Young Blood Reverses Age-Related Cognitive Impairment

Heterochronic parabiosis is a process of linking the circulatory systems of an old and a young laboratory animal, such as mice. It is an investigative technique used by researchers in efforts to identify the differences in circulating proteins between old and young tissue environments, and which of these changes are important or can be altered to produce benefits in old animals. The entry point for much of this research is stem cell biology, the study of regeneration, tissue maintenance, and especially why stem cell activity declines with age, and the precise mechanisms behind this decline.

Stem cell treatments show great potential as therapies for many age-related conditions, but in order for these therapies to be as effective as they might be for the old, the problem of stem cell decline has to be solved, or at the very least worked around while a solution is created. The true solution for this, as for all aspects of aging, is to implement methods of repair that can remove the low-level cellular and molecular damage that causes aging. But in the meanwhile, it might be possible to gain some benefits and improve the outcome of stem cell treatments by overriding the protein signals in aged tissue to make native and transplanted stem cells behave as though in young tissue - at least for a while, long enough to make a difference.

Cancer is a real concern in these matters, however. The consensus position on declining stem cell activity with aging is that it is an evolved response to aging that has the effect of suppressing cancer incidence. Fewer active stem cells means less of a chance that any one of those cells gains just the wrong set of mutations to run amok as the seed of a new cancer. The cost to this is that we all suffer progressive failure of tissue maintenance and a slow, drawn out decline leading to death by organ failure. New biotechnologies mean that researchers can start to alter this balance of risk, however: perhaps it will be acceptable to put old stem cells back to work for a few months at a time in order to somewhat repair some forms of damage in portions of the aged body. Worn joints, for example, or weakened muscles. That would not be true rejuvenation, as all too much of the damage of aging has nothing to do with stem cells per se. It would be better than nothing, however, and it appears to be increasingly plausible as an option in the next decade or so.

As researchers continue in their investigations of parabiosis, they are cataloging the various systems and cell populations that benefit from the youthful blood of the younger partner in the pairing. Here is an interesting example:

In Revival of Parabiosis, Young Blood Rejuvenates Aging Microglia, Cognition

Aging brings with it not only a decline in cognition but also a smoldering inflammation within the innate immune system. In the brain, this manifests as an abnormal state of that organ's main resident immune cell, the microglia. To see whether this is an internal affair of the aging brain or influenced by the periphery, [researchers]returned to a blood-sharing experiment called parabiosis. [They had] previously used it to show that a young systemic environment can essentially rejuvenate neurogenesis and other aspects of the aging brain.

[Researchers] said that pairing an 18-month-old with a 3-month-old mouse, and letting them live together for five weeks, reversed microglial aging. Microglial activation as measured by CD68 expression was down in the brains of old mice exposed to young blood. In the electron microscope, the old mice's microglia looked like those of young mice. [The team compared] the microglial transcriptome from old mice paired with other old mice to that from old mice paired with young mice. They saw that blood supplied by a young mouse did indeed largely reverse the gene expression phenotype of microglial aging.

Whether these changes at the molecular and cellular level amount to better function is difficult to assess in parabiotic mice. The pairs run the rotarod together, but rigorous behavior assays are not possible. Instead, the [scientists] decided to model parabiosis by transferring young plasma into an old mouse once every three days for three weeks. In this study, old mice injected with plasma from young mice outperformed untreated old mice in the radial arm water maze and a fear-conditioning test. The treated mice also recapitulate other previously shown parabiosis phenotypes, including more neurogenesis, synaptic plasticity, spine density, and less neuroinflammation.


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