Cellular senescence

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Senescent cells (SCs) are cells that have stopped dividing and are no longer able to grow or divide, a phenomenon known as the "Hayflick limit".[1] SCs have been hypothesized to be drivers of aging and are associated to aging and age-related diseaeses.[2] Cellular senescence is considered to be one of the hallmarks of aging.[3]

Mechanism

Senescent cells produce pro-inflammatory signalling molecules such as the senescence-associated secretory phenotype (SASP), releasing various factors that can trigger inflammation and dysfunction, while promoting apoptosis (cell death) in nearby tissues.

Cellular senescence and aging

Due to the negative impact that SCs may have in neighbouring cells and tissues, some scientists believe that the clearance of senescent cells via senolytics may have therapeutic benefits, especially for treating age-related diseases such as cancer, cardiovascular disease or neurodegeneration.[2] Cellular senescence has also been suggested as a driver of fibrotic pulmonary disease.[4]

Cellular senescence can be viewed as a necessary, adaptive response of the body in response to injury, infection or other stresses.[5] It also serves key purposes during tissue remodelling, wound repair or embryogenesis. However, chronic senescence can be maladaptive and lead to age-related diseases.[6]

It is not clear whether removing senescent cells might have deleterious effects in vivo, and several studies are suggesting that they play a fundamental role in physiology and thus might be detrimental to remove them, even when accumulated chronically. For instance, eliminating senescent cells in mice promoted the development and progression of pulmonary hypertension.[7]

Senolytics

See the full article on senolytics.

Senescent cells survive their own SASP, since they are protected by networks of senescent cell anti-apoptotic pathways (SCAPs). One mechanism of senolytics, therefore, is to interfere with these networks, so that the SASP also induce apoptosis in the senescent cells themselves. Senescent cells take time to re-build once they are ablated. Hence, an advantage of senolytic treatment is that it can be done in a "hit-and-run" fashion, thus avoiding off-target effects in comparison to other types of treatments.

A way to track if senolytics have any effect is to check out for senescent biomarkers. Some known markers of SCs are p16, p21 and senescence-associated β-galactosidase activity (SA-β-gal).

https://brain.forever-healthy.org/display/EN/Dasatinib+and+Quercetin+Senolytic+Therapy

Negligible senescence

See the full article on negligible senescence.

The phenomenon of showing no signs of senescence, such as age-related dysfunctions.

  1. Shay, J., Wright, W. Hayflick, his limit, and cellular ageing. Nat Rev Mol Cell Biol 1, 72–76 (2000). https://doi.org/10.1038/35036093
  2. 2.0 2.1 van Deursen JM. The role of senescent cells in ageing. Nature. 2014 May 22;509(7501):439-46. doi: 10.1038/nature13193. PMID: 24848057; PMCID: PMC4214092.
  3. López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194-1217.
  4. Schafer MJ, White TA, Iijima K, Haak AJ, Ligresti G, Atkinson EJ, Oberg AL, Birch J, Salmonowicz H, Zhu Y, Mazula DL, Brooks RW, Fuhrmann-Stroissnigg H, Pirtskhalava T, Prakash YS, Tchkonia T, Robbins PD, Aubry MC, Passos JF, Kirkland JL, Tschumperlin DJ, Kita H, LeBrasseur NK. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun. 2017 Feb 23;8:14532. doi: 10.1038/ncomms14532. PMID: 28230051; PMCID: PMC5331226.
  5. Tchkonia T, Morbeck DE, Von Zglinicki T, Van Deursen J, Lustgarten J, Scrable H, Khosla S, Jensen MD, Kirkland JL. Fat tissue, aging, and cellular senescence. Aging Cell. 2010 Oct;9(5):667-84. doi: 10.1111/j.1474-9726.2010.00608.x. Epub 2010 Aug 15. PMID: 20701600; PMCID: PMC2941545.
  6. Huang, W., Hickson, L.J., Eirin, A. et al. Cellular senescence: the good, the bad and the unknown. Nat Rev Nephrol 18, 611–627 (2022). https://doi.org/10.1038/s41581-022-00601-z
  7. Born, E. et al. (2022) “Eliminating senescent cells can promote pulmonary hypertension development and progression,” Circulation[Preprint]. Available at: https://doi.org/10.1161/circulationaha.122.058794.