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Inhibition of nucleotide synthesis promotes replicative senescence of human mammary epithelial cells

senescence nucleotides

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#1 smithx

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Posted 26 July 2019 - 08:26 PM


Cellular senescence is a mechanism by which cells permanently withdraw from the cell cycle in response to stresses including telomere shortening, DNA damage, or oncogenic signaling. Senescent cells contribute to both age-related degeneration and hyperplastic pathologies, including cancer. In culture, normal human epithelial cells enter senescence after a limited number of cell divisions, known as replicative senescence. Here, to investigate how metabolic pathways regulate replicative senescence, we used LC-MS–based metabolomics to analyze senescent primary human mammary epithelial cells (HMECs). We did not observe significant changes in glucose uptake or lactate secretion in senescent HMECs. However, analysis of intracellular metabolite pool sizes indicated that senescent cells exhibit depletion of metabolites from nucleotide synthesis pathways. Furthermore, stable isotope tracing with 13C-labeled glucose or glutamine revealed a dramatic blockage of flux of these two metabolites into nucleotide synthesis pathways in senescent HMECs. To test whether cellular immortalization would reverse these observations, we expressed telomerase in HMECs. In addition to preventing senescence, telomerase expression maintained metabolic flux from glucose into nucleotide synthesis pathways. Finally, we investigated whether inhibition of nucleotide synthesis in proliferating HMECs is sufficient to induce senescence. In proliferating HMECs, both pharmacological and genetic inhibition of ribonucleotide reductase regulatory subunit M2 (RRM2), a rate-limiting enzyme in dNTP synthesis, induced premature senescence with concomitantly decreased metabolic flux from glucose into nucleotide synthesis. Taken together, our results suggest that nucleotide synthesis inhibition plays a causative role in the establishment of replicative senescence in HMECs.



Takeaways seem to be:

  • Stimulating telomerase could be a good thing (again) - how best to do this (other than exercise and astragalus root extracts)?
  • Could we reverse senescence via nucleotide supplementation?

  • Informative x 1

#2 Lazarus Long

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Posted 27 July 2019 - 12:56 PM

I apologize. I looked but hadn't found that anyone had posted about this research before I posted about it in the Theories of Aging area.

For now I suspect that it serves our purpose to let them follow their separate thread courses.


Edited by Lazarus Long, 27 July 2019 - 12:58 PM.

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