In an orchestra that has been playing the same symphony for years, the musicians gradually start to drift: each one plays on their own, yet the notes remain the same. That is roughly what happens to cells as they age. Scientists have come up with a way to measure this discord, that is, how faithfully each cell follows the shared program of gene expression.
The new method requires no pre-set markers of aging. For each cell, it calculates how far the expression of every gene deviates from the predicted value that the model learns from the entire cell population. Technical noise from sequencing is accounted for separately. In simulations, coordinated changes barely increased dyscoordination, whereas independent noise did. This means the measure captures the loss of coordination itself, not a shift in the program.
In the bone marrow of mice and humans, dyscoordination rose monotonically with age in hematopoietic stem and progenitor cells, but not in terminally differentiated cells. In 30-month-old mice, it is on average 40% higher than in 1-month-old mice, and monocytes show no such increase. In T cells, dyscoordination was higher in large clones and in highly malignant tumors, and it decreased after immunotherapy. The picture in kidneys and liver is similar: with age, cells increasingly play out of step, especially in zones where active renewal takes place.
Genes that lose expression precision are enriched in genome maintenance and proteostasis pathways, while genes activated in highly dyscoordinated cells are enriched in inflammatory and fibrotic programs. This links molecular discord to functional decline in tissues. Previously it was unclear whether loss of precision could be separated from coordinated changes of state. Now it is clear that dyscoordination is a distinct, measurable property that increases with age in regenerative compartments, correlates with mitotic age and genomic instability, and can decrease after therapy.
The method can be applied to any single-cell data without retraining. This opens the way to marker-free assessment of cellular aging in single-cell atlases. The orchestra keeps playing, but now we have the score to hear who is falling out of tune.
In mouse hematopoietic stem cells, dyscoordination rises with age almost linearly: in 30-month-old mice it is on average 40% higher than in 1-month-old mice. Yet terminally differentiated monocytes show no such increase, even though they age too.
In Greg Egan's novel Permutation City, people digitize their consciousness but run into the problem of copy degradation from accumulated random errors. A similar idea underlies this work: cellular aging can be seen as a gradual loss of fidelity in reproducing the program, not just as a change in the program itself.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.