DAMPs, ageing, and cancer: The ‘DAMP Hypothesis’

Abstract

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.

Damage-associated molecular patterns and their pathological relevance in diabetes mellitus

“…Under normal conditions in healthy living cells, these endogenous molecules are sequestered from the immune system to prevent pathological inflammation and autoimmunity (Chen and Nuñez, 2010;Kono and Rock, 2008;Seong and Matzinger, 2004). DAMPs play an important role in normal cell homeostasis (Huang et al, 2014;Kono and Rock, 2008;Rosin and Okusa, 2011). For example, HMGB1, an abundant DNA-binding protein in all mammalian nuclei, facilitates the assembly of recombination and transcriptional complexes at the minor groove of DNA, thereby contributing to recombination and transcriptional activation (Thomas and Travers, 2001).…”

“…Accumulating evidence indicates that DAMPs and their receptors provide a molecular link between diabetes and ageing by mediating sterile inflammation. As in diabetes, aberrant expression and release of DAMPs have been reported in ageing (Huang et al, 2014). In the healthy condition, DAMPs usually play an important Page 26 of 45 A c c e p t e d M a n u s c r i p t 26 role in sustaining normal cellular homeostasis (Huang et al, 2014;Kono and Rock, 2008;Rosin and Okusa, 2011).…”

“…As in diabetes, aberrant expression and release of DAMPs have been reported in ageing (Huang et al, 2014). In the healthy condition, DAMPs usually play an important Page 26 of 45 A c c e p t e d M a n u s c r i p t 26 role in sustaining normal cellular homeostasis (Huang et al, 2014;Kono and Rock, 2008;Rosin and Okusa, 2011). However, the release of DAMPs into the extracellular environment from damaged or dying cells after cellular stress or injury ultimately induces excessive sterile inflammation, likely leading to a functional decline in multiple organs and in turn promoting the ageing process.…”

“…Therefore, ageing is a significant risk factor for multiple chronic inflammation-associated diseases, especially diabetes (Huang et al, 2014). Accumulating evidence indicates that DAMPs and their receptors provide a molecular link between diabetes and ageing by mediating sterile inflammation.…”

“…Ageing is associated with the accumulation of damage at the cellular and tissue levels, followed by low-grade chronic inflammation (sterile inflammation) in multiple organs that leads to functional decline with advancing age (Huang et al, 2014). Therefore, ageing is a significant risk factor for multiple chronic inflammation-associated diseases, especially diabetes (Huang et al, 2014).…”