Upregulation of Autophagy via mTOR Inhibition Reduces Tendon Stem Cell Senescence

One of the more interesting studies of cellular senescence in recent years was the demonstration that topical treatment with rapamycin, an inhibitor of mTOR signaling, over a period of months meaningfully reduced the burden of cellular senescence in the skin of aged individuals, leading to improvement in skin quality. It did not achieve this goal by directly destroying senescent cells, as rapamycin is not a senolytic drug. It acts instead to prevent some damaged cells from becoming senescent, or blunt the accumulation of damage in some vulnerable cells, or otherwise reduce the pace at which cells become senescent. That in turn means that senescent cell clearance must still be operational even in very old people: the aged immune system can destroy these cells, it is just falling behind.

It is an open question as to whether preventing cells from entering a senescent state is a good idea or not. This will likely depend on the details of the method used. Very selectively sabotaging the triggers of senescence would allow damaged cells to continue to undertake activity, which would likely raise the risk of cancer. We know that long term mTOR inhibition does not have this effect in mice, however; cancer risk is in fact reduced. So it is likely doing something to reduce the impact of the aged environment on the quality of cells. Given that we know that mTOR inhibition produces - in addition to a slowing of aging - greater cellular maintenance activities, such as greater autophagy to break down and recycle damaged proteins and structures in the cell, this seems a reasonable place to start looking.

Today's open access paper is an investigation of mTOR inhibition, upregulated autophagy, and cellular senescence in tendon stem cells, in order to better understand how mTOR inhibitors such as rapamycin can reduce the number of senescent cells following exposure to a toxic environment that induces DNA damage. For the reasons given above, it is good to know how it functions to produce this outcome. Is upregulation of autophagy over the long term universally a useful strategy to reduce senescent cell levels in older people, albeit taking six months to achieve what a senolytic drug would do in a few days?

Rapamycin Treatment of Tendon Stem/Progenitor Cells Reduces Cellular Senescence by Upregulating Autophagy

The number of tendon stem cells (TSCs) and their self-renewal potentials is reduced in elderly tendinopathy patients compared to young patients, leading to a possible role of impaired stem cell potential and differentiation in the tendon structure during aging. The correlation of cellular senescence and age-associated tissue dysfunction has been hypothesized. TSCs from aged/degenerated human Achilles tendon biopsies exhibit proliferation and clonogenicity deficits accompanied by premature entry into cellular senescence by upregulation of p16Ink4a. The stem cells become exhausted during tendon aging and degeneration, in terms of size and functional fitness. Sufficient healthy stem cells are essential for tendon tissue regeneration. Our study links the reversal of tendon stem cell senescence to rapamycin, potentially through induction of autophagy. This study may have important implications for preventing cell senescence and aging-induced tendinopathy, as well as for the selection of novel therapeutic targets of chronic tendon diseases.

Our results showed that the treatment of bleomycin, a DNA damaging agent, induced rat patellar TSC (PTSC) cellular senescence. The senescence was characterized by an increase in the senescence-associated β-galactosidase activity, as well as senescence-associated changes in cell morphology. On the other hand, rapamycin could extend lifespan in multiple species, including yeast, fruit flies, and mice, by decelerating DNA damage accumulation and cellular senescence. As an inhibitor of mTOR, rapamycin is a prospect of pharmacological rejuvenation of aging stem cells. Our findings show that rapamycin partially decreases the senescence-associated β-gal activity and morphological alterations, which indicate that rapamycin reverses senescence in rat PTSCs at both molecular and cellular levels.

Autophagy is a major mechanism for maintaining cellular homeostasis via autophagic cell death. Studies have shown that the activity of autophagy is constitutively high in mesenchymal, hematopoietic, dermal, and epidermal stem cells. Autophagy plays a key role in the control of self-renewal and the stemness of stem cells, and growing evidences have linked autophagy and the mTOR signaling pathway. Some proposed underlying antiaging mechanisms by rapamycin include downregulated translation, increased autophagy, altered metabolism, and increased stress resistance. In this study, we have demonstrated that bleomycin treatment increases the p62 expression, while decreases LC3 II/LC3 I ratio, and rapamycin treatment reverses these molecular changes induced by bleomycin, thus reroutes the senescent TSCs to autophagic signaling. These findings support the idea that the beneficial effects of rapamycin for the TSC senescence might be through the mechanism of autophagy induction.


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