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<p>Plasma circulating cell-free nucleic acids (ccfNAs) have emerged as promising non-invasive biomarkers of aging. While age-associated changes have been reported, data in relation to extreme aging and longevity remain scarce. Here, we assessed ccfNA levels and integrity, and ccfDNA methylation in a cohort of 86 individuals, analyzed both overall and stratified by sex, including nonagenarians (NON: 90–98&#xa0;years, <i>n</i> = 29), centenarians (CEN: 100–109&#xa0;years, <i>n</i> = 28), and a middle-aged control group (CG: 38–67&#xa0;years, <i>n</i> = 29) of nonagenarians’ and centenarians’ offspring, using our previously optimized multiparametric analysis workflow targeting nuclear (ccfnDNA) and mitochondrial (ccfmtDNA) DNA, ribosomal RNA (ccfrRNA), messenger RNA (ccfmRNA), and microRNAs (ccfmiRNAs). ccfnDNA levels followed non-linear trajectories, decreasing from CG to nonagenarians (28%–64.5%, significant in nonagenarian men compared to CG), then slightly increasing in centenarians. ccfmRNA and ccfmtDNA followed the opposite pattern, with significantly lower ccfmRNA levels in centenarians (44.5%), and both were strongly correlated (<i>r</i> = 0.59–0.83, <i>p</i> &lt; 0.0001), suggesting a shared regulatory mechanism. Additionally, ccfnDNA integrity significantly decreased from CG to CEN (20.7%), while ccfmtDNA and ccfrRNA integrities, and ccfDNA methylation, did not vary. Among the seven ccfmiRNAs analyzed, <i>miR-93-5p</i>, <i>miR-126-3p</i>, and liver-specific <i>miR-122-5p</i>, exhibited significant age-related decreases (40.5%–70.3%), reaching their lowest levels in centenarians. Our study thereby provides novel findings regarding age- and sex- related changes in ccfNAs, highlighting both dynamic and stable characteristics linked to longevity. It identified potential ccfNA-based longevity biomarkers, and supports ccfmiRNAs as the most promising and sensitive biomarkers of longevity.</p>

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Multiparametric profiling of plasma cell-free nucleic acids in nonagenarians and centenarians highlights age-related differences associated with longevity

  • 期刊论文

  • 发表日期：

    2025年11月29日

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  • Nicolas P. Tessier,
  • Lise M. Hardy,
  • Florence Mauger,
  • Antoine Daunay,
  • Christian Daviaud,
  • Caroline Horgues,
  • Hélène Blanché,
  • Mourad Sahbatou,
  • Jean-François Deleuze,
  • Alexandre How-Kit

摘要

Plasma circulating cell-free nucleic acids (ccfNAs) have emerged as promising non-invasive biomarkers of aging. While age-associated changes have been reported, data in relation to extreme aging and longevity remain scarce. Here, we assessed ccfNA levels and integrity, and ccfDNA methylation in a cohort of 86 individuals, analyzed both overall and stratified by sex, including nonagenarians (NON: 90–98 years, n = 29), centenarians (CEN: 100–109 years, n = 28), and a middle-aged control group (CG: 38–67 years, n = 29) of nonagenarians’ and centenarians’ offspring, using our previously optimized multiparametric analysis workflow targeting nuclear (ccfnDNA) and mitochondrial (ccfmtDNA) DNA, ribosomal RNA (ccfrRNA), messenger RNA (ccfmRNA), and microRNAs (ccfmiRNAs). ccfnDNA levels followed non-linear trajectories, decreasing from CG to nonagenarians (28%–64.5%, significant in nonagenarian men compared to CG), then slightly increasing in centenarians. ccfmRNA and ccfmtDNA followed the opposite pattern, with significantly lower ccfmRNA levels in centenarians (44.5%), and both were strongly correlated (r = 0.59–0.83, p < 0.0001), suggesting a shared regulatory mechanism. Additionally, ccfnDNA integrity significantly decreased from CG to CEN (20.7%), while ccfmtDNA and ccfrRNA integrities, and ccfDNA methylation, did not vary. Among the seven ccfmiRNAs analyzed, miR-93-5p, miR-126-3p, and liver-specific miR-122-5p, exhibited significant age-related decreases (40.5%–70.3%), reaching their lowest levels in centenarians. Our study thereby provides novel findings regarding age- and sex- related changes in ccfNAs, highlighting both dynamic and stable characteristics linked to longevity. It identified potential ccfNA-based longevity biomarkers, and supports ccfmiRNAs as the most promising and sensitive biomarkers of longevity.