Senescence-associated secretory phenotype

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, and other bioactive factors.[3] 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.[4][5]

SASP is heterogenous, with the exact composition dependent upon the senescent-cell inducer and the cell type.[6] 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.[7] Tumor necrosis factor (TNF) is increased 32-fold in stress-induced senescence, 8-fold in replicative senescence, and only slightly in proteosome-inhibited senescence.[7] Interleukin 6 (IL-6) and interleukin 8 (IL-8) are the most conserved and robust features of SASP.[8]

An online SASP Atlas serves as a guide to the various types of SASP.[6]

SASP is one of the three main features of senescent cells, the other two features being arrested cell growth, and resistance to apoptosis.[9] SASP factors can include the anti-apoptotic protein Bcl-xL,[10] but growth arrest and SASP production are independently regulated.[11] Although SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP.[12]

Causes

SASP expression is induced by a number of transcription factors, including C/EBPβ, of which the most important is NF-κB.[13][14] NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4.[15][16] GATA4 is activated by the DNA damage response factors, which induce cellular senescence.[15] Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.[17]

mTOR (mechanistic target of rapamycin) is also a key initiator of SASP.[16] 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.[18][19] Translation of mRNA for IL1A is highly dependent upon mTOR activity.[20] mTOR activity increases levels of IL1A, mediated by MAPKAPK2.[18] mTOR inhibition of ZFP36L1 prevents this protein from degrading transcripts of numerous components of SASP factors.[21][22]

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[23] The high-mobility group proteins (HMGA) can induce senescence and SASP in a p53-dependent manner.[24]

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.[24] cGAS is essential for induction of cellular senescence by DNA damage.[25]

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.[22] SASP factors cause non-senescent cells to become senescent.[26] SASP factors induce insulin resistance.[27] SASP disrupts normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.[28] Chronic inflammation associated with aging has been termed inflammaging, although SASP may be only one of the possible causes of this condition.[29] Chronic inflammation due to SASP can suppress immune system function,[3] which is one reason elderly persons are more vulnerable to COVID-19.[30]

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells,[31] thereby reducing the capacity for DNA repair and sirtuin activity in non-senescent cells.[32] SASP induction of the NAD+ degrading enzyme CD38 on non-senescent cells may be responsible for most of this effect.[33] By contrast, NAD+ contributes to the secondary (pro-inflammatory) manifestation of SASP.[5]

SASP induces an unfolded protein response in the endoplasmic reticulum because of an accumulation of unfolded proteins, resulting in proteotoxic impairment of cell function.[34]

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.[13][28] Cancer invasiveness is promoted primarily though the actions of the SASP factors metalloproteinase, chemokine, interleukin 6 (IL-6), and interleukin 8 (IL-8).[35][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]

Benefits

SASP can aid in signaling to immune cells for senescent cell clearance,[36][37][38][39] with specific SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system.[37] Autophagy is upregulated to promote survival.[34]

SASP factors can maintain senescent cells in their senescent state of growth arrest, thereby preventing cancerous transformation.[40]

SASP can play a beneficial role by promoting wound healing.[41] However, in contrast to the persistent character of SASP in chronic inflammation, beneficial SASP in wound healing is transitory.[41]

SASP may play a role in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.[42] In development, SASP also may be used to signal for senescent cell clearance to aid tissue remodeling.[43]

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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