Understanding the epigenetic mechanisms behind premature aging of the brain

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.

The researchers used single-cell sequencing techniques to analyze gene expression in NSCs and newly generated neurons across different life stages in mice. This enabled them to map the key molecular changes that NSCs undergo from birth through early adulthood, along with the corresponding alterations in their ability to produce new neurons.

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.

Overall, the results highlight the unknown role of Setd8 in NSC aging, which has strong implications from a biomedical standpoint. “Understanding how Setd8 affects neural stem cell aging opens the possibility of developing new therapies to slow down or reverse early brain aging. This could help preserve memory and learning ability, and may lead to future treatments for age-related conditions like Alzheimer’s disease,” remarks Dr. Matsuda. “This aligns with our laboratory’s research on cellular reprogramming technologies, which we hypothesized could make it possible to 'rejuvenate' aged, functionally declined cells.”

While further efforts will be needed to translate these findings into therapeutic solutions and clinical practice, Dr. Matsuda looks forward to continuing this exciting line of research. “I am deeply honored to be able to advance reprogramming research at the NAIST, where Professor Shinya Yamanaka initiated his groundbreaking work on induced pluripotent stem cells,” he concludes.

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Resource

Title: Epigenetic regulation of neural stem cell aging in the mouse hippocampus by Setd8 downregulation

Authors: Shuzo Matsubara, Kanae Matsuda-Ito, Haruka Sekiryu, Hiroyoshi Doi, Takumi Nakagawa, Naoya Murao, Hisanobu Oda, Kinichi Nakashima, and Taito Matsuda

Journal: The EMBO Journal

DOI: 10.1038/s44318-025-00455-8

Information about the Laboratory of Neural Regeneration and Brain Repair (Matsuda Lab) can be found at the following website: https://bsw3.naist.jp/matsuda/

About Nara Institute of Science and Technology (NAIST)

Established in 1991, the Nara Institute of Science and Technology (NAIST) is a national university located in Kansai Science City, Japan. In 2018, NAIST underwent an organizational transformation to promote and continue interdisciplinary research in the fields of biological sciences, materials science, and information science. Recognized as one of the most prestigious research institutions in Japan, NAIST lays a strong emphasis on integrated research and collaborative co-creation with diverse stakeholders. NAIST envisions conducting cutting-edge research in frontier areas and training students to become future leaders in science and technology.