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Transfusion of Young Blood Associates TIMP2 with Aging and Cognitive Function

A growing collection of studies and projects have emerged from parabiosis experiments in which the circulatory systems of a young and an old individual are joined. The old individual experiences a modest reduction in the impact of aging, in measures such as regeneration, stem cell activity, and more. This has prompted researchers to search for proteins in young blood that might act as signals to improve function when delivered to old tissues, though the field is young enough and complex enough that there is considerable uncertainty over whether or not youthful signals are in fact the mechanism of interest. There is good evidence for the effects to result from a dilution of harmful factors in old blood instead, for example, which might explain past failures to obtain benefits from transfusion of young blood - though human trials are still ongoing on that front. The paper noted below stands somewhat in opposition to this position, in that the researchers involved have identified another candidate factor in young blood that appears to improve health in old animals. Young fields of research are usually characterized by this sort of apparently incompatible evidence.

Considering the bigger picture, the teams involved in this area of research are essentially engaged in a process of cataloging the differences in types and amounts of proteins found in young blood versus old blood. They are carrying out transfusion experiments and building other interventions to try to pin down which of these proteins are involved in age-related decline or in maintaining youthful function - a matter of needles in haystacks. It is plausible that in the years ahead this might be an alternative road to capturing some of the benefits of present stem cell therapies, those that largely work though signals produced by the transplanted cells, and a way to adjust the behavior of native cell populations. It would override cellular reactions to the rising damage of aging, and push cells into a more youthful pattern of behavior. This carries risk, as damaged cells working harder raises the possibility of cancer. That stem cell therapies can be made to work with a minimal cancer risk should give us hope on that front, however.

As the research results below suggest, there are other possibilities beyond that of enhancing regeneration. Improvements in faltering neurogenesis and synaptic plasticity in the brain are a possibility, for example, with the potential to provide greater resilience to cognitive decline in old age. All of these things will likely operate within the same bounds of the possible and the plausible as are observed for stem cell therapies: it is a road to improvements, not to a reversal of aging. Forcing youthful behavior doesn't remove the underlying damage that has caused age-related changes in cellular behavior, and that damage will still win if not repaired. Methods of enhanced regeneration and neural plasticity may still be beneficial enough to spend time on, however. We shall see.

Young human blood makes old mice smarter

For decades, researchers have studied the effects of young blood on ageing in mice through a technique called parabiosis, in which an old mouse is sewn together with a younger one so that they share a circulatory system. Until now, the rejuvenating properties of young blood had only been demonstrated in mouse-to-mouse transfers. Nevertheless, the work has inspired ongoing clinical trials by at least two companies in which elderly people are infused with blood from younger adult donors and then tested for physical improvements. In one of the clinical trials researchers have started testing plasma collected from the umbilical cords of newborn babies. Their goal is to find out how very young human blood might affect the symptoms of ageing.

Infusing this human plasma into the veins of elderly mice, they found, improved the animals' ability to navigate mazes and to learn to avoid areas of their cages that deliver painful electrical shocks. When the researchers dissected the animals' brains, they found that cells in the hippocampus - the region associated with learning and memory - expressed genes that caused neurons to form more connections in the brain. This didn't happen in mice treated with blood from older human donors.

The researchers then compared a slate of 66 proteins found in umbilical cord plasma to the proteins in plasma from older people, and to proteins identified in the mouse parabiosis experiments. They found several potential candidates, and injected them, one at a time, into the veins of old mice. The team then ran the animals through the memory experiments. Only one of these proteins, TIMP2, improved the animals' performance. It did not, however, result in regeneration of brain cells that are lost during normal ageing. Injections of human umbilical cord plasma lacking TIMP2 had no effect on memory. The researchers don't yet know how TIMP2, which is known to be involved in maintaining cell and tissue structure, exerts its effect on memory. And although it is expressed in the brains of young mice, TIMP2 has never before been linked to learning or memory. Researchers suspect that the protein functions as a 'master regulator' of genes involved in the growth of cells and blood vessels, and that increasing its levels affects many pathways simultaneously.

Human umbilical cord plasma proteins revitalize hippocampal function in aged mice

Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown.

We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.

Comments

Since TIMP2 is the main inhibitor of MMP2, matrix metalloproteinase-2, possibly other MMP2 inhibitors, e.g., tetracycline derivatives and some flavonoids like luteolin might also have a beneficial effect.

Posted by: Lou Pagnucco at April 20th, 2017 1:44 PM

As Reason has already pointed out, this study (like essentially all parabiosis studies) did not control for the substantial effects of generic dilution of "pro-aging" factors in old blood by the umbilical plasma injections documented in Conboy's painstaking SENS Research Foundation-funded work, nor did they look to see (as her work found in some cases) if the change in TIMP2 was because of TIMP2 present in the injected plasma or because the plasma injection altered the target organism's production thereof due to some key upstream effect.

It's also important to note that others have reported that TIMP2 is elevated in the CSF of people with neurodegenerative diseases, including Parkinson's, ALS, and especially Alzheimer's and Huntington's. Now, that doesn't necessarily mean that TIMP2's role in these diseases is pathlological: it could be elevated precisely as a compensatory response to the toxic assault on the brain - but I would await more direct evidence before jumping on this train, especially after the GDF-11 debacle.

Posted by: Michael at April 20th, 2017 2:28 PM

Actually, I retract most of what I just wrote, aside from the general caution about TIMP2 in particular. Apologies.

Posted by: Michael at April 20th, 2017 3:01 PM

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