Research into the underlying causes and consequences of ageing has long been of interest to scientists, and has resulted in a widely accepted set of “hallmarks of ageing”. These hallmarks include both DNA damage and mitochondrial dysfunction. In our recent paper (link) we set out to discover if mitochondrial DNA damage can accumulate over a lifetime, and further whether this accumulation can be linked to other hallmarks of ageing.
With the central role mitochondria have in cell energy production, mutations in mtDNA can have catastrophic consequences for cell health. Each cell has thousands of mitochondria constantly replicating and dying, and malfunctions might not become noticeable until they have spread through the cell. Think of a neighbourhood powered by solar panels, if one breaks then the lights stay on, but break enough of them and you guarantee a power cut!
Most studies focus on bulk tissue, a city made up of these solar powered neighbourhoods in our analogy. But by averaging across thousands of cells these studies might miss that many neighbourhoods are without power, and all for different reasons! We instead looked at single-cell data which lets us zoom in to find the problem in each neighbourhood. These ‘cryptic’ mutations are invisible in bulk studies but turn out to make up the majority of mutations in a tissue, and we aimed to see if their number (the number of neighbourhoods affected) or heteroplasmy (the number of solar panels in a neighbourhood affected) increased with age.
We found that these mutations build up with age in a non-linear way, reaching noticeable levels in mid-to-late life in humans. We further found that in mice and rats this threshold is reached sooner, in accord with their shorter lifespans, hinting at an evolutionary constraint to these mutations.
Even more striking, we found that these somatic mutations are not under the same selective pressure as those that are inherited from our mothers. Inherited mutations affect all our cells and cause a power cut across the tissue, and tissue failure is a lot more noticeable to the body than cell failure. This means that mutations which cause cellular malfunction could be free to spread in cells provided that they occur after a tissue has fully formed. We compared cells carrying those mutations to cells without and found that the presence of these somatic mutations could be linked to 5 of 9 hallmarks of ageing.
These results, while exciting, were not entirely surprising to us. Before looking at any data we did some back-of-the-envelope calculations using approximate mitochondrial values from the literature. The maths suggested that mutations would reach high levels by around 100 years, close enough to human lifespan to get us interested. Of course, those rough estimates could have been way off, with mutations either rising too early to matter or too late to matter. Instead, we found that this calculation was basically correct and mutations reach levels likely to have real effects at the time when ageing symptoms become noticeable. What we did not expect was the results in rats and mice where mutations accumulated much sooner, though this only strengthened the case that these mutations are meaningful. That discrepancy pushed us to think more carefully about how to build a model to explain what we were seeing.
Our paper provides a simple mathematical model for the spread of these mutations. By changing just two aspects, the number of mitochondria in cells and how fast they turnover, we can dramatically shift how fast these mutations spread. We looked at one known anti-ageing intervention in rats, calorie restriction, which is known to increase the number of mitochondria in cells, and excitingly found that, when comparing calorie restricted rats to their freely fed counterparts, the calorie restricted rats had fewer mutations at high heteroplasmies. In short, the tiny solar panels in our cells may quietly accumulate flaws with age, but by protecting mitochondrial health we might one day keep the lights on longer. Ali and Nick.
