Multi-Systemic Biological Risk and Cancer Mortality: The NHANES III Study

Abstract

Multi-systemic biological risk (MSBR), a proxy for allostatic load, is a composite index of biomarkers representing dysregulation due to responses to chronic stress. this study examined the association of an MSBR index with cancer mortality. the sample included n = 13,628 adults aged 20-90 from the NHANES III Linked Mortality File (1988)(1989)(1990)(1991)(1992)(1993)(1994). The MSBR index included autonomic (pulse rate, blood pressure), metabolic (HoMA ir , triglycerides, waist circumference), and immune (white blood cell count, C-reactive protein) markers. We fit Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CI) of overall cancer mortality risk, according to quartiles (q) of the index. In multivariable models, compared to those in q1, q4 had a 64% increased risk for cancer mortality (HR = 1.64, 95% CI:1.13-2.40). The immune domain drove the association (HR per unit = 1.19, 95% CI:1.07-1.32). In stratified analyses, the HR for those with a BMI ≥ 25 was 1.12 per unit (95% CI:1.05-1.19) and those with a BMI < 25 was 1.04 per unit (95% CI:0.92-1.18). MSBR is positively associated with risk for cancer mortality in a US sample, particularly among those who are overweight or obese. The utilization of standard clinical measures comprising this index may inform population cancer prevention strategies.Multi-systemic biological risk (MSBR) is a proxy for allostatic load (AL). It is a metric of health risk that captures the complex biological cascade that occurs in autonomic, metabolic, and immune domains in response to chronic environmental and psychosocial stress 1-3 . The validity of the AL construct is established and demonstrates common variance and statistical coherence between, prominent primary mediators of the stress response (i.e., stress hormones), and secondary mediators reflecting the resulting biological alterations in autonomic, metabolic, and immune domains that accumulate over time [4][5][6][7][8] . Importantly, summary AL indices have demonstrated a non-additive, stronger magnitude of association with outcomes compared with the individual components of the index 9 .Previous research has shown that autonomic, metabolic, and immune disorders, share common risk factors with cancer outcomes 10-12 . Moreover, there is a strong physiological link between over-activation of the stress response and regulation of the tumor microenvironment [13][14][15] . In mechanistic animal studies where stress can demonstrably be reproduced, chronic responses to stress influence processes involved in tumorigenesis [16][17][18][19] . However, observational studies assessing self-report of stressful life events and cancer outcomes have generally been inconsistent [20][21][22][23][24][25] .Epidemiological studies show positive associations between higher levels of AL indices and cardiovascular disease (CVD), as well as mortality risk 26,27 . However, we are not aware of any studies that have examined an index of AL with cancer outcomes. With cancer being the second leading cause of de...

Allostatic Load in Cancer: A Systematic Review and Mini Meta-Analysis

“…The 12 articles selected for review were published between 2013 and 2020, from studies conducted in USA (Acheampong et al, 2020;Beydoun et al, 2019;Hughes Halbert et al, 2020;Levine & Crimmins, 2014;Mattei et al, 2010;Parente et al, 2013;Santacroce & Crandell, 2014;Xing et al, 2020), Taiwan (Hwang et al, 2014), Italy (Ruini et al, 2015), China (Ye et al, 2017), and Scotland (Robertson et al, 2017). As shown in Table 1, 6 studies used a cohort design (Acheampong et al, 2020;Beydoun et al, 2019;Hwang et al, 2014;Levine & Crimmins, 2014;Robertson et al, 2017;Xing et al, 2020), while 5 used a cross-sectional design (Hughes Halbert et al, 2020;Mattei et al, 2010;Parente et al, 2013;Ruini et al, 2015;Santacroce & Crandell, 2014). Only one study was a randomized controlled trial (Ye et al, 2017).…”

“…Table 2 describes the details of the study populations. Eight studies used data from large population databases (Acheampong et al, 2020;Beydoun et al, 2019;Hwang et al, 2014;Levine & Crimmins, 2014;Mattei et al, 2010;Parente et al, 2013;Robertson et al, 2017;Xing et al, 2020 A total of 47,520 participants were enrolled in these 12 studies. Among the studies using population databases, sample sizes ranged from 409 (Xing et al, 2020) to 13,628 (Acheampong et al, 2020), with an average of about 5,889 participants.…”

“…The remaining studies examined cancer-related outcomes associated with AL. Cancer-specific mortality was examined in 5 studies (Acheampong et al, 2020;Beydoun et al, 2019;Hwang et al, 2014;Levine & Crimmins, 2014;Robertson et al, 2017). Two studies did not find that AL predicted cancer-specific mortality (Beydoun et al, 2019;Robertson et al, 2017).…”

“…However, among the various methods to assess mortality risk, biological age had the strongest association with cancer-specific mortality (see Table 2). Another study that examined the MSBR, a proxy for AL, reported that participants in the highest quartile of MSBR had 64% increased risk for cancer mortality compared to the lowest quartile (Acheampong et al, 2020). The increased risk was primarily driven by the immune domain with a stronger association observed in overweight/obese individuals (Acheampong et al, 2020).…”

“…The construct validity of AL is established and studies have demonstrated common variance and statistical coherence between prominent primary mediators of stress response and secondary mediators reflecting biological alterations in autonomic, metabolic, and immune domains (Galen Buckwalter et al, 2016;Wiley et al, 2016). Although researchers agree that the AL construct is valid and its measurement should include biomarkers from neuroendocrine and immunological domains (Acheampong et al, 2020;Goldman et al, 2006;Karlamangla et al, 2002;Seeman et al, 2004), there is still no "gold standard" for AL estimation and disagreements exist on which combination of biomarkers best reflect a "gold standard" (Beckie, 2012;Duong et al, 2017;Gallo et al, 2014;Mauss et al, 2015). An alternative method to measure AL in clinical practice-the clinimetric criteria, was introduced in 2010 (Fava et al, 2010) and later revised in 2017 (Fava et al, 2017).…”