Cell senescence, rapamycin and hyperfunction theory of aging

Abstract

A hallmark of cellular senescence is proliferation-like activity of growth-promoting pathways (such as mTOR and MAPK) in non-proliferating cells. When the cell cycle is arrested, these pathways convert arrest to senescence (geroconversion), rendering cells hypertrophic, beta-Gal-positive and hyperfunctional. The senescence-associated secretory phenotype (SASP) is one of the numerous hyperfunctions. Figuratively, geroconversion is a continuation of growth in non-proliferating cells. Rapamycin, a reversible inhibitor of growth, slows down mTOR-driven geroconversion. Developed two decades ago, this model had accurately predicted that rapamycin must extend life span of animals. However, the notion that senescent cells directly cause organismal aging is oversimplified. Senescent cells contribute to organismal aging but are not strictly required. Cell senescence and organismal aging can be linked indirectly via the same underlying cause, namely hyperfunctional signaling pathways such as mTOR.

Keywords: Senescence; geroconversion; geroscience; gerostatics; healthspan; rapalogs; sirolimus.

Figure 1.

Representation of proliferation, quiescence and senescence.

Figure 2.

The clogged sink analogy for proliferation, quiescence and senescence.

Figure 3.

Geroconversion is a form of “twisted” growth.

Figure 4.

The analogy between cell senescence and organismal aging.

Figure 5.

Linking cell senescence to organismal aging.

Figure 6.

Two-dimensional representation of proliferation P, quiescence Q and senescence S in normal cells.

Figure 7.

Four combinations of growth and cycling: formal approach.