The senescence-associated secretome as an indicator of age and medical risk
Marissa J. Schafer, Xu Zhang, Amanika Kumar, Elizabeth J. Atkinson, Yi Zhu, Sarah Jachim, Daniel L. Mazula, Ashley K. Brown, Michelle Berning, Zaira Aversa, Brian Kotajarvi, Charles J. Bruce, Kevin L. Greason, Rakesh M. Suri, Russell P. Tracy, Steven R. Cummings, Thomas A. White, Nathan K. LeBrasseur
Marissa J. Schafer, Xu Zhang, Amanika Kumar, Elizabeth J. Atkinson, Yi Zhu, Sarah Jachim, Daniel L. Mazula, Ashley K. Brown, Michelle Berning, Zaira Aversa, Brian Kotajarvi, Charles J. Bruce, Kevin L. Greason, Rakesh M. Suri, Russell P. Tracy, Steven R. Cummings, Thomas A. White, Nathan K. LeBrasseur
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Research Article Aging

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

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.

Authors

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

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Figure 3

Circulating SASP factors are associated with increased risk of adverse postoperative outcomes.

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Circulating SASP factors are associated with increased risk of adverse p...
Levels of circulating SASP factors among older adults who underwent surgery for severe aortic stenosis and (A) experienced at least 1 adverse event (n = 42) or (B) were rehospitalized within 12 months of hospital discharge (n = 28) (black circles) were compared with counterparts who did not experience adverse outcomes (no adverse event, n = 55; no rehospitalization, n = 69) (gray circles). (C) Among older women who underwent surgery for ovarian cancer, circulating SASP factors were compared for participants who were admitted to the ICU within 30 days of surgery (n = 12) (black triangles) versus those who were not (n = 24) (gray triangles). (A–C: median ± 95% confidence interval are indicated with Kruskal-Wallis rank sum test results.) ROC AUCs indicating the adverse outcome risk discriminatory ability of a panel of 7 SASP factors (GDF15, FAS, OPN, TNFR1, ACTIVIN A, CCL3, and IL-15), a single top SASP factor (GDF15 or FAS), frailty score, or age plus sex for older adults undergoing surgery for (D and E) severe aortic stenosis or (F) age for older adults undergoing surgery for ovarian cancer. (G) All study participants in which accumulation of deficit frailty status was determined and all proteins were measured (n = 343) were clustered based on the presence of any postsurgical adverse event, frailty score, and chronological age. Six phenotypic clusters emerged: (1) nonfrail, younger, and no adverse events (n = 32); (2) nonfrail, older, and no adverse events (n = 25); (3) lower frailty score and no adverse events (n = 42); (4) intermediate frailty score and no adverse events (n = 82); (5) higher frailty score and adverse events (n = 53); (6) higher frailty score and no adverse events (n = 109). (H) Scaled concentration comparison of the 7 SASP proteins identified by GBM as associated with adverse events among the 6 clusters.