Biomarkers of cellular senescence in idiopathic pulmonary fibrosis

Abstract

Background Cellular senescence is a cell fate in response to diverse forms of age-related damage and stress that has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The associations between circulating levels of candidate senescence biomarkers and disease outcomes have not been specifically studied in IPF. In this study we assessed the circulating levels of candidate senescence biomarkers in individuals affected by IPF and controls and evaluated their ability to predict disease outcomes. Methods We measured the plasma concentrations of 32 proteins associated with senescence in Lung Tissue Research Consortium participants and studied their relationship with the diagnosis of IPF, parameters of pulmonary and physical function, health-related quality of life, mortality, and lung tissue expression of P16, a prototypical marker of cellular senescence. A machine learning approach was used to evaluate the ability of combinatorial biomarker signatures to predict disease outcomes. Results The circulating levels of several senescence biomarkers were significantly elevated in persons affected by IPF compared to controls. A subset of biomarkers accurately classified participants as having or not having the disease and was significantly correlated with measures of pulmonary function, health-related quality of life and, to an extent, physical function. An exploratory analysis revealed senescence biomarkers were also associated with mortality in IPF participants. Finally, the plasma concentrations of several biomarkers were associated with their expression levels in lung tissue as well as the expression of P16. Conclusions Our results suggest that circulating levels of candidate senescence biomarkers are informative of disease status, pulmonary and physical function, and health-related quality of life. Additional studies are needed to validate the combinatorial biomarkers signatures that emerged using a machine learning approach.

Calorie restriction reduces biomarkers of cellular senescence in humans

“…Results from this study are complementary to previous analy- and with clinical measures of biological age and functional limitations (Aversa et al, 2023;Fielding et al, 2022;Schafer et al, 2020;Tanaka et al, 2018Tanaka et al, , 2020 were quantifiable in their plasma and were, at least in part, longitudinally reduced by the CR intervention.…”

“…Unfortunately, none of the SASP components studied to date is unique to senescent cells and, certainly, the secretome of other cell types may be affected by CR. We note, however, that the circulating biomarkers assessed in this study were based on an expanded panel of biologically diverse senescence‐related proteins we previously developed by reviewing the literature, screening their abundance in in vitro models of senescence, and demonstrating detectability in human blood in contexts associated with increased senescent cell burden (Aversa et al., 2023 ; Fielding et al., 2022 ; Schafer et al., 2020 ). In addition, our in silico analysis of an RNA sequencing data set derived from the adipose tissue specimens of a small subset of CALERIE™ participants randomized to CR (Spadaro et al., 2022 ) demonstrated a significant reduction in the SenMayo gene set at both 12 and 24 months compared to baseline.…”

“…Results from this study are complementary to previous analyses of the CALERIE™ study and further highlight the potential of nutritional interventions to counter biological aging. Participants in the CALERIE™ study were healthy, young to middle‐aged individuals of normal weight to moderately overweight, yet several senescence‐related proteins previously associated with chronological age and with clinical measures of biological age and functional limitations (Aversa et al., 2023 ; Fielding et al., 2022 ; Schafer et al., 2020 ; Tanaka et al., 2018 , 2020 ) were quantifiable in their plasma and were, at least in part, longitudinally reduced by the CR intervention. For example, PARC, TARC, TNFR1, TNFR2, and VEGF were reduced by the CR intervention and exhibited positive associations with chronological age in at least two of three prior studies in which they were examined (Schafer et al., 2020 ; Tanaka et al., 2018 , 2020 ).…”

“…To gain new insights, we studied plasma samples obtained at different timepoints from CALERIE™ phase 2 trial participants to test the hypothesis that CR would lower the circulating levels of candidate senescence biomarkers to a great extent than an AL diet. Although not unique to senescent cells, the biomarker panel used here represents the diversity of cytokines, chemokines, matrix remodeling proteins, and growth factors robustly secreted by several human cell types when driven to senesce in vitro and shown to be detectable and increase in the blood of humans with advanced chronological age or clinical evidence of advanced biological age (e.g., frailty or functional decline), consistent with an increase in senescent cell burden (Aversa et al., 2023 ; Basisty et al., 2020 ; Fielding et al., 2022 ; Schafer et al., 2020 ; Tanaka et al., 2018 , 2020 ). Moreover, most of the measured biomarkers are represented in senescence‐focused gene sets (Coppé et al., 2010 ; Saul et al., 2022 ) and/or their circulating concentrations are elevated in mouse models with high senescent cell burden (Englund et al., 2023 ; Yousefzadeh et al., 2020 ).…”

Hungry for biomarkers of aging

“…As an example, we exploited the literature and the secretome of several human cell types induced to senescence in vitro to develop a candidate panel of senescence biomarkers, comprised of cytokines, chemokines, matrix remodeling proteins, growth factors, and other proteins, that could be reliably measured in the blood of humans (Schafer et al., 2020 ). We have observed expected changes in their circulating abundance in conditions associated with increased senescent cell burden, including advanced chronological age, frailty, disability, and chronic disease (Aversa, Atkinson, et al., 2023 ; Fielding et al., 2023 ; Schafer et al., 2020 ). Most recently, we studied biospecimens and clinical data from the Comprehensive Assessment of Long‐term Effects of Reducing Intake of Energy (CALERIE™) study and demonstrated that participants randomized to 2 years of calorie restriction had reduced concentrations of senescence biomarkers at Year 1 and Year 2 compared to those randomized to an ad libitum diet (Aversa, White, et al., 2023 ).…”