Inflammatory networks during cellular senescence: causes and consequences.
Open accessAbstract
Chronic inflammation is associated with aging and plays a causative role in several age-related diseases such as cancer, atherosclerosis and osteoarthritis. The source of this chronic inflammation is often attributed to the progressive activation of immune cells over time. However, recent studies have shown that the process of cellular senescence, a tumor suppressive stress response that is also associated with aging, entails a striking increase in the secretion of pro-inflammatory proteins and might be an important additional contributor to chronic inflammation. Here, we list the secreted factors that make up the pro-inflammatory phenotype of senescent cells and describe the impact of these factors on tissue homeostasis. We also summarize the cellular pathways/processes that are known to regulate this phenotype – namely, the DNA damage response, microRNAs, key transcription factors and kinases and chromatin remodeling.
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The SASP includes proteins that can help senescent cells evade immune recognition and clearance.
“Finally, the SASP also includes proteins that can help senescent cells evade immune recognition and clearance (92, 93).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [93]
The “Multiple roles of the SASP” section says the SASP might signal the immune system to clear senescent cells. It also describes SASP-associated cytokines and enzymes promoting clearance in mouse models. The cited paper thus makes the contrary point, rather than identifying proteins that help senescent cells evade recognition or clearance. Page numbers were not available in our copy. (LLM, conf=0.84)
Checked by a reasoning model — may be wrong.
Experimental — accuracy not yet measuredSpecialized SASP chemokines attract distinct immune cell subsets, including NK cells, neutrophils, dendritic cells, monocytes/macrophages, B cells and T cells.
“Specialized SASP chemokines are able to attract distinct subsets of immune cells, including NK cells, neutrophils, dendritic cells, monocytes/macrophages, B cells and T cells75,151,152.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [152]
The sections “Senescent cells as a source of chronic inflammation” and “Multiple roles of the SASP” say that the SASP includes chemokines and can stimulate immune clearance, including clearance by NK cells. “Chronic inflammation might propel basic aging processes” also describes senescent-cell cytokines as attractors of innate immune cells. The paper does not establish that specialized SASP chemokines attract each of the other listed subsets—neutrophils, dendritic cells, monocytes/macrophages, B cells and T cells. (LLM, conf=0.87)
Experimental — accuracy not yet measuredProlonged secretion of SASP factors, such as IL-1β and MMP, could drive cancer development.
“Therefore, prolonged secretion of SASP factors, such as interleukin (IL)‐1β and MMP, could drive cancer development.44, 45, 46”
From Cellular senescence and senescence-associated secretory phenotype via the cGAS-STING signaling pathway in cancer (2020) · cites this paper as [44]
The ‘Senescent cells as a source of chronic inflammation’ section identifies MMP-1, MMP-3 and IL-1 as secreted SASP factors and reports that senescent cells can promote the growth and invasion of malignant or premalignant cells. It does not identify IL-1β specifically or establish that its prolonged secretion drives cancer development; its discussion of IL-1α instead concerns regulation of the SASP. (LLM, conf=0.85)
Experimental — accuracy not yet measuredThe secretion of these inflammatory proteins by senescent cells is predicted to cause chronic inflammation locally and possibly systemically.
“The secretion of these and similar proteins by senescent cells is predicted to cause chronic inflammation, at least locally and possibly systemically (91–93, 107).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [93]
Many components of the senescence-associated secretory phenotype promote inflammation, either directly or indirectly.
“many SASP components directly or indirectly promote inflammation (59, 92, 93, 107, 108).”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [93]
Senescent cells, presumably via SASP-derived factors, can stimulate infiltration of leukocytes, which produce reactive toxic moieties that can cause DNA damage.
“Senescent cells, presumably by virtue of SASP-derived factors, can stimulate the infiltration of leukocytes (93, 131, 132), which produce reactive toxic moieties that can cause DNA damage.”
From Aging, Cellular Senescence, and Cancer (2013) · cites this paper as [93]
Nfkb1 (p50) and Cebpb were upregulated in a subset of cells in lineage 1-2-3-4.
“Notably, Nfkb1 (p50) and Cebpb, two well-known TF coding genes that have been reported to regulate SASP (Freund et al., 2010), were also upregulated in a subset of cells in the lineage 1-2-3-4 (Figure 4C)”
From Single-Cell Transcriptome Analysis Reveals Six Subpopulations Reflecting Distinct Cellular Fates in Senescent Mouse Embryonic Fibroblasts (2020) · cites this paper as Freund et al., 2010
Mir-146a/b comprise a negative feedback loop to dampen NF-κB activity.
“which comprise a negative feedback loop to dampen NF-κB activity (Taganov et al., 2006; Freund et al., 2010).”
From Four faces of cellular senescence (2011) · cites this paper as Freund et al., 2010
SASP components IL-6, IL-8, and MCP-1 are increased in obese adults and adolescents and could contribute to a proinflammatory state.
“Components of the SASP, such as interleukin (IL)-6, IL-8, and MCP-1, are increased in obese adults and adolescents and could contribute to such a proinflammatory state, together with effects of macrophages and other mediators of inflammation (31,53,54).”
From Cellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity (2015) · cites this paper as [31]
NF-κB dependent pro-inflammatory factors are key components of SASP with IL-6 and IL-8 being most conserved and robustly expressed cytokines.
“However, NF-κB dependent pro-inflammatory factors are the key components of SASP with IL-6 and IL-8 being the most conserved and robustly expressed cytokines (Hardy et al., 2005; Davalos et al., 2010; Freund et al., 2010; Soto-Gamez and Demaria, 2017).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Freund et al., 2010
Main components of SASP include soluble signaling factors: pro-inflammatory cytokines, chemokines, growth modulators, angiogenic factors, proteases, bioactive lipids, extracellular matrix components, and MMPs.
“The main components of SASP include a plethora of soluble signaling factors, such as, pro-inflammatory cytokines, chemokines, growth modulators, angiogenic factors, proteases, bioactive lipids, extracellular matrix components, and matrix metalloproteinases (MMPs) (Coppé et al., 2010a; Freund et al., 2010; Acosta et al., 2013; Lopes-Paciencia et al., 2019).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Freund et al., 2010
Consistent SASP elements in the majority of senescent cells are IL-1α, IL-1β, IL-6, IL-8, IL-18, and TNF-α, all of which are clinically validated CVD risk factors.
“Consistent SASP elements in the majority of senescent cells are IL-1α, IL-1β, IL-6, IL-8, IL-18, and TNF-α,15,105,110 all of which are clinically validated CVD risk factors.1,5”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [15]
Cellular senescence can be a consequence of replicative exhaustion (telomere dependent) and exposure to cardiovascular risk factors (stress-induced).
“As depicted in Figure 3, cellular senescence can be a consequence of two processes which may run in parallel and are intertwined. The first is replicative exhaustion resulting from chronological age or intense proliferation (telomere dependent)20,124,125 and the latter is exposure to cardiovascular risk factors (stress-induced).13–18”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [15]
Senescence may impact on these same pathways via positive or negative feedback loops as well as other intracellular pathways and extracellular processes, such as immune modulation, inflammation, extracellular matrix regulation, and angiogenesis.
“In turn, senescence may impact on these same pathways via positive or negative feedback loops as well as other intracellular pathways and extracellular processes, such as the immune modulation, inflammation [16], regulation, and maintenance of the extracellular matrix, and angiogenesis [17].”
From Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies (2020) · cites this paper as [16]
Senescent fibroblasts have short telomeres, high activity of the enzyme beta-galactosidase, high expression of gamma-H2Ax, constitutive activation of p53 and p38 MAPK, and the cyclin inhibitor p16.
“These cells have short telomeres, high activity of the enzyme galactosidase, show high expression of the DNA repair complex associated protein H2Ax and constitutive activation of p53 and p38 map kinase (p38 MAPK), as well the cyclin inhibitor p16 [9, 27] (Table 1).”
From Senescence of T Lymphocytes: Implications for Enhancing Human Immunity (2016) · cites this paper as [27]
Senescent cells release a set of inflammatory mediators known as the senescence-associated secretory phenotype.
“Senescent cells themselves secrete a raft of inflammatory mediators, termed the senescence associated secretory phenotype (SASP) (16).”
From The impact of ageing on monocytes and macrophages (2021) · cites this paper as [16]
Cellular senescence is thought to propagate nearby tissue aging through metabolic compromise and altered secretory factors that promote aging and sterile inflammation.
“Cellular senescence is thought to further propagate nearby tissue aging through intracellular metabolic compromise (eg, mitochondrial dysfunction) (Sahin et al, 2011) and altered production of secretory factors that promote aging by increasing degradation of nearby tissue and sterile inflammation (Coppe et al, 2010a, b;Freund et al, 2010) (ie, senescence-associated secretory phenotype, SASP).”
From Sleep health: Reciprocal regulation of sleep and innate immunity (2017) · cites this paper as Freund et al, 2010
MK2 stabilizes mRNAs and upregulates expression of many cytokines.
“It has been observed that MK2 stabilizes the mRNAs and upregulate the expression of many cytokines”
From Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism (2017) · cites this paper as Freund et al., 2010
HIV-associated inflammation and/or exposure to nucleoside analogues have been associated with changes in telomere-related and other key biologic pathways.
“HIV-associated inflammation and/or exposure to nucleoside analogues have been associated with changes in these and other key biologic pathways (33–40).”
From HIV and Aging: State of Knowledge and Areas of Critical Need for Research. A Report to the NIH Office of AIDS Research by the HIV and Aging Working Group (2012) · cites this paper as [38]
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The extracellular matrix at a glance
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Cellular senescence in ageing: from mechanisms to therapeutic opportunities
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An Essential Role for Senescent Cells in Optimal Wound Healing through Secretion of PDGF-AA
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“It remains unclear why senescent cells express a SASP given its prominent inflammatory components and mostly detrimental consequences (Freund et al., 2010).”
Self-citationFour faces of cellular senescence
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“, 2009), which are required for the expression of many SASP proteins (Fig. 3; Acosta et al., 2008; Kuilman et al., 2008; Freund et al., 2010).”
Self-citationCellular senescence and the senescent secretory phenotype: therapeutic opportunities
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Programmed cell senescence during mammalian embryonic development
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Cytoplasmic chromatin triggers inflammation in senescence and cancer
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Senescence is a developmental mechanism that contributes to embryonic growth and patterning
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Lamin B1 loss is a senescence-associated biomarker
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Self-citationChronic inflammation induces telomere dysfunction and accelerates ageing in mice
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Tissue damage and senescence provide critical signals for cellular reprogramming in vivo
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Astrocyte Senescence as a Component of Alzheimer’s Disease
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Senescent cell clearance by the immune system: Emerging therapeutic opportunities
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Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging
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p53-dependent release of Alarmin HMGB1 is a central mediator of senescent phenotypes
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Self-citationBRD4 Connects Enhancer Remodeling to Senescence Immune Surveillance
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“Conversely, senescent cells activate the expression of genes known to influence the tissue microenvironment, including matrix remodeling enzymes, growth factors, and immunemodulatory cytokines (22, 23).”
Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration
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Cellular senescence: a link between cancer and age-related degenerative disease?
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Self-citationCellular Senescence in Type 2 Diabetes: A Therapeutic Opportunity
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Tumor Microenvironment and Differential Responses to Therapy
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Source of chronic inflammation in aging
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Aging, obesity, and inflammatory age-related diseases
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Inflammaging decreases adaptive and innate immune responses in mice and humans
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Cellular senescence: putting the paradoxes in perspective
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Rapamycin inhibits the secretory phenotype of senescent cells by a Nrf2-independent mechanism
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SIRT1 protects against emphysema via FOXO3-mediated reduction of premature senescence in mice
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Mitochondrial dysfunction and cell senescence: deciphering a complex relationship
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Senescence of T Lymphocytes: Implications for Enhancing Human Immunity
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Cellular Senescence in the Kidney
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Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence
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DNA damage response and metabolic disease
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Cellular senescence and the aging brain
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Self-citationThe impact of ageing on monocytes and macrophages
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Exercise Prevents Diet-Induced Cellular Senescence in Adipose Tissue
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Immune cells and inflammation in AKI to CKD progression
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Cellular senescence and Alzheimer disease: the egg and the chicken scenario
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Immune aging, dysmetabolism, and inflammation in neurological diseases
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Epithelial-Mesenchymal Transition Induced by Senescent Fibroblasts
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Self-citationCell Senescence: Role in Aging and Age-Related Diseases
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Senescence and Cancer: A Review of Clinical Implications of Senescence and Senotherapies
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“In turn, senescence may impact on these same pathways via positive or negative feedback loops as well as other intracellular pathways and extracellular processes, such as the immune modulation, inflammation [16], regulation, and maintenance of the extracellular matrix, and angiogenesis [17].”
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Glucocorticoids suppress selected components of the senescence‐associated secretory phenotype
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Self-citationA complex systems approach to aging biology
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Cell cycle arrest is not senescence
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Immunosurveillance of senescent cells: the bright side of the senescence program
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The Cancer SENESCopedia: A delineation of cancer cell senescence
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Senescent Cardiac Fibroblast Is Critical for Cardiac Fibrosis after Myocardial Infarction
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Therapeutic interventions for aging: the case of cellular senescence
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Histone variant H2A.J accumulates in senescent cells and promotes inflammatory gene expression
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The role of cellular senescence in ageing of the placenta
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Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis
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Senescence in Wound Repair: Emerging Strategies to Target Chronic Healing Wounds
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The World Goes Bats: Living Longer and Tolerating Viruses
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- Authors
- Freund, A., Orjalo, A. V., Desprez, P.-Y., & Campisi, J.
- Affiliations
- Buck Institute for Research on Aging (US)
- Corresponding author
- Campisi, Judith
- Venue
- Trends in Molecular Medicine
- Publisher
- Elsevier BV
- Published
- 2010-05
- Volume
- 16
- Issue
- 5
- Pages
- 238-246
- ISSN
- 1471-4914 (ISSN-L)
- PMC
- PMC2879478
- OpenAlex
- W2108273756
- Semantic Scholar
- 8123cb6b710081dd80220a3cd9089f7301c783df
- Cited by
- 1,354
- References
- 78
- Citations by year
- 2026: 62 · 2025: 89 · 2024: 105 · 2023: 92 · 2022: 115 · 2021: 109 · 2020: 110 · 2019: 88 · 2018: 103 · 2017: 88 · 2016: 78 · 2015: 75 · 2014: 69 · 2013: 61 · 2012: 54
- FWCI
- 5.50
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Trends in Molecular Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Science Foundation
- Larry L. Hillblom Foundation
- National Institute for Health and Care Research
- National Institutes of Health
- National Institute on Aging (R56AG009909, AG017242, RL1AG032117, AG-09909, P01AG025901, R37AG009909, P30AG025708, AG032117, AG025708, P01AG017242, AG025901, T32AG000266)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Keywords
- cellular senescence, chronic inflammation, senescence-associated secretory phenotype, aging, age-related diseases, DNA damage response, microRNA, transcription factors, kinases, chromatin remodeling, tissue homeostasis, immune cell activation
- MeSH terms
- Animals, Humans, Inflammation, Models, Biological, Transcription Factors, Cellular Senescence, MicroRNAs
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