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

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

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

Causes

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SASP expression is induced by a number of transcription factors, including MLL1 (KMT2A),[17] C/EBPβ, and NF-κB.[18][19] NF-κB and the enzyme CD38 are mutually activating.[20] NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4.[21][22] GATA4 is activated by the DNA damage response factors, which induce cellular senescence.[21] SASP is both a promoter of DNA damage response and a consequence of DNA damage response, in an autocrine and paracrine manner.[23] Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.[24][25]

Demethylation of DNA packaging protein Histone H3 (H3K27me3) can lead to up-regulation of genes controlling SASP.[17]

mTOR (mammalian target of rapamycin) is also a key initiator of SASP.[22][26] 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.[27][28][29] Translation of mRNA for IL1A is highly dependent upon mTOR activity.[30] mTOR activity increases levels of IL1A, mediated by MAPKAPK2.[27] mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors.[31][32] Inhibition of mTOR supports autophagy, which can generate SASP components.[33]

Ribosomal DNA (rDNA) is more vulnerable to DNA damage than DNA elsewhere in the genome such that rDNA instability can lead to cellular senescence, and thus to SASP[34] The high-mobility group proteins (HMGA) can induce senescence and SASP in a p53-dependent manner.[35]

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.[35] cGAS is essential for induction of cellular senescence by DNA damage.[36]

SASP secretion can also be initiated by the microRNAs miR-146 a/b.[37]

Senescent cells release mitochondrial double-stranded RNA (mt-dsRNA) into the cytosol driving the SASP via RIGI/MDA5/MAVS/MFN1. Moreover, senescent cells are hypersensitive to mt-dsRNA-driven inflammation due to reduced levels of PNPT1 and ADAR1.[38]

Pathology

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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.[32] SASP factors cause non-senescent cells to become senescent.[39][40][41] SASP factors induce insulin resistance.[42] SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[43] Transforming growth factor beta family members secreted by senescent cells impede differentiation of adipocytes, leading to insulin resistance.[44]

SASP factors IL-6 and TNFα enhance T-cell apoptosis, thereby impairing the capacity of the adaptive immune system.[45]

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells,[46] thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells.[47] SASP induction of the NAD+ degrading enzyme CD38 on non-senescent cells (macrophages) may be responsible for most of this effect.[37][48][49] 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.[50]

SASP cytokines can result in an inflamed stem cell niche, leading to stem cell exhaustion and impaired stem cell function.[37]

SASP can either promote or inhibit cancer, depending on the SASP composition,[39] notably including p53 status.[51] 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][43] Cancer invasiveness is promoted primarily through the actions of the SASP factors metalloproteinase, chemokine, interleukin 6 (IL-6), and interleukin 8 (IL-8).[52][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.[53]

Benefits

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SASP can aid in signaling to immune cells for senescent cell clearance,[54][55][56][57] with specific SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system.[55] The SASP cytokine CCL2 (MCP1) recruits macrophages to remove cancer cells.[58] Although transient expression of SASP can recruit immune system cells to eliminate cancer cells as well as senescent cells, chronic SASP promotes cancer.[59] Senescent hematopoietic stem cells produce a SASP that induces an M1 polarization of macrophages which kills the senescent cells in a p53-dependent process.[60]

Autophagy is upregulated to promote survival.[50]

SASP factors can maintain senescent cells in their senescent state of growth arrest, thereby preventing cancerous transformation.[61] 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.[26]

SASP can play a beneficial role by promoting wound healing.[62][63] SASP may play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.[64] In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling.[65] The ability of SASP to clear senescent cells and regenerate damaged tissue declines with age.[66] In contrast to the persistent character of SASP in the chronic inflammation of multiple age-related diseases, beneficial SASP in wound healing is transitory.[62][63] Temporary SASP in the liver or kidney can reduce fibrosis, but chronic SASP could lead to organ dysfunction.[67][68]

Modification

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Senescent cells have permanently active mTORC1 irrespective of nutrients or growth factors, resulting in the continuous secretion of SASP.[69] By inhibiting mTORC1, rapamycin reduces SASP production by senescent cells.[69]

SASP has been reduced through inhibition of p38 mitogen-activated protein kinases and janus kinase.[70]

The protein hnRNP A1 (heterogeneous nuclear ribonucleoprotein A1) antagonizes cellular senescence and induction of the SASP by stabilizing Oct-4 and sirtuin 1 mRNAs.[71][72]

SASP Index

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A SASP index composed of 22 SASP factors has been used to evaluate treatment outcomes of late life depression.[73] Higher SASP index scores corresponded to increased incidence of treatment failure, whereas no individual SASP factors were associated with treatment failure.[73]

Inflammaging

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Main article: Inflammaging

Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of this condition.[74] Chronic systemic inflammation is associated with aging-associated diseases.[51] 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.[75]

See also

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References

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