Rejuvenating the blood and bone marrow to slow aging-associated cognitive decline and Alzheimer’s disease

Abstract

Parabiosis, blood exchange and plasma transfer experiments have highlighted the rejuvenating properties of young blood. Our Communications Biology study demonstrated that young bone marrow transplantation attenuates cognitive decline in old mice, with preservation of hippocampal synapses and reduced microglial reactivity. We now discuss subsequent studies that shed additional light on how blood impacts cognitive function, and potential clinical applications, including ongoing clinical trials with young plasma and experimental strategies targeting the hematopoietic system to slow or reverse cognitive decline. Preservation and rejuvenation of cognition during aging by young blood Cumulative evidence from parabiosis, blood exchange and plasma transfer experiments has demonstrated that young blood can rejuvenate multiple organs in old mice, including the brain, liver, muscle, and heart, and that old blood accelerates aging in young mice (reviewed in refs. 1,2). Heterochronic parabiosis studies, in which old and young mice are surgically joined so they share a circulatory system, have suggested that circulating components of young blood can induce brain rejuvenation in old parabionts, including improvement of hippocampal learning and memory (reviewed in ref. 3). A single blood exchange between old and young mice (without organ sharing, which might confound parabiosis experiments) had similar outcomes 4 , and plasma transfer experiments implicated soluble factors in the circulation 5,6. Together these studies suggest that young and old blood contain varying levels of youthful and pro-aging factors, and that manipulation of those factors represents a promising therapeutic approach for the treatment of human aging-associated diseases such as Alzheimer's disease 7 .

The Impact of Ageing on the CNS Immune Response in Alzheimer’s Disease

“…One novel strategy could be in the form of transfusions of plasma or specific plasma constituents from young donors to elderly or AD recipients. Murine models of plasma transfusion including parabiosis studies have shown improvement in both neuropathological changes with reduction of Ab and tau burden and improvement in cognition (142,143). Various clinical trials exploring different types of therapeutic plasma exchange (TPE) in patients with established AD have generally yielded promising results, the findings of which are summarized by Imbimbo and colleagues (144).…”

“…Therefore, it has been posited that increased inflammatory cytokine levels in old plasma increase VCAM1 expression on BECs, resulting in peripheral leukocyte recruitment and BEC inflammation, in turn activating microglia (146). Another theory for the mechanism of TPE in AD is that old and young plasma may contain youthful and pro-aging factors that influence that ultimately influence the CNS environment and immune response (142). Just as old plasma may contain higher levels of pro-aging pro-inflammatory cytokines, young plasma may contain factors that promote healthy aging of the CNS (142).…”

“…Just as old plasma may contain higher levels of pro-aging pro-inflammatory cytokines, young plasma may contain factors that promote healthy aging of the CNS (142). For example, systemic administration of growth differentiation factor 11 (GDF11) was shown to increase neural stem cell numbers and vascular remodeling in the hippocampi of aged mice (142). However, more research is required to identify these factors in old and young plasma before specific supplementation with these factors can be considered as a viable therapeutic approach for AD.…”

Considering Cause and Effect of Immune Cell Aging on Cardiac Repair after Myocardial Infarction

“…Heterochronic (young to old) bone marrow transplant in 20-22 month old mice improves angiogenesis via upregulation of Cxcl12, Vegf and the inflammatory response post-MI [172,174,208]. Young bone marrow cell transplantation can also improve cognitive function and muscle repair in aged mice, implying a greater scope for bone marrow cell aging on systemic tissue aging [209][210][211]. Of note, cognitive improvements in old mice with young bone marrow is caused by changes in both neurons and microglia, the immune cell population in the brain [209,212].…”

Transfusion of Plasma from Young Exercise mice ameliorates Aging-associated Cognitive Impairments on Learning and Memory through activation of Autophagy. (c2022)

“…The benefits of exercise on the aging brain are associated with increased neurogenesis, and plasticity, as well as improved learning and memory, but little information is known about the released factors that promote these effects. Corroborative evidence on plasma transfusions, parabiosis, and blood transfer studies show that young blood could possibly reduce age-related loss of excitability and plasticity, and can cause brain rejuvenation in aged animals, such as improving learning and memory performance in the hippocampus (Bouchard and Villeda, 2015;Kang et al, 2020). Pairing one young and one aged mouse in parabiosis led to several transcriptional changes linked to synaptic plasticity in the hippocampus of aged mice.…”