What makes some people live to 100 and beyond? This is one of the oldest and hardest questions in medical science. A new study analyzing the blood proteomics of 517 centenarians from 5 European countries identified 5 proteins that differ significantly from those of people who lived to 75-80. The study was published in Nature Aging on February 22, 2026.
Lead researcher is Prof. Claudio Franceschi, a pioneering gerontologist at the University of Bologna who coined the term inflammaging — the slow-burning inflammation that accompanies aging. His team collaborated with researchers at Karolinska Institutet in Stockholm, the Medical University of Vienna, and Albert Einstein College of Medicine in New York.
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How 517 Centenarians Were Found
The researchers collected blood samples from three groups:
— 517 centenarians (aged 100–113), aging naturally
— 417 nonagenarians (aged 90–99) as elderly controls
— 200 younger adults aged 75–80 for broader comparison
Each sample was analyzed using the Olink Proximity Extension Assay — an exceptionally sensitive proteomics platform that simultaneously measures 1,463 proteins at femtogram-per-mL precision. Researchers applied comparative genomics models, correcting for confounders including age class and kidney function.
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The 5 Proteins That Mark Extreme Longevity
In the blood of centenarians, the research team identified 5 key proteins:
1. PCSK9 — lower than in peers in their 70s–80s. This protein regulates LDL receptors in the liver. Lower PCSK9 means more receptors actively clearing LDL cholesterol — protecting cardiovascular health at extreme age.
2. GDF15 — lower. Growth Differentiation Factor 15 is a marker of inflammation and metabolic stress. In normally aging individuals it typically rises sharply. Centenarians had GDF15 levels lower than expected for their age, signaling better mitochondrial stress management.
3. VEGFD — higher. Vascular Endothelial Growth Factor D (a subtype of VEGF) is associated with vascular remodeling and lymphatic circulation. In centenarians it was elevated, indicating better vascular flexibility even at extreme age.
4. Cystatin C — lower. A marker of kidney filtration efficiency. Lower Cystatin C confirms better kidney function — the kidneys of centenarians continue to work exceptionally well.
5. TNFR1 — lower. The Tumor Necrosis Factor receptor 1 is a marker of chronic inflammation. Lower TNFR1 in centenarians confirms that their inflammatory systems remain controlled even at age 100+. This directly counters the inflammaging phenomenon.
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“Resilient Aging” — A New Theory of Life
The finding is significant: centenarians are not simply better preserved. They show active signs of biological resilience — new RNA and proteins that typically appear only in younger cells. Franceschi calls this the aging hacker phenotype.
“They do not age slowly because they don’t decay — they age slowly because their bodies keep working efficiently,” says Franceschi. “These 5 proteins represent a biological language of resilience that is particularly effective.”
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What This Means for Future Medicine
The 5 proteins are not just aging markers — they are potential therapeutic targets. PCSK9 is already blocked by approved drugs (evolocumab, alirocumab). TNFR1 is a candidate target for new anti-aging therapy. VEGFD could lead to vascular regeneration therapies in aging patients.
“Centenarians are the best final analysis of aging because they succeeded doubly: they lived long and lived well,” says Nir Barzilai, a senior gerontology researcher at Albert Einstein College of Medicine and co-investigator. “These 5 proteins tell us what wins the biological lottery of longevity.”
The researchers are now designing an interventional study with anti-TNFR1 biologics in animal models, while establishing a diagnostic validation panel using the 5 proteins as decade-of-life biomarkers — a POSEIDON-LONGEVITY study involving 15 European centers.
The research was funded by Horizon Europe (HEALTHY LONGEVITY), the Swedish Research Council, and NIH NIA R01 AG073786. Full datasets are available via the European Proteomics Archive.