The findings add to growing evidence that aging may be strongly influenced by the hypothalamus, a small but powerful brain region that regulates metabolism, hormones, body temperature, sleep, and stress responses. Researchers increasingly view the hypothalamus as a central command center for aging itself.

A Brain Protein That Declines With Age

The study, led by Lige Leng and colleagues at Xiamen University in China, focused on Menin, a protein that helps suppress inflammation in the brain. Earlier work had already shown that Menin plays an important role in controlling neuroinflammatory activity. The team wanted to know whether losing this protective protein might contribute to aging.

Their experiments revealed that Menin levels dropped sharply in the hypothalamus as mice grew older. The decline occurred specifically in neurons within the ventromedial hypothalamus (VMH), a region linked to metabolism and systemic aging. Interestingly, Menin levels did not significantly decrease in nearby support cells such as astrocytes or microglia.

To investigate what this loss might mean, the researchers engineered mice in which Menin activity could be selectively reduced. The effects were striking. Younger mice with lower Menin levels developed increased brain inflammation, thinning skin, lower bone mass, impaired balance, memory problems, and a shorter lifespan compared with normal mice.

The results suggest that Menin may act as a protective “anti-aging” factor inside the brain.

The D-Serine Connection

One of the most surprising discoveries involved D-serine, an amino acid that also functions as a neurotransmitter in the brain. D-serine helps regulate communication between neurons and is important for learning and memory.

When Menin levels fell, D-serine production also dropped. The researchers traced this effect to reduced activity of an enzyme required for D-serine synthesis, which itself appears to be regulated by Menin.

D-serine naturally occurs in foods including soybeans, eggs, fish, and nuts, and it is also sold as a dietary supplement.

The connection caught researchers’ attention because other studies have linked declining D-serine levels with aging-related cognitive impairment and reduced synaptic plasticity, the brain’s ability to strengthen neural connections involved in memory and learning.

Reversing Signs of Aging in Mice

The researchers then tested whether restoring Menin could reverse age-related decline.

They delivered the Menin gene directly into the hypothalamus of elderly mice that were about 20 months old, roughly equivalent to late-life aging in humans. Just 30 days later, the animals showed measurable improvements in learning, memory, balance, skin thickness, and bone density.

The improvements were accompanied by increased D-serine levels in the hippocampus, a brain region essential for memory formation.

The team also tested whether D-serine supplementation alone could help. After three weeks of supplementation, older mice displayed better cognitive performance, although the treatment did not reverse the physical aging markers seen in skin and bone tissue.

That distinction suggests Menin likely affects aging through several interconnected biological pathways, not just D-serine production alone.

Why the Hypothalamus Is Becoming a Major Focus in Aging Research

Interest in the hypothalamus has grown rapidly in recent years as scientists uncover evidence that this brain region may coordinate many aspects of aging throughout the body.

More recent research has explored how age-related changes in hypothalamic DNA methylation and hormone signaling could contribute to neurodegenerative diseases such as Alzheimer’s. One 2024 study in Nature Communications found that the hypothalamus undergoes distinctive epigenetic changes with age and may influence pathways involving oxytocin and gonadotropin-releasing hormone (GnRH), both linked to aging and brain health.

Together, these findings strengthen the idea that aging is not simply the result of wear and tear across the body. Instead, some scientists suspect the brain may actively regulate parts of the aging process through inflammation, metabolism, and hormonal signaling.

Could D-Serine Help Humans?

Despite the excitement surrounding the findings, the research remains early and was conducted in mice, not humans. Scientists still do not know whether boosting Menin or supplementing with D-serine could safely slow aging or improve cognition in people.

Researchers also caution that altering powerful brain signaling pathways could have unintended consequences. More work is needed to understand why Menin declines with age, how long any benefits might last, and whether D-serine supplementation could produce side effects over time.

Still, the study offers an intriguing glimpse into how aging may one day be targeted more directly.

Leng said, “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 also noted, “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.”

There are two forms of vitamin D supplements available: vitamin D2 and vitamin D3. Researchers have found that taking vitamin D2 supplements can lead to a drop in the body’s concentration of vitamin D3, which is the form our bodies naturally produce from sunlight and use most effectively to raise overall vitamin D levels.  

The study, published in Nutrition Reviews, analyzed data from randomized controlled trials and found that vitamin D2 supplementation resulted in a reduction in vitamin D3 levels compared to those not taking a vitamin D2 supplement. In many of the studies, the vitamin D3 levels went lower than in the control group. 

Emily Brown, PhD Research Fellow and Lead Researcher of the study from the University of Surrey’s Nutrition, Exercise, Chronobiology & Sleep Discipline, said: 

“Vitamin D supplements are important, especially between October and March, when our bodies cannot make vitamin D from sunlight in the UK.  However, we discovered that vitamin D2 supplements can actually decrease levels of vitamin D3 in the body, which is a previously unknown effect of taking these supplements. This study suggests that subject to personal considerations, vitamin D3 supplements may be more beneficial for most individuals over vitamin D2.”  

Professor Cathie Martin, Group Leader at the John Innes Centre, said:  

“This meta-analysis highlights the importance of ensuring plant-based vitamin D3 is accessible in the UK.” 

This research supports a previous study published in Frontiers in Immunology, led by Professor Colin Smith from the University of Surrey, which suggests that vitamin D2 and D3 do not have identical roles in supporting immune function. Vitamin D3 has a modifying effect on the immune system that could fortify the body against viral and bacterial diseases.   

Professor Colin Smith said: 

“We have shown that vitamin D3, but not vitamin D2, appears to stimulate the type I interferon signalling system in the body – a key part of the immune system that provides a first line of defence against bacteria and viruses. Thus, a healthy vitamin D3 status may help prevent viruses and bacteria from gaining a foothold in the body.” 

Further research into the different functionalities of vitamin D2 and D3 should be a priority in deciding whether vitamin D3 should be the first-line choice of vitamin D supplement, subject to individual requirements. 

Professor Martin Warren, Chief Scientific Officer at the Quadram Institute, said: 

 “Vitamin D deficiency represents a significant public health concern, especially during the winter months with significant deficiency across the UK population. This collaborative research effort aligns well with the Quadram Institute’s mission to deliver healthier lives through food innovation to enhance the nutrient density of the food we eat. Tackling this with the most effective form of vitamin D supplementation or fortification is of the utmost importance to the health of the nation.” 

The study also identified similar molecular patterns in human tissue, suggesting that important aspects of obesity-related nerve damage may occur in both mice and people. The findings were published in the journal Nature.

Obesity is known to affect much more than body weight and metabolism. It can alter immune activity, disrupt nerve structures, and reshape tissues throughout the body, increasing the risk of conditions such as type 2 diabetes, cardiovascular disease, stroke, neuropathy, and cancer. Despite these widespread effects, scientists have lacked tools capable of studying disease-related changes across an entire intact body in high detail.

To address that challenge, a research team led by Prof. Ali Ertürk, Director of the Institute for Biological Intelligence (iBIO) at Helmholtz Munich and Professor at LMU, developed MouseMapper. The AI framework uses foundation-model-based deep learning algorithms to analyze massive whole-body imaging datasets.

The system can automatically identify and segment 31 organs and tissue types while also mapping nerves and immune cells throughout the body. This allows researchers to examine how diseases affect multiple organ systems at the same time in intact mice.

“MouseMapper is built on a foundation model, which means it generalizes far beyond the data it was originally trained on,” says Ying Chen, co-first author of the study.

Transparent Mice and Whole-Body Imaging

To build the body maps, researchers first tagged nerves and immune cells in mice using fluorescent markers that glow under a microscope. They then used tissue-clearing methods to make the mice transparent while preserving the fluorescent signals, allowing scientists to see deep inside the body without cutting tissues apart.

Next, the team used advanced light-sheet microscopy to capture detailed three-dimensional images of entire mice. The process generated enormous datasets containing tens of millions of cellular structures from organs and tissues across the body.

MouseMapper then analyzed the images automatically, identifying anatomical regions, nerve networks, and immune-cell clusters throughout the animals.

This approach allowed the researchers to pinpoint exactly where inflammation and tissue damage appeared in organs such as fat tissue, muscle, liver, and peripheral nerves. Unlike earlier methods, scientists did not need to choose specific regions to study beforehand.

Obesity Linked to Facial Nerve Damage

To explore how obesity changes the body, the researchers fed mice a high-fat diet that produced obesity and metabolic problems similar to those seen in humans.

Using MouseMapper, the team found widespread alterations in immune-cell organization and nerve structures across the body. One of the most surprising discoveries involved the trigeminal nerve, a major facial nerve responsible for facial sensation and certain motor functions.

In obese mice, these sensory nerves showed a major reduction in branches and nerve endings, suggesting impaired nerve function. Behavioral tests supported that conclusion, showing that obese mice were less responsive to sensory stimulation compared to lean mice.

The researchers then focused on the trigeminal ganglion, which contains the cell bodies of facial sensory neurons. Through spatial proteomics analysis, they identified molecular changes linked to inflammation and nerve remodeling.

Importantly, many of the same molecular signatures were also found in trigeminal tissue from people with obesity. This suggests that the nerve-related changes observed in mice may also occur in humans.

“We revealed previously unknown structural and molecular changes in the trigeminal ganglion and its facial branches, and the same molecular signature was conserved in human tissue. This kind of finding simply cannot emerge from studying one organ at a time,” says Dr. Doris Kaltenecker, senior scientist at the Institute for Diabetes and Cancer (IDC) at Helmholtz Munich and first author of the study.

A New Tool for Studying Complex Diseases

The researchers believe MouseMapper could become an important tool for studying diseases that affect many organ systems simultaneously, including diabetes, cancer, neurodegenerative diseases, and autoimmune disorders.

Unlike earlier approaches focused on individual tissues or organs, MouseMapper provides an integrated whole-body analysis system that can identify disease hotspots throughout an organism.

The team has also made the whole-body datasets publicly available online so researchers around the world can explore obesity-related changes across organs and tissues.

“Our goal is to create a comprehensive framework for understanding how diseases affect the body as an interconnected system,” says Ali Ertürk. “Our long-term vision is to build truly realistic digital twins of mice in health and disease: cell-level atlases that we can query, perturb and screen in silico computationally. That would let us pinpoint the earliest changes a disease causes, design interventions to prevent them, and accelerate the discovery of new treatments while reducing the number of physical experiments we need to run.”

The work was supported by the European Research Council (Consolidator Grant CALVARIA to A. Ertürk; grant 949017 to M. Rohm), the German Research Foundation (DFG) under Germany’s Excellence Strategy within the Munich Cluster for Systems Neurology (SyNergy, ID 390857198, EXC 2145), DFG SFB 1052 (A9) and TR 296 (P03), the Collaborative Research Centre CRC 1744, the German Federal Ministry of Education and Research (NATON collaboration, 01KX2121, and HIVacToGC), the Vascular Dementia Research Foundation, the Nomis Heart Atlas Project Grant (Nomis Foundation), the Else-Kröner-Fresenius-Stiftung, the Edith-Haberland-Wagner Stiftung, the Helmut Horten Foundation, the EFSD and Novo Nordisk A/S Programme for Diabetes Research in Europe (to D. Kaltenecker), and the China Scholarship Council (to Y. Chen).