MOLECULAR ATLAS OF AGING. META-GROUP 15. EXTRACELLULAR MATRIX FRAGMENTS AND DAMPs: SCAFFOLDING TURNED INTO A DISTRESS SIGNAL. INTEGRATIVE APPROACH IN THE CONTEXT OF THE THEORY OF META-ENVIRONMENTS AND META-REGULATORS

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Authors

Publication Details

Journal
Zenodo (CERN European Organization for Nuclear Research)
Published
2026-09-09
DOI
https://doi.org/10.5281/zenodo.22670736
Primary Topic
Connective tissue disorders research
Type
preprint
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preprint

MOLECULAR ATLAS OF AGING. META-GROUP 15. EXTRACELLULAR MATRIX FRAGMENTS AND DAMPs: SCAFFOLDING TURNED INTO A DISTRESS SIGNAL. INTEGRATIVE APPROACH IN THE CONTEXT OF THE THEORY OF META-ENVIRONMENTS AND META-REGULATORS

Лагода
Zenodo (CERN European Organization for Nuclear Research)
Connective tissue disorders research
preprint

MOLECULAR ATLAS OF AGING. META-GROUP 15. EXTRACELLULAR MATRIX FRAGMENTS AND DAMPs: SCAFFOLDING TURNED INTO A DISTRESS SIGNAL. INTEGRATIVE APPROACH IN THE CONTEXT OF THE THEORY OF META-ENVIRONMENTS AND META-REGULATORS

Лагода
preprint en

Abstract

Relevance. The extracellular matrix (ECM) is not just a passive scaffold, but a dynamic signaling network that maintains the shape of organs, directs cell migration, and stores growth factors. In youth, the ECM is constantly renewed through the balance between synthesis and degradation. However, with age, this balance is disrupted: synthesis slows down, and degradation accelerates. Fragments of the decay of the matrix — fragments of elastin, collagen, hyaluronic acid, and fibronectin — enter the blood and tissues. These fragments are powerful DAMPs — danger signals that the immune system recognizes as "damage". They bind to Toll-like receptors (TLR2, TLR4) and trigger an inflammatory cascade, creating a self-sustaining vicious cycle: degradation of the matrix → fragments → inflammation of the → protease → even greater degradation. Aim. To present fragments of the extracellular matrix and DAMPs as the fifteenth level of molecular aging — "saboteurs" that turn the structural support of the body into a source of chronic inflammation and systemic aging. To substantiate the need for systemic restoration of the matrix balance through the tuning of meta-regulators. Results. Serum elastin, hyaluronic acid and fibronectin fragments have been shown to be positively correlated with age. Elastin fragments, especially those containing the oligopeptide VGVAPG (E-motif), have the most potent lifespan shortening effect in mice and are positively correlated with different measures of aging in a cohort of 1068 individuals. Mechanism of action: E-motif activates monocytes and macrophages via NEU1, a component of the elastin receptor complex, inducing an inflammatory response. Long-term administration of E-motif leads to an increased proportion of lymphocytes, an effect mediated by monocytes/macrophages. NEU1 inhibitor prolongs lifespan in wild mice by 17% and attenuates aging phenotypes. VGVAPG also disrupts proteostasis and autophagy in neurons by inhibiting the SEL1L-HRD1 complex, leading to SIRT2 accumulation, ER stress, and neurodegeneration. Low molecular weight hyaluronic acid fragments (< 20 kDa) activate TLR2/4, triggering NF-κB and MAPK signaling. Low molecular weight HA fragments create a positive feedback loop that supports inflammation. Type II collagen fragments activate CD4⁺ T cells, promoting their differentiation into TH17 cells and IL-17 secretion. A multimodal approach (Quatotron technique) to physiologically restore matrix balance by stimulating synthesis, suppressing excessive degradation, and blocking pro-inflammatory signaling of fragments has been proposed. Conclusion. Extracellular matrix fragments and DAMPs are the fifteenth level of molecular aging — critical drivers that turn the structural support of the body into a source of chronic inflammation. Their systemic recovery through the control of meta-regulators opens up new opportunities for the prevention of age-associated diseases and healthy longevity.

Zenodo (CERN European Organization for Nuclear Research)
Life in Land
Connective tissue disorders research
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