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In a new study, researchers have found that the zinc-finger transcription factor Slug is responsible for repressing p16Ink4a, a compound that promotes senescence in human tissue. The researchers suggest that Slug is worth exploring as a treatment for sarcopenia [1].

Satellite cells

Satellite cells are specialized stem cells that form new muscle cells when the muscle is injured [2]. Populations of satellite stem cells remain quiescent in normal muscle tissue, only becoming activated through physical damage of some sort. This allows the tissue to heal properly, restoring function and allowing for natural regeneration. However, in both humans and mice, old age leads to increased p16Ink4a, which causes defects in this regeneration [1].

Signaling, senescence, and stem cells

This study shows a relationship between three separate hallmarks of aging.

Slug and p16ink4a are signaling chemicals, which are used to inform cells about what to do. The signaling environment is enormously important for the growth and function of stem cells, and it declines with age. This decline is known as altered intercellular communication, and one of its many harmful effects is that it pollutes the stem cell niche, reducing the ability of stem cells and related therapies to function correctly. [3]

The p16Ink4a pathway drives cellular senescence. Senescent cells do not support their tissues; rather, they emit chemicals that cause nearby cells to also become senescent, compounding the problem and causing chronic inflammation. Normally, these harmful cells would destroy themselves in a process known as apoptosis; however, with age, they fail to do so.

By promoting senescence in stem cells, a lack of Slug leads to a third hallmark: stem cell exhaustion. Stem cells, including satellite cells in skeletal muscle, are responsible for replacing somatic (ordinary) cell populations, thereby allowing the body to heal from injury and other losses. However, as these cells are lost and not replaced, we lose our ability to heal, and our tissues dwindle over time. When this occurs in skeletal muscle, the result is the age-related muscle weakness known as sarcopenia [1].

Abstract

Activation of the p16Ink4a-associated senescence pathway during aging breaks muscle homeostasis and causes degenerative muscle disease by irreversibly dampening satellite cell (SC) self-renewal capacity. Here, we report that the zinc-finger transcription factor Slug is highly expressed in quiescent SCs of mice and functions as a direct transcriptional repressor of p16Ink4a. Loss of Slug promotes derepression of p16Ink4a in SCs and accelerates the entry of SCs into a fully senescent state upon damage-induced stress. p16Ink4a depletion partially rescues defects in Slug-deficient SCs. Furthermore, reduced Slug expression is accompanied by p16Ink4a accumulation in aged SCs. Slug overexpression ameliorates aged muscle regeneration by enhancing SC self-renewal through active repression of p16Ink4a transcription. Our results identify a cell-autonomous mechanism underlying functional defects of SCs at an advanced age. As p16Ink4a dysregulation is the chief cause for regenerative defects of human geriatric SCs, these findings highlight Slug as a potential therapeutic target for aging-associated degenerative muscle disease.

Conclusion

While this is a mouse study and the effects of Slug have not been demonstrated in human beings, a compound that could halt p16Ink4a-related senescence would be of obvious benefit as a therapy. By halting a direct cause of cellular senescence in skeletal muscle, it may be possible to effectively treat sarcopenia, restoring muscle function and perhaps independence to millions of elderly people.

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Literature

[1] Zhu, W. Y. W. F. Z. Y. W. C. G. P. Z. (2019). The transcription factor Slug represses p16Ink4a and regulates murine muscle stem cell aging. Nature Communications 10(1), p. 2568.

[2] Morgan, J. E., & Partridge, T. A. (2003). Muscle satellite cells. The international journal of biochemistry & cell biology, 35(8), 1151-1156.

[3] Drummond-Barbosa, D. (2008). Stem cells, their niches and the systemic environment: an aging network. Genetics, 180(4), 1787-1797.

About the author
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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 rejuvenation biotechnology, and avid player of the strange game called "real life." Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.
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