Could ageing be driven by imbalanced genes?

Since our genes are the cookbook for our body, surely they have no small part to play in the process of ageing. The mystery of what causes ageing is still very much up for debate, but a recent study has hinted that ageing might be driven by an imbalance in your genes.

Will - Different genes code for different things and as a result, some are shorter and some are longer. Every cell in your body has to equalise the expression of long and short genes in case they become imbalanced. Usually having imbalanced genes means it's time to buy a belt, but in this case it might be a driving mechanism behind ageing here to explain his lead author on this particular study from Northwestern University Thomas Stoeger.

Thomas - Compared to younger cells, genes change the activity in a very particular way. There are genes that become more active relative to other genes and other genes that become less active compared to other genes. So different genes carry out different functions in our body depending on the function that they carry out, some genes are shorter and some are longer because the components that they encode also need to be bigger. And we found that basically genes that are shorter tend to become upregulated relative to other genes and genes that are longer tend to be downregulated.

Will - So as we age, the balance in our cells shift towards favouring the use of shorter genes. But as I said, length of a gene does not necessarily equate to its complexity.

Thomas - Generally, some of the short ones can also be complex. And some longer ones can also be complex. It really seems to be primarily the lengths alone.

Will - So how could this accelerate ageing? Well, have you ever been moved to a different seat in an aeroplane so that it had better weight distribution? If everyone sat on one side, it would require more fuel to keep the aeroplane stable and airborne. To quote senior author on this study, Luis Amaral, 'small changes in genes do not seem like a big deal, but these subtle changes are bearing down on you requiring more effort.'

Thomas - So when we map this back to humans, we found the genes that are short, those that tend to become relatively more active during ageing, Also preferentially encode for genes that when they're active actually shorten lifespans and genes that are long basically enrich for genes that would extend lifespan. So there seems to be some really surprising organisation of the genome according to size and effect on lifespan.

Will - So why might the body be doing this? Well, Thomas has a very interesting theory about what becomes more prevalent as we get older.

Thomas - Some of the genes that are short are genes that are involved in fighting pathogens. So basically when there's something harmful in our environment, there are certain genes that need to be active to fight those. And genes that are shorter, it's quicker to activate those than genes that are longer. So there could be a short-term benefit under some circumstances, but a long-term disadvantage. If these genes are permanently active.

Will - Perhaps we are then having to fight disease harder as we get older. Creating a vicious cycle that requires shorter genes with that imbalance only accelerating the process of ageing. But now that we've identified a potential mechanism, could this have practical applications in gene therapies based around ageing?

Thomas - This phenomenon that we have found has also been described outside of ageing. And outside of ageing, people notice that this can happen when that enzyme that reads genes and activates information in there. And there is the same principle also when it runs too fast, but also too slow. So it might indicate that therapies on ageing might be most effective if they target an intermediate level of activity. Don't try to push things into one extreme or other, but maintaining intermediate levels will be a conceptual departure from many existing strategies to extend lifespan.