Brain-Aging Gene Find Could Unlock New Alzheimer’s and Anti-Aging Treatments

The researchers derived a genetic measure that they call differential aging — the difference between an individual's apparent age and his or her actual age.

Among seniors who are the same age, some individuals inevitably look younger than others. Of course, the aging process is more than skin deep. Aging discrepancies also linger in the brain, with some people showing more obvious signs of aging in the frontal cortex, the brain region responsible for higher mental functions.

Aging differences in this region of the brain are tied to variants of a gene called TMEM106B, according to a Columbia University Medical Center (CUMC) study published today in the journal Cell Systems. This common genetic variant greatly impacts normal aging, starting around the age of 65.

"People who have two 'bad' copies of this gene have a frontal cortex that, by various biological measures, appears 12 years older than those who have two normal copies," said Asa Abeliovich, professor of pathology and neurology in the Taub Institute for Alzheimer's Disease and the Aging Brain at CUMC and co-leader of the study.

Abeliovich and her partner Herve Rhinn, assistant professor of clinical pathology at Columbia University, knew that TMEM106B and another gene called GRN were previously found to be associated with frontotemporal dementia, which is a rare, devastating neurodegenerative disorder. With this in mind, they set out to address the question: What, on a genetic level, is driving healthy brain aging?

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The researchers analyzed genetic data from autopsied brain samples taken from 1,904 people with neurodegenerative disease. They looked at the subjects' transcriptomes, which are initial products of gene expression, and complied an average picture of the brain biology of people at the same age. Then they compared each person's transcriptome to the average transcriptome of people at the same age, intensively exploring about 100 genes whose expression were found to increase or decrease with aging.

Based on this comparison, the researchers derived a measure that they call differential aging, which is the difference between an individual's apparent (or biological) age and his or her true (or chronological) age.

In addition to TMEM106B, the GRN gene also stood out to the researchers as a driver of brain aging.

"A striking finding of our study is that when we queried in an unbiased fashion all common genetic variants in the genome for their association with aging rate in the frontal cortex, the two variants that we identified are precisely the ones associated with frontotemporal dementia," Rhinn said. "While further studies are planned to dissect more precisely their mechanism of action in the context of brain aging, our preliminary data point at a role in modulating neuroinflammation, but we have not ruled out additional mechanisms."

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The approximate age of 65 years seems to be the magic number when TMEM106B becomes "a limiting factor or a bottleneck in the process through which the human brain copes with aging," Rhinn said. He explained that aging manifestations in a given tissue are not linear with time and that changes that occur in a brain between age 30 and 50 differ both quantitatively and qualitatively with the ones that occur between age 70 and 90. The same can be said for patterns of gene expression changes in the same brain region for different age frames.

The genetic variant identified to be associated with the brain aging rate at the TMEM106B locus is also extremely frequent: 80 percent of the population carries at least one copy of the allele associated with increased aging rate in their genome, Rhinn said.

This discovery could point toward a biomarker that can be used to test anti-aging interventions and also uncover potential new targets for the prevention or treatment of Alzheimer's disease, the researchers said. The framework of the study can also be applied to other bodily tissues to potentially provide a more holistic view of the aging process throughout the human body.

Since the TMEM106B genetic variant on brain aging was also apparent in patients with Alzheimer's disease, Rhinn explained that "one interpretation is that TMEM106B is a critical element of a resilience network in the frontal cortex that limits the extent of neuronal loss and gliosis."

While the TMEM106B genetic variant associated with aging rate in the brain was not found to be associated with the risk of developing Alzheimer's disease, it's possible that it affects the rate of cognitive decline in Alzheimer's patients.

"This is a hypothesis we are looking forward to studying," Rhinn said.

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