Introducing Developmental Signaling into Adults in Order to Produce Regeneration

Is it possible to safely introduce developmental signaling characteristic of the developing embryo and fetus into an aged adult in order to spur greater regeneration of tissues? The past decades of work on embryonic stem cell therapies and induced pluripotent stem cell therapies, and the slow investigation of how most of these therapies produce their benefits via cell signaling, suggest that this goal is in principle possible. Similarly, research into species capable of proficient regeneration, such as salamanders and zebrafish, suggests broad similarities between the biochemistry of organ development and the biochemistry of organ regrowth.

The issue for we mammals has all along been the question of cancer. Would developmental signaling result in an unacceptable cancer risk, either by directly breaking regulatory systems important in tissue maintenance, or by forcing greater cell activity in an environment of age-related damage?

Researchers continue to investigate the mechanisms of stem cell therapies, the contents of pro-regenerative extracellular vesicles and their effects on bystander cells, and partial cell reprogramming in vivo. As this work progresses, numerous potential approaches are arising to the delivery of specific developmental signals. The paper here takes a look at one very narrow slice of this part of the regenerative medicine field, what is know of developmental peptide signals, and particularly thymosin beta-4, that might be exploited to boost adult regeneration in later life.

Utilizing Developmentally Essential Secreted Peptides Such as Thymosin Beta-4 to Remind the Adult Organs of Their Embryonic State - New Directions in Anti-Aging Regenerative Therapies

Reversing age-related alterations of the body is a long-desired goal of humankind. Despite the extravagant premise, the dream of returning to our youth may not be so far-fetched. Nature actually provides an enormous list of molecules, some of which are silenced after birth but could serve as a potential treatment to reverse age, at least at the level of a single yet complicated organ such as the heart. The question remains: can postnatal increase of developmentally relevant proteins and peptides reverse organ ageing or damage in a beneficial way? We believe the answer to this question is yes. In our earlier research, we introduced a naturally secreted small molecule, Thymosin beta-4 (TB4), which is capable of such miracles not only regarding the heart but in the brain and kidneys.

TB4 was first purified from the thymus and binds and alters the cytoskeletal actin filaments by sequestering actin monomers and in doing so, influences actin filament assembly and regulates migration of various cell types such as endothelial cells, myocardial cells, or epicardial progenitors. It equally inhibits cellular death by activating and binding numerous players in the focal adhesion complex, which, eventually, results in the activation of Akt, a proven substrate of ILK with wide-ranging signalling functions that affect growth, survival, and motility. Naturally, all the other mechanisms by which TB4 initiates the increase of cardiac function are still under investigation by a host of scientists worldwide. Undoubtedly, its capability in activating the adult epicardium and its ability to resemble its embryonic function without risking injury suggests grounds for hope that the molecule does achieve the same in other organs.

Reminding adult cells of their highly proliferative state is not without risk, as the applied treatment may easily result in unwanted malignancies. Although TB4 was reported to be a prognostic marker for highly metastatic cancer states and its tumor promo-ting properties were equally demonstrated, its true nature regarding tumorigenesis is controversial. In our hands, the molecule significantly inhibited the progression of pancreatic cancer following systemic administration in mice in vivo. An additional factor supporting this result is that TB4 was equally introduced as a candidate tumor suppressor in male breast cancer and was demonstrated to have a tumor suppressive function in myeloma development by other research teams. In addition, the high safety profile observed in Phase I and Phase II clinical trials this far strongly anticipate that TB4 will be safe and efficacious at the applied local or systemic dose for broad clinical applications in the future.

We still do not know all the details regarding this special molecule; however, we genuinely believe there are more like it concealed in the human body, awaiting discovery. With their help, we may be capable of fulfilling our dream of reversing age.

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