DAMPs, ageing, and cancer: The ‘DAMP Hypothesis’
Open accessAbstract
Ageing is a complex and multifactorial process characterized by the accumulation of many forms of damage at the molecular, cellular, and tissue level with advancing age. Ageing increases the risk of the onset of chronic inflammation-associated diseases such as cancer, diabetes, stroke, and neurodegenerative disease. In particular, ageing and cancer share some common origins and hallmarks such as genomic instability, epigenetic alteration, aberrant telomeres, inflammation and immune injury, reprogrammed metabolism, and degradation system impairment (including within the ubiquitin-proteasome system and the autophagic machinery). Recent advances indicate that damage-associated molecular pattern molecules (DAMPs) such as high mobility group box 1, histones, S100, and heat shock proteins play location-dependent roles inside and outside the cell. These provide interaction platforms at molecular levels linked to common hallmarks of ageing and cancer. They can act as inducers, sensors, and mediators of stress through individual plasma membrane receptors, intracellular recognition receptors (e.g., advanced glycosylation end product-specific receptors, AIM2-like receptors, RIG-I-like receptors, and NOD1-like receptors, and toll-like receptors), or following endocytic uptake. Thus, the DAMP Hypothesis is novel and complements other theories that explain the features of ageing. DAMPs represent ideal biomarkers of ageing and provide an attractive target for interventions in ageing and age-associated diseases.
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HMGB1 acts mainly as an alarmin released outside the cell to induce SASP-mediated paracrine senescence and alert the immune system.
“HMGB1 functions mainly as one of the damage-associated molecular patterns, also known as alarmins109, that are released extracellularly to induce SASP-mediated paracrine senescence and alert the immune system110.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [109]
Section 4.1 (HMGB1; page unavailable) identifies HMGB1 as a DAMP and says extracellular HMGB1 can mediate inflammatory and immune responses, including senescence-associated inflammation. It does not say HMGB1 induces SASP-mediated paracrine senescence. The section also describes substantial nuclear functions, so it does not establish that HMGB1 acts mainly as an extracellular alarmin. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe aging BM microenvironment is composed of increasing amounts of damage-associated molecular patterns.
“Furthermore, the aging BM microenvironment is composed of increasing amounts of damageassociated molecular patterns.69”
From Inflammatory bone marrow microenvironment (2019) · cites this paper as [69]
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- [145]Tang D PAMPs and DAMPs: Signal 0’s that Spur Autophagy and Immunity Immunol Rev 2012 PMC3662247 22889221
- [185]Polanska E HMGB1 gene knockout in mouse embryonic fibroblasts results in reduced telomerase activity and telomere dysfunction Chromosoma 2012 121 4 419 31 22544226
- [189]Livesey KM p53/HMGB1 complexes regulate autophagy and apoptosis Cancer Res 2012 72 8 1996 2005 22345153 PMC3417120
- [198]Kang R The HMGB1/RAGE inflammatory pathway promotes pancreatic tumor growth by regulating mitochondrial bioenergetics Oncogene 2013 PMC3795800 23318458
- [218]Chen R Release and activity of histone in diseases Cell death & disease 2014 5 e1370 25118930 PMC4454312
Cited by
Sorted by citations
Cellular senescence in ageing: from mechanisms to therapeutic opportunities
Di Micco, R., Krizhanovsky, V., Baker, D., & d’Adda di Fagagna, F. (2021) · Nature Reviews Molecular Cell Biology · doi:10.1038/s41580-020-00314-w · Cited by 2,277 · see citing works
A proteomic atlas of senescence-associated secretomes for aging biomarker development
Basisty, N., Kale, A., Jeon, O. H., Kuehnemann, C., Payne, T., Rao, C., Holtz, A., Shah, S., Sharma, V., Ferrucci, L., et al. (2020) · PLOS Biology · doi:10.1371/journal.pbio.3000599 · Cited by 1,348 · see citing works
The senescence-associated secretory phenotype and its regulation
Lopes-Paciencia, S., Saint-Germain, E., Rowell, M.-C., Ruiz, A. F., Kalegari, P., & Ferbeyre, G. (2019) · Cytokine · doi:10.1016/j.cyto.2019.01.013 · Cited by 601 · see citing works
The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis
Desai, O., Winkler, J., Minasyan, M., & Herzog, E. L. (2018) · Frontiers in Medicine · doi:10.3389/fmed.2018.00043 · Cited by 314 · see citing works
Danger signals in stroke and their role on microglia activation after ischemia
Gülke, E., Gelderblom, M., & Magnus, T. (2018) · Therapeutic Advances in Neurological Disorders · doi:10.1177/1756286418774254 · Cited by 321 · see citing works
Proteomic Insight into the Molecular Function of the Vitreous
Skeie, J. M., Roybal, C. N., & Mahajan, V. B. (2015) · PLOS ONE · doi:10.1371/journal.pone.0127567 · Cited by 93 · see citing works
Inflammatory bone marrow microenvironment
Leimkühler, N. B., & Schneider, R. K. (2019) · Hematology · doi:10.1182/hematology.2019000045 · Cited by 82 · see citing works
Alarmins in chronic noncommunicable diseases: Atherosclerosis, diabetes and cancer
Boteanu, R. M., Suica, V. I., Uyy, E., Ivan, L., Dima, S. O., Popescu, I., Simionescu, M., & Antohe, F. (2017) · Journal of Proteomics · doi:10.1016/j.jprot.2016.11.006 · Cited by 38 · see citing works
Implications of inflammatory states on dysfunctional immune responses in aging and obesity
Thomas, A. L., Alarcon, P. C., Divanovic, S., Chougnet, C. A., Hildeman, D. A., & Moreno-Fernandez, M. E. (2021) · Frontiers in Aging · doi:10.3389/fragi.2021.732414 · Cited by 35 · see citing works
- Authors
- Huang, J., Xie, Y., Sun, X., Zeh, H. J., Kang, R., Lotze, M. T., & Tang, D.
- Affiliations
- Central South University (CN)
- Third Affiliated Hospital of Guangzhou Medical University (CN)
- University of Pittsburgh (US)
- Corresponding author
- Tang, Daolin
- Venue
- Ageing Research Reviews
- Publisher
- Elsevier BV
- Published
- 2015-11
- Volume
- 24
- Issue
- Pt A
- Pages
- 3-16
- ISSN
- 1568-1637 (ISSN-L)
- PMC
- PMC4416066
- OpenAlex
- W2081732708
- Cited by
- 144
- References
- 303
- Citations by year
- 2026: 9 · 2025: 8 · 2024: 12 · 2023: 8 · 2022: 16 · 2021: 19 · 2020: 19 · 2019: 18 · 2018: 9 · 2017: 5 · 2016: 11 · 2015: 10
- FWCI
- 1.10
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Ageing Research Reviews (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- UPCI (P30CA047904)
- National Institutes of Health (R01 CA160417, R01 CA181450)
- Pancreatic Cancer Action Network-AACR Career Development Award (13-20-25-TANG)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- aging, cancer, chronic inflammation, genomic instability, epigenetic modifications, telomeres, ubiquitin-proteasome system, autophagy, HMGB1, S-100 protein, heat shock proteins, AIM2-like receptors, RIG-I-like receptors, Toll-like receptors, endocytic uptake, aging biomarkers, age-related diseases
- MeSH terms
- Aging, Animals, Humans, Neoplasms, Receptors, Pattern Recognition
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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