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 after parabiosis. For each cell type, we cataloged 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 new 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][214][215][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][220][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.…”

Functional and multi-omic aging rejuvenation with GLP-1R agonism

“…Discovering effective strategies to counteract aging-associated changes is a significant scientific pursuit with profound societal implications, given the potential to improve overall well-being and extend healthy lifespan. Numerous anti-aging strategies have shown promising experimental data, including mammalian target of rapamycin (mTOR) inhibitors 1,2 , senolytics 3,4 , nicotinamide adenine dinucleotide boosters [5][6][7] , taurine supplements 8 , intermittent fasting and calorie restriction [9][10][11] , cellular reprogramming 12,13 , and circulating factor or protein-based rejuvenation [14][15][16][17][18][19][20][21][22] . Studies testing these methods have significantly advanced our understanding of the aging process and enhanced our ability to counteract it.…”

A high-resolution view of the heterogeneous aging endothelium

“…Findings of decreased expression of classical BBB junction genes (e.g., Ocln, Cldn5 ) [ 30 ] in aged BECs are in line with this. In some studies, aged BECs also commonly exhibited upregulation of genes related to the hypoxia response (e.g., Hif1a, Ldha, Aldoa ), and genes involved in oxidative stress pathways (e.g., Sod1, Alpl , Apoe ), indicating an increased cellular stress response [ 16 , 28 ]. Increased oxidative stress in BECs has been associated with age-induced impairment of the cerebral microvascular system and neurovascular uncoupling [ 13 , 24 , 35 ], age-related alterations of vascular reactivity [ 36 ] and reduced pericyte coverage of cerebral microvessels [ 37 , 38 ], which could ultimately contribute to neuronal cell death [ 15 ].…”

“…Increased oxidative stress in BECs has been associated with age-induced impairment of the cerebral microvascular system and neurovascular uncoupling [ 13 , 24 , 35 ], age-related alterations of vascular reactivity [ 36 ] and reduced pericyte coverage of cerebral microvessels [ 37 , 38 ], which could ultimately contribute to neuronal cell death [ 15 ]. Another common finding was the age-related upregulation of Vwf , a key regulator of hemostatic control, various Krüppel-like factors (e.g., Klf2, Klf4, Klf6 ), important for vasoprotection and response to injury, and genes involved in cell adhesion and/or extracellular matrix (ECM) organization (e.g., Adamts1, Itga6, Cyr61 ) [ 16 , 28 , 31 ]. Angiogenic signaling pathways, such as insulin-like growth factor-1 receptor (IGF-1R) , vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-β),were also upregulated in aged BECs, indicated by the upregulation of genes such as Igf1r , Kdr , Flt1 , Edn1 , Eng , Id1 , Bmpr2 , and Acvrl1 [ 16 , 28 , 30 , 31 ].…”

“…Another common finding was the age-related upregulation of Vwf , a key regulator of hemostatic control, various Krüppel-like factors (e.g., Klf2, Klf4, Klf6 ), important for vasoprotection and response to injury, and genes involved in cell adhesion and/or extracellular matrix (ECM) organization (e.g., Adamts1, Itga6, Cyr61 ) [ 16 , 28 , 31 ]. Angiogenic signaling pathways, such as insulin-like growth factor-1 receptor (IGF-1R) , vascular endothelial growth factor (VEGF) and transforming growth factor beta (TGF-β),were also upregulated in aged BECs, indicated by the upregulation of genes such as Igf1r , Kdr , Flt1 , Edn1 , Eng , Id1 , Bmpr2 , and Acvrl1 [ 16 , 28 , 30 , 31 ]. These findings are in contrast with the well-known phenomenon of capillary rarefaction in aging tissues [ 39 ], including the brain [ 40 ], suggesting that these genes may be activated in a counteracting attempt to restore the lost vascular density.…”