Leeuwenburgh, Christiaan

Abstract Studies in mice and cross-sectional studies in humans support the premise that cellular senescence is a contributing mechanism to age-associated deficits in physical function. We tested the hypotheses that circulating proteins secreted by senescent cells are (i) associated with the incidence of major mobility disability (MMD), the development of persistent mobility disability (PMMD), and decrements in physical functioning in older adults, and (ii) influenced by physical activity (PA). Using samples and data obtained longitudinally from the Lifestyle Interventions in Elders Study clinical trial, we measured a panel of 27 proteins secreted by senescent cells. Among 1 377 women and men randomized to either a structured PA intervention or a healthy aging (HA) intervention, we observed significant associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and matrix metallopeptidase 7 (MMP7), and the onset of both MMD and PMMD. Moreover, VEGFA, GDF15, osteopontin, and other senescence biomarkers were associated with reductions in short physical performance battery scores. The change in senescence biomarkers did not differ between PA and HA participants. In the whole cohort, higher levels of PA were associated with significantly greater reductions in 10 senescence-related proteins at 12 and/or 24 months. These data reinforce cellular senescence as a contributing mechanism of age-associated functional decline and the potential for PA to attenuate this hallmark of aging. Clinical Trials Registration Number: NCT01072500

ABSTRACT Background: High density lipoprotein (HDL) can be readily oxidized in inflammatory conditions and exhibit pro-inflammatory and dysfunctional (Dys-HDL) characteristics. We hypothesize that Dys-HDL may predict adverse outcomes and correlate with inflammatory cytokines in sepsis. Methods: Emergency department (ED) patients with sepsis were enrolled. Blood was drawn at enrollment and after 48 h. Dys-HDL, expressed as HDL inflammatory index (HII), and cytokines were measured. Multivariable logistic regression was used to determine the predictive ability of Dys-HDL for adverse outcomes (death, discharge to hospice, or nursing home). Results: Thirty-five patients were included in the study. HII was not significantly different at baseline or 48 h between patients with adverse outcomes versus those without. However, there was a significant difference in change in HII over the first 48 h between those with adverse outcomes (+0.21, 95% CI −0.13 to 0.31) versus those without (−0.11, 95% CI −1 to 0.11) (P = 0.025). Logistic regression revealed increasing HII to be an independent predictor of adverse outcomes (OR 5.2, 95% CI 1.1–25.1 P = 0.040). Of the 24 patents with cytokine measurements at both time points, significant inverse correlations between change in HII and change in GRO (rs = −0.52, P = 0.0088) and monocyte chemotactic protein-1 (rs = −0.61, P = 0.0014) concentrations over 48 h were observed. Conclusion: Increasing Dys-HDL concentrations in the first 48 h of sepsis are associated with an ongoing inflammatory response and adverse clinical outcomes. Early changes in HII may be a potential biomarker in ED patients admitted with sepsis.