Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types

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.

Current and Future Treatments of Vascular Cognitive Impairment

“…213–216 Some recent interesting relevant advancements in the past decade also include revealing the detrimental impact of aging peripheral circulation on the brain and its vascular system, 217,218 and young plasma transfusion rejuvenates the aging brain in animals. 219–221 In fact, improving the circulatory profile may also partly explain the observed neurovascular benefits of several experimental interventions with reported anti-brain-aging effects (eg, GLP-1 RA). 202,203 Currently, it remains to be tested whether any of these experimental therapeutic strategies can ameliorate age-related neurovascular dysfunction in human subjects.…”

The “Rejuvenating Factor” - Platelet Factor 4 in Platelet Transfusion - Myth or Reality?

“…1a). The SDA-PCs were also subdivided into three categories based on storage time: 0, [1][2][3], and [3][4][5] days. Stored SDA-PCs could be transfused until study day 5 at the time of the study.…”

“…2d). Initially considering age group followed by processing and storage time, we noted that PFA levels were higher and signi cant at storage time [0] compared to [1][2][3] days of storage for all donor ages (Fig. 2e).…”

“…More recently, heterochronic parabiosis connecting aged and young mice, demonstrated systemic rejuvenating properties. 1,2 In addition, blood plasma transfer from young to older mice reversed agerelated cognitive impairment, although the mechanisms involved are unclear. [1][2][3][4][5] Few molecules were highlighted in these processes.…”

“…1,2 In addition, blood plasma transfer from young to older mice reversed agerelated cognitive impairment, although the mechanisms involved are unclear. [1][2][3][4][5] Few molecules were highlighted in these processes. Eotaxin-1 or TIMP-2 detected in blood components prepared for transfusion have been associated with cognitive function and ageing 6 as well as Platelet Factor 4 (PF4), mainly released by platelets.…”