Arguing for Hypothalamic Neural Stem Cell Signaling to Support Function in Other Tissues

Researchers here argue for neural stem cells in the hypothalamus to support a youthful environment in many other tissues via secreted factors carried into circulation in exosomes. To the degree that this signaling falters with age, it contributes to the burden of aging and age-related dysfunction - though as ever it is challenging to assign a relative importance to this mechanism versus all of the others identified to date, or a firm place in a network of cause and consequence. I don't think that describing either the signaling or its reduction with age as a program is helpful. We might expect component parts of a complex system to evolve a dependency on the behavior of other component parts. There are any number of well-established examples of the interdependence of internal organ function in the aging body. This is just the way things work.

In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial inactivation of a "longevity program" aimed at maintaining youthfulness in organisms. Supporting this hypothesis, age-related changes in organisms can be reversed by factors circulating in young blood. Concordantly, the endocrine secretion of exosomal microRNAs (miRNAs) by hypothalamic neural stem cells (htNSCs) regulates the aging rate by enhancing physiological fitness in young animals. However, the specific molecular mechanisms through which hypothalamic-derived miRNAs exert their anti-aging effects remain unexplored.

Using experimentally validated miRNA-target gene interactions and single-cell transcriptomic data of brain cells during aging and heterochronic parabiosis, we identify the main pathways controlled by these miRNAs and the cell-type-specific gene networks that are altered due to age-related loss of htNSCs and the subsequent decline in specific miRNA levels in the cerebrospinal fluid (CSF). Our bioinformatics analysis suggests that these miRNAs modulate pathways associated with senescence and cellular stress response, targeting crucial genes such as Cdkn2a, Rps27, and Txnip. The oligodendrocyte lineage appears to be the most responsive to age-dependent loss of exosomal miRNA, leading to significant derepression of several miRNA target genes.

Furthermore, heterochronic parabiosis can reverse age-related upregulation of specific miRNA-targeted genes, predominantly in brain endothelial cells, including senescence promoting genes such as Cdkn1a and Btg2. Our findings support the presence of an anti-senescence mechanism triggered by the endocrine secretion of htNSC-derived exosomal miRNAs, which is associated with a youthful transcriptional signature.