Source: Columbia University Medical Center

Key finding

Researchers at Columbia University Medical Center (CUMC) report the discovery of a widely carried genetic variant that strongly influences normal aging of the frontal cortex in older adults. According to the study, which appears in the journal Cell Systems, people carrying two copies of a specific variant in the gene TMEM106B show biological markers in the frontal cortex that are, on average, up to 12 years older than individuals with two non-risk copies. The effect becomes apparent around age 65 and may affect vulnerability to age-associated brain disorders.

Background and motivation

Although certain genes have already been linked to specific neurodegenerative diseases—APOE and Alzheimer’s disease, for example—those single-gene associations explain only a fraction of risk. Aging itself remains the dominant risk factor for brain disorders. The research team asked a related question: beyond disease-causing mutations, what genetic differences influence the way a healthy brain ages?

Methods

The investigators analyzed genetic and transcriptomic data from autopsied frontal cortex tissue sampled from 1,904 individuals who did not have neurodegenerative disease. For each person the team compiled a transcriptome profile—the pattern of gene expression products present in the tissue—and compared it to an age-specific average transcriptome derived from the cohort. They focused on a set of roughly 100 genes whose expression either increases or decreases in a predictable manner with normal aging.

From this comparison the researchers derived a metric they call differential aging: the difference between an individual’s apparent biological age (as estimated from gene expression patterns in frontal cortex) and the person’s chronological age. Positive differential aging indicates that the tissue looks older than expected, while negative differential aging indicates a younger biological profile. The team then conducted a genomic search to identify variants associated with increased differential aging.

Results

One variant emerged strongly from the analysis: variants in TMEM106B. The gene is common in the population—about one-third of people carry two copies of the risk variant and another third carry one copy—yet its influence on brain aging becomes pronounced only after about age 65. According to the investigators, individuals with two risk copies displayed multiple biological measures in the frontal cortex consistent with accelerated aging, by as much as 12 years compared with those who carry two non-risk copies.

The study also identified a second variant, within the progranulin gene, that contributes to brain aging, though its effect was smaller than that of TMEM106B. Progranulin and TMEM106B lie on different chromosomes but participate in related signaling pathways. Both genes have previously been implicated in frontotemporal dementia, a rare neurodegenerative disorder.

Interpretation and implications

The study focused on healthy brain tissue rather than clinical disease, so it does not directly establish that these variants cause neurodegenerative illness. However, the findings suggest a model in which inherited genetic differences influence how resilient the aging brain is to stressors that emerge later in life. If brain tissue ages more rapidly because of genetic variants, that accelerated aging could increase vulnerability to neurodegenerative processes. Conversely, disease processes can further accelerate biological aging, creating a potential feedback loop.

These results open several avenues for further work: validating TMEM106B and related signatures as biomarkers to evaluate anti-aging or neuroprotective interventions; investigating the molecular pathways by which TMEM106B and progranulin influence cellular responses to age-related stress; and exploring whether modulating these pathways can reduce age-related vulnerability to brain disease.

Funding and disclosures

The study received support from the National Institute on Aging (grant AG042317), the National Institute of Neurological Disorders and Stroke, and the Michael J. Fox Foundation for Parkinson’s Research. Dr. Asa Abeliovich is a co-founder of and consultant for Alector; Dr. Herve Rhinn serves as a consultant for Alector. The authors reported no other financial conflicts of interest.

Publication

The findings were published in the journal Cell Systems. The report presents evidence that common genetic variation can substantially influence the biological aging trajectory of human frontal cortex tissue and points to TMEM106B as a prominent contributor to that process.