Abstract
Aging is a complex process involving transcriptomic changes associated with deterioration across multiple tissues and organs, including the brain. Recent studies using heterochronic parabiosis have shown that various aspects of aging-associated decline are modifiable or even reversible. To better understand how this occurs, we performed single-cell transcriptomic profiling of young and old mouse brains following parabiosis. For each cell type, we catalogued alterations in gene expression, molecular pathways, transcriptional networks, ligand-receptor interactions, and senescence status. Our analyses identified gene signatures demonstrating that heterochronic parabiosis regulates several hallmarks of aging in a cell-type-specific manner. Brain endothelial cells were found to be especially malleable to this intervention, exhibiting dynamic transcriptional changes that affect vascular structure and function. These findings suggest novel strategies for slowing deterioration and driving regeneration in the aging brain through approaches that do not rely on disease-specific mechanisms or actions of individual circulating factors.
Competing Interest Statement
L.L.R. is a founder of Elevian, Rejuveron, and Vesalius Therapeutics, a member of their scientific advisory boards and a private equity shareholder. All are interested in formulating approaches intended to treat diseases of the nervous system and other tissues. He is also on the advisory board of Alkahest, a Grifols company, focused on the plasma proteome. None of these companies provided any financial support for the work in this paper. A.J.W. is a scientific advisor for Frequency Therapeutics, and is a founder of Elevian, Inc and a member of their scientific advisory board and shareholder. Elevian Inc. also provides sponsored research to the Wagers lab. A.R. is a founder and equity holder of Celsius Therapeutics, an equity holder in Immunitas Therapeutics and a scientific advisory board member of Syros Pharmaceuticals, Thermo Fisher Scientific, Neogen.