Development of Sensitive and Specific Proteomic Biomarkers of Aging, Health, Frailty, and Morbidity in Human and Mouse Cohorts

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

To overcome the technical challenges associated with plasma proteomics, we developed workflows that utilize nanoparticle-based enrichment coupled with MS enabled comprehensive characterization of plasma and serum samples with high dynamic range. the secretome from senescent monocytes in culture in serum-supplemented culture conditions. Our results highlight a novel approach to study the cellular secretome under physiological conditions and the most comprehensive approach for proteomic analysis in mouse serum to date. To further our human research program goals, our efforts leveraged two longitudinal aging cohort studies, the Baltimore Longitudinal Study on Aging (BLSA) and InCHIANTI. Building on our previous efforts to develop senescence biomarker signatures in humans, we showed that monocyte SASP factors are highly associated with aging-associated clinical phenotypes, particularly mobility and obesity-associated clinical phenotypes. This study identifies possible biomarkers of senescence that could inform future senotherapeutic trials in obese and aged individuals. In ongoing work in humans, we are developing tissue-specific senescence biomarker signatures that associate with tissue-specific health parameters. In the mouse studies, we applied our novel proteomic workflow at scale in the Study of Longitudinal Aging in Mice - a large longitudinal mouse aging study. We identified the most comprehensive plasma proteomic signatures of mouse aging to date, identifying key proteins and pathways associated with aging, and the effects of covariates such as genetic background and sex. Additionally, we developed the first blood-based proteomic aging clock in mice, both longitudinal and cross-sectional. In ongoing work, we are identifying circulating proteins associated with a swath of aging phenotypes, such as frailty, mortality, multimorbidity, and senescence burden, among many others. We hypothesize that developing proteomic and multi-omic models from longitudinally collected serum across aging will enable the prediction of aging outcomes and senescence burdens in tissues. Additionally, we hypothesize that, when refined with longitudinal data collection in mice given effective aging interventions, these models can predict the outcomes of aging intervention trials. Finally, in both the mouse and human research programs, we have performed large-scale proteomic studies in the context of known aging interventions. In humans, we are leveraging the CALERIE study to identify the effects of Calorie Restriction, a well known aging intervention, on biological age and aging phenotypes in humans. In mice, we are conducting a novel intervention study that utilize two robust aging interventions: calorie restriction and rapamycin to achieve similar goals. Importantly, these intervention studies will enable us to identify 'intervention-responsive' biomarker signatures, which are critically important for conducting clinical trials that will facilitate the translation of aging-interventions into humans.