Rapamycin and the inhibition of the secretory phenotype

@article{Wang2017RapamycinAT,
  title={Rapamycin and the inhibition of the secretory phenotype},
  author={Rong Wang and Bharath Sunchu and Viviana I. P{\'e}rez},
  journal={Experimental Gerontology},
  year={2017},
  volume={94},
  pages={89-92}
}

Cell senescence, rapamycin and hyperfunction theory of aging

TLDR
Developed two decades ago, this model had accurately predicted that rapamycin must extend life span of animals, and the notion that senescent cells directly cause organismal aging is oversimplified.

Senescence in the aging process

TLDR
The aim is to gain a better understanding of how the senescent cell phenotype varies between different individuals and tissues, discover how senescence predisposes to organismal frailty, and develop mechanisms by which the deleterious effects of senescent cells can be ameliorated.

Rapamycin promotes endothelial–mesenchymal transition during stress-induced premature senescence through the activation of autophagy

TLDR
It is revealed that although rapamycin functions to inhibit senescence and suppress SASP in HCAECs undergoing SIPS, EndMT is induced due to the activation of autophagy, which led to activation of the TGF-β pathway, contributed to EndMT induction.

Rapamycin and Rapalogs

TLDR
The evidence that negative side effects of rapamycin are largely mediated by off-target inhibition of a second mTOR Complex (mTORC2) is discussed and the time is ripe for the development of therapies based on the safe and selective inhibition of mTORC1 for the treatment or prevention of diseases of aging.

Optimisation of a screening platform for determining IL-6 inflammatory signalling in the senescence-associated secretory phenotype (SASP)

TLDR
This paper describes optimisation and validation of a cell-based biosensor HEK cell line for measurement of IL-6 concentrations within the range secreted into conditioned medium by primary senescent fibroblasts, adapted for a 384 well plate format suitable for library screening applications.

Rapamycin, Acarbose and 17α-estradiol share common mechanisms regulating the MAPK pathways involved in intracellular signaling and inflammation

TLDR
The inhibition of age-dependent p38MAPK pathways and acute phase responses is triggered in both sexes by all three drugs, suggesting new approaches to prevention or reversal of age -related inflammatory changes in a clinical setting independent of lifespan effects.

Senolytics in Disease, Ageing and Longevity

TLDR
The biological significances of cellular senescence in aging are discussed, some of the known naturally occurring and targeted senolytic agents and their targets are summarized, and development of more specific and potent senolytics are urgently needed to improve healthy aging in humans.

Rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation

TLDR
It is reported here that epigenetic ageing is not affected by replicative senescence, telomere length, somatic cell differentiation, cellular proliferation rate or frequency and is instead retarded by rapamycin, the potent inhibitor of the mTOR complex which governs many pathways relating to cellular metabolism.

Targeted Senolytic Strategies Based on the Senescent Surfaceome

TLDR
The ongoing efforts to design targeted senolytics are discussed, with special focus on the utilization of the extracellular epitopes displayed by the senescent surfaceome, and the avenues of research that have shown the most promising results so far are summarized.

Immunosenescence: a key player in cancer development

TLDR
The characteristics of immunosenescence and its impact on malignant tumors and immunotherapy are highlighted, especially the future directions of tumor treatment through senescence-focused strategies.

References

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mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype

TLDR
A mechanism by which mTOR controls the SASP is reported by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1.

MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation

TLDR
It is shown that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells, which might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.

Rapamycin decelerates cellular senescence

TLDR
It is demonstrated that the duration of cell cycle arrest determines a progressive loss of proliferative capacity, and the data demonstrate that senescence can be pharmacologically suppressed.

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TLDR
A senescence-associated secretory phenotype (SASP) is acquired that turns senescent fibroblasts into proinflammatory cells that have the ability to promote tumor progression.

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Senescence associated secretory phenotype profile from primary lung mice fibroblasts depends on the senescence induction stimuli

TLDR
The results showed important variations in the 62 cytokines analyzed, while SIPS and RS showed an increase in the secretion of most cytokines, and in PIIPS only 13 were incremented, suggesting that the senescence induction pathway might encompass dissimilar responses in adjacent cells and promote different outcomes.

p38MAPK is a novel DNA damage response‐independent regulator of the senescence‐associated secretory phenotype

TLDR
It is shown that diverse senescence‐inducing stimuli activate the stress‐inducible kinase p38MAPK in normal human fibroblasts and assign p38 MAPK a novel role in SASP regulation—one that is necessary, sufficient, and independent of previously described pathways.

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TLDR
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