Scientists discover protein that rejuvenates aging brain cells

Neural stem cells are responsible for generating new neurons, which play an essential role in learning and memory. As people age, these stem cells gradually lose their ability to renew themselves, contributing to cognitive decline.

Investigating DMTF1 in Aging Brain Cells

The study was led by Assistant Professor Ong Sek Tong Derrick, with Dr. Liang Yajing as first author, from the Department of Physiology and the Healthy Longevity Translational Research Programme at NUS Medicine. The team set out to uncover the biological changes that cause neural stem cells to weaken over time, with the goal of identifying targets for future therapies aimed at slowing neurological aging.

To understand how DMTF1 functions, the researchers examined neural stem cells derived from humans and from laboratory models designed to mimic premature aging. They used genome binding and transcriptome analyses to map how DMTF1 influences gene activity. A key focus was how this protein interacts with stem cells affected by telomere dysfunction. Telomeres are the protective ends of chromosomes that gradually shorten each time a cell divides. This shortening is widely recognized as a marker of aging.

Restoring Regeneration in Aged Stem Cells

The team found that levels of DMTF1 were significantly reduced in "aged" neural stem cells. When they restored DMTF1 expression, the cells regained their ability to regenerate. This suggests that DMTF1 could serve as a promising therapeutic target for restoring stem cell function in the aging brain.

Further analysis revealed how DMTF1 exerts its effects. The protein regulates helper genes (Arid2 and Ss18) that loosen tightly packed DNA, allowing growth-related genes to become active. Without these helper genes, neural stem cells cannot effectively renew themselves.

"Impaired neural stem cell regeneration has long been associated with neurological aging. Inadequate neural stem cell regeneration inhibits the formation of new cells needed to support learning and memory functions. While studies have found that defective neural stem cell regeneration can be partially restored, its underlying mechanisms remain poorly understood," said Asst Prof Ong. "Understanding the mechanisms for neural stem cell regeneration provides a stronger foundation for studying age-related cognitive decline."

Potential Therapies to Slow Brain Aging

The findings indicate that strategies designed to increase DMTF1 levels or enhance its activity could potentially reverse or delay the decline in neural stem cell function linked to aging.

Although the current results are based largely on in vitro experiments, the researchers plan to investigate whether boosting DMTF1 can increase neural stem cell numbers and improve learning and memory in conditions involving telomere shortening and natural aging, without raising the risk of brain tumours. Over the long term, the team hopes to identify small molecules capable of safely stimulating DMTF1 activity to rejuvenate aging neural stem cells.

"Our findings suggest that DMTF1 can contribute to neural stem cell multiplication in neurological aging," Dr. Liang said. "While our study is in its infancy, the findings provide a framework for understanding how aging-associated molecular changes affect neural stem cell behavior, and may ultimately guide the development of successful therapeutics."