Chronic inflammation and multiple dimensions of aging among women in the Philippines

Chronic systemic inflammation is a robust predictor of all-cause mortality, as well as age-related increases in cardiometabolic diseases and declines in physical and cognitive abilities [1, 2]. Concentrations of inflammatory biomarkers typically increase with age [3], and self-perpetuating cycles of tissue damage and inflammatory responses are potentially important drivers of biological aging across multiple organs and physiological systems—a process described as “inflammaging” [4, 5]. Research on inflammation and aging has been conducted almost exclusively in high income, post-epidemiologic transition populations with high levels of chronic inflammation and obesity [6, 7]. However, the global population is rapidly aging, and 80% of people over the age of 60 are forecast to live in lower- and middle-income nations by 2050 [8]. The extent to which chronic inflammation contributes to age-related morbidity and mortality in these settings is not known, with only a handful of studies providing mixed results [7, 9, 10]. Higher levels of endemic infectious diseases and relatively low but rapidly rising rates of overweight and obesity are two potentially important factors that might influence patterns of association among inflammation, aging, and chronic disease globally. C-reactive protein (CRP)—an acute phase protein and key component of innate immune defenses—is routinely assayed in blood to assess systemic inflammation in clinical and epidemiological settings [11-13]. However, transient increases in CRP in response to infection or injury can complicate efforts to capture chronic levels of inflammatory activity from samples collected at a single time point, particularly in ecological settings where infectious exposures are common [14, 15]. Recently, the methylome has been identified as a promising source of information on circulating proteins, including inflammatory biomarkers such as CRP [16]. DNA methylation (DNAm) is a reversible epigenetic process that involves the binding of methyl groups to cytosine residues, with potential effects on patterns of gene expression [17]. The application of novel bioinformatic methods to epigenome-wide DNAm data has generated several surrogate measures of chronic inflammation that predict a wide range of aging-related health outcomes [18-22]. These measures also appear to be less sensitive to acute fluctuation than CRP [18, 23]. The objective of this study is to test the hypothesis that chronic inflammation predicts trajectories of aging among a cohort of older women in the Philippines. While life expectancy has increased along with educational and economic opportunities, the Philippines remains a lower-middle income nation experiencing recent increases in the prevalence of overweight/obesity, rising burdens of diabetes, heart disease, and stroke, and a backdrop of communicable diseases that continue to cause substantial morbidity and mortality [24-26]. It is also an aging nation, with a rapidly growing population of older adults [27]. In prior analyses with this cohort we have reported concentrations of CRP that are substantially lower than age-matched adults in the US [28]. We also document weaker associations between waist circumference and CRP in the Philippines [29], suggesting that the relationships among adiposity, chronic inflammation, and aging outcomes may differ from higher income countries with greater prevalences of overweight, obesity, and chronic inflammation. In this study we measure chronic inflammation with plasma CRP, as well as a recently validated DNAm-based surrogate measure (DNAm-CRP) that performed well across a diverse set of test cohorts [23]. Correlations between DNAm-CRP and plasma CRP range from 0.26 to 0.53 in cohorts of younger and older adults; in our cohort of older Filipino women, the correlation is 0.47 [30]. We evaluate CRP and DNAm-CRP as predictors of multiple dimensions of aging, including physical capacity, cognitive function, and cardiometabolic morbidities, with assessments at baseline and seven years later. 1. Furman, D., J. Campisi, E. Verdin, P. Carrera-Bastos, S. Targ, C. Franceschi, L. Ferrucci, D.W. Gilroy, A. Fasano, and G.W. Miller, Chronic inflammation in the etiology of disease across the life span. Nature Medicine, 2019. 25(12): p. 1822-1832. 2. Proctor, M.J., D.C. McMillan, P.G. Horgan, C.D. Fletcher, D. Talwar, and D.S. 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