The hypothalamus is an area of the brain responsible for regulating a wide range of bodily functions, including metabolism, body temperature, and hormone production. This region also plays a key role in regulating the body’s circadian rhythms and the sleep-wake cycle, both of which undergo significant dysregulation as we age. These changes can have a cascading effect on other physiological systems, leading to a decline in overall health and an increased risk of age-related diseases such as diabetes, cardiovascular disease, and neurodegenerative disorders. For this reason, maintaining hypothalamic function has been considered important in maintaining good overall health while aging.

Inflammation is found to be increased in the tissues of aging organisms and is thought to exacerbate the aging phenotype—so much so that the term “inflamm-aging” has been derived from this phenomenon. It has been reported that the hormone menin is a crucial inhibitor of neuroinflammation in the hypothalamus. A recent study has investigated the importance of maintaining hypothalamic function and how diminished menin levels contribute to age-related dysfunction (Leng L, Yuan Z, Su X, et al. Hypothalamic Menin regulates systemic aging and cognitive decline. PLOS Biology, 2023: 21(3):e3002033

While it is primarily known for its role in regulating cell growth, menin also plays a critical role in the hypothalamus, where it modulates the hypothalamic secretion of various hormones involved in the regulation of organismal growth and metabolism. Menin interacts with a variety of proteins in the hypothalamus to regulate the expression and secretion of these hormones, and disruptions to menin’s function can lead to abnormal hormone levels and associated health problems. As a result, menin is an important hypothalamic hormone, taking a central role in regulating hormone secretion and maintaining overall health.

Age-related decline in menin has led researchers to consider its role in the context of aging. To elucidate the effects of decreased menin, researchers designed a genetically modified mouse that allowed them to express lower amounts of this hormone in the hypothalamus. This modification resulted in a mouse with characteristics of accelerated aging. Their findings revealed that decreasing menin in younger mice resulted in elevated hypothalamic neuroinflammation and several aging-related characteristics such as decreased bone mass and skin thickness, cognitive decline, and a slightly reduced lifespan.

Loss of menin also led to reduced levels of serine, an amino acid known for its neurotransmitter activity. The authors demonstrated that this reduction was caused by a decrease in the activity of an enzyme involved in its synthesis, which was regulated by menin. Surprisingly, reducing levels of menin in the hypothalamus also led to a reduction of serine levels in the hippocampus, suggesting some interplay between these two regions of the brain with regard to serine biosynthesis. A separate region of the brain, the hippocampus is the center for memory and learning.

To determine whether restoring menin levels could reverse age-related physiological changes, the researchers induced the expression of the menin gene in the hypothalamus of elderly mice (20 months old). Thirty days later, they observed an improvement in skin thickness and bone mass, as well as enhanced learning, cognition, and balance. These positive cognitive effects were associated with increased serine levels in the hippocampus. In addition to cognitive improvements, menin overexpression was sufficient to extend lifespan.

To investigate serine’s ability to rescue the age-associated detriments of an impaired hypothalamus, genetically modified mice lacking menin and, consequently, having low levels of hypothalamic and hippocampal serine, were supplemented with dietary serine. These mice were designed to emulate the neuroinflammation of aging and were previously shown to have impaired memory and cognition. Although serine supplementation showed improvement in the cognition and memory of these mice, it was not sufficient to extend the lifespan or produce benefits observed when menin had been overexpressed. This might be due to additional downstream actions of menin independent of serine biosynthesis.

Aging is known to be coincident with the degradation of multiple physiological systems. In the absence of the ability to treat a central underlying cause of aging, therapies that can discretely bolster individual systems would be effective in maintaining a quality of life with advanced age. With age, a decline in cognitive faculties is an unavoidable reality. This study provides evidence that dietary supplementation with serine, found at high levels in soybeans, eggs, fish, and nuts, might delay the onset of age-related cognitive impairment.

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