these are thinking about biological age based on biomarkers. So we look at their cholesterol levels, for example, and the different cell counts in the blood, the lymphocytes and neutrophils. But there's also phenotypic ageing, their muscle function or their bone mineral density. There's a lot of ways that we can try and get a window on a person's biological age because it's actually very difficult to assess without some quite invasive biomarkers, as you can imagine, to actually look at the amount of senescence in the different tissues. So we try to use these proxies for ageing itself and think about the inherited variation. So which genes are pushing people towards ageing phenotypes? And does that tell us something about biology and why some people are more likely to get disease and ageing versus others.

Will - To end it on a slightly lighter note, as you said, it's far more about the experiences you have in the healthy parts of your life rather than just trying to live as long as possible.

Luke - Absolutely. And there's a lot that people can do actually because the genes that we find that come out for biological ageing and things like this are genes that we know for cardiovascular disease and hypertension. A lot of things where people know about the risk factors for these already. So people can overcome their inherited genetic predisposition to some of these outcomes by eating a healthy diet and not smoking and being active. That has a massive impact on someone's health span in later life.