- A new study in mice proposes for the first time a novel factor that drives aging processes.
- The authors of the study report that a reduction in the protein menin in the brain’s hypothalamus results in neuroinflammation that may cause characteristics of aging.
- The study suggests that supplements of menin and the amino acid D-serine may be able one day to reverse aspects of aging in humans.
A study led by Dr. Lige Leng of Xiamen University in China has identified a previously unknown trigger of aging in mice, and potentially humans. It involves the age-related reduction of a protein called menin in the brain’s hypothalamus.
The study finds that, as levels of menin decrease, the hypothalamus experiences an increase in neuroinflammation that promotes metabolic and cognitive disorders that occur with aging.
The hypothalamus is considered a critically important control center for the body, so when neuroinflammation prevents it from performing its normal function, a wide variety of age-related health issues may arise.
The authors of the study also determined that a loss of menin causes a reduction in levels of an enzyme required for the production of the neurotransmitter, the amino acid D-serine.
The study is published in PLOS Biology.
Why the hypothalamus is important
The hypothalamus, when healthy, influences the autonomic nervous system and hormones to regulate heart rate, temperature, blood pressure, immune function, hunger and thirst, the sleep cycle, mood, satiety, and sex drive.
“The hypothalamus is important for many aspects of healthy aging, including metabolic and cognitive health, the stress response, and maintenance of circadian rhythms,” explained Dr. Ashley E. Webb, Richard and Edna Salomon assistant professor of molecular biology, cell biology, and biochemistry at Brown University in Providence, RI, who was not involved in the study.
“This study,” Dr. Webb said, “advances our understanding of how the part of the brain known as the hypothalamus impacts the aging process, including metabolic and cognitive changes that occur with age.”
She noted that “[h]ypothalamic inflammation is likely to broadly impact aging across tissues and other parts of the brain, such as the hippocampus, which is essential for learning and memory.”
Menin and D-serine in mice
The study findings were supported by several experiments performed on mice.
To assess the effect of menin insufficiency, the researchers worked with middle-aged purpose-bred — or “knockout” — mice whose menin levels they could manipulate.
After reducing the mice’s menin levels, the researchers saw that the rodents exhibited aging biomarkers, such as reduced muscle fiber size, skin thickness, bone mass, tail tendon collagen cross-linking, and clock gene expression.
Increased ventricular muscle thickness and DNA methylation levels were also observed. The mice also experienced cognitive decline, and their lifespan was shortened slightly.
On the other hand, when the researchers supplemented menin levels in elderly, 20-month-old mice for 30 days, the mice exhibited improved learning and memory, bone mass, skin thickness, and tail tendon collagen cross-linking.
These mice also had better inflammation levels, food intake, and metabolic circadian rhythm. They also lived longer than would have otherwise.
Increased levels of menin in the older mice also apparently prompted an increase in D-serine in the hippocampus.
“D-serine is important for communication between neurons to maintain optimal brain function with age,” explained Dr. Webb.
When the researchers administered three weeks of D-serine supplements directly, they found that cognition improved, though not the physiological improvements seen with menin supplementation.
Could the findings apply to humans?
When research involves mice, often its findings do not ultimately carry over to humans.
However, Dr. Santosh Kesari, director of Neuro-oncology, and chair and professor in the Department of Translational Neurosciences at the Pacific Neuroscience Institute, who was not involved in the study, told Medical News Today: “I think for the most part, much of the biology is very similar, and I think this will extrapolate into humans.“
He suggested that “there are some studies that can be done to look at the hypothalamic, pituitary, adrenal access and other aging and metabolism and inflammation markers in the blood of humans.”
What this study means
“This paper really identifies, uniquely I think, a critical regulation of aging due to this protein called menin, which is expressed in the hypothalamus,” said Dr. Kesari.
“The implication,” according to Dr. Webb, “is that menin activity in a small number of neurons may be a key control point for D-serine levels which, in turn, maintain metabolic and cognitive health.”
The authors of the study assert that menin may be the key protein that connects genetic, inflammatory, and metabolic aging factors.
Dr. Webb noted:
“Menin protein is found in other places in addition to the hypothalamus, including the pituitary and thyroid glands. This study is focused on menin’s activity in a small subset of neurons in the hypothalamus. It will be important to learn more about whether Menin’s activity in other places in the body impacts aging.”
The function of menin appears to be tissue-specific, acting in opposite ways in different places. For example, it is considered a tumor suppressor in the lung, prostate, bone, liver, and breast, and at the same time, a factor in the development of leukemia.
The precise mechanism by which menin produces neuroinflammation in the hypothalamus is beyond the scope of this study that otherwise opens a new and intriguing research pathway for our understanding of aging.
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