Cell senescence

from Wikipedia, the free encyclopedia
(Top) Primary embryonic fibroblast cells (MEFs) of the mouse before senescence, with spindle-shaped morphology.
(Bottom) MEFs, aged after further passages in cell culture. The cells are larger, flatter and express senescence - associated β-galactosidase (SABG, blue areas), a marker for cellular senescence.

Cellular senescence is a phenomenon in which cells stop dividing . In their experiments from the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of about 50 cell population doublings before they age. This phenomenon is known as replicative senescence or Hayflick's limit . Hayflick's discovery that normal cells are mortal overturned a 60-year-old dogma in cell biology that says that all cells grown are immortal. Hayflick found that the only immortal cells in culture are cancer cells. The cellular senescence is often caused byTumor suppressor mechanisms that have to be inactivated to prevent progression towards senescence and thus enable cancer to develop. By overcoming or bypassing these tumor suppressor mechanisms, cancer cells escape the control of the cell cycle, leading to genomic instability and uncontrolled proliferation. MicroRNAs (miRNAs) have proven to be essential factors that contribute to or prevent cellular senescence.

Cellular Mechanisms

Mechanistically, cellular senescence can be triggered by a change in the DNA that results from the shortening of the telomeres during each cell division process. In this special case, one speaks of replicative senescence. However, cells can also be made to senesce independently of the number of cell divisions, for example via DNA damage in response to increased reactive oxygen species (ROS), via activation of oncogenes and via cell-cell fusion. The number of aging cells in tissue increases significantly during normal aging. Although aging cells can no longer multiply, they remain metabolically active and generally adopt an immunogenic phenotype, which includes a pro-inflammatory secretome and the upregulation of immune ligands. Senescence-associated β-galactosidase , together with CDK inhibitor 2A (CDKN2A) ( cyclin dependent kinase inhibitor 2A , also known as p16), is a good biomarker for cellular senescence. Nevertheless, this leads to false positive signals, since maturing tissue macrophages also show senescence-associated β-galactosidase, just as T cells express CDKN2A. The DNA Damage Response (DDR) blocks the course of the cell cycle until damage, such as double-strand breaks (DSBs), is repaired. Senescent cells show persistent sites of DNA damage that appear to be resistant to endogenous DNA repair activities. Senescent cells in culture and in the tissue of aged mammals retain their DSBs associated with DDR markers. It has been suggested that these DSBs are important drivers of the aging process .

Role of telomeres

Recently, the role of telomeres in cellular senescence has attracted interest, particularly with regard to the potential side effects of cloning . With each cell cycle , the chromosomal telomeres gradually shorten, which means that the number of divisions of the cell can be limited. This process contributes to aging. Telomere shortening, for example, also changes the mechanisms involved in alternative RNA splicing . This produces toxins such as progerin , which induce an aging process through the breakdown and functional impairment of tissues. For example, in the Hutchinson-Gilford progeria syndrome , the progerin that is produced in the event of faulty splicing instead of lamin A is permanently bound to the nuclear membrane of a cell, resulting in changed nuclear morphology, increased DNA damage, epigenetic and metabolic changes, and transcriptional dysregulation , Loss of protein homeostasis, stem cell dysfunction, accelerated senescence, and cell death.

Other features of senescent cells

A Senescence Associated Secretory Phenotype (SASP), consisting of inflammatory cytokines , growth factors and proteases , is another characteristic feature of senescent cells. The SASP is linked to many age-related diseases, including type 2 diabetes and atherosclerosis . This has motivated researchers to develop senolytic drugs ( senolytics ) to kill or eliminate senescent cells in order to improve the health of the elderly. Their positive effect has already been shown in mice. The nucleus of aging cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin changes that intensify senescence (DNA-SCARS). Senescent cells enable tumor suppression, wound healing, and embryonic / placental development, although they play a pathological role in age-related diseases.

Organisms without senescence

Cellular senescence is not observed in all organisms. In the species in which cellular senescence is observed, cells become post- mitotic , that is, they no longer replicate through the process of mitosis. You are thus in a state of replicative senescence. How and why some cells become post-mitotic in some species has been the subject of much research and speculation, but it is believed that cellular senescence and the like may occur. a. designed to prevent cancer from occurring and spreading . Somatic cells that have divided often have more DNA - mutations and therefore run the risk of developing cancer if the division continues. The aging cells also seem to develop an immunogenic phenotype (see above) that enables the immune system to recognize and eliminate them.

See also

Individual evidence

  1. ↑ M. Collado, MA Blasco, M. Serrano: Cellular senescence in cancer and aging. In: Cell . Volume 130, Number 2, July 2007, pp. 223-233, doi : 10.1016 / j.cell.2007.07.003 , PMID 17662938 (review).
  2. ↑ M Hayat: tumor dormancy, quiescence, and senescence, Volume 2: aging, cancer, and noncancer pathologies . Springer, 2014, p. 188.
  3. ↑ T Tollefsbol: Epigenetics of aging . Springer, 2010, ISBN 978-1-4419-0638-0 , p. 227.
  4. ^ JW Shay, WE Wright: Hayflick, his limit, and cellular aging. In: Nature reviews. Molecular cell biology. Volume 1, number 1, 10 2000, pp. 72-76, doi : 10.1038 / 35036093 , PMID 11413492 .
  5. ↑ M. Neault, F. Couteau et al. a .: Molecular Regulation of Cellular Senescence by MicroRNAs: Implications in Cancer and Age-Related Diseases. In: International review of cell and molecular biology. Volume 334, 2017, pp. 27-98, doi : 10.1016 / bs.ircmb.2017.04.001 , PMID 28838541 (review).
  6. ↑ a b c d B. G. Childs, M. Durik u. a .: Cellular senescence in aging and age-related disease: from mechanisms to therapy. In: Nature medicine. Volume 21, number 12, December 2015, pp. 1424-1435, doi : 10.1038 / nm.4000 , PMID 26646499 , PMC 4748967 (free full text) (review).
  7. ↑ K. Cao, CD Blair, DA Faddah, JE Kieckhaefer, M. Olive, MR Erdos, EG Nabel, FS Collins: Progerin and telomere dysfunction collaborate to trigger cellular senescence in normal human fibroblasts. In: The Journal of clinical investigation. Volume 121, number 7, July 2011, pp. 2833-2844, doi : 10.1172 / JCI43578 , PMID 21670498 , PMC 3223819 (free full text).
  8. ↑ Davor Lessel, Christian Kubisch: Genetically determined syndromes with signs of premature aging. In: Deutsches Ärzteblatt. Volume 116, Issue 29 f., July 22, 2019, pp. 489–496, here: pp. 491–493.
  9. ↑ N. Malaquin, A. Martinez, F. Rodier: Keeping the senescence secretome under control: Molecular reins on the senescence-associated secretory phenotype. In: Experimental Gerontology . Volume 82, 09 2016, pp. 39-49, doi : 10.1016 / j.exger.2016.05.010 , PMID 27235851 (review).
  10. ^ AR Mendelsohn, JW Larrick: Cellular Senescence as the Key Intermediate in Tau-Mediated Neurodegeneration. In: Rejuvenation research. Volume 21, number 6, December 2018, pp. 572-579, doi : 10.1089 / rej.2018.2155 , PMID 30489222 .
  11. ^ F. Rodier, J. Campisi: Four faces of cellular senescence. In: Journal of Cell Biology . Volume 192, number 4, February 2011, pp. 547-556, doi : 10.1083 / jcb.201009094 , PMID 21321098 , PMC 3044123 (free full text) (review).
  12. ↑ DG Burton, V. Krizhanovsky: Physiological and pathological Consequences of cellular senescence. In: Cellular and molecular life sciences: CMLS. Volume 71, number 22, November 2014, pp. 4373-4386, doi : 10.1007 / s00018-014-1691-3 , PMID 25080110 , PMC 4207941 (free full text) (review).
  13. ↑ DG Burton, RG Faragher: Cellular senescence: from growth arrest to immunogenic conversion. In: Age. Volume 37, number 2, 2015, p. 27, doi : 10.1007 / s11357-015-9764-2 , PMID 25787341 , PMC 4365077 (free full text) (review).