AgeX Developing Antiaging by Working to Restore Full Regeneration

Humans are able to fully regenerative when we are less than 8 weeks after cell germination. We are still in the womb 3-8 weeks after cell germination, then we can fully regenerate.

If we can restore full regeneration then this could also be the key to immortalizing our bodies.

Placental mammals show a global loss of regenerative potential in numerous tissues during development in utero. Although the timing of the repression of scarless regeneration in humans depends on the tissue type, it is commonly associated with the EFT. In humans, this transition occurs at the completion of Carnegie Stage 23 (8 weeks of development). In the case of the mouse, this corresponds approximately with the close of Theiler Stage 23 (16 days post coitum). Consequently, regeneration during the EFT can be easily studied in marsupial mammals because the animals emerge and enter the pouch while still in the embryonic prefetal state where they are readily accessible for experimentation. Thus it has been determined that scarring begins around pouch day 9 near the EFT.

The mammalian heart appears to be under regulation by the NT and thus provides an important target organ model system to study the relationship between NT and regeneration. Unlike most organs, the heart retains an unusually high degree of regenerative potential after EFT, beyond NT and into the first postnatal week during which time cardiomyocytes begin to become binucleate. Damaging the left anterior descending artery in 1-day old mice results in severe ischemic damage that is nevertheless completely regenerated scarlessly within 7 days. However, a similar injury induced in 7-day-old mice results in scarring instead of regeneration. With regard to the mechanism, tracing studies argue in favor of the hypothesis that the regenerated myocardium in such perinatal mammals originates from the de-differentiation of mature myocardium as opposed to the competing theory that it originates from a mobilized pool of resident myocardial progenitors

Reprogramming somatic cells to pluripotency demonstrates the possibility of restoring telomerase and embryonic regeneration pathways and thus reversing the age-related decline in regenerative capacity. A unified model of aging and loss of regenerative potential is emerging that may ultimately be translated into new therapeutic approaches for establishing induced tissue regeneration and modulation of the embryo-onco phenotype of cancer.

AgeX Working on Small Molecules and Cell Lines to Package Exosomes With mRNA and Telomerase to Change Cells in the Body to Restore Full Regeneration and Enable Antiaging

AgeX Discussion of Aging and Regeneration from AgeX on Vimeo.

It may be possible to use reprogramming approaches to unlock latent regenerative plasticity by transiently restoring cells to a ‘pre-EFT’ state. AgeX designated this strategy-iTR (Induced Tissue Regeneration). Given the importance of telomerase repression and telomere shortening with aging, AgeX envision that iTR would also benefit from the transient induction of telomerase, therefore, whether or not telomere length is modulated in the course of iTR, AgeX will refer to both strategies simply as iTR.

The challenge of iTR-related approaches is to reprogram the epigenetic age and other hallmarks of aging in adult cells in a manner that maintains cell identity while restoring the regenerative potential to pre-EFT levels but not increasing the risk of an embryo-onco phenotype and cancer. Accordingly, it is important to note that pluripotency-related pathways are increasingly recognized as playing an important role in oncogenesis. Indeed, the expression of reprogramming factors such as Klf4, Oct4, Sox2 and Myc in mice has been reported to generate pluripotent cells and teratomas in vivo. While teratomas are benign counterparts of malignant teratocarcinomas, teratomas themselves can adversely affect health. Therefore, Ocampo et al. used a strategy of limiting the expression of reprogramming factors (i.e., cyclic expression) to achieve a partially reprogrammed state, which resulted in prolonging lifespan in a mouse progeria model and in increased regeneration following muscle and pancreatic injury in naturally aged wild-type mice. Moreover, they reported that numerous markers of aging were reversed including the restoration of young H3K9Me3 levels. Similarly, another study demonstrated that partial reprogramming in vivo resulted in improved wound healing with reduced scar formation. Additionally, alternative approaches such as chemical induction of reprogramming may also influence regeneration potential. For example, a chemical cocktail shown to promote reprogramming in vitro had a protective effect against liver damage in vivo. Although in their early stages, these studies and other ongoing efforts to reverse aging without triggering oncogenesis indicate the potential for the eventual translation of iTR approaches into simple, safe and cost-effective therapies. Indeed, iTR could have important implications for aging, epimorphic regeneration, and cancer diagnosis and therapy.

SOURCES – Nextbigfuture AgeX Michael West Interview 2017, AgeX 2019 Research Paper and Video
Written by Brian Wang, Nextbigfuture.com

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