In heterochronic parabiosis, one joins the circulatory system of an old mouse and a young mouse. The old mouse exhibits reversal of manifestations of aging, and the young mouse exhibits an acceleration of manifestations of aging. Research initially focused on factors in young blood that might be producing benefits in older individuals, and work continues on GDF11 as one such factor, with Elevian heading towards human trials. More data has accumulated in recent years to suggest that the bulk of the effect is due to harmful factors in old blood, however, and benefits in old mice in parabiosis are simply a matter of diluting those factors.
A series of experiments run in recent years have results in ways to safely and simply dilute blood in old mice, using as few additional components as possible, in order to make the results quite clearly the outcome of dilution alone. As demonstrated here, diluting blood in old mice results in reduced inflammation and consequent improvement in tissue function. This reinforces the idea that the research community should focus on what makes old blood harmful, rather than on what might be making young blood beneficial.
Parabiosis studies have yielded a plethora of insights regarding mechanisms that underlie the aging of stem cell niches. It was shown that old partners have better health in multiple tissues when they shared blood with a younger animal. A prominent interpretation of heterochronic parabiosis is that aging is malleable and that the aging process can be slowed or even reversed. Brain aging in particular is associated with a progressive loss of functionality and is thought to be in large part the result of an excessive activation of microglia, the brain-resident myeloid cells. The age-related declines in brain function and cognition (among many other functions in the body) were once considered inevitable and permanent. Parabiosis studies, interestingly, have challenged this notion by illustrating the plasticity of brain maintenance and function after changing the age of the blood.
Several systemic proteins and young plasma infusions were suggested to influence the plasticity of brain aging, albeit with some controversy to the actual age-specific levels of some of these candidate factors, such as GDF11, B2M, CCL11, and TIMP2. There was also a lack of health span increase in young plasma infusion studies; and while safety trials were successful, the young blood approaches have not been demonstrated to be effective in improving the health of the brain or any other tissue in clinic. In concert, heterochronic blood transfusion exchange experiments have shown that in the absence of the organ sharing and environmental enrichment of parabiosis, young blood does not rejuvenate the old brain.
As we investigate and form an evolutionary conserved paradigm of systemic rejuvenation, our data demonstrated that young blood is not the primary determinant, and instead, dilution of old blood plasma yields a robust resetting of the systemic signaling milieu to youth and health, rejuvenating multiple tissues. The study of the brain in that report was limited to hippocampal neurogenesis; here we expand the work to other important facets of brain health: neuroinflammation and cognition. Our data demonstrate that neuroinflammation (specifically the activation of microglia), declines and the cognitive capacity of old mice, improves after a single treatment of blood dilution. Considering that therapeutic plasma exchange (TPE) is FDA approved, this study suggests a use of this procedure to prevent, attenuate, and possibly even reverse the degenerative and inflammatory diseases of the brain.