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Giving Old Stem Cells Lasting Youthful Powers

Cells from very old people behaved like youthful cells.

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Researchers publishing in Cell Proliferation have described factors that appear to give old muscle stem cells the ability to effectively proliferate and differentiate for a very long time.

When renewal runs out

Many of the problems that elderly people face in daily life, such as frailty, can be traced back to a decline of cellular self-renewal abilities. With aging comes stem cell senescence [1] and a corresponding lack of cellular self-renewal ability; the cells of older people stop replacing themselves, predictably leading to a loss of function, which, for muscle cells, manifests as weakness and sarcopenia [2].

Finding the key elements

The researchers began exploring this problem by looking at what differentiates older cells from very young, embryonic, cells. After a careful examination, they found three key factors that have to do with rapid embryonic muscle development: LIN28, telomerase reverse transcriptase (TERT), and the tumor suppressor p53, which is a very multifunctional molecule that plays various, occasionally contradictory, roles in cellular senescence and has been associated with cachexia, a muscle-wasting disease [3]. All three of these factors are very tightly regulated during embryonic development.

The researchers chose not to target factors that are likely to lead to cancer, and they also avoided the Yamanaka factors, which are associated with pluripotency. Instead, they found that when LIN28, TERT, and a silencing RNA against p53 were combined to form LTS and given to cells, those cells remained functionally youthful in many key respects.

While the division of unaffected cells petered out after about a month, LTS-affected cells continued to divide. The senescence marker was nearly universal after 100 days in unaffected cells and almost nonexistent in affected cells. These cells did not show signs of being cancerous and maintained their protections against DNA damage, and when properly stimulated, they were able to differentiate into functional muscle tissue cells. While some of the biomarkers of muscle development were slightly weaker in some respects and stronger in others, the cells appeared to be able to serve their purpose.

Amazingly, all three of the LTS factors were required for cells to maintain their doubling and subsequent differentiation abilities. Administering only one or two of them did not have any positive effect.

Testing for potential effectiveness

For an in vivo test, elderly people with cachexia had some stem cells removed, exposed to LTS factors, and encouraged to divide. After demonstrating that these cells do not form tumors when injected under the skin of mice, the researchers placed populations of these cells directly into the muscles of the animals, as simple under-skin injections do not engraft to muscle.

While there were no experiments on the animals’ physical abilities, fluorescent staining showed that these stem cell populations remained effective even after a full year, with the engrafted cells maintaining a reserve population that was able to regularly differentiate into functional cells. Elderly people with a dangerous muscle-wasting disease were the source of what appeared to be entirely stable, effectively youthful, stem cells.

Still in its initial stages

It should be little surprise that a few factors could be responsible for a large change in the proliferative ability of older cells. We have previously written about how the aged microenvironment affects stem cell proliferation and that introducing young stem cells to treat sarcopenia may have more to do with signals than with the cells themselves. LTS may be having similar effects.

Of course, while this paper has led to some interesting conclusions and may pave to the way for targeted treatments, this work is still in a preclinical stage. As human cells were able to take root and appear to function in an animal model, it can be hoped that this research will pave the way for effective treatments in people.

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Literature

[1] Lau, A., Kennedy, B. K., Kirkland, J. L., & Tullius, S. G. (2019). Mixing old and young: enhancing rejuvenation and accelerating aging. The Journal of clinical investigation, 129(1), 4-11.

[2] Blau, H. M., Cosgrove, B. D., & Ho, A. T. (2015). The central role of muscle stem cells in regenerative failure with aging. Nature medicine, 21(8), 854-862.

[3] Schwarzkopf, M., Coletti, D., Sassoon, D., & Marazzi, G. (2006). Muscle cachexia is regulated by a p53–PW1/Peg3-dependent pathway. Genes & development, 20(24), 3440-3452.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called β€œreal life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
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