Menin Upregulation in the Hypothalamus Improves Cognitive Function and Modestly Extends Life in Mice

Researchers here manipulate levels of menin, a regulator of inflammation in the hypothalamus of mice. Menin expression in the hypothalamus diminishes with age, leading to increased inflammation. Upregulation of menin expression improves health and lifespan, while also improving cognitive function. One might take this as one of many examples of the chronic inflammation that is characteristic of later life being harmful to health and disruptive to tissue function. Given the complexity of regulatory systems in cells, there are many possible approaches to suppress chronic inflammation, but the challenge is to find an approach that only reduces the unwanted, excess inflammation, and doesn't sabotage the inflammatory responses necessary in wound healing and defense against pathogens.

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.