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.”

New research suggests those early people changed their surroundings far more than scientists once believed.

Computer Models Reveal Early Human Impact

An international team led in part by researchers at Aarhus University used advanced computer simulations to examine how climate, large animals, natural fires, and humans shaped European vegetation during two past warm periods. The team then compared those simulations with extensive fossil pollen data from the same eras. By matching the models with real world evidence preserved in pollen, they were able to estimate how much each factor influenced plant cover.

The results point to a clear conclusion. Both Neanderthals and later Mesolithic hunter-gatherers significantly altered vegetation patterns across Europe, long before agriculture began.

“The study paints a new picture of the past,” says Jens-Christian Svenning, professor of biology at Aarhus University. The project involved experts in archaeology, geology, and ecology from The Netherlands, Denmark, France, and UK.

“It became clear to us that climate change, large herbivores and natural fires alone could not explain the pollen data results. Factoring humans into the equation — and the effects of human-induced fires and hunting — resulted in a much better match,” says Jens-Christian Svenning.

The findings were recently published in PLOS One.

Humans and the Decline of Megafauna

The researchers focused on two specific warm intervals in European history.

The first was the Last Interglacial period around 125,000-116,000 years ago, when Neanderthals were the only humans living in Europe. The second was the Early Holocene, 12,000-8,000 years ago, just after the last Ice Age, when Mesolithic hunter-gatherers from our own species, Homo sapiens, inhabited the region.

During the Last Interglacial, Europe supported a wide range of megafauna. Elephants and rhinoceroses lived alongside bison, aurochs, horses, and deer.

By the Mesolithic period, that picture had changed. Many of the largest animals had vanished or their numbers had dropped sharply. This reflected the broader wave of megafauna losses that followed the global spread of Homo sapiens.

A New View of Prehistoric Europe

“Our simulations show that Mesolithic hunter-gatherers could have influenced up to 47% of the distribution of plant types. The Neanderthal effect was smaller, but still measurable — approximately 6% for plant type distribution and 14% for vegetation openness,” says Anastasia Nikulina.

Human influence showed up in two main ways. One was the use of fire, which burned trees and shrubs. The other was hunting large herbivores, a factor that has often been overlooked.

“The Neanderthals did not hold back from hunting and killing even giant elephants. And here we’re talking about animals weighing up to 13 tonnes. Hunting also had a strong indirect effect: fewer grazing animals meant more overgrowth and thus more closed vegetation. However, the effect was limited, because the Neanderthals were so few that they did not do eliminate the large animals or their ecological role — unlike Homo sapiens in later times,” says Jens-Christian Svenning.

According to Nikulina and Svenning, these findings challenge the idea that Europe was an untouched wilderness before farming began.

“The Neanderthals and the Mesolithic hunter-gatherers were active co-creators of Europe’s ecosystems,” says Jens-Christian Svenning. “The study is consistent with both ethnographic studies of contemporary hunter-gatherers and archaeological finds, but goes a step further by documenting how extensive human influence may have been tens of thousands of years ago — that is, before humans started farming the land,” elaborates Anastasia Nikulina.

AI Simulations and Interdisciplinary Research

Nikulina emphasizes that the project brought together multiple fields, including ecology, archaeology and palynology (knowledge about pollen). The team also developed detailed computer models to simulate ancient ecosystems.

“This is the first simulation to quantify how Neanderthals and Mesolithic hunter-gatherers may have shaped European landscapes. Our approach has two key strengths: it brings together an unusually large set of new spatial data spanning the whole continent over thousands of years, and it couples the simulation with an optimization algorithm from AI. That let us run a large number of scenarios and identify the most possible outcomes,” says Anastasia Nikulina.

Svenning adds that the modeling made one thing clear.

“The computer modeling made it clear to us that climate change, the large herbivores such as elephants, bison and deer, and natural wildfires alone cannot explain the changes seen in ancient pollen data. To understand the vegetation at that time, we must also take human impacts into account — both direct and indirect. Even without fire, hunter-gatherers changed the landscape simply because their hunting of large animals made the vegetation denser,” says Jens-Christian Svenning.

Even with these advances, gaps remain in our knowledge about how early humans influenced their environments.

Nikulina and Svenning note that similar simulations could be applied to other regions and time periods. North and South America and Australia are especially intriguing because they were not inhabited by earlier hominin species before Homo sapiens. That makes it possible to compare more recent landscapes with and without human presence.

“And although the large models paint a broad picture, detailed local studies are absolutely essential to improve our understanding of the way humans shaped the landscape in prehistoric times,” says Jens-Christian Svenning.

In a formal comment published in Global Ecology and Conservation, scientists from Utah State University and Colorado State University argue that a 2025 paper by Ripple et al. overstated how much wolf recovery reshaped Yellowstone National Park’s ecosystem.

“Ripple et al. argued that carnivore recovery produced one of the world’s strongest trophic cascades,” said Dr. Daniel MacNulty, lead author and wildlife ecologist at Utah State University. “But our re-analysis shows their conclusion is invalid because it relies on circular reasoning and violations of basic modeling assumptions.”

The 1500% Willow Growth Claim

The original study reported a 1,500% surge in willow crown volume after wolves returned. That estimate was derived from plant height measurements using a regression model that both calculated and predicted crown volume from height alone.

“Because height was used both to compute and to predict volume,” MacNulty explained, “the relationship is circular — mathematically guaranteed to look strong even if no biological change occurred.”

In other words, the statistical method made the connection appear powerful by design, even if willow growth had not meaningfully changed.

Methodological Concerns and Sampling Bias

The researchers also pointed to several additional concerns:

• The height to volume model was applied to heavily browsed willows with misshapen growth forms, violating the model’s assumptions and inflating apparent increases.
• Willow plots compared between 2001 and 2020 were mostly different locations, making it difficult to separate real ecological change from sampling bias.
• Comparisons with trophic cascades around the world assumed ecological equilibrium, which does not apply to Yellowstone’s still recovering, non equilibrium system.
• Selective photographs and the exclusion of factors such as human hunting further complicated efforts to establish clear cause and effect.

According to the authors, once these issues are addressed, the evidence no longer supports claims of a dramatic ecosystem wide rebound driven by wolves.

“Once these problems are accounted for, there is no evidence that predator recovery caused a large or system-wide increase in willow growth,” said Dr. David Cooper, co author and emeritus senior research scientist at Colorado State University. “The data instead support a more modest and spatially variable response influenced by hydrology, browsing, and local site conditions.”

A More Nuanced View of Predator Effects

The researchers stress that their findings do not dismiss the ecological importance of large carnivores. Instead, they argue that complex food web dynamics require careful analysis and strong evidence.

“Our goal is to clarify the evidence, not downplay the role of predators,” MacNulty said. “Predator effects in Yellowstone are real but context-dependent — and strong claims require strong evidence.”

The new paper helps explain why scientists analyzing the same dataset reached different conclusions. Ripple et al. (2025) described wolf recovery as triggering a powerful trophic cascade. In contrast, Hobbs et al. (2024), who gathered the data during 20 years of field experiments, reported only weak cascade effects.