Cellular senescence increases with age and contributes to age-related declines and pathologies. We identified circulating biomarkers of senescence associated with diverse clinical traits in humans to facilitate future non-invasive assessment of individual senescence burden and efficacy testing of novel senotherapeutics. Using a novel nanoparticle-based proteomic workflow, we profiled the senescence-associated secretory phenotype (SASP) in monocytes and examined these proteins in plasma samples (N = 1060) from the Baltimore Longitudinal Study of Aging (BLSA). Machine learning models trained on monocyte SASP associated with several age-related phenotypes in a test cohort, including body fat composition, blood lipids, inflammation, and mobility-related traits, among others. Notably, a subset of SASP-based predictions, including a high impact SASP panel that predicts age- and obesity-related clinical traits, were validated in InCHIANTI, an independent aging cohort. These results demonstrate the clinical relevance of the circulating SASP and identify relevant biomarkers of senescence that could inform future clinical studies.

The authors have declared no competing interest.

This work was supported by the National Institute on Aging (NIA) Intramural Research Program (IRP), NIH. N.B. was supported by a SenNet NIH Common Fund Grant (NIA U54 AG079779, PI: Elisseeff) and a Hevolution GRO grant (HF-GRO-23-1199068-44).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The BLSA protocol (03AG0325) was approved by the institutional review board of the National Institute of Environmental Health Science, part of the National Institutes of Health. The BLSA approved and provided access to the BLSA study data. InCHIANTI study (exemption #11976) protocol was approved by Medstar Research Institute (Baltimore, Maryland), the Italian National Institute of Research and Care of Aging Institutional Review, and the Internal Review Board of the National Institute for Environmental Health Sciences (NIEHS). The InCHIANTI study team approved and provided access to the InCHIANTI study data.

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Data Availability: All raw mass spectrometry data files and associated quantitative and statistical reports, metadata, and supplemental data are available on MassIVE (dataset identifier: MSV000095315). FTP download link: ftp://massive.ucsd.edu/v08/MSV000095315/. Code Availability: R scripts for the core elastic net analysis described are available at https://github.com/geroproteomics/EN_Repeat/blob/main/EN_Repeat. Other data are available upon reasonable request to the authors.

ftp://massive.ucsd.edu/v08/MSV000095315/

https://github.com/geroproteomics/EN_Repeat/blob/main/EN_Repeat.