Work on heterochronic parabiosis, in which an old and young mouse have their circulatory systems joined, has led to a wide variety of investigations into which signal molecules present in the bloodstream might be important in aging. The signaling environment changes in response to rising levels of molecular damage with age, leading to alterations in cellular behavior, some of which help to compensate, and some of which cause further harm.
At the same time, there is a rising level of interest in the roles played by various forms of extracellular vesicle in intracellular communication. These membrane-wrapped packages contain a diverse set of signal molecules, and are passed promiscuously back and forth between cells. That vesicles are conveniently packaged and distinguishable by size makes it comparatively easy to harvest them from cell cultures or blood samples, and from there they can be analyzed, or perhaps used as the basis for a therapy to change the behavior of cells in old tissues.
Changing the signaling environment may produce benefits large enough to be worth chasing, as the stem cell research community has demonstrated over the past twenty years. Most first generation cell therapies work because of the signals generated by transplanted cells, not because the cells manage to survive and integrate into tissue. Unfortunately, this approach doesn't target the underlying damage that causes aging, and thus will always be limited as to how great the benefits can be at the end of the day. If the molecular damage of aging remains unrepaired, it will continue to cause pathology.
Understanding the regulatory mechanisms and the involved molecules underlying aging has aroused interest to prevent or delay aging or aging-associated diseases. It has been reported that the upregulated or downregulated miRNAs induce cellular senescence. In cell-to-cell signaling in systemic aging, miRNAs are reported to be released in circulation and transferred to remote tissues. The released miRNAs can affect their levels in circulation in aged individuals, and in a recent study, they served as regulatory molecules to control aging speed. Therefore, they are strongly considered as aging-associated biomarkers, possibly determined by minimally invasive or noninvasive methods. So far, several studies comparing miRNA expression profiles from the blood of young and old animals have revealed differences in the expression levels of several miRNAs with aging.
One of the ways by which miRNAs are released in circulation is via vesicles blebbed out from cellular membranes. A representative type of these vesicles is exosomes, which are tens to hundreds of nanometers in diameter. The exosomes released from parent cells enter systemic circulation, which thus explains the signaling process among remote tissues. Cells under stress would release more exosomes in vitro to dispose unnecessary molecules or communicate their signals to the surrounding cells. Actually, aging is a type of cellular stress; thus, exosomes are secreted at higher levels from senescent cells than from normal cells. However, limited information is available on changes in the miRNA contents of exosomes in naturally aged individuals and their effects in the aging process. Therefore, the identification of miRNA molecules deregulated in exosomes in the aging process would be required to understand the mechanisms underlying aging and may have potential applications in evaluating or reversing the aging status of an individual.
In this study, we primarily identified differentially expressed miRNAs in exosomes from aged mice and compared them with those from young mice. If the miRNAs in exosomes have regulatory capability in systemic aging, their increased levels in young exosomes were expected to exert a reversing effect on tissues of old mice. Therefore, after intravenously injecting exosomes from young mice to aged mice, changes in aging-associated molecule levels were analyzed in aged mice. In the aged tissues injected with young exosomes, mmu-miR-126b-5p levels were reversed in the lungs and liver. Expression changes in aging-associated molecules in young exosome-injected mice were obvious: p16Ink4A, mTOR, and IGF1R were significantly downregulated in the lungs and/or liver of old mice. In addition, telomerase-related genes such as Men1, Mre11a, Tep1, Terf2, Tert, and Tnks were significantly upregulated in the liver of old mice after injection of young exosomes. These results indicate that exosomes from young mice could reverse the expression pattern of aging-associated molecules in aged mice. Eventually, exosomes may be used as a novel approach for the treatment and diagnosis of aging animals.