Senescence and SASP can also occur in post-mitotic cells, notably neurons.[12] The SASP in senescent neurons can vary according to cell type, the initiator of senescence, and the stage of senescence. [12]
An online SASP Atlas serves as a guide to the various types of SASP.[8]
SASP is one of the three main features of senescent cells, the other two features being arrested cell growth, and resistance to apoptosis.[13] SASP factors can include the anti-apoptotic protein Bcl-xL,[14] but growth arrest and SASP production are independently regulated.[15] Although SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP.[16]
History
The concept and abbreviation of SASP was first established by Judith Campisi and her group, who first published on the subject in 2008.[1]
mTOR (mammalian target of rapamycin) is also a key initiator of SASP.[22][25]Interleukin 1 alpha (IL1A) is found on the surface of senescent cells, where it contributes to the production of SASP factors due to a positive feedback loop with NF-κB.[26][27][28] Translation of mRNA for IL1A is highly dependent upon mTOR activity.[29] mTOR activity increases levels of IL1A, mediated by MAPKAPK2.[26] mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors.[30][31] Inhibition of mTOR supports autophagy, which can generate SASP components.[32]
Ribosomal DNA (rDNA) is more vulnerable to DNA damage than DNA elsewhere in the genome such than rDNA instability can lead to cellular senescence, and thus to SASP[33]
The high-mobility group proteins (HMGA) can induce senescence and SASP in a p53-dependent manner.[34]
SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells,[43] thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells.[44] SASP induction of the NAD+ degrading enzyme CD38 on non-senescent cells (macrophages) may be responsible for most of this effect.[36][45][46] By contrast, NAD+ contributes to the secondary (pro-inflammatory) manifestation of SASP.[7]
SASP cytokines can result in an inflamed stem cell niche, leading to stem cell exhaustion and impaired stem cell function.[36]
SASP can either promote or inhibit cancer, depending on the SASP composition,[37] notably including p53 status.[48] Despite the fact that cellular senescence likely evolved as a means of protecting against cancer early in life, SASP promotes the development of late-life cancers.[18][40] Cancer invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, interleukin 6 (IL-6), and interleukin 8 (IL-8).[49][1] In fact, SASP from senescent cells is associated with many aging-associated diseases, including not only cancer, but atherosclerosis and osteoarthritis.[2] For this reason, senolytic therapy has been proposed as a generalized treatment for these and many other diseases.[2] The flavonoidapigenin has been shown to strongly inhibit SASP production.[50]
Benefits
SASP can aid in signaling to immune cells for senescent cell clearance,[51][52][53][54] with specific SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system.[52] The SASP cytokine CCL2 (MCP1) recruits macrophages to remove cancer cells.[55] Although transient expression of SASP can recruit immune system cells to eliminate cancer cells as well as senescent cells, chronic SASP promotes cancer.[56] Senescent hematopoietic stem cells produces a SASP that induces an M1 polarization of macrophages which kills the senescent cells in a p53-dependent process.[57]
SASP factors can maintain senescent cells in their senescent state of growth arrest, thereby preventing cancerous transformation.[58] Additionally, SASP secreted by cells that have become senescent because of stresses can induce senescence in adjoining cells subject to the same stresses. thereby reducing cancer risk.[25]
SASP can play a beneficial role by promoting wound healing.[59][60] SASP may play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.[61] In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling.[62] The ability of SASP to clear senescent cells and regenerate damaged tissue declines with age.[63] In contrast to the persistent character of SASP in the chronic inflammation of multiple age-related diseases, beneficial SASP in wound healing is transitory.[59][60] Temporary SASP in the liver or kidney can reduce fibrosis, but chronic SASP could lead to organ dysfunction.[64][65]
Modification
Senescent cells have permanently active mTORC1 irrespective of nutrients or growth factors, resulting in the continuous secretion of SASP.[66] By inhibiting mTORC1, rapamycin reduces SASP production by senescent cells.[66]
The protein hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1) antagonizes cellular senescence and induction of the SASP by stabilizing Oct-4 and sirtuin 1 mRNAs.[68][69]
SASP Index
A SASP index composed of 22 SASP factors has been used to evaluate treatment outcomes of late life depression.[70] Higher SASP index scores corresponded to increased incidence of treatment failure, whereas no individual SASP factors were associated with treatment failure.[70]
Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of this condition.[71] Chronic systemic inflammation is associated with aging-associated diseases.[48]Senolytic agents have been recommended to counteract some of these effects.[11] Chronic inflammation due to SASP can suppress immune system function,[3] which is one reason elderly persons are more vulnerable to COVID-19.[72]
^Thiers, B.H. (January 2008). "Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas". Yearbook of Dermatology and Dermatologic Surgery. 2008: 312–313. doi:10.1016/s0093-3619(08)70921-3. ISSN0093-3619.
Han, X., Lei, Q., Xie, J., Liu, H., Li, J., Zhang, X., ... & Gou, X. (2022). Potential Regulators of the Senescence-Associated Secretory Phenotype During Senescence and Aging. The Journals of Gerontology: Series A, 77(11), 2207-2218. PMID35524726doi:10.1093/gerona/glac097
Ohtani, N. (2022). The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis?. Inflammation and Regeneration, 42(1), 1-8. PMID35365245PMC8976373doi:10.1186/s41232-022-00197-8
Pan, Y., Gu, Z., Lyu, Y., Yang, Y., Chung, M., Pan, X., & Cai, S. (2022). Link Between Senescence and Cell Fate: Senescence-Associated Secretory Phenotype and Its Effects on Stem Cell Fate Transition. Rejuvenation Research, 25(4), 160-172. PMID35365245PMC8976373doi:10.1186/s41232-022-00197-8
Park, M., Na, J., Kwak, S. Y., Park, S., Kim, H., Lee, S. J., ... & Shim, S. (2022). Zileuton Alleviates Radiation-Induced Cutaneous Ulcers via Inhibition of Senescence-Associated Secretory Phenotype in Rodents. International Journal of Molecular Sciences, 23(15), 8390. PMID35955523PMC9369445doi:10.3390/ijms23158390