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Senescence-associated secretory phenotype

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Senescence-associated secretory phenotype (SASP) is a phenotype associated with senescent cells wherein those cells secrete high levels of inflammatory cytokines, immune modulators, growth factors, and proteases.[1][2] SASP may also consist of exosomes and ectosomes containing enzymes, microRNA, DNA fragments, chemokines, and other bioactive factors.[3][4] Soluble urokinase plasminogen activator surface receptor is part of SASP, and has been used to identify senescent cells for senolytic therapy.[5] Initially, SASP is immunosuppressive (characterized by TGF-β1 and TGF-β3) and profibrotic, but progresses to become proinflammatory (characterized by IL-1β, IL-6 and IL-8) and fibrolytic.[6][7] SASP is the primary cause of the detrimental effects of senescent cells.[4]

SASP is heterogenous, with the exact composition dependent upon the senescent-cell inducer and the cell type.[4][8] Interleukin 12 (IL-12) and Interleukin 10 (IL-10) are increased more than 200-fold in replicative senescence in contrast to stress-induced senescence or proteosome-inhibited senescence where the increases are about 30-fold or less.[9] Tumor necrosis factor (TNF) is increased 32-fold in stress-induced senescence, 8-fold in replicative senescence, and only slightly in proteosome-inhibited senescence.[9] Interleukin 6 (IL-6) and interleukin 8 (IL-8) are the most conserved and robust features of SASP.[10]

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.[11] SASP factors can include the anti-apoptotic protein Bcl-xL,[12] but growth arrest and SASP production are independently regulated.[13] Although SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP.[14]

Causes

SASP expression is induced by a number of transcription factors, including C/EBPβ, of which the most important is NF-κB.[15][16] NF-κB and the enzyme CD38 are mutually activating.[17] NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4.[18][19] GATA4 is activated by the DNA damage response factors, which induce cellular senescence.[18] Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.[20]

mTOR (mechanistic target of rapamycin) is also a key initiator of SASP.[19][21] 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.[22][23][24] Translation of mRNA for IL1A is highly dependent upon mTOR activity.[25] mTOR activity increases levels of IL1A, mediated by MAPKAPK2.[22] mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors.[26][27]

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[28] The high-mobility group proteins (HMGA) can induce senescence and SASP in a p53-dependent manner.[29]

Activation of the retrotransposon LINE1 can result in cytosolic DNA that activates the cGAS–STING cytosolic DNA sensing pathway upregulating SASP by induction of interferon type I.[29] cGAS is essential for induction of cellular senescence by DNA damage.[30]

Pathology

Senescent cells are highly metabolically active, producing large amounts of SASP, which is why senescent cells consisting of only 2% or 3% of tissue cells can be a major cause of aging-associated diseases.[27] SASP factors cause non-senescent cells to become senescent.[31][32] SASP factors induce insulin resistance.[33] SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[34] Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of this condition.[35] Chronic inflammation due to SASP can suppress immune system function,[3] which is one reason elderly persons are more vulnerable to COVID-19.[36] Transforming growth factor beta family members secreted by senescent cells impede differentiation of adipocytes, leading to insulin resistance.[37]

SASP factors IL-6 and TNFα enhance T-cell apoptosis, thereby impairing the capacity of the adaptive immune system.[38]

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells,[39] thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells.[40] SASP induction of the NAD+ degrading enzyme CD38 on non-senescent cells may be responsible for most of this effect.[41][42] By contrast, NAD+ contributes to the secondary (pro-inflammatory) manifestation of SASP.[7]

SASP induces an unfolded protein response in the endoplasmic reticulum because of an accumulation of unfolded proteins, resulting in proteotoxic impairment of cell function.[43]

SASP can either promote or inhibit cancer, depending on the SASP composition.[31] 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.[15][34] Cancer invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, interleukin 6 (IL-6), and interleukin 8 (IL-8).[44][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 flavonoid apigenin has been shown to strongly inhibit SASP production.[45]

Benefits

SASP can aid in signaling to immune cells for senescent cell clearance,[46][47][48][49] with specific SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system.[47] The SASP cytokine CCL2 (MCP1) recruits macrophages to remove cancer cells.[50] Although transient expression of SASP can recruit immune system cells to eliminate cancer cells as well as senescent cells, chronic SASP promotes cancer.[51] Senescent hematopoietic stem cells produces a SASP that induces an M1 polarization of macrophages which kills the senescent cells in a p53-dependent process.[52]

Autophagy is upregulated to promote survival.[43]

SASP factors can maintain senescent cells in their senescent state of growth arrest, thereby preventing cancerous transformation.[53] 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.[21]

SASP can play a beneficial role by promoting wound healing.[54] However, in contrast to the persistent character of SASP in chronic inflammation, beneficial SASP in wound healing is transitory.[54] Similarly, temporary SASP in the liver or kidney can reduce fibrosis, but chronic SASP could lead to organ dysfunction.[55][56]

SASP may play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.[57] In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling.[58]

Modification

The protein hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1) antagonizes cellular senescence and induction of the SASP by stabilizing Oct-4 and sirtuin 1 mRNAs.[59][60]

SASP Index

A SASP index composed of 22 SASP factors has been used to evaluate treatment outcomes of late life depression.[61] Higher SASP index scores corresponded to increased incidence of treatment failure, whereas no individual SASP factors were associated with treatment failure.[61]

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]

See also

References

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For further reading

  • 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. PMID 35524726 doi: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. PMID 35365245 PMC 8976373 doi: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. PMID 35365245 PMC 8976373 doi: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. PMID 35955523 PMC 9369445 doi:10.3390/ijms23158390
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