Transfusion of blood fractions from young individuals into old individuals has so far produced quite variable animal data and disappointing human clinical trial outcomes. Even so, researchers continue to search for molecules in young blood that might be a basis for therapy. That transfusions have not performed as desired doesn't rule out the existence of specific molecules that might be delivered in larger amounts than exist in a transfusion in order to produce benefits. That stem cell therapies produce benefits based on signals secreted by the transplanted cells indicates that cell signaling is important, a path to favorably altering the behavior of native cells in order to reduce inflammation, improve tissue function, and so forth. It is a question of identifying the right signals and the right doses.
Thus a steady flow of publications is emerging, with today's open access paper as an example of the type, in which researchers report on the discovery of one or more specific molecules mined from young blood that appear to produce benefits in older animals. It is a little early to say whether or not this will lead to a sizable number of novel potential therapies and biotech companies to develop those therapies, but some of the early demonstrations of benefits in mice are quite interesting. As with other investigations of cell signaling derived from young tissues, reduced inflammation is the most common outcome.
There is a progressive decline in physiological function with age, and aging is associated with increased susceptibility to injury and infection. However, several reports have indicated that the agility of youth is characterized by transferable rejuvenating molecular factors, as was observed previously in heterochronic parabiosis experiments. These experiments demonstrated a rejuvenating effect of young blood in old animals.
There have been several efforts to characterize these youthful or maturation-associated factors in the young blood. In this report, we demonstrate the resilience of young mice, at or before puberty, to polymicrobial sepsis and show an age-dependent effect of small extracellular vesicles (EVs) from plasma on the outcome following sepsis. The EVs from the young mice were cytoprotective, anti-inflammatory, and reduced cellular senescence markers.
MicroRNA sequencing of the EVs showed an age-associated signature and identified miR-296-5p and miR-541-5p to progressively reduce their levels in the blood plasma with increasing age. We further show that the levels of these miRNAs decline with age in multiple organs. The miRNAs miR-296-5p and miR-541-5p showed a reparatory effect in an in vitro wound healing model and the miR-296-5p, when given intraperitoneally, reduced mortality in the mouse model of sepsis.
In summary, our studies demonstrate that EVs from very young mice have a reparative effect on sepsis, and the reparative factors are likely maturation-dependent. Our observation that miR-296-5p and miR-541-5p are plasma EV constituents that significantly reduce with age and can reduce inflammation suggests a therapeutic potential for these microRNAs in inflammation and age-associated diseases.
View the full article at FightAging
