Research Article: Cell cycle arrest is not yet senescence, which is not just cell cycle arrest: terminology for TOR-driven aging

Date Published: March 5, 2012

Publisher: Impact Journals LLC

Author(s): Mikhail V. Blagosklonny.



Cell cycle arrest is not yet senescence. When the cell cycle is arrested, an inappropriate growth-promotion converts an arrest into senescence (geroconversion). By inhibiting the growth-promoting mTOR pathway, rapamycin decelerates geroconversion of the arrested cells. And as a striking example, while causing arrest, p53 may decelerate or suppress geroconversion (in some conditions). Here I discuss the meaning of geroconversion and also the terms gerogenes, gerossuppressors, gerosuppressants, gerogenic pathways, gero-promoters, hyperfunction and feedback resistance, regenerative potential, hypertrophy and secondary atrophy, pro-gerogenic and gerogenic cells.

Partial Text

A year ago, I wrote a perspective “Cell cycle arrest is not senescence”, intended to clarify a new meaning of cellular senescence [1]. The perspective was not completely understood in part due to its title. The title was missing the word “yet”, which is now included. As discussed in the article, cell cycle arrest is not yet senescence and senescence is not just arrest: senescence can be driven by growth-promoting pathways such as mTOR, when actual growth is impossible. (This mechanism connects cellular senescence, organismal aging and age-related diseases, predicting anti-aging agents [2-6]). In brief, senescence can be caused by growth stimulation, when the cell cycle is arrested [7, 8]. As one hallmark, senescent cells loose proliferative potential (PP) – the potential to resume proliferation. Importantly, inhibitors of mTOR suppress hallmarks of senescence during cell cycle arrest so cells stay quiescent but not senescent [9-13]. Such quiescent cells, with inhibited mTOR, retain PP. Once again, cells may be arrested but retain PP, the ability to restart proliferation, when allowed. In certain conditions, p53 causes arrest but can preserve PP by inhibiting the mTOR pathway [14-16]. However, this phenomenon should not be misunderstood to indicate that “p53 induces proliferation or prevents arrest or keeps cells proliferating” or “arrested cells retain proliferation”; rather, p53 instead regulates proliferative potential. Although we tried to explain what p53 does exactly (causes arrest, while preserving PP) misunderstanding nonetheless ensued. One solution is not to use the term PP altogether, substituting for it the term RP (regenerative potential). In the organism, stem cells and wound-healing cells, while quiescent, are capable to regenerate tissues after cell loss. Unlike non-senescent cells, senescent cells cannot divide in response to cell loss and therefore lose the potential to regenerate tissues. In cell culture, quiescent cells preserve RP. If the cell cycle is blocked, activation of mTOR causes loss of RP [17]. New concepts need new terminology. Instead of squeezing novel meaning into the old terms, here we present new terms for a new meaning of the aging process. And a central term is gerogenic conversion or geroconversion.





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