Geroconversion: irreversible step to cellular senescence

Abstract

Cellular senescence happens in 2 steps: cell cycle arrest followed, or sometimes preceded, by gerogenic conversion (geroconversion). Geroconvesrion is a form of growth, a futile growth during cell cycle arrest. It converts reversible arrest to irreversible senescence. Geroconversion is driven by growth-promoting, mitogen-/nutrient-sensing pathways such as mTOR. Geroconversion leads to hyper-secretory, hypertrophic and pro-inflammatory cellular phenotypes, hyperfunctions and malfunctions. On organismal level, geroconversion leads to age-related diseases and death. Rapamycin, a gerosuppressant, extends life span in diverse species from yeast to mammals. Stress-and oncogene-induced accelerated senescence, replicative senescence in vitro and life-long cellular aging in vivo all can be described by 2-step model.

Keywords: aging; cell cycle arrest; gerogenic conversion; mTOR; oncogenic trsnformation.

Figure 1.

Proliferation versus arrest. (A) Proliferation: Growth factors (GF) activate MAPK and mTOR pathways, driving cell growth (in size) and cell cycle. Cellular growth is balanced by cell division. (B) Quiescence: In the absence of GF, cell growth and cycle are at rest. (C) Pro-senescent cycle arrest: When the cycle cycle is blocked by p21 or p16, the growth promoting pathway (MAPK/mTOR) causes growth in size (hypertrophy).

Figure 2.

Senescence vs. quiescence.

Figure 3.

The dual role of p53 in senescence. P53 causes Arrest that is followed by geroconversion (green arrow). Yet, at very high levels, p53 can inhibit mTOR, suppressing geroconversion (yellow arrow) and leading to quiescence.

Figure 4.

Arrest-Geroconversion model. Schematic representation of types of senescence (Arrest- red stop sign. Geroconversion – green arrow). (A) Typical arrest-induced senescence. DNA damage-induced senescence. CDK (p21 and 16)–induced senescence. (B) In the presence of rapamycin: geroconversion is slowed down and extended. (C) Oncogene-induced senescence. Oncogenes such as Ras empower growth, cause arrest and then empower geroconversion. (D) Replicative senescence of human cells in culture. Telomere shortening during cell proliferation eventually causes Arrest. Then geroconversion ensures senescence. (E) Replicative senescence of rodent cells in culture. Ovestumulation of mTOR by mitogen/nutrient/oxygen rich medium causes cellular hypertrophy.