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]

Contents

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

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

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 than 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 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

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 though 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

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 produces 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

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

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

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

Related Research Articles

Senescence or biological aging is the gradual deterioration of functional characteristics in living organisms. Whole organism senescence involves an increase in death rates or a decrease in fecundity with increasing age, at least in the later part of an organism's life cycle. However, the resulting effects of senescence can be delayed. The 1934 discovery that calorie restriction can extend lifespans by 50% in rats, the existence of species having negligible senescence, and the existence of potentially immortal organisms such as members of the genus Hydra have motivated research into delaying senescence and thus age-related diseases. Rare human mutations can cause accelerated aging diseases.

<span class="mw-page-title-main">Fibrosis</span> Excess connective tissue in healing

Fibrosis, also known as fibrotic scarring, is a pathological wound healing in which connective tissue replaces normal parenchymal tissue to the extent that it goes unchecked, leading to considerable tissue remodelling and the formation of permanent scar tissue.

<span class="mw-page-title-main">Interleukin 6</span> Cytokine protein

Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the IL6 gene.

<span class="mw-page-title-main">NF-κB</span> Family of transcription factor protein complexes

Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) is a family of transcription factor protein complexes that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, heavy metals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection. Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, septic shock, viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.

mTOR Mammalian protein found in humans

The mammalian target of rapamycin (mTOR), also referred to as the mechanistic target of rapamycin, and sometimes called FK506-binding protein 12-rapamycin-associated protein 1 (FRAP1), is a kinase that in humans is encoded by the MTOR gene. mTOR is a member of the phosphatidylinositol 3-kinase-related kinase family of protein kinases.

<span class="mw-page-title-main">Interleukin 1-alpha</span> Protein-coding gene in the species Homo sapiens

Interleukin-1 alpha also known as hematopoietin 1 is a cytokine of the interleukin 1 family that in humans is encoded by the IL1A gene. In general, Interleukin 1 is responsible for the production of inflammation, as well as the promotion of fever and sepsis. IL-1α inhibitors are being developed to interrupt those processes and treat diseases.

p16 Mammalian protein found in humans

p16, is a protein that slows cell division by slowing the progression of the cell cycle from the G1 phase to the S phase, thereby acting as a tumor suppressor. It is encoded by the CDKN2A gene. A deletion in this gene can result in insufficient or non-functional p16, accelerating the cell cycle and resulting in many types of cancer.

Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. A 2020 review concluded that the adaptive immune system is affected more than the innate immune system. Immunosenescence involves both the host's capacity to respond to infections and the development of long-term immune memory. Age-associated immune deficiency is found in both long- and short-lived species as a function of their age relative to life expectancy rather than elapsed time.

<span class="mw-page-title-main">MAPKAPK2</span> Protein-coding gene in the species Homo sapiens

MAP kinase-activated protein kinase 2 is an enzyme that in humans is encoded by the MAPKAPK2 gene.

<span class="mw-page-title-main">HMGB2</span> Protein-coding gene in the species Homo sapiens

High-mobility group protein B2 also known as high-mobility group protein 2 (HMG-2) is a protein that in humans is encoded by the HMGB2 gene.

<span class="mw-page-title-main">Cellular senescence</span> Phenomenon characterized by the cessation of cell division

Cellular senescence is a phenomenon characterized by the cessation of cell division. In their experiments during the early 1960s, Leonard Hayflick and Paul Moorhead found that normal human fetal fibroblasts in culture reach a maximum of approximately 50 cell population doublings before becoming senescent. This process is known as "replicative senescence", or the Hayflick limit. Hayflick's discovery of mortal cells paved the path for the discovery and understanding of cellular aging molecular pathways. Cellular senescence can be initiated by a wide variety of stress inducing factors. These stress factors include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors, among many other things.

<span class="mw-page-title-main">NKG2D</span> Protein-coding gene in the species Homo sapiens

NKG2D is an activating receptor (transmembrane protein) belonging to the NKG2 family of C-type lectin-like receptors. NKG2D is encoded by KLRK1 (killer cell lectin like receptor K1) gene which is located in the NK-gene complex (NKC) situated on chromosome 6 in mice and chromosome 12 in humans. In mice, it is expressed by NK cells, NK1.1+ T cells, γδ T cells, activated CD8+ αβ T cells and activated macrophages. In humans, it is expressed by NK cells, γδ T cells and CD8+ αβ T cells. NKG2D recognizes induced-self proteins from MIC and RAET1/ULBP families which appear on the surface of stressed, malignant transformed, and infected cells.

<span class="mw-page-title-main">Genetics of aging</span> Overview of the genetics of aging

Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.

Androgen deprivation-induced senescence refers to the induction of cellular senescence as a result of androgen deprivation therapy. ADIS is observed in prostate cancer cells that are dependent on androgens for cell proliferation. Androgen withdrawal induces cells to undergo cellular senescence by up-regulating intracellular reactive oxygen species (ROS) that cause DNA damage. ADIS is maintained through the up-regulation of the cell cycle regulator p16ink4a.

An epigenetic clock is a biochemical test that can be used to measure age. The test is based on DNA methylation levels, measuring the accumulation of methyl groups to one's DNA molecules.

A senolytic is among a class of small molecules under basic research to determine if they can selectively induce death of senescent cells and improve health in humans. A goal of this research is to discover or develop agents to delay, prevent, alleviate, or reverse age-related diseases. Removal of senescent cells with senolytics has been proposed as a method of enhancing immunity during aging.

Judith Campisi was an American biochemist and cell biologist. She was a professor of biogerontology at the Buck Institute for Research on Aging. She was also a member of the SENS Research Foundation Advisory Board and an adviser at the Lifeboat Foundation. She was co-editor in chief of the Aging Journal, together with Mikhail Blagosklonny and David Sinclair, and founder of the pharmaceutical company Unity Biotechnology. She is listed in Who's Who in Gerontology. She was widely known for her research on how senescent cells influence aging and cancer — in particular the Senescence Associated Secretory Phenotype (SASP).

Senotherapeutic's refers to therapeutic agents/strategies that specifically target cellular senescence. Senotherapeutic's include emerging senolytic/senoptotic small molecules that specifically induce cell death in senescent cells and agents that inhibit the pro-inflammatory senescent secretome. Senescent cells can be targeted for immune clearance, but an ageing immune system likely impairs senescent cell clearance leading to their accumulation. Therefore, agents which can enhance immune clearance of senescent cells can also be considered as senotherapeutic.

<span class="mw-page-title-main">Inflammaging</span> Chronic low-grade inflammation that develops with advanced age

Inflammaging is a chronic, sterile, low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals.

Aging is characterized by a progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. The hallmarks of aging are the types of biochemical changes that occur in all organisms that experience biological aging and lead to a progressive loss of physiological integrity, impaired function and, eventually, death. They were first listed in a landmark paper in 2013 to conceptualize the essence of biological aging and its underlying mechanisms.

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