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Ximerakis M, Holton KM, Giadone RM, Ozek C, Saxena M, Santiago S, Adiconis X, Dionne D, Nguyen L, Shah KM, Goldstein JM, Gasperini C, Gampierakis IA, Lipnick SL, Simmons SK, Buchanan SM, Wagers AJ, Regev A, Levin JZ, Rubin LL. Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types. Nat Aging, March 9, 2023
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Icahn School of Medicine at Mount Sinai
This exciting work from Lee Rubin’s group is a fantastic resource for the expanding field of blood-CNS aging research. Ximerakis, Holton, and colleagues set out to characterize how, at single-cell resolution, the aged or young mouse brain responds to sharing of either young or aged blood, respectively. Particularly striking changes are present in brain endothelial cells, with many of these changes altered in both “rejuvenation” and “aging acceleration” contexts.
This work dovetails nicely with the group’s prior work showing that exposure to young blood through heterochronic parabiosis rejuvenates the aged brain vasculature (Katsimpardi et al., 2014). Based on their new analyses, endothelial cells appear to be among the most responsive, which might be expected given their proximity to the circulating signals that likely mediate blood-brain communication, as highlighted in recent work (Yang et al., 2020).
Interestingly, exposure to young blood in aged mice appears to upregulate pathways associated with mitochondrial function, which are downregulated in aged mice compared to young mice. This finding is particularly convincing, given that a previous whole-body, single-cell RNA-Seq dataset in heterochronic parabionts found similar changes in mitochondrial activity-associated pathways in various tissues (Pálovics et al., 2022).
Intriguingly, the study also implicates parabiosis in reprogramming of transcriptional signatures in the brain, raising the possibility of identifying epigenetic mediators in future work. Beyond endothelial cells, the new dataset also points to oligodendrocytes and other glia as being particularly responsive to these factors. These new insights and other intersections with the growing number of atlases of aging interventions should surely shed light on the molecular pathways governing blood-CNS communication.
Taken together, these results add to the growing body of evidence revealing that diverse classes of CNS cells respond to circulating factors. Many groups, including the Rubin group, have put forth intriguing candidates that mediate some of these rejuvenation or age acceleration effects (Castellano et al., 2017; Katsimpardi et al., 2014; Khrimian et al., 2017; Smith et al., 2015; Villeda et al., 2011). This work argues there is much to be learned from understanding the cellular programs altered by exposure to blood factors, programs that represent plausible targets for therapies for age-associated disorders.
Future work can characterize the extent to which these programs, identified in the context of the parabiosis model, are recapitulated in other, clinically amenable models, including plasma transfer or treatments with proteins such as GDF11 or others, and the extent to which altered cellular programs exhibit brain region-specific sensitivity to blood-sharing. Ultimately, how these programs can be exploited therapeutically to target age-related brain disorders will be a key direction.
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