A team of scientists has identified seven genes they believe are linked to particularly fast ageing of the brain, after analysis of data from nearly 40 000 people – although 13 drugs and supplements, including hydrocortisone and testosterone, might reduce these effects, they wrote.
The activity of many genes contributes to the difference between our actual age and the biological age of our brains, defined by how old our cells indicate we are, which creates what is known as a brain age gap.
To find genes that accelerate brain ageing and widen this gap, reports New Scientist, Zhengxing Huang at Zhejiang University in China and his colleagues trained a deep-learning model called 3D-ViT on some medical records and used others to check it gave accurate responses.
They then used it to analyse data from nearly 39 000 people who had health, genetic and lifestyle information, along with biological samples, stored in the UK Biobank. These participants were 64-years-old, on average, and about half were women.
3D-ViT identified signatures in the participants’ MRI scans that could be used to estimate their biological brain age. Signs of accelerated ageing particularly appeared in brain regions known as the lentiform nucleus, which is involved in cognition, such as attention and working memory, and the posterior limb of the internal capsule, which connects various regions to the brain’s cerebral cortex – used for thought and language processing.
Huang and his colleagues also found that the participants’ scores on cognition tests dropped as their brain age gap increased.
Comparing their gene variants with the size of their estimated brain gaps flagged 64 influential genes, but Huang and his colleagues focused on seven: MAPT, TNFSF12, GZMB, SIRPB1, GNLY, NMB and C1RL, partly because these all have a particularly strong effect on brain ageing.
They added that they had “rediscovered … with evidence from clinical trials of ageing” that their activity can be targeted by 13 drugs or supplements. These include cholecalciferol, a supplement for vitamin D deficiency; dasatinib, a leukaemia drug; diclofenac, a non-steroidal anti-inflammatory; doconexent, an omega-3 fatty acid; estradiol, the type of oestrogen commonly used in hormone replacement therapy; hydrocortisone, commonly used to treat eczema; and mecamylamine, a drug that lowers blood pressure.
The others were nicotine; prasterone, which relieves vaginal pain during sex during the menopause; the supplements quercetin and resveratrol; sirolimus, which is commonly used to suppress the immune system after a kidney transplant; and testosterone.
But the researchers write in their findings, published in Science Advances, that people should “consider the potential risks associated with taking medications or supplements for slowing down ageing as these interventions may have unintended negative consequences”.
Many genes have an effect on brain ageing, but here the authors have used an approach that prioritises those with the largest effect, said Dario Valenzano at the Leibniz Institute on Ageing in Jena, Germany. “The work provides concrete targets for direct follow-up experimental and clinical interventions.”
However, it is hard to tell how large an effect on brain ageing these genes actually have, said Richard Siow at King’s College London. “Just because you have a certain genetic profile doesn’t mean the genes will always play a role.”
Genes can be silenced or switched on by various lifestyle and environmental factors, he added, such as smoking and high alcohol consumption. These can also predispose people to cognitive decline or brain ageing.
Because the study used data in the UK Biobank, it was not clear whether the findings translate to people around the world. “Work is needed in other populations, such as those in Africa, South America and East Asia, to find that out,” Slow said.
Study details
Genetically supported targets and drug repurposing for brain ageing: A systematic study in the UK Biobank
Fan Yi, Jing Yuan, Zhengxing Huang et al.
Published in Science Advances on 12 March 2025
Abstract
Brain age gap (BAG), the deviation between estimated brain age and chronological age, is a promising marker of brain health. However, the genetic architecture and reliable targets for brain ageing remains poorly understood. In this study, we estimate magnetic resonance imaging (MRI)–based brain age using deep learning models trained on the UK Biobank and validated with three external datasets. A genome-wide association study for BAG identified two unreported loci and seven previously reported loci. By integrating Mendelian Randomisation (MR) and colocalisation analysis on eQTL and pQTL data, we prioritised seven genetically supported druggable genes, including MAPT, TNFSF12, GZMB, SIRPB1, GNLY, NMB, and C1RL, as promising targets for brain aging. We rediscovered 13 potential drugs with evidence from clinical trials of aeging and prioritised several drugs with strong genetic support. Our study provides insights into the genetic basis of brain ageing, potentially facilitating drug development for brain ageing to extend the health span.
New Scientist article –The 13 drugs and supplements that could slow brain ageing (Open access)
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