Cell Senescence, Rapamycin and Hyperfunction Theory of Aging

Overview

Journal Cell Cycle

Specialty Cell Biology

Date 2022 Mar 31

PMID 35358003

Authors

Mikhail V Blagosklonny

Affiliations

Soon will be listed here.

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.

Citing Articles

Single-Cell Analysis Dissects the Effects of Vitamin D on Genetic Senescence Signatures Across Murine Tissues.

Sosa-Diaz E, Reyes-Gopar H, Anda-Jauregui G, Hernandez-Lemus E Nutrients. 2025; 17(3).

PMID: 39940287 PMC: 11820085. DOI: 10.3390/nu17030429.

PD-1-Enhanced Treg Cell Senescence in Advanced Maternal Age.

Gong G, Zhang Y, Hu X, Lin X, Liao A Adv Sci (Weinh). 2024; 12(6):e2411613.

PMID: 39716882 PMC: 11809324. DOI: 10.1002/advs.202411613.

Elucidation of anti-human melanoma and anti-aging mechanisms of compounds from green seaweed Caulerpa racemosa.

Wicaksono D, Taslim N, Lau V, Syahputra R, Alatas A, Putra P Sci Rep. 2024; 14(1):27534.

PMID: 39528552 PMC: 11555072. DOI: 10.1038/s41598-024-78464-6.

Resveratrol inhibits pancreatic cancer proliferation and metastasis by depleting senescent tumor-associated fibroblasts.

Jiang H, Wang G, Wang Z, Ma Q, Ma Z World J Gastrointest Oncol. 2024; 16(9):3980-3993.

PMID: 39350997 PMC: 11438786. DOI: 10.4251/wjgo.v16.i9.3980.

mTOR and SGLT-2 Inhibitors: Their Synergistic Effect on Age-Related Processes.

Troise D, Mercuri S, Infante B, Losappio V, Cirolla L, Netti G Int J Mol Sci. 2024; 25(16).

PMID: 39201363 PMC: 11354721. DOI: 10.3390/ijms25168676.

References

Wang R, Yu Z, Sunchu B, Shoaf J, Dang I, Zhao S . Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism. Aging Cell. 2017; 16(3):564-574. PMC: 5418203. DOI: 10.1111/acel.12587. View

Walters H, Deneka-Hannemann S, Cox L . Reversal of phenotypes of cellular senescence by pan-mTOR inhibition. Aging (Albany NY). 2016; 8(2):231-44. PMC: 4789579. DOI: 10.18632/aging.100872. View

Lee B, Han J, Im J, Morrone A, Johung K, Goodwin E . Senescence-associated beta-galactosidase is lysosomal beta-galactosidase. Aging Cell. 2006; 5(2):187-95. DOI: 10.1111/j.1474-9726.2006.00199.x. View

Leontieva O, Blagosklonny M . CDK4/6-inhibiting drug substitutes for p21 and p16 in senescence: duration of cell cycle arrest and MTOR activity determine geroconversion. Cell Cycle. 2013; 12(18):3063-9. PMC: 3875680. DOI: 10.4161/cc.26130. View

Gems D . The hyperfunction theory: An emerging paradigm for the biology of aging. Ageing Res Rev. 2022; 74:101557. PMC: 7612201. DOI: 10.1016/j.arr.2021.101557. View

Blagosklonny M . The hyperfunction theory of aging: three common misconceptions. Oncoscience. 2021; 8:103-107. PMC: 8448505. DOI: 10.18632/oncoscience.545. View

Laberge R, Zhou L, Sarantos M, Rodier F, Freund A, de Keizer P . Glucocorticoids suppress selected components of the senescence-associated secretory phenotype. Aging Cell. 2012; 11(4):569-78. PMC: 3387333. DOI: 10.1111/j.1474-9726.2012.00818.x. View

Gao C, Ning B, Sang C, Zhang Y . Rapamycin prevents the intervertebral disc degeneration via inhibiting differentiation and senescence of annulus fibrosus cells. Aging (Albany NY). 2018; 10(1):131-143. PMC: 5811247. DOI: 10.18632/aging.101364. View

Lin A, Barradas M, Stone J, Van Aelst L, Serrano M, Lowe S . Premature senescence involving p53 and p16 is activated in response to constitutive MEK/MAPK mitogenic signaling. Genes Dev. 1998; 12(19):3008-19. PMC: 317198. DOI: 10.1101/gad.12.19.3008. View

10.

Leontieva O, Demidenko Z, Blagosklonny M . Contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program. Proc Natl Acad Sci U S A. 2014; 111(24):8832-7. PMC: 4066505. DOI: 10.1073/pnas.1405723111. View

11.

Christy B, Demaria M, Campisi J, Huang J, Jones D, Dodds S . p53 and rapamycin are additive. Oncotarget. 2015; 6(18):15802-13. PMC: 4599238. DOI: 10.18632/oncotarget.4602. View

12.

Laberge R, Sun Y, Orjalo A, Patil C, Freund A, Zhou L . MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation. Nat Cell Biol. 2015; 17(8):1049-61. PMC: 4691706. DOI: 10.1038/ncb3195. View

13.

PLOTZ C, KNOWLTON A, RAGAN C . The natural history of Cushing's syndrome. Am J Med. 1952; 13(5):597-614. DOI: 10.1016/0002-9343(52)90027-2. View

14.

Chang B, Broude E, Fang J, Kalinichenko T, Abdryashitov R, Poole J . p21Waf1/Cip1/Sdi1-induced growth arrest is associated with depletion of mitosis-control proteins and leads to abnormal mitosis and endoreduplication in recovering cells. Oncogene. 2000; 19(17):2165-70. DOI: 10.1038/sj.onc.1203573. View

15.

Coppe J, Desprez P, Krtolica A, Campisi J . The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010; 5:99-118. PMC: 4166495. DOI: 10.1146/annurev-pathol-121808-102144. View

16.

Velarde M, Demaria M . Targeting Senescent Cells: Possible Implications for Delaying Skin Aging: A Mini-Review. Gerontology. 2016; 62(5):513-8. DOI: 10.1159/000444877. View

17.

Bent E, Gilbert L, Hemann M . A senescence secretory switch mediated by PI3K/AKT/mTOR activation controls chemoprotective endothelial secretory responses. Genes Dev. 2016; 30(16):1811-21. PMC: 5024680. DOI: 10.1101/gad.284851.116. View

18.

Gu Z, Tan W, Ji J, Feng G, Meng Y, Da Z . Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway. Aging (Albany NY). 2016; 8(5):1102-14. PMC: 4931856. DOI: 10.18632/aging.100925. View

19.

Luo Y, Li L, Zou P, Wang J, Shao L, Zhou D . Rapamycin enhances long-term hematopoietic reconstitution of ex vivo expanded mouse hematopoietic stem cells by inhibiting senescence. Transplantation. 2013; 97(1):20-9. PMC: 3877183. DOI: 10.1097/TP.0b013e3182a7fcf8. View

20.

Chang B, Watanabe K, Broude E, Fang J, Poole J, Kalinichenko T . Effects of p21Waf1/Cip1/Sdi1 on cellular gene expression: implications for carcinogenesis, senescence, and age-related diseases. Proc Natl Acad Sci U S A. 2000; 97(8):4291-6. PMC: 18232. DOI: 10.1073/pnas.97.8.4291. View