Decline in the Hypothalamus Menin May Play a Key Role in Aging, According to a New Study Published March 16e in the open access journal PLOS Biology by Lige Leng of Xiamen University, Xiamen, China, and colleagues. The findings reveal a previously unknown cause of physiological aging and suggest that supplementation with a simple amino acid may reduce some age-related changes.
The hypothalamus has been recognized as an important mediator of physiological aging, through an increase in the process of neuroinflammatory signaling over time. In turn, inflammation promotes multiple age-related processes, both in the brain and in the periphery.
Recently, Leng and colleagues showed that Menin, a hypothalamic protein, is an important inhibitor of hypothalamic neuroinflammation, leading them to wonder what role Menin might play in aging. Here they saw that the level of Menin in the hypothalamus, but not astrocytes or microglia, decreases with age. To investigate this decline, they created conditional knockout mice, in which Menin activity could be inhibited. They found that reduction of Menin in younger mice led to an increase in hypothalamic neuroinflammation, aging-related phenotypes including reduction in bone mass and skin thickness, cognitive decline and modestly reduced lifespan.
Another change caused by the loss of Menin was a drop in levels of the amino acid D-serine, known as a neurotransmitter and sometimes used as a dietary supplement in soybeans, eggs, fish and nuts. The authors showed that this decline was due to the loss of activity of an enzyme involved in its synthesis (which was in turn regulated by Menin).
Can reversing age-related Menin loss reverse the signs of physiological aging? To test that, the authors delivered the gene for Menin into the hypothalamus of older (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 an increase in D-serine in the hippocampus, a central brain region important for learning and memory. Remarkably, similar benefits on cognition, but not on the peripheral signs of aging, may be produced by three weeks of dietary supplementation with D-serine.
Much remains to be learned about Menin’s role in aging, including the upstream processes leading to its decline, and much remains to be learned about the potential to exploit this pathway, including how much phenotypic aging can be slowed down and for how long, and whether supplementation with D-serine can cause other changes has yet to be discovered.
Nevertheless, 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 linking the genetic, inflammatory and metabolic factors of aging. D -serine is a potentially promising therapy for cognitive decline.”
Adds Leng: “Ventromedial hypothalamus (VMH) Menin signaling decreased in older mice, contributing to systemic aging phenotypes and cognitive deficits. The effects of Menin on aging are mediated by neuroinflammatory changes and signaling of the metabolic pathway accompanied by serine deficiency in VMH, while restoration of Menin in VMH reversed aging-related phenotypes.”
In your reporting, use this URL to provide access to the freely available newspaper in PLOS Biology: http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3002033
Quote: Leng L, Yuan Z, Su X, Chen Z, Yang S, Chen M, et al. (2023) Hypothalamus Menin regulates systemic aging and cognitive decline. PLoS Biol 21(3): e3002033. https://doi.org/10.1371/journal.pbio.3002033
Author Countries: China, United States of America
financing: see manuscript
Subject of research
Competing Interests: The authors have declared that no competing interests exist.
disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of press releases posted on EurekAlert! by contributing institutions or for the use of information through the EurekAlert system.