Study Finds Gene Variant Tied to Brain Aging

Just like the body, human brains age at different rates from person to person. Researchers believe that uncovering what makes brains age at different rates could lead to breakthroughs in treating or preventing dementia and other age-related brain disorders.

Scientists at Columbia University Medical Center (CUMC) recently discovered a genetic variant associated with brain aging that they say may bring them one step closer to understanding the role genes play in the normal brain-aging process. While previous studies have pointed to associations between genetic variants and age-related brain diseases—such as the APOE4 gene and Alzheimer’s disease—this genetic variant is believed to be the first to be linked with the normal aging process.

The gene in question is known as TMEM106B. This gene encodes a protein, called Transmembrane protein 106B, that helps maintain a waste storage and disposal system in cells.

According to Asa Abeliovich, Ph.D., a professor of pathology and neurology at CUMC’s Taub Institute for Alzheimer’s Disease and the Aging Brain, people with two copies of the “aging” variant have frontal cortices that appear 12 years older on average than those of people who have two normal copies.

To identify this gene, Abeliovich and colleague Herve Rhinn, Ph.D., an assistant professor of pathology and cell biology at the Taub Institute, first developed a genetic measure of aging by collecting gene expression data from postmortem brain tissue samples of 716 adults of varying ages. All of the samples were from the frontal cortex—a region involved in higher-order thinking, such as executive function and decision making. All samples also came from adults who did not have a neurodegenerative disease.

An analysis of these data revealed some 3,300 genes in which expression was higher or lower in relation to age.

The gene expression profiles for each individual were then compared with the group average to create a score called differential aging (D-aging). High D-aging scores reflected brains that aged more rapidly than the average brain, whereas low D-aging scores reflected those that were aging more slowly.

Finally, the researchers scanned the genomes of the brain tissue with very high or low D-aging scores to see if there were any genetic similarities among these people. This uncovered TMEM106B, a gene that has previously been linked with frontotemporal dementia (FTD), as being highly correlated with accelerated aging.

What was interesting about the relationship between the TMEM106B variant and aging, said the authors, was that the effects were most pronounced in tissue samples from people 65 and older; younger people with the variant still had relatively average D-aging scores.

To explore whether these differences in “brain age” resulted in any clinical disparities, the researchers obtained genetic samples from nearly 5,000 people who were participating in a study funded by the National Institute on Aging. As part of the study, the participants received periodic cognitive assessments. People over age 65 who had two copies of the aging variant had lower cognitive scores on average than those with one or zero copies. In younger people, there was no connection between TMEM106B status and cognitive performance.

Rhinn told Psychiatric News that the delayed onset of noticeable aging effects in people with the TMEM106B variant may be the result of the gradual breakdown of TMEM106B activity—which buffers brain cells from potential damage by helping remove waste and debris caused by inflammation and other stressors. The variant protein may not be as effective and therefore debris accumulates more rapidly, Rhinn said, eventually reaching a tipping point that triggers a cascade of events that accelerates aging and makes the cortex more vulnerable to degeneration.

If that is the case, Rhinn suggested it might be possible that lifestyle interventions that reduce cellular stress might help delay or reduce this accelerated aging.

Still, he noted that while identifying a gene variant that contributes to brain aging may help scientists better understand this natural process, having the TMEM106B variant is only one of many genes involved in aging.

“Remember, aging is a complex process that involves many interconnected tissues, so we cannot look at one gene in a vacuum,” he said.

The study, which was published in the March 22 issue of Cell Systems, was supported by grants from the National Institute on Aging, National Institute of Neurological Disorders and Stroke, and the Michael J. Fox Foundation. ■

“Differential Aging Analysis in Human Cerebral Cortex Identifies Variants in TMEM106B and GRN That Regulate Aging Phenotypes” can be accessed here.