Deep and quantitative proteomic profiling of low-volume mouse serum in a cross-sectional analysis of aging.

Amit K Dey, Bradley Olinger, Mozhgan Boroumand, Maria Emilia Fernandez, Simonetta Camandola, Nathan L Price, Rafael de Cabo, Nathan Basisty

Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA.Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD, USA. · pubmed

Paper

Abstract

Assessing and validating circulating biomarkers is essential for developing preclinical measures of biological aging in mice. However, comprehensive serum proteomics are limited by technical challenges and low sample volumes. Here we present a quantitative nanoparticle-based enrichment workflow coupled with data-independent acquisition mass spectrometry for deep proteomic profiling of low-volume mouse serum. This approach increased proteomic coverage by 3-6-fold with median coefficient of variation <10%. In 30 mice aged 12, 24 and 30 months, we uncovered 3,992 protein groups from 20 µl of serum and revealed age- and sex-specific changes, and capturing senescence-associated circulating proteins. With 1 µl additional serum,the proximity extension assay quantified 43 cytokines not detected by mass spectrometry. Comparison with plasma proteomics from the Baltimore Longitudinal Study of Aging identified conserved age-associated circulating proteins, several of which were linked to frailty in humans, notably COL6A3. These results establish a scalable approach for discovering aging biomarkers in sample-limited mouse studies with translational relevance to human health.

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Research summary

The paper demonstrates that a nanoparticle-based enrichment workflow coupled with data-independent acquisition mass spectrometry can achieve deep proteomic profiling of low-volume mouse serum, identifying age- and sex-specific changes and conserved human aging biomarkers. This is relevant because it provides a scalable, high-sensitivity technical method for discovering circulating biomarkers of biological aging in preclinical models, which is essential for validating interventions that target the root causes of aging, although the study itself is primarily methodological and cross-sectional rather than demonstrating a lifespan-extending intervention.

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