Hypothalamic Menin regulates systemic aging and cognitive decline

Aging is a systemic process, which is a risk factor for impaired physiological functions, and finally death. The molecular mechanisms driving aging process and the associated cognitive decline are not fully understood. The hypothalamus acts as the arbiter that orchestrates systemic aging through neuroinflammatory signaling. Our recent findings revealed that Menin plays important roles in neuroinflammation and brain development. Here, we found that the hypothalamic Menin signaling diminished in aged mice, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in ventromedial nucleus of hypothalamus (VMH) of aged mice extended lifespan, improved learning and memory, and ameliorated aging biomarkers, while inhibiting Menin in VMH of middle-aged mice induced premature aging and accelerated cognitive decline. We further found that Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism. Aging-associated Menin reduction led to impaired D-serine release by VMH-hippocampus neural circuit, while D-serine supplement rescued cognitive decline in aged mice. Collectively, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.

Automated summary

Aging is a systemic process that poses a risk to physiological functions and eventual death. The molecular mechanisms underlying aging and cognitive decline are not fully understood. Recent findings show that Menin plays a role in neuroinflammation and brain development. In aged mice, there is a decrease in Menin signaling in the hypothalamus, which correlates with systemic aging and cognitive deficits. Restoring Menin expression in the ventromedial nucleus of the hypothalamus in aged mice improves lifespan, learning and memory, and aging biomarkers, while inhibiting Menin in middle-aged mice accelerates aging and cognitive decline. Menin epigenetically regulates neuroinflammatory and metabolic pathways, including D-serine metabolism, and the reduction of Menin in aging leads to impaired D-serine release in the VMH-hippocampus neural circuit. Supplementation of D-serine rescues cognitive decline in aged mice. In conclusion, VMH Menin serves as a key regulator of systemic aging and aging-related cognitive decline.