Cellular senescence is the phenomenon by which normal diploid cells cease to divide and enter a new form of being. In culture, fibroblasts can reach 50 cell divisions before becoming senescent. Under holistic conditions, a little more. This phenomenon is known as “replicative senescence”, or the Hayflick limit. (1).
Senescent cells are derived from this cellular senescence program, they are like cellular zombies: not exactly dead, but not dynamically alive any more either, and deadly to all those around them. Senescent cells lose their normal function in the tissue, cease dividing, and begin secreting a deadly mix of inflammatory and tissue-degrading factors collectively known as the senescence-associated secretory phenotype (SASP) that damages local tissues, especially with constant showers of inflammation. Evidence has accumulated to show senescent cells involved in everything from atherosclerosis, to osteoarthritis, to diabetes, cataracts and more.
These senescent cells (ie, replicative senescence) results from multiple processes, a central one of which is telomere shortening (TS), which ultimately triggers a DNA damage response (DDR).
Cells can also be induced to senesce via DNA damage in response to elevated reactive oxygen species (ROS), activation of oncogenes, radiation, poisons and cell-cell fusion, all of which are independent of telomere length. As such, cellular senescence represents a qualitative change in “cell state” rather than a cell becoming “aged” as the name confusingly suggests.
Although senescent cells can no longer replicate, they are resistant to die, as such they remain metabolically active and commonly adopt an immunogenic phenotype consisting of a pro-inflammatory secretome that we mentioned above (SASP), made up of many molecules like cytokines, growth factors and proteases. In addition, they activate the up-regulation of immune ligands, a pro-survival response, promiscuous gene expression (pGE) and stain positive for senescence-associated β-galactosidase activity. (2).
The nucleus of senescent cells is characterized by senescence-associated heterochromatin foci (SAHF) and DNA segments with chromatin alterations reinforcing the cellular state of senescence (DNA-SCARS) (3)
Senescent cells also affect tumour suppression, wound healing, embryonic/placental development and a pathological role in age-related diseases. (4) New studies have also shown that these zombie cells’ microenvironment can also promote malignant metastases.
“These results indicate that the senescent microenvironment, while promoting further transdifferentiations in cells with genome instability, is able to propel the progression of premalignant cells towards a malignant, cell stem-like state”. (5)
The experimental elimination of senescent cells from transgenic progeroid mice (6) and non-progeroid, naturally-aged mice (7) with what is called senolytics led to greater resistance against aging-associated diseases.
Bio-tech anti-aging companies are hopeful to find an anti senescent cell drug, clinical human trials are ongoing, but significant side effects are to be expected. This is why the Institute prefers a more holistic approach connected to the reinforcement of the immune system, the microbiota and a few other body system whose homeostasis systems tend to get out of whack with the passage of time. (See Therapy section)
Meanwhile, it is important to realize that cellular senescence may be the main driver to most aged-related chronic diseases, from osteoarthritis, to CVD, Kidney diseases, autoimmunity and even cancer. (8) This biological mechanism is therefore one of the key processes that decides both health and lifespans.
Reference and Precision Notes
(1). Hayflick L; Moorhead PS (December 1961). “The serial cultivation of human diploid cell strains”. Exp. Cell Res. 25: 585–621.
(2). Campisi, Judith (February 2013). “Aging, Cellular Senescence, and Cancer”. Annual Review of Physiology. 75: 685–705.
(3). Rodier, F.; Campisi, J. (14 February 2011). “Four faces of cellular senescence”. The Journal of Cell Biology. 192 (4): 547–556.
(4). Burton, Dominick G. A.; Krizhanovsky, Valery (31 July 2014). “Physiological and pathological consequences of cellular senescence”. Cellular and Molecular Life Sciences. 71 (22): 4373–4386.
(5). Carcinogenesis, Volume 36, Issue 10, 1 October 2015, Pages 1180–1192, https://doi.org/10.1093/carcin/bgv101
(6). Baker, D.; Wijshake, T.; Tchkonia, T.; LeBrasseur, N.; Childs, B.; van de Sluis, B.; Kirkland, J.; van Deursen, J. (10 November 2011). “Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders”. Nature. 479: 232–6.
(7). Xu, M; Palmer, AK; Ding, H; Weivoda, MM; Pirtskhalava, T; White, TA; Sepe, A; Johnson, KO; Stout, MB; Giorgadze, N; Jensen, MD; LeBrasseur, NK; Tchkonia, T; Kirkland, JL (2015). “Targeting senescent cells enhances adipogenesis and metabolic function in old age”. eLife. See also Quick, Darren (February 3, 2016). “Clearing out damaged cells in mice extends lifespan by up to 35 percent”. www.gizmag.com. Retrieved 2016-02-04. See also Regalado, Antonio (February 3, 2016). “In New Anti-Aging Strategy, Clearing Out Old Cells Increases Life Span of Mice by 25 Percent”. And this source: Horvath S (2013). “DNA methylation age of human tissues and cell types”. Genome Biology. 14: R115.
(8). With increasing age, the prevalence of osteoarthritis increases and the efficacy of articular cartilage repair decreases. As chondrocytes age, they synthesize smaller, less uniform aggrecan molecules and less functional link proteins, their mitotic and synthetic activity decline, and their responsiveness to anabolic mechanical stimuli growth factors and the restoration of articular cartilage decreased. (J Bone Joint Surg Am. 2003;85-A Suppl 2:106-10. “The role of chondrocyte senescence in the pathogenesis of osteoarthritis and in limiting cartilage repair” Martin JA1, Buckwalter JA.)