Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2022 Jul;21(14):1456-1467.
doi: 10.1080/15384101.2022.2054636. Epub 2022 Mar 31.

Cell senescence, rapamycin and hyperfunction theory of aging

Mikhail V Blagosklonny  1
Affiliations
Review

Cell senescence, rapamycin and hyperfunction theory of aging

Mikhail V Blagosklonny. Cell Cycle. 2022 Jul.

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.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Representation of proliferation, quiescence and senescence.
Figure 2.
Figure 2.
The clogged sink analogy for proliferation, quiescence and senescence.
Figure 3.
Figure 3.
Geroconversion is a form of “twisted” growth.
Figure 4.
Figure 4.
The analogy between cell senescence and organismal aging.
Figure 5.
Figure 5.
Linking cell senescence to organismal aging.
Figure 6.
Figure 6.
Two-dimensional representation of proliferation P, quiescence Q and senescence S in normal cells.
Figure 7.
Figure 7.
Four combinations of growth and cycling: formal approach.
See this image and copyright information in PMC

References

    1. Blagosklonny MV. Rapamycin, proliferation and geroconversion to senescence. Cell Cycle. 2018;17(24):2655–2665. - PMC - PubMed
    1. Serrano M, Lin AW, McCurrach ME, et al. Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997;88(5):593–602. - PubMed
    1. Lin AW, Barradas M, Stone JC, et al. Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998;12(19):3008–3019. - PMC - PubMed
    1. Blagosklonny MV. The mitogen-activated protein kinase pathway mediates growth arrest or E1A-dependent apoptosis in SKBR3 human breast cancer cells. Int J Cancer. 1998;78(4):511–517. - PubMed
    1. Deschenes-Simard X, Gaumont-Leclerc MF, Bourdeau V, et al. Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation. Genes Dev. 2013;27(8):900–915. - PMC - PubMed