Yi and colleagues demonstrate that age-induced degradation of extracellular matrix generates elastin-derived fragments that activate the innate and adaptive immune system, which evokes systemic inflammaging.
A new Nature Aging study reports that fragments of elastin—the long-lived structural protein critical for arterial elasticity, lung compliance, and skin integrity—are not passive signs of tissue deterioration but active pro-aging signals. These elastin-derived peptides, or “elastokines,” increase with age and trigger a coordinated inflammatory cascade that accelerates metabolic decline, immune dysregulation, and multi-organ aging. Crucially, the paper also identifies a druggable node in this pathway: NEU1, an enzyme in the elastin receptor complex whose inhibition by the small molecule DANA extends lifespan when administered late in life.
The researchers found that circulating elastin fragments rise steadily in mice and humans across adulthood. To test causality, healthy mice were infused with elastin-derived peptides, including the key hexapeptide VGVAPG (“E-motif”). These peptides were sufficient to induce canonical aging phenotypes: increased fat mass, decreased lean mass, elevated IL-1 and IL-6, impaired physical function, and shortened lifespan. This establishes that elastin fragmentation is not merely correlated with aging but capable of driving systemic decline.
Mechanistic analysis showed that the fragments are sensed by monocytes and macrophages via a NEU1-containing elastin receptor complex. Activation of this pathway reprograms the innate immune system, which then reshapes adaptive immunity. Single-cell transcriptomics revealed expansion of IFN-γ–producing Th1 cells, cytotoxic-like CD4 T cells, and inflammatory CD8 subsets typical of “inflammaging.” Transferring these reprogrammed T cells into immunodeficient mice propagated the inflammatory-metabolic dysfunction, demonstrating that the immune system becomes a vector of elastin-fragment–induced aging.
The most notable translational finding comes from blocking NEU1. Administration of the neuraminidase inhibitor DANA in mice exposed to elastin fragments normalized inflammatory cytokines, restored metabolic parameters, reduced liver and kidney stress markers, and improved tissue histology. The intervention was then applied to naturally aging mice, starting in late life (around 60–65 weeks). Weekly DANA injections produced a significant extension of median lifespan—approximately 17% in males and 12% in females—along with measurable improvements in grip strength, endurance, locomotion, body composition, and reductions in p16-linked cellular senescence. These effects occurred without dietary manipulation and were observed in otherwise healthy wild-type animals, underscoring the therapeutic relevance of blocking this extracellular-matrix-to-immune signaling axis.
A combination arm pairing DANA with rapamycin demonstrated even greater survival benefits than either treatment alone. The synergy suggests that mitigating extracellular-matrix–derived inflammatory signaling (via NEU1 inhibition) and suppressing nutrient-sensing pathways (via mTOR modulation) act through complementary mechanisms and may represent a next-generation, multi-target longevity strategy.
Complementary experiments showed that senescent cells are major generators of elastin fragments through elevated elastase activity. Treating old mice with the senolytics dasatinib plus quercetin reduced circulating elastin fragments, reinforcing the view that senescence and ECM degradation are tightly coupled upstream drivers of age-related inflammation.
Human cross-sectional data from over 1,000 adults revealed that higher elastin fragments correlate with worse metabolic, renal, and cardiovascular markers and higher blood pressure at all ages. While observational, these patterns align with the mechanistic mouse data and suggest that elastin fragments may serve as biomarkers of biological aging.
Longevity Implications
This research identifies a previously underappreciated axis of systemic aging: elastin fragmentation → NEU1 activation → myeloid inflammation → T-cell remodeling → metabolic and organ decline. Protecting elastin integrity—through smoking avoidance, air-quality protection, tight blood-pressure control, metabolic optimization, periodontal care, structured exercise, and UV avoidance—may reduce upstream elastase activity. The late-life lifespan extension achieved through NEU1 inhibition is especially notable: it positions the extracellular matrix as a viable, druggable longevity target, potentially synergistic with established pathways such as mTOR and senescent-cell clearance.
Source Research Paper (Open Access): Elastin-derived extracellular matrix fragments drive aging through innate immune activation
