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] But some SASP components are anti-inflammatory.^[11]

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.^[12] SASP factors can include the anti-apoptotic protein Bcl-xL,^[13] but growth arrest and SASP production are independently regulated.^[14] Although SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP.^[15]

The concept and abbreviation of SASP was first established by Judith Campisi and her group, who first published on the subject in 2008.^[1]

SASP expression is induced by a number of transcription factors, including MLL1 (KMT2A),^[16] C/EBPβ, and NF-κB.^[17][18] NF-κB and the enzyme CD38 are mutually activating.^[19] NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4.^[20][21] GATA4 is activated by the DNA damage response factors, which induce cellular senescence.^[20] SASP is both a promoter of DNA damage response and a consequence of DNA damage response, in an autocrine and paracrine manner.^[22] Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.^[23] Demethylation of DNA packaging protein Histone H3 (H3K27me3) can lead to up-regulation of genes controlling SASP.^[16]

mTOR (mammalian target of rapamycin) is also a key initiator of SASP.^[21][24] 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.^[25][26][27] Translation of mRNA for IL1A is highly dependent upon mTOR activity.^[28] mTOR activity increases levels of IL1A, mediated by MAPKAPK2.^[25] mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors.^[29][30] Inhibition of mTOR supports autophagy, which can generate SASP components.^[31]

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^[32] The high-mobility group proteins (HMGA) can induce senescence and SASP in a p53-dependent manner.^[33]

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.^[33] cGAS is essential for induction of cellular senescence by DNA damage.^[34]

SASP secretion can also be initiated by the microRNAs miR-146 a/b.^[35]

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.^[30] SASP factors cause non-senescent cells to become senescent.^[36][37] SASP factors induce insulin resistance.^[38] SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.^[39] Transforming growth factor beta family members secreted by senescent cells impede differentiation of adipocytes, leading to insulin resistance.^[40]

SASP factors IL-6 and TNFα enhance T-cell apoptosis, thereby impairing the capacity of the adaptive immune system.^[41]

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells,^[42] thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells.^[43] SASP induction of the NAD+ degrading enzyme CD38 on non-senescent cells (macrophages) may be responsible for most of this effect.^[35][44][45] 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.^[46]

SASP cytokines can result in an inflamed stem cell niche, leading to stem cell exhaustion and impaired stem cell function.^[35]

SASP can either promote or inhibit cancer, depending on the SASP composition,^[36] notably including p53 status.^[47] 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.^[17][39] Cancer invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, interleukin 6 (IL-6), and interleukin 8 (IL-8).^[48][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.^[49]

SASP can aid in signaling to immune cells for senescent cell clearance,^{[50][51][52][53]} with specific SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system.^[51] The SASP cytokine CCL2 (MCP1) recruits macrophages to remove cancer cells.^[54] Although transient expression of SASP can recruit immune system cells to eliminate cancer cells as well as senescent cells, chronic SASP promotes cancer.^[55] Senescent hematopoietic stem cells produces a SASP that induces an M1 polarization of macrophages which kills the senescent cells in a p53-dependent process.^[56]

Autophagy is upregulated to promote survival.^[46]

SASP factors can maintain senescent cells in their senescent state of growth arrest, thereby preventing cancerous transformation.^[57] 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.^[24]

SASP can play a beneficial role by promoting wound healing.^[58][59] SASP may play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.^[60] In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling.^[61] The ability of SASP to clear senescent cells and regenerate damaged tissue declines with age.^[62] In contrast to the persistent character of SASP in the chronic inflammation of multiple age-related diseases, beneficial SASP in wound healing is transitory.^[58][59] Temporary SASP in the liver or kidney can reduce fibrosis, but chronic SASP could lead to organ dysfunction.^[63][64]

Senescent cells have permanently active mTORC1 irrespective of nutrients or growth factors, resulting in the continuous secretion of SASP.^[65] By inhibiting mTORC1, rapamycin reduces SASP production by senescent cells.^[65]

SASP has been reduced through inhibition of p38 mitogen-activated protein kinases and janus kinase.^[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.^[67][68]

A SASP index composed of 22 SASP factors has been used to evaluate treatment outcomes of late life depression.^[69] Higher SASP index scores corresponded to increased incidence of treatment failure, whereas no individual SASP factors were associated with treatment failure.^[69]

Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of this condition.^[70] Chronic systemic inflammation is associated with aging-associated diseases.^[47] 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.^[71]

• Cellular senescence