HYPOTHALAMIC MENIN LOSS ASSOCIATED WITH AGING

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HYPOTHALAMIC MENIN LOSS ASSOCIATED WITH AGING

Cognition, bone mass, skin thickness, and lifespan are all affected by Menin's decline.





Decline in the hypothalamic Menin may play a key role in aging, according to a new study published on March 16 in the open-access journal PLOS Biology by Lige Leng of Xiamen University, Xiamen, China, and colleagues. The findings reveal a previously unknown driver of physiological aging and suggest that supplementation with a simple amino acid may mitigate some age-related changes.

The hypothalamus has been recognized as a critical mediator of physiological aging through increased neuroinflammatory signaling. In turn, inflammation promotes multiple age-related processes in the brain and periphery.

Recently, Leng and colleagues showed that Menin, a hypothalamic protein, is a crucial inhibitor of hypothalamic neuroinflammation, leading them to ask what role Menin may play in aging. Here, they observed that the level of Menin in the hypothalamus, but not astrocytes or microglia, declines with age. They created conditional knockout mice to explore this decline, in which Menin activity could be inhibited. They found that reduction of Menin in younger mice led to increased hypothalamic neuroinflammation, aging-related phenotypes including reductions in bone mass and skin thickness, cognitive decline, and modestly reduced lifespan.

Another change induced by the loss of Menin was a decline in levels of the amino acid D-serine, known to be a neurotransmitter and sometimes used as a dietary supplement found in soybeans, eggs, fish, and nuts. The authors showed this decline was due to the loss of activity of an enzyme involved in its synthesis (which was, in turn, regulated by Menin).

Could reverse age-related Menin loss reverse signs of physiological aging? To test that, the authors delivered the gene for Menin into the hypothalamus of elderly (20-month-old) mice. Thirty days later, they found improved skin thickness and bone mass, along with better learning, cognition, and balance, which correlated with increased D-serine within the hippocampus, a central brain region important for learning and memory. Remarkably, similar benefits on cognition, though not on the peripheral signs of aging, could be induced by three weeks of dietary supplementation with D-serine.

Much remains to be learned about Menin's role in aging, including the upstream processes that lead to its decline. There is much to learn about the potential for exploiting this pathway, including how much phenotypic aging can be slowed and how long and whether supplementation with D-serine may trigger other changes, yet to be discovered.

Nonetheless, 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 adds, "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."

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