In a house where different families live, some age faster, others slower. The same goes for the brain: neurons of different types age at different rates. Some cells vanish by middle age, others hold out into deep old age. Why this happens remained a mystery for a long time. Now researchers have looked inside individual cells and seen that each has its own internal clock, and it does not run the way the shared clock of the whole body does.
To separate shared and internal aging, the researchers took brain samples from 69 people aged 24 to 94. They measured the activity of thousands of genes in each cell individually. Then they built a model that first predicted a person's age from shared signals, and then iteratively refined the prediction, fishing out signals specific to each cell. This made it possible to separate 'tissue age' from 'cell age'.
The paradox: why are cells that are young by molecular clocks more vulnerable? It turned out that they produce energy in their mitochondria more actively. This process is like an engine running nonstop, which wears out faster. Such cells do not manage to switch on the protective programs that are already active in 'older' cells. For example, interneurons that release somatostatin had the lowest internal age and the highest vulnerability.
The researchers went further and compared these data with the genomes of 240 mammal species. They found 427 regulatory regions that are open in vulnerable neurons and are linked to a shorter life in animals. In long-lived species, these regions are more often closed, as if evolution were switching off dangerous genes. One of these regions has been preserved next to an important gene in mammals, birds and reptiles for hundreds of millions of years.
Now it is clear why some neurons die earlier than others: their internal clocks run too slowly, and they do not manage to age properly. This knowledge could help create drugs that protect precisely the vulnerable cells. In the house of the brain, we have learned to see which apartments need renovation first.
In long-lived mammalian species, the regulatory regions linked to neuronal vulnerability are more often closed, meaning evolution seems to 'switch off' dangerous stretches of the genome. The MIR181A1HG locus has kept its connection to its enhancer for hundreds of millions of years across mammals, birds, and reptiles, which points to its ancient and important function.
The idea of molecular clocks that predict cell vulnerability echoes the film Blade Runner, where replicants have a limited lifespan but the vulnerability of different organs and cells is not the same. In Greg Egan's novel Permutation City, the possibility of controlling aging at the cellular level is discussed, which partly reflects the goal of this work.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.