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Researchers Identify Two Genes Responsible for Brain’s Aging

A duo of researchers at Columbia University has identified two genes (TMEM106B and GRN) that greatly impact normal brain aging, starting at around age 65.

This drawing shows several of the most important brain structures. Image credit: National Institute for Aging.

This drawing shows several of the most important brain structures. Image credit: National Institute for Aging.

“If you look at a group of seniors, some will look older than their peers and some will look younger. The same differences in aging can be seen in the frontal cortex, the brain region responsible for higher mental processes,” said Professor Asa Abeliovich, lead co-author of the study, published online today in the journal Cell Systems.

“Our findings show that many of these differences are tied to variants of a gene called TMEM106B.”

“People who have two ‘bad’ copies of this gene have a frontal cortex that, by various biological measures, appears 12 years older that those who have two normal copies.”

Prof. Abeliovich and his colleague, Dr. Herve Rhinn, analyzed genetic data from autopsied human brain samples taken from 1,904 people without neurodegenerative disease.

First, they looked at the subjects’ transcriptomes (the initial products of gene expression), compiling an average picture of the brain biology of people at a given age.

Next, each person’s transcriptome was compared to the average transcriptome of people at the same age, looking specifically at about 100 genes whose expression was found to increase or decrease with aging.

From this comparison, the authors derived a measure that they call differential aging: the difference between an individual’s apparent (biological) age and his or her true (chronological) age.

They then searched the genome of each individual, looking for genetic variants that were associated with an increase in differential age.

“One variant stood out: TMEM106B. It’s very common. About one-third of people have two copies and another third have one copy,” Dr. Rhinn said.

“TMEM106B begins to exert its effect once people reach age 65,” Prof. Abeliovich added.

“Until then, everybody’s in the same boat, and then there’s some yet-to-be-defined stress that kicks in.”

“If you have two good copies of the gene, you respond well to that stress. If you have two bad copies, your brain ages quickly.”

The team also found a second variant — inside the progranulin gene (GRN) — that contributes to brain aging, though less so than TMEM106B.

GRN and TMEM106B are located on different chromosomes but are involved in the same signaling pathway.

Both have also been associated with a rare neurodegenerative disease called frontotemporal dementia.

“The study did not address what role the two genetic variants might have in neurodegenerative disease. We were studying healthy individuals, so it is not about disease, per se,” Prof. Abeliovich said.

“But of course, it’s in healthy tissue that you start to get disease. It appears that if you have these genetic variants, brain aging accelerates and that increases vulnerability to brain disease. And vice versa: if you have brain disease, the disease accelerates brain aging. It’s a vicious cycle.”


Herve Rhinn Asa Abeliovich. Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN that Regulate Aging Phenotypes. Cell Systems, published online March 16, 2017; doi: 10.1016/j.cels.2017.02.009

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