Characterization of Serum Extracellular Vesicles with Human Age

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Recent data indicate a decline in overall longevity in the United States. Mid life mortality rates were increasing even prior to the COVID-19 pandemic. Life expectancy disparities have persisted in the United States for racial and ethnic groups and for individuals living at low socioeconomic status. These continued trends in mortality indicate the importance of examining biomarkers of mortality at midlife in at-risk populations. Chronic inflammatory diseases are a major contributor to the global burden of mortality. It is estimated that over half of worldwide deaths can be linked to inflammatory-related diseases. Our previous work examining the link between EV inflammatory proteins and mortality suggested that examining serum circulating levels of cytokines and inflammatory markers might provide another perspective on systemic chronic inflammation and mortality among HANDLS participants. In this study, we examined the relationship of inflammatory proteins with mortality in HANDLS participants (n = 1122; mean age = 47.8 years). Nine different biomarkers (IFN-γ, IL-6, TNF-α trimer, E-Selectin, MCP-1, sRAGE, SAA, P-Selectin, fibrinogen) were chosen and assayed based on their potential roles as inflammatory markers in age-associated diseases and conditions. We examined whether these inflammatory-related proteins were associated with mortality over approximately 12-years. As race, sex, and poverty all remain risk factors for mortality, this study also explored interactions between these inflammatory proteins and these variables. We found significant differences in inflammatory-related protein serum levels between African American and White middle-aged adults. E-selectin and fibrinogen were significantly higher in African American adults. IFN-γ, TNF-α trimer, MCP-1, soluble receptor for advanced glycation end-products (sRAGE) and P-selectin were significantly higher in White participants compared to African American participants. Higher levels of E-selectin, MCP-1 and P-selectin were associated with a higher mortality risk. Furthermore, there was a significant interaction between sex and IL-6 with mortality. IL-6 levels were associated with an increased risk of mortality, an association that was significantly greater in women than men. In addition, White participants with high levels of sRAGE had significantly higher survival probability than White participants with low levels of sRAGE, while African American participants had similar survival probabilities across sRAGE levels. By selecting inflammatory markers for our panel from a variety of inflammatory pathways, our work highlights the fact that many etiologies of inflammation play a role in mortality risk. In addition, we provide additional evidence that some of the proteins associated with the senescence-associated secretory phenotype (SASP) are also associated with mortality. SASP, comprised of factors that are significantly altered between pre-senescent and senescent cells includes interleukins (e.g., IL-6), chemokines (MCP-1), and other inflammatory molecules (IFN-γ), soluble receptors (TNF-α), non-protein soluble protein factors and insoluble factors has been associated with chronic disease, advanced biologic age, frailty, medical risk and other adverse health outcomes. We have demonstrated that even at middle age, senescence-associated proteins are linked with mortality, supporting the hypothesis that health disparities related to mortality may be propelled in part by the accelerated aging phenotype as well as inflammation.