Mouse research suggests that brain aging is caused by a loss of control over how genes are regulated.

As we age, epigenetic markers that control gene expression in the brain can be ‘erased’, which can snowball and cause unintended consequences, a new mouse study suggests.

Small 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. But identifying aging processes that could be slowed or reversed requires data from far more places, especially the brain.

Now, a new study published March 11 in the journal Cell maps these tags throughout the mouse brain, aggregating data from more than 200,000 cells into the most complex epigenetic atlas of aging ever created. The study reveals how aging affects different areas of the brain and provides a stepping stone to similar studies of the human brain.

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Overall, the study paints a picture of a genome that is gradually losing its most important functions over time.

“This shows that aging is not just wasting; it’s a loss of control over how genes are regulated,” said Harvard University geneticist David Sinclair, who was not involved in the study.

How do you use your DNA?

Despite the incredible diversity of cell types in the body, all cells retain the same genome, regardless of their role.

“The DNA sequence alone is not enough to tell us how to make cells,” said Joseph Ecker, a geneticist at the Salk Institute in San Diego and co-author of the new study. Instead, epigenetic regulation determines how a cell’s genes are expressed. Tight epigenetic control is particularly important in the brain, where neurons must persist for life and cannot afford to disrupt gene expression or change physiology.

In the new study, Dr. Ecker worked closely with Margarita Behrens, a neuroscientist at the Salk Institute. The researchers examined the brains of mice at three ages: infancy (2 months), adulthood (9 months), and old age (18 months). They cut these brains into 18 ultra-thin slices. They extracted DNA-packed cell nuclei from the slices and analyzed key epigenetic signals.

One is called methylation, which adds small chemical tags called methyl groups to DNA bases. Methylation tends to “turn off” gene expression, and Ecker’s team found that the mouse genome loses methyl tags as it ages.

For example, in brain immune cells called microglia in aged mice, immune genes were expressed more actively than usual due to a decrease in methyl groups that suppress the expression of immune genes.

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This demethylation occurred genome-wide and at the sites of transposons, or “jump genes,” so it may have had a synergistic effect. These are repetitive DNA sequences that can be copied and pasted elsewhere in the genome. Repeated gene “jumps” can disrupt the expression of many other genes in the process, affecting brain function. These genetic factors are becoming less obvious, Sinclair said. “These are genes that we have largely overlooked, but they track aging surprisingly well, suggesting that we may be losing control of parts of the genome that are central to brain aging,” he said.

The researchers also analyzed the structure of chromatin, the complex of DNA and proteins that organizes genes into tightly packed chromosomes. The researchers found that increased gene expression in the aging brain changes chromatin structure and adds very small, tight loops called topologically associated domains (TADs), compartments in the genome that organize gene expression. . The researchers write in their study that an increase in the number of TADs may act as a new sign of aging.

Is epigenetics the key to “super aging”?

When the genome loses control over its functions, it can have important effects on how the body works in older people. Ecker and Behrens said the body responds to increased activity of the jumping gene by producing an immune response that kills brain cells and can destroy delicate neural structures. They pointed to a recent paper in Nature showing that “super-old people” who maintain good memory as they age have more progenitor cells in their brain’s memory centers. Ecker and Behrens told Live Science that very old people may have lower levels of jump gene activation, which may allow these and other important neurons to stay alive longer.

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

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