Research outcomes
Discovery of the Mechanism Behind Neural Stem Cell Aging in the Brain
— Toward the Development of Cell Rejuvenation Techniques —
Discovery of the Mechanism Behind Neural Stem Cell Aging in the Brain
— Toward the Development of Cell Rejuvenation Techniques —
Summary
Dr. Taito Matsuda (Associate Professor) and Dr. Kanae Matsuda (Project Researcher) from the Laboratory of Neural Regeneration and Brain Repair at NAIST have discovered that the age-related decline in the function of hippocampal neural stem cells—important for memory—is caused by reduced activity of an epigenetic regulator called Setd8. Setd8 controls reversible chemical modifications on chromatin without changing the DNA sequence.
They further found that artificially suppressing Setd8 in mouse hippocampal neural stem cells accelerates stem cell depletion, reduces new neuron production, and impairs memory and learning. However, they also showed that when Setd8 activity is temporarily blocked, the stem cell function declines only transiently, and can recover once Setd8 is reactivated.
These results suggest that the aging-related changes in gene expression and chromatin structure caused by Setd8 loss are reversible, and that it may be possible to "rejuvenate" aged neural stem cells by manipulating this pathway. The study provides a foundation for future cell rejuvenation reprogramming technologies and potential treatments for age-related brain disorders.
This research will be published in the international journal The EMBO Journal on June 3, 2025, 7:00 PM (JST).
(DOI: 10.1038/s44318-025-00455-8)
Background and Purpose
To uncover how neural stem cells age, the team used single-cell analysis to examine gene expression and epigenetic changes over time. They discovered that aging-related molecular changes begin surprisingly early in life and are linked to a decrease in Setd8, an enzyme responsible for adding a chemical mark (H4K20me1) to histone proteins that package DNA.
Neural stem cells in the hippocampus gradually lose their number and function with age, leading to cognitive decline. However, the exact molecular mechanisms behind these changes had remained unclear. In particular, how aging affects gene expression and its connection to epigenetic modifications had not been fully understood.
Research Details
Using single-cell RNA sequencing (scRNA-seq) and single-cell ATAC sequencing (scATAC-seq), the team analyzed how gene expression and chromatin accessibility change with age in mouse hippocampal neural stem cells and their lineage.
They found that even in early adulthood, stem cells already begin to show aging-like changes. These include reduced expression of cell cycle genes and increased activity of genes related to inflammation and interferon responses.
A key driver of these changes was the decline of Setd8, the only enzyme that adds a methyl group to the 20th lysine on histone H4 (H4K20me1). When Setd8 levels drop, chromatin becomes disorganized, reducing the ability of neural stem cells to proliferate or become neurons.
Importantly, when Setd8 was temporarily suppressed, stem cell function decreased but recovered once Setd8 activity returned, showing that these aging effects are at least partially reversible.
Future Prospects
This study reveals that aging in neural stem cells is driven by epigenetic changes due to loss of Setd8, and that these changes can be reversed. This is a major step toward rejuvenation reprogramming, which aims to restore youthful functions in aged cells. The team will next investigate whether Setd8 plays similar roles in other aging stem cells or brain cells. Targeting Setd8 with drugs or gene delivery tools could lead to new therapies for age-related cognitive decline and neurodegenerative diseases like Alzheimer’s. Moreover, the comprehensive single-cell dataset from this work will also be a valuable resource for future research in aging and regenerative medicine.
Message from the Corresponding Author
"This study is based on the PhD thesis of Dr. Matsubara, the first author. It took over 8 years from the start of the experiments to publication. The scRNA-seq and scATAC-seq data were collected 7 years ago.
If you are someone who is passionate about doing meaningful science — even if it takes time — and wants to help patients in the future, I’d be happy to hear from you. I welcome students and postdocs who share this vision."
Published Paper
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, Taito Matsuda
Journal: The EMBO Journal
DOI: 10.1038/s44318-025-00455-8
Laboratory of Neural Regeneration and Brain Repair
Lab Introduction Page: https://bsw3.naist.jp/courses/courses314.html
Lab Homepage: https://bsw3.naist.jp/matsuda/
( June 05, 2025 )
