Brain aging results from a loss of control over how genes are regulated, mouse study suggests

Aging may "erase" the epigenetic markers that control gene expression in the brain, and this may snowball to cause 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'' that track the loss of these epigenetic tags at specific locations in the genome. However, data from far more locations, particularly the brain, are needed to identify aging processes that could be slowed or reversed.

Now, a new study published March 11 in the journal Cell has mapped these tags across the mouse brain, aggregating data from over 200,000 cells into the most complex epigenetic atlas of aging ever created. The study has revealed how aging affects different areas of the brain and is a stepping stone toward similar studies of the human brain.

Overall, the research paints a picture of genomes that gradually lose grip over their most essential functions over time.

''It shows that aging isn't just wear and tear; it's a loss of control over how genes are regulated,'' said David Sinclair, a geneticist at 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 sufficient to direct how you make a cell,'' said Joseph Ecker, a geneticist 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 especially important in the brain, where neurons must last a lifetime and cannot afford to mess up gene expression and alter their physiology.

In the new study, Ecker worked closely with Margarita Behrens, a neuroscientist 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 ultrathin slices. They extracted DNA-packed cellular nuclei from the slices and analyzed key epigenetic signals.

One, called methylation, involves the addition of a small chemical tag called a methyl group to DNA bases. Methylation tends to switch gene expression ''off,'' and Ecker's team saw that their mice's genomes lost their methyl tags with age.

For example, immunity genes were expressed more actively than usual in brain immune cells called microglia in elderly mice because of a drop in methyl groups that silence these genes.

This demethylation happened across the genome and could have had a multiplier effect because it occurred at the sites of transposons, or ''jumping 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 on brain function. These genetic elements have gone under the radar, according to Sinclair. ''These are genes we've largely overlooked, yet they track remarkably well with aging, suggesting we may be losing control over 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 protein that organizes our genes into densely packed chromosomes. The team found that increased gene expression in the aging brain altered chromatin structure, adding extra 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 increased TAD counts could serve as a new signature of aging.

Is epigenetics the key to ''super-aging''?

Genomes' loss of control over their functions could have important consequences for how our bodies work in old age. Ecker and Behrens said the body reacts to increases in jumping genes' activity with brain-cell-killing immune responses that could potentially disrupt delicate neural architecture. They pointed to a recent paper in the journal Nature showing that ''super-agers'' who retain high memory performance in old age have more precursor cells in their brains' memory centers. Ecker and Behrens told Live Science that super-agers may have lower levels of jumping-gene activation, which may, in turn, keep these and other important neurons alive longer.

For these scientists, the current research is a step toward achieving a larger goal: the epigenetic sequencing of the human brain.

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