Why do we grow old and die? The question is a scientific conundrum, as well as an existential one. While scientific answers are sparse, two biologists from the Institute for Ageing and Health at Newcastle University believe they’ve found a new clue. They report the findings in the Proceedings of the National Academy of Sciences.
The accumulation of mutated mitochondria in single cells of aged organisms is a hallmark of aging found in many mammalian species. These mutated mitochondria, suffering from mutations where sizeable sections of mitochondrial DNA (mtDNA) have been deleted, have a curious habit of replicating rabidly and overwhelming wild-type mtDNAs.
All genes on the mtDNA are needed to encode proteins for the production of ATP, so if the majority of the cellular mtDNA population consists of deletion mutants the cell is not producing the amount of energy that it normally would. Since the biochemical consequences are dire, the success of these mutants has been a real mystery.
Axel Kowald and Tom Kirkwood propose a novel mechanism to explain this observation. They imagine a set of genes that are responsible for negative feedback on transcription. Since transcription (the first step of gene expression) also primes replication, if that set of feedback genes was deleted through a mutation, the mutant form of mtDNA could overtake the wild type in the cell.
“We first had this idea,” says Kowald, “and then looked for experimental support. […] I was actually pleasantly surprised to see that there is really a stretch of mtDNA that is deleted in practically all studies we looked at. And that is even true across several species.”
They compared single-cell data for rats, humans and rhesus monkeys and found a region of overlap between all or almost all deletions. This mechanism, if true, is an elegant solution to explain why these animals exhibit similar biochemical aging patterns, despite having vastly different lifespans. It also explains why deletions don’t accumulate in plant mitochondria.
Plant mtDNA is very large, reaching more than 11 mega base pairs in Silene conica, for example. Replication is primed by a specialized primase. “Because this decouples the connection between transcription and replication, deletions can no longer influence the initiation of replication and hence there should be no accumulation of deletion mutants in plants,” the authors write.
Kowald and Kirkwood would like to see this theory experimentally tested. It is their hope this proposed mechanism will offer new targets for intervention. The idea is also satisfying, they say, for its simplicity.
“Our paper offers an answer that we believe makes this part of the biology of aging much easier to understand,” says Kirkwood.