Senescence-associated secretory phenotype (SASP)

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, proteases, exosomes and ectosomes containing enzymes, microRNA, DNA fragments, chemokines, and other bioactive factors.

Soluble urokinase plasminogen activator surface receptor is part of SASP, and has been used to identify senescent cells.

Initially, SASP is immunosuppressive and 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.

SASP is the primary cause of the detrimental effects of senescent cells.

SASP is heterogenous, with its composition dependent upon the senescent-cell inducer and the cell type.

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.

Tumor necrosis factor (TNF) is increased 32-fold in stress-induced senescence, 8-fold in replicative senescence, and only slightly in proteosome-inhibited senescence.

Interleukin 6 (IL-6) and interleukin 8 (IL-8) are the most vigorous.  features of SASP.

SASP is one of the three main features of senescent cells, the other two features being arrested cell growth, and resistance to apoptosis.

SASP from senescent cells can kill neighboring normal cells, the apoptosis-resistance of senescent cells protects those cells from SASP.

SASP expression is induced by a number of transcription factors, including NF-κB.

NF-κB and the enzyme CD38 are mutually activating.

NF-κB is expressed as a result of inhibition of autophagy-mediated degradation of the transcription factor GATA4.

GATA4 is activated by the DNA damage response factors, which induce cellular senescence.

Aberrant oncogenes, DNA damage, and oxidative stress induce mitogen-activated protein kinases, which are the upstream regulators of NF-κB.

mTOR is also a key initiator of SASP.

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.

Translation of mRNA for IL1A is highly dependent upon mTOR activity.

mTOR activity increases levels of IL1A, mediated by MAPKAPK2.

mTOR inhibition prevents this protein from degrading transcripts of numerous components of SASP factors.

Ribosomal DNA (rDNA) is more vulnerable to DNA damage than DNA elsewhere in the genome.

 Such rDNA instability can lead to cellular senescence, and thus to SASP.

The high-mobility group proteins (HMGA) can induce senescence and SASP.

Senescent cells are highly metabolically active, that produce large amounts of SASP.

Senescent cells consisting of only 2% or 3% of tissue cells can be a major cause of aging-associated diseases.

SASP factors cause cells to become senescent, induce insulin resistance, disrupt normal tissue function by producing chronic inflammation, induction of fibrosis and inhibition of stem cells.

Chronic inflammation associated with aging has been termed inflammaging.

 SASP may be only one of the possible causes of inflammaging.

Chronic inflammation due to SASP can suppress immune system function.

Chronic inflammation due to SASP is one reason elderly persons are more vulnerable to COVID-19.

Transforming growth factor beta family members secreted by senescent cells impede differentiation of adipocytes, leading to insulin resistance.

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

SASP factors from senescent cells reduce nicotinamide adenine dinucleotide (NAD+) in non-senescent cells, thereby reducing the capacity for DNA repair in non-senescent cells.

By contrast, NAD+ contributes to the pro-inflammatory manifestation of SASP.

SASP induces an unfolded protein response in the endoplasmic reticulum resulting in proteotoxic impairment of cell function.

SASP can either promote or inhibit cancer.

Cellular senescence likely evolved as a means of protecting against cancer early in life, but promotes the development of late-life cancers.

Cancer invasiveness is promoted primarily though SASP factors metalloproteinase, chemokine, interleukin 6 (IL-6), and interleukin 8 (IL-8).

In fact, SASP from senescent cells is associated with many aging-associated diseases, including not only cancer, but atherosclerosis and osteoarthritis.

The flavonoid apigenin has been show to strongly inhibit SASP production.

SASP aids in signaling to immune cells for senescent cell clearance,with SASP factors secreted by senescent cells attracting and activating different components of both the innate and adaptive immune system.

The SASP cytokine CCL2 recruits macrophages to remove cancer cells.

Although transient expression of SASP can recruit immune system cells to eliminate cancer cells as well as senescent cells, chronic SASP promotes cancer.

Senescent hematopoietic stem cells produces a SASP that induces polarization of macrophages which kills the senescent cells in a p53-dependent process.

Autophagy is upregulated to promote survival.

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

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.

SASP can play a beneficial role by promoting wound healing, which is 

is transitory.

There is a persistent character of SASP in chronic inflammation.

Temporary SASP in the liver or kidney can reduce fibrosis, but chronic SASP could lead to organ dysfunction.

SASP helps in tissue regeneration by signaling for senescent cell clearance by immune cells, allowing progenitor cells to repopulate tissue.

SASP also is used to signal for senescent cell clearance to aid tissue remodeling.

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