Hypothalamic Menin regulates systemic aging and cognitive decline

• Published in: PLoS biology Vol. 21; no. 3; p. e3002033
• Main Authors: Leng, Lige, Yuan, Ziqi, Su, Xiao, Chen, Zhenlei, Yang, Shangchen, Chen, Meiqin, Zhuang, Kai, Lin, Hui, Sun, Hao, Li, Huifang, Xue, Maoqiang, Xu, Jun, Yan, Jingqi, Chen, Zhenyi, Yuan, Tifei, Zhang, Jie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.03.2023; Public Library of Science (PLoS)
• Subjects: Aging; Aging (artificial); Aging - genetics; Aging - metabolism; Animals; Biology and Life Sciences; Biomarkers; Circuits; Cognitive ability; Cognitive Dysfunction - genetics; Cognitive Dysfunction - metabolism; D-Serine; DNA methylation; Hypothalamus; Hypothalamus (ventromedial); Hypothalamus - metabolism; Inflammation; Life span; Medicine and Health Sciences; Metabolic pathways; Metabolism; Mice; Molecular modelling; Neurons; Physiological effects; Protein expression; Proteins; Risk factors; Serine - metabolism; Signaling; Social Sciences; Transcription Factors - metabolism; Tumor necrosis factor-TNF; Ventromedial nucleus
• ISSN: 1545-7885; 1544-9173; 1545-7885
• DOI: 10.1371/journal.pbio.3002033

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.