Understanding the Epigenetic Mechanisms Behind Premature Aging of the Brain

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Understanding the Epigenetic Mechanisms ...

Researchers identify the role of the Setd8 gene associated with the age-related decline in neural stem cell activity and proliferation

Professor Nakashima Kinichi
Faculty of Medical Sciences

Ikoma, Japan—Age often brings a gradual decline in the ability to learn new things and retain memories. This phenomenon, often associated with the elderly, is linked to the brain’s deteriorating capacity to generate new neurons—a process that primarily occurs in the hippocampus —as neural stem cells (NSCs) divide and mature. Recent research suggests this decline begins much earlier in life than previously thought, potentially starting in early adulthood.

While it is established that overall decline in brain function is associated with dwindling NSCs, the precise underlying molecular changes and their timelines remain unclear. Epigenetic changes—modifications that affect gene expression without altering the DNA sequence—play crucial roles in cellular aging, but their impact on NSCs remains unknown.

In this vein, a research team comprising Shuzo Matsubara, Kanae Matsuda-Ito, Haruka Sekiryu, Hiroyoshi Doi, Takumi Nakagawa, and Kinichi Nakashima from Kyushu University, Naoya Murao from the University of Miyazaki, and Hisanobu Oda from Saiseikai Kumamoto Hospital, and led by Associate Professor Taito Matsuda from the Laboratory of Neural Regeneration and Brain Repair at the Nara Institute of Science and Technology (NAIST), Japan, set out to uncover the early aging processes in NSCs. Their study was made available online on June 3, 2025 and published on July 01, 2025, in Volume 44, Issue 13 of The EMBO Journal.

A key discovery was linked to a gene called Setd8, which controls the addition of a chemical tag (molecule) on DNA-packaging proteins called histones. The researchers found that Setd8 showed a marked decrease in expression as the brain aged. In turn, this reduction in Setd8 levels was directly linked to impaired NSC activity and proliferation, as well as noticeable problems in memory in mice. The team also demonstrated that artificially lowering Setd8 levels mimicked various molecular signatures of aging NSCs, suggesting it could be a critical biomarker of early aging.