Gene variants for accelerated brain ageing discovered

Two common variants of TMEM106B and progranulin (GRN) genes have been discovered to accelerate normal brain ageing.

US researchers found the frontal cortex of individuals over age 65 with two copies of TMEM106B appeared 12 years older than individuals with two normal copies.

'TMEM106B begins to exert its effect once people reach age 65,' said Dr Asa Abeliovich, professor of pathology and neurology at Columbia University Medical Centre, and co-leader of the study. '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 researchers analysed samples of brain tissue from 1904 autopsied individuals who did not have neurodegenerative disease during their lifetime, and determined the levels of gene expression in each sample.

Next, they identified 100 genes known to increase or decrease in expression with ageing, and compared the levels of expression between autopsied individuals, and the 'average' level of expression from age-matched brains. The difference between the apparent age of brain tissue according to gene expression and the actual age of the individual showed whether individual brains had aged more or less than expected. This measure was named the 'differential age'.

For individuals whose brains appeared older than expected, they carried out a genome wide association study (GWAS) to see whether they could link particular genetic variants to an increase in differential age; this identified TMEM106B and GRN. Both genes are involved in the same signalling pathway though are located on different chromosomes.

Both of these genes have previously been linked to frontotemporal dementia, and TMEM106B is also linked to inflammation. Around one-third of people have two copies of TMEM106B, and another third have one copy.

The authors hypothesize that the variants could affect risk for age-related diseases.

'By far, the major risk factor for neurodegenerative diesease is ageing,' said Dr Herve Rhinn, assistant professor at the Taub Institute. 'Something changes in the brain as you age that makes you more susceptible to brain disease.'

Dr David Reynolds, chief scientific officer of Alzheimer's Research UK, said: 'There is a pressing need to understand the biological mechanisms that separate those who age well from those who don't... Piecing together these genetic clues can help build a clearer understanding of biological processes most susceptible to decline as we get older.'

Projections by the Nuffield Trust have suggested that two-fifths of all national health spending in the UK is on the over-65s.

The research was published in Cell Systems.