Scientists restore a brain protein and reverse signs of aging in mice

The findings came from a study published on March 16, 2023, in the open access journal PLOS Biology, led by Lige Leng of Xiamen University in Xiamen, China, and colleagues. The work identified a possible connection between brain inflammation, metabolism, and aging throughout the body. Research published since then has added to that picture, while also showing why the supplement findings require careful interpretation.

How a Brain Protein Could Influence Aging

The researchers focused on the hypothalamus, a small brain region that helps coordinate metabolism and other essential functions. It also appears to influence how the body ages. As inflammatory signaling increases in this region, it can contribute to changes both within the brain and in tissues elsewhere in the body.

Before the 2023 study, Leng and colleagues had found that Menin helps restrain inflammation in the hypothalamus. That raised an important question: Could losing some of this protection help set age-related decline in motion?

The team found that Menin levels fell with age in certain neurons within the ventromedial hypothalamus, an area involved in regulating metabolism. The same decline was not seen in astrocytes and microglia, two types of cells that support and protect the brain. This suggested that the change was specific to particular cells rather than a uniform loss across the region.

To investigate whether Menin loss could actually contribute to aging, rather than simply accompany it, the researchers created conditional knockout mice. These animals were genetically engineered so that Menin could be selectively removed. Reducing Menin in younger mice increased hypothalamic inflammation and brought on several aging-related traits, including lower bone mass, thinner skin, cognitive decline, and a modestly shorter lifespan.

The D-Serine Connection

Menin loss also disrupted a chemical pathway important for communication between brain cells. Mice with less Menin had lower levels of D-serine, an amino acid that helps activate receptors involved in learning and memory. These receptors help neurons adjust the strength of their connections, a process essential for storing information.

An enzyme involved in D-serine production (which was in turn regulated by Menin) became less active, reducing the amino acid’s supply. The findings suggested that Menin could influence cognition not only through inflammation, but also by helping maintain the chemistry that supports brain signaling.

D-serine is sometimes used as a dietary supplement, but an important distinction can get lost in discussions of food sources. Serine occurs in foods such as soybeans, eggs, fish, and nuts, while the form incorporated into dietary proteins is L-serine. The body can convert L-serine into D-serine, but the two forms are not interchangeable, and eating these foods is not equivalent to receiving the experimental D-serine treatment.

Restoring Menin in Older Mice

The researchers next tested whether raising Menin levels could improve the condition of elderly (20-month-old) mice. They delivered the gene for Menin into the hypothalamus, allowing cells in that region to produce more of the protein.

Thirty days later, the treated mice had improvements in skin thickness and bone mass, along with better performance on tests of learning, cognition, and balance. The changes were accompanied by higher D-serine levels in the hippocampus, a brain region essential for learning and memory. The study also reported that restoring Menin extended lifespan in the treated mice.

A separate experiment tested a simpler approach: giving mice D-serine in their drinking water for three weeks. This improved cognitive performance, including in older animals. However, the supplement did not reproduce the broader improvements in physical aging traits seen after Menin restoration. The distinction matters: the study did not show that taking D-serine reversed aging throughout the body.

At the time, Leng described the potential significance of the findings:

“We speculate that the decline of Menin expression in the hypothalamus with age may be one of the driving factors of aging, and Menin may be the key protein connecting the genetic, inflammatory, and metabolic factors of aging. D-serine is a potentially promising therapeutic for cognitive decline.”

Leng added, “Ventromedial hypothalamus (VMH) Menin signaling diminished in aged mice, which contributes to systemic aging phenotypes and cognitive deficits. The effects of Menin on aging are mediated by neuroinflammatory changes and metabolic pathway signaling, accompanied by serine deficiency in VMH, while restoration of Menin in VMH reversed aging-related phenotypes.”

What Later Research Has Added

Subsequent studies have explored related mechanisms, although they should not be treated as direct confirmation of the entire Menin aging pathway.

A study published in the Journal of Physiology and Biochemistry in March 2024 examined Menin in cultured mouse hippocampal cells exposed to the stress hormone corticosterone. A compound called itaconate increased Menin levels and reduced inflammation and a form of cell death. When the researchers silenced Menin, that protection disappeared. The result supported a protective role for Menin in another experimental setting, but it was a cell study, not a demonstration of slower aging in animals or people.

Other work has strengthened the case that communication between the hypothalamus and the rest of the body can influence aging. In a 2024 Cell Metabolism study, researchers at Washington University School of Medicine identified a different group of hypothalamic neurons that communicates with fat tissue. Interventions that maintained or stimulated this system increased physical activity and extended lifespan in mice. The study involved a different molecular pathway from Menin, but reinforced the broader idea that brain signals can affect aging beyond the brain.

A much larger view emerged in January 2025, when an Allen Institute team reported an analysis of roughly 1.2 million mouse brain cells in Nature. Some of the cell types most sensitive to aging were concentrated around the hypothalamus’s third ventricle, a fluid-filled cavity. Many showed reduced activity in genes associated with neuronal function alongside increased activity in genes related to immune responses. That study mapped changes associated with aging rather than testing a treatment, but it highlighted the hypothalamus as an important area for further investigation.

Why More D-Serine Is Not Necessarily Better

Later research also complicates the idea that increasing D-serine should always benefit an aging brain.

In April 2025, a study in Cellular and Molecular Life Sciences examined mice engineered to develop features of Alzheimer’s disease. In that model, an early rise in D-serine accompanied disruptions in brain signaling. Genetically removing the enzyme that produces D-serine prevented or reduced several later cognitive problems. This was a different biological setting from the Menin experiments, but it demonstrated that D-serine can have different effects depending on the underlying disease process.

Research published on September 16, 2026, in the Journal of Alzheimer’s Disease pointed in another direction. In a different Alzheimer’s mouse model, a diet enriched with L-serine increased blood levels of both L-serine and D-serine and partially restored measures of new neuron production in the hippocampus. It did not improve the buildup of amyloid, a protein associated with Alzheimer’s disease. Importantly, this experiment tested L-serine and the production of new neurons, not D-serine supplementation as a treatment for human aging.

Taken together, these findings suggest that serine metabolism is a promising research target, but not a simple case of more being better. The form of serine, the condition being studied, and the outcome being measured all matter. Neither study directly confirms or overturns the original Menin results.

What the Findings Mean for People

There is some human research on D-serine, although it does not establish an aging treatment. A small randomized study published in 2016, before the Menin work, tested a single dose in 50 healthy older adults. Participants improved on one measure of a computerized maze task, but the researchers found no significant benefit on the other cognitive tests or mood measures. The experiment did not establish lasting memory benefits, slower aging, or the safety of prolonged use in older adults.

The Menin findings leave several important questions unresolved. Researchers still need to determine what causes the protein to decline with age, how much of the resulting physical and cognitive deterioration can be prevented, and how long any benefits might last. They also need to understand whether altering Menin or supplementing D-serine could produce unintended effects.

The central possibility remains compelling: some changes associated with aging may be influenced by signals originating in a small part of the brain. Understanding those signals could reveal ways to protect function later in life. For now, however, the evidence points to an experimental pathway worth investigating, not a supplement proven to turn back human aging.