Brain aging results from a loss of control over how genes are regulated, mouse study suggests
Aging can “erase” epigenetic markers that control gene expression in the brain, which could lead to unintended consequences, a new mouse study suggests.
Tiny chemical messages attached to our genetic code, called epigenetic markers, change with age in many organs of the human body, leading to the development of ”aging clocks” which track the loss of these epigenetic tags at specific locations in the genome. However, data from many more places, particularly the brain, is needed to identify aging processes that could be slowed or reversed.
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Overall, the research paints a picture of genomes that gradually lose control of their most essential functions over time.
“This shows that aging is not just wear and tear; “it’s a loss of control over how genes are regulated,” said David Sinclaira geneticist from Harvard University who was not involved in the study.
How do you use your DNA?
Despite the incredible diversity of cell types in the body, every cell, regardless of its role, harbors the same genome.
“The DNA sequence alone is not enough to determine how you make a cell,” said Joseph Eckergeneticist at the Salk Institute in San Diego and co-author of the new study. Instead, epigenetic control decides how a cell’s genes are expressed. Tight epigenetic control is particularly important in the brain, where neurons must last a lifetime and cannot afford to disrupt gene expression and change their physiology.
These are genes that we have largely neglected, but they change remarkably well with aging, suggesting that we may be losing control of parts of the genome that are critical to brain aging.
David Sinclair, geneticist at Harvard University
In the new study, Ecker worked closely with Margarita Behrensneuroscientist at the Salk Institute. The researchers examined the brains of mice at three ages: early life (2 months), adulthood (9 months), and old age (18 months). They cut these brains into 18 ultra-thin slices. They extracted slices of the DNA-filled cell nuclei and analyzed key epigenetic signals.
One, called methylation, involves adding a small chemical tag called a methyl group to DNA bases. Methylation tends to turn off gene expression, and Ecker’s team found that the genomes of their mice lost their methyl tags with age.
For example, immunity genes were expressed more actively than usual in brain immune cells called microglia in aged mice due to a decline in the methyl groups that silence these genes.
This demethylation occurred across the genome and could have had a multiplier effect because it occurred at transposon sites, or ”skipping genes» These are repetitive DNA sequences that can copy and paste themselves elsewhere in the genome. Repeated gene “jumping” can disrupt the expression of many other genes in the process, potentially leading to consequences for brain function. These genetic elements have gone unnoticed, according to Sinclair. “These are genes that we have largely neglected, but they track aging remarkably well, suggesting that we may be losing control of parts of the genome that are central to brain aging,” he said.
The team also analyzed the structure of chromatin, the complex of DNA and proteins that organizes our genes into densely packed chromosomes. The team found that increased gene expression in the aging brain changed the structure of chromatin, adding very small, tight loops called topologically associated domains (TADs), which are partitions within the genome that organize gene expression. . The team wrote in the study that increasing TAD counts could serve as a new signature of aging.
Is epigenetics the key to “super-aging”?
The loss of control of genomes over their functions could have important consequences on the functioning of our bodies in old age. Ecker and Behrens said the body responds to increased jumping gene activity with brain cell-destroying immune responses that could potentially disrupt delicate neuronal architecture. They pointed to a recent paper in the journal Nature showing that “super-agers” who retain high memory performance into old age have more precursor cells in the memory centers of their brain. Ecker and Behrens told Live Science that super-aged people may have lower levels of jumping gene activation, which can, in turn, keep these and other important neurons alive longer.
For these scientists, the current research is a step toward achieving a larger goal: epigenetic sequencing of the human brain.
Zeng, Q., Wang, W., Tian, W., Klein, A., Bartlett, A., Liu, H., Nery, J.R., Castanon, RG, Osteen, J., Johnson, ND, Ding, W., Chen, H., Altshul, J., Kenworthy, M., Valadon, C., Owens, W., Wu, Z., Amaral, ML, Zemke, NR, . . . Ecker, J.R. (2026). Cell type-specific transposon demethylation and TAD remodeling in the aging mouse brain. Cell. https://doi.org/10.1016/j.cell.2026.02.015
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