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Elastin-derived extracellular matrix fragments drive aging through innate immune activation
Junzhi Yi1,2, Yixuan Wang1,2, Hairu Sui1,2
1Department of Sports Medicine of the Second Affiliated Hospital and Liangzhu Laboratory, Zhejiang University School of Medicine, Hangzhou, China.
Nature Aging
|September 30, 2025
Summary
Degraded extracellular matrix fragments, particularly from elastin, drive aging by activating immune cells and causing inflammation. Inhibiting NEU1 significantly extends lifespan and improves aging phenotypes in mice and pigs.
Area of Science:
- Biogerontology
- Immunology
- Extracellular Matrix Biology
Background:
- Cellular roles in aging are well-studied, but the extracellular matrix (ECM) and its degradation's impact on aging remain largely unexplored.
- Systemic aging involves complex molecular and cellular changes, with potential contributions from circulating factors.
- The aging process is associated with altered tissue composition and function, including changes in the ECM.
Purpose of the Study:
- To investigate the role of extracellular matrix fragments in systemic aging.
- To identify specific ECM-derived fragments that correlate with age and influence lifespan.
- To elucidate the molecular mechanisms by which ECM fragments affect aging and to explore therapeutic interventions.
Main Methods:
- Serum analysis of age-correlated fragments from elastin, hyaluronic acid, and fibronectin.
- Lifespan studies in mice exposed to elastin-derived fragments.
- Human cohort study correlating fragment levels with aging indicators (n=1,068).
- Mechanistic studies involving NEU1 (neuraminidase 1) and monocyte/macrophage activation.
- Therapeutic intervention using a NEU1 inhibitor in aged mice, immune-humanized mice, and pigs.
Main Results:
- Serum levels of elastin-, hyaluronic acid-, and fibronectin-derived fragments increase with age.
- Elastin-derived fragments showed the strongest lifespan-shortening effects in mice and correlated with aging indicators in humans.
- The VGVAPG oligopeptide (E-motif) from elastin fragments activates monocytes/macrophages via NEU1, inducing inflammation.
- NEU1 inhibition extended lifespan by up to 17% in aged mice and ameliorated aging phenotypes across species.
Conclusions:
- Degraded extracellular matrix fragments, especially elastin fragments, act as circulating drivers of aging.
- The NEU1-mediated inflammatory pathway activated by elastin fragments is a key mechanism in aging.
- Targeting NEU1 represents a promising therapeutic strategy for combating aging and age-related diseases.
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