The senescence-associated secretome as an indicator of age and medical risk.

Marissa J Schafer,Rakesh M Suri,Russell P Tracy,Nathan K Lebrasseur,Yi Zhu,Thomas A White,Michelle Berning,Zaira Aversa,Ashley K Brown,Daniel L Mazula,Elizabeth J Atkinson,Kevin L Greason,Xu Zhang,Sarah Jachim,Brian Kotajarvi,Charles J Bruce,Steven R Cummings,Amanika Kumar

doi:10.1172/jci.insight.133668

Abstract

Produced by senescent cells, the senescence-associated secretory phenotype (SASP) is a potential driver of age-related dysfunction. We tested whether circulating concentrations of SASP proteins reflect age and medical risk in humans. We first screened senescent endothelial cells, fibroblasts, preadipocytes, epithelial cells, and myoblasts to identify candidates for human profiling. We then tested associations between circulating SASP proteins and clinical data from individuals throughout the life span and older adults undergoing surgery for prevalent but distinct age-related diseases. A community-based sample of people aged 20-90 years (retrospective cross-sectional) was studied to test associations between circulating SASP factors and chronological age. A subset of this cohort aged 60-90 years and separate cohorts of older adults undergoing surgery for severe aortic stenosis (prospective longitudinal) or ovarian cancer (prospective case-control) were studied to assess relationships between circulating concentrations of SASP proteins and biological age (determined by the accumulation of age-related health deficits) and/or postsurgical outcomes. We showed that SASP proteins were positively associated with age, frailty, and adverse postsurgery outcomes. A panel of 7 SASP factors composed of growth differentiation factor 15 (GDF15), TNF receptor superfamily member 6 (FAS), osteopontin (OPN), TNF receptor 1 (TNFR1), ACTIVIN A, chemokine (C-C motif) ligand 3 (CCL3), and IL-15 predicted adverse events markedly better than a single SASP protein or age. Our findings suggest that the circulating SASP may serve as a clinically useful candidate biomarker of age-related health and a powerful tool for interventional human studies.

Highlights

Aging is the strongest risk factor for the majority of chronic diseases
To develop a candidate panel of senescence-associated secretory phenotype (SASP) biomarkers for human application, conditioned media were collected from 5 senescent versus nonsenescent human cell types: endothelial and epithelial cells, preadipocytes, fibroblasts, and myoblasts
Preadipocytes, and fibroblasts produced a more robust SASP relative to epithelial cells and myoblasts, with distinct proteins increased per cell type (Figure 1, B and C; and Supplemental Tables 1 and 2)

Summary

Introduction

Aging is the strongest risk factor for the majority of chronic diseases. Recent scientific advances have led to the transformative hypothesis that interventions targeting the fundamental biology of aging have the potential to delay, if not prevent, the onset of age-associated conditions and extend human health span [1]. Senescent cells accumulate with advancing age [5,6,7]. Preclinical studies in rodents have established that transgenic strategies and drugs that selectively kill senescent cells improve numerous yet pathologically distinct conditions of aging, including idiopathic pulmonary fibrosis [8], cardiovascular disease [9, 10], hepatic steatosis [11], osteoporosis [12], diabetes [13], physical decline [14, 15], and brain dysfunction [16,17,18]. Reducing SASP abundance and subsequent action is a likely mechanism by which senescent cell elimination improves aging conditions [8, 10, 19, 20]. There is great interest in human translation [21]

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Conclusion