Picture an old house where every room ages in its own way: in one, the wallpaper has faded; in another, the floorboards creak; and in a third, everything looks brand new. The brain ages much the same way: different cell types accumulate changes at different rates, and until recently we had no tool to peer into each "room" and measure its age separately.
In a new study, researchers took the largest dataset to date on chromatin openness in human brain cells: 1.5 million cells from the prefrontal cortex of 357 donors aged 15 to 100. Chromatin is DNA packaged with proteins, and which stretches of DNA are open or closed affects how genes work. The researchers trained models to predict age separately for each cell type, such as excitatory and inhibitory neurons, astrocytes, microglia, oligodendrocytes, and their precursors.
The most surprising part: a clock trained on human prefrontal cortex cells could predict age in other brain regions, as well as in mice and even in zebrafish. This required aligning genomic coordinates between species, but after that the models worked without retraining. Moreover, the clock detected slowed aging in mice with overexpression of the SIRT6 gene and accelerated aging in Alzheimer's and Parkinson's diseases, especially in microglia, the brain's immune cells.
So we now have a tool that not only predicts age but also shows which regulatory elements in DNA contribute to the aging of each cell type. It's as if, in that old house, we didn't just notice a creaking floor in one room but also pinpointed exactly which floorboard had come loose. This approach paves the way for testing anti-aging interventions and for understanding why some cells age faster than others.
A clock trained on human prefrontal cortex cells managed to predict age in the zebrafish retina, an animal whose last common ancestor with humans lived more than 400 million years ago.
The idea of an "aging clock" that can be turned back echoes Oscar Wilde's novel The Picture of Dorian Gray, in which aging is transferred to a portrait, as well as the film Cloverfield Paradox, where accelerated aging is used as a dramatic device.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.