Transplantation of Young Bone Marrow Improves Brain Function in Old Mice

The immune cells of the brain are somewhat different in character and function from those of the body. They have a greater portfolio of tasks beyond chasing down pathogens, clearing out waste, and assisting in regeneration. For example, the immune cells known as microglia are involved in the maintenance of synaptic connections between neurons. Interestingly, microglia are not produced in the bone marrow by stem cells or progenitor cells, so in the research here in which young bone marrow is transplanted into old mice, one can be fairly sure that any beneficial effects on microglia result from signaling differences on the part of the rest of the immune system.

At the surface, this seems like a case of improvement in function resulting from a reduction in chronic inflammation. That is perhaps reasonable to expect if the immune system becomes less damaged by age, is given more competent cells capable of managing the inflammatory process. Inflammation without end is very problematic in all tissues, the brain included, and is a significant contributing factor in the many dysfunctions of aging. It disrupts the normal behavior of near all cell types. Microglia in particular are prone to behaving unhelpfully in an inflamed environment, contributing to damage rather than helping to repair it or maintain normal function.

Surgically attaching old mice to young mice so that they share a circulatory system (heterochronic parabiosis) has been reported to rejuvenate old mice and accelerate aging in young mice. Rejuvenation of the brain, heart, liver, and pancreas of old parabionts by young blood is thought to be partly due to effects on stem cell populations. In particular, improved cognitive function has been attributed to increased neurogenesis and synaptic plasticity, as well as better brain vascularization and myelination. A single blood exchange between old and young mice, which replaces the blood without organ sharing or complications associated with the parabiosis procedure, has also recently been reported to have similar effects.

Circulating levels of CCL11 and β2-microglobulin have previously been reported to increase with age in mice and humans, and shown to promote brain aging when administered to young mice. Both CCL11 and β2-microglobulin can be produced by a diverse range of cell types, and the tissues or organs responsible for their elevated levels during aging have not been defined. Thus, the role of the hematopoietic system in these effects is unclear. CCL11 and β2-microglobulin are thought to act by suppressing neurogenesis in the hippocampus. However, the role of neurogenesis in the adult brain is controversial. Thus other mechanisms may be responsible for the rejuvenated cognitive function in old mice undergoing heterochronic parabiosis or plasma transfer. Indeed, while stem cell populations in the neurogenic niche have been closely examined, it is not known whether aging-associated changes in glial cells are also reversed.

We therefore established a heterochronic bone marrow transplant (BMT) model to determine the specific influence of systemic hematopoietic aging on cognitive function, including glial cells in the hippocampus. This approach also allowed us to evaluate the long-term beneficial impact of a young hematopoietic system on the aging brain, and define the role of the hematopoietic system in aging-associated elevation of circulating levels of CCL11 and β2-microglobulin. We found that reconstitution of old mice with young, but not old, hematopoietic cells prevented cognitive decline. BMT achieved preservation of cognitive function for at least 6 months. Microglial activation was reduced, and synaptic connections were maintained. Our data also attribute the aging-associated elevation of circulating β2-microglobulin levels to non-hematopoietic cells. In contrast, the increased CCL11 appears either to be of hematopoietic origin or to be produced by non-hematopoietic cells under hematopoietic control, and our data implicate CCL11 in aging-associated microglial activation and synaptic loss.

Link: https://doi.org/10.1038/s42003-019-0298-5

Comments

As the living tissues are really complicated with multiple levels of feedback loops it is not surprising to get an improvement in a remote organ by fixing something else. As Reason said the inflammation is one of the big items.

But there could be others too, like improved vascular function, general improvement in the immune system, so indirectly reducing the pathogenic load.

I wonder if it is feasible to grow personalized "young/brand new" bone marrow and transplant it back to humans...

Posted by: cuberat at February 21st, 2019 10:39 AM

Turn.bio

Posted by: david.gobel@gmail.com at February 21st, 2019 3:41 PM

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