Biomarkers of cellular senescence and risk of death in humans

Abstract

A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76-0.82) than the covariates alone (0.70, CI: 0.67-0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.

Keywords: GDF15; aging; cohort study; inflammation; mortality; senescence-associated secretory phenotype (SASP).

FIGURE 1

Circulating biomarkers of cellular senescence predict mortality beyond traditional risk factors. (a) The five senescence biomarkers with the strongest associations with mortality from LASSO regression models that include age, sex, race, and presence of a chronic disease at baseline (grey shaded portion of the plot). (b) The C‐statistics indicating the ability of covariates alone, senescence biomarkers alone, and covariates plus biomarkers to predict death. *** indicates a p value <0.001 for the change in C‐statistic between the covariates model alone and the model that includes both covariates and biomarkers (training data).

FIGURE 2

Results of LASSO models run separately for men and women. Hazard ratios are presented for the top five biomarkers that were significant in overall models for men and women. (a) Senescence biomarkers associated with mortality in men in LASSO regression models including age, race, and presence of a chronic disease at baseline. (b) C‐statistics indicating the ability of covariates alone, senescence biomarkers alone, and covariates plus biomarkers to predict death in men. (c) Senescence biomarkers associated with mortality in women in LASSO regression models including age, race, and presence of a chronic disease at baseline. (d) The C‐statistics indicating the ability of covariates alone, senescence biomarkers alone, and covariates plus biomarkers to predict death in women. *** and ** denote p < 0.001 and 0.004, respectively.