Adaptive Metabolic and Inflammatory Responses Identified Using Accelerated Aging Metrics Are Linked to Adverse Outcomes in Severe SARS-CoV-2 Infection
Alejandro Márquez‐Salinas, Carlos A. Fermín‐Martínez, Neftali Eduardo Antonio‐Villa, Arsenio Vargas‐Vázquez, Enrique C. Guerra, Alejandro Campos-Muñoz, Lilian Zavala‐Romero, Roopa Mehta, Jessica Paola Bahena-López, Edgar Ortíz‐Brizuela, María Fernanda González-Lara, Carla M. Román‐Montes, Bernardo Alfonso Martínez-Guerra, Alfredo Ponce‐de‐León, José Sifuentes‐Osornio, Luis Miguel Gutiérrez‐Robledo, Carlos A. Aguilar‐Salinas, Omar Yaxmehen Bello‐Chavolla
Abstract
BACKGROUND: Chronological age (CA) is a predictor of adverse coronavirus disease 2019 (COVID-19) outcomes; however, CA alone does not capture individual responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we evaluated the influence of aging metrics PhenoAge and PhenoAgeAccel to predict adverse COVID-19 outcomes. Furthermore, we sought to model adaptive metabolic and inflammatory responses to severe SARS-CoV-2 infection using individual PhenoAge components. METHOD: In this retrospective cohort study, we assessed cases admitted to a COVID-19 reference center in Mexico City. PhenoAge and PhenoAgeAccel were estimated using laboratory values at admission. Cox proportional hazards models were fitted to estimate risk for COVID-19 lethality and adverse outcomes (intensive care unit admission, intubation, or death). To explore reproducible patterns which model adaptive responses to SARS-CoV-2 infection, we used k-means clustering using PhenoAge components. RESULTS: We included 1068 subjects of whom 222 presented critical illness and 218 died. PhenoAge was a better predictor of adverse outcomes and lethality compared to CA and SpO2 and its predictive capacity was sustained for all age groups. Patients with responses associated to PhenoAgeAccel >0 had higher risk of death and critical illness compared to those with lower values (log-rank p < .001). Using unsupervised clustering, we identified 4 adaptive responses to SARS-CoV-2 infection: (i) inflammaging associated with CA, (ii) metabolic dysfunction associated with cardiometabolic comorbidities, (iii) unfavorable hematological response, and (iv) response associated with favorable outcomes. CONCLUSIONS: Adaptive responses related to accelerated aging metrics are linked to adverse COVID-19 outcomes and have unique and distinguishable features. PhenoAge is a better predictor of adverse outcomes compared to CA.