Human hypothalamic neural stem cells transplantation ameliorates age-associated dysfunction through SNS/eNAMPT axis activation in aged mice

Abstract The hypothalamus is the brain region that regulates systemic body metabolism and multiple brain functions. The adult hypothalamus harbors neural stem/precursor cell (NSC)-like cells. Along with age-related body changes, the hypothalamic NSC (htNSC) population declines, indicating the potential of htNSC replacement as an anti-aging strategy. Here, we developed protocol to generate htNSCs from human pluripotent stem cells (hPSCs). Implanting the hPSC-derived htNSCs into the hypothalamus of aged mice ameliorated age-related declines in metabolic fitness, physical capacity, and cognitive function. Mechanistically, these anti-aging effects were mediated by inter-tissue communication: enhanced neuronal activity in the htNSC-transplanted hypothalamus stimulated adipose tissues to produce and release the anti-aging molecule eNAMPT into systemic circulation via the sympathetic nervous system. Concurrently, the aged inflammatory environment in the hypothalamus was alleviated by peripheral anti-aging signals. Collectively, our findings support the potential of anti- or healthy aging therapies by targeting hypothalamus. Competing Interest Statement The authors have declared no competing interest. Footnotes We shorten the descriptive bulk- and sc-RNAseq part to make it concise and moving related figures to Supplemental Data; thus merging Figure 1 and Figure 2. We change the H&E staining of adipocyte tissue into black and white for better contrast. We added a mechanism study by using beta-blocker to inhibit SNS to show that htNSC relies on SNS signaling for its anti-aging properties. Moreover, we also added eNAMPT inhibition experiment that proved eNAMPT is also needed for anti-aging signaling. We add blood ketone (represented by BHB) another biomarker that is modulated by htNSC-transplantation that positively associated with good physiological outcome.