The results of a study led by researchers at Xiamen University revealed that a hypothalamic protein called Menin may play a key role in aging. The findings, reported by Lige Leng, Ph.D., and colleagues in the journal PLOS Biology, revealed what they describe as a previously unknown driver of physiological aging.
In vivo studies have shown that Menin signaling from the hypothalamus is reduced in aged mice and is associated with systemic aging and cognitive deficits. Further experiments showed that restoring Menin expression in the ventral nucleus of the hypothalamus (VMH) extended the lifespan of older mice, improved learning and memory, and associated with a reduction in aging biomarkers. In contrast, blocking the Menin VMH in middle-aged mice caused premature aging and accelerated cognitive decline. In further studies, the team also discovered that the aging-related decline in Menin led to a decrease in the release of D-serine in the VMH-hippocampal nervous system and that administering D-serine to aged mice could help rescue cognitive decline.
Leng stated, “Ventromedial hypothalamus (VMH) Menin signaling diminished in aged mice, which contributes to systemic aging phenotypes and cognitive deficits. The effects of Menin on aging mediate by neuroinflammatory changes and metabolic pathway signaling, accompanied by serine deficiency in VMH, while restoration of Menin in VMH reversed aging-related phenotypes.”
Research In Mice
The researchers described their findings in a paper titled “Hypothalamic Menin regulates systemic aging and cognitive decline,” in which they concluded, “the results explored a novel role of Menin in regulating systemic aging and cognitive function … we have identified the importance of VMH Menin in the orchestration of aging pace. Menin levels may indicate the aging status and serve as an anti-aging target.”
Aging characterizes by a gradual and general decline in physiological functions that eventually leads to death. Although the molecular mechanisms driving the aging process and associated cognitive decline not fully understand, the hypothalamus has identified as a key mediator of physiological aging, and neuroinflammatory signaling increases over time, the authors noted. “The hypothalamus acts as an arbiter in orchestrating systemic aging through neuroinflammatory signaling. This inflammation, in turn, contributes to many age-related processes, both in the brain and in the periphery.
Leng and colleagues recently showed that Menin, a hypothalamic protein, is a key inhibitor of hypothalamic neuroinflammation, prompting them to ask what role Menin might play in aging. “Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development,” they further noted. “It is plausible that decreased Menin signaling contribute to the activated neuroinflammation in the hypothalamus.”
How To Reverse It
Their research in young and old mice showed that Menin levels in the hypothalamus, but not in astrocytes or microglia, decrease with age. “…we first examined the development of Menin in 7 brain regions of young and old mice and found that the decrease in Menin in the hypothalamus is most significant with age, which associates with increased neuroinflammation in the hypothalamus,” they said. “… we found that Menin expression was significantly reduced only in VMH SF-1 [steroidogenic factor-1] neurons, but not in astrocytes and microglia in aged mouse brains.” They also noted that previous studies have implicated SF-1 neurons, which project exclusively to the VMH of the hypothalamus, as important metabolic regulators.
In order to examine the reduction of Menin in these neurons, conditional knockout (ScKO) mice generated in which the function of Menin in SF-1 neurons could blocked. They found that depletion of Menin in younger mice led to increased hypothalamic neuroinflammation. Aging-related phenotypes including reduced bone mass and skin thickness, cognitive decline, and modestly shortened lifespan.
Another change caused by the loss of Menin was a decrease in the concentration of the amino acid D-serine, which acts as a neurotransmitter. The authors showed that this reduction is due to the loss of activity of an enzyme, phosphoglycerate dehydrogenase (PHGDH), involved in the synthesis, which in turn regulates by Menin.
To test whether reversing the age-related loss of Menin could reverse the signs of physiological aging. The authors injected the Menin gene into the hypothalamus of aged (20-month-old) mice. Thirty days later, they found that the treated animals had skin thickness and bone mass, as well as better learning, cognition and balance. This associates with an increase in D-serine in the hippocampus, a central brain region important for learning. and memory. “Overall, up-regulating Menin in VMH of 20-month-old mice could successfully increase mouse lifespan without significant changes in body weight, brain weight, and neuron number in hypothalamus and hippocampus,” they said.
Similar cognitive benefits, although not peripheral signs of aging, can induce by feeding older mice with D-serine for three weeks. “These results suggest that D-serine reduction play a vital role in the cognition decline, and its complement can attenuate the cognition decline in ScKO mice and old mice,” the researchers said. “Our data indicates that the remission of aging phenotype by D-serine limits to cognitive improvement, leaving peripheral systems aging phenotypes unchanged.”
The authors acknowledged that more research need to better understand Menin’s role in aging and to identify the processes that lead to its decline. “Currently, the upstream regulators for Menin are unclear,” said the authors. Further research will also need to explore the potential of exploiting the pathway in question, including how much phenotypic aging can slow, for how long, and what other effects D-serine administration may have.