Hypothalamus-specific NSCs derived from hPSCs ameliorate age-associated dysfunction upon transplantation into aged mouse hypothalamus

The hypothalamus is the brain region that regulates systemic body metabolism and multiple functions in other brain regions. In adult mice, the hypothalamus harbors neural stem/precursor cell (NSC)-like cells. Along with the dysregulation of body metabolism and physiology that occurs during aging, the NSC population in the hypothalamus declines with age. Here, we introduce a novel protocol that yields scalable and storable hypothalamus-specific NSCs (htNSCs) from human pluripotent stem cells (hPSCs). Implanting htNSCs into the medio-basal hypothalami of aged mice conspicuously ameliorated age-related declines in metabolic fitness, physical capacity, and cognitive function and produced corresponding histologic changes in various body tissues. Single transcriptome and immunohistochemical analyses of the grafted hypothalamic tissues showed that the anti-aging effects were attained by correcting glial NF-κB, TNF-α, and NLRP3 inflammasome pathways. Collectively, our findings support the potential of anti- or healthy aging therapies that target htNSCs and hypothalamic inflammation. One Sentence Summary hPSC-derived hypothalamus NSCs mitigate age-associated physiological decline upon transplantation into the hypothalamus of aged mice. ### Competing Interest Statement The authors have declared no competing interest.