Midlife Systemic Inflammation Is Associated With Frailty in Later Life: The ARIC Study

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Abstract

<div class="section"> <a class="named-anchor" id="s1">  </a> <h5 class="section-title" id="d7924266e196">Background</h5> <p id="d7924266e198">Evidence suggests that systemic inflammation may have a mechanistic role in age-related frailty, yet prospective data is limited. We examined whether systemic inflammation during midlife was associated with late-life frailty within the community-based Atherosclerosis Risk in Communities Study. </p> </div><div class="section"> <a class="named-anchor" id="s2">  </a> <h5 class="section-title" id="d7924266e201">Methods</h5> <p id="d7924266e203">Plasma levels of four inflammatory markers (fibrinogen, von Willebrand factor, and Factor VIII, and white blood cell count) were measured during Visit 1 (1987–1989; mean age: 52 [5]), standardized into z-scores, and combined to create an inflammation composite score. High-sensitivity C-reactive protein (CRP) was measured 3 (Visit 2, 1990–1992) and 9 (Visit 4, 1996–1999) years later. Frailty was evaluated in 5,760 participants during late life (Visit 5, 2011–2013; mean age: 75 [5]). Analyses were adjusted for demographic and physiological variables, and midlife medical comorbidity using logistic regression. </p> </div><div class="section"> <a class="named-anchor" id="s3">  </a> <h5 class="section-title" id="d7924266e206">Results</h5> <p id="d7924266e208">A 1 <i>SD</i> increase in midlife inflammation composite score was associated with higher odds of frailty 24 years later (odds ratio [OR] = 1.39, 95% confidence interval [CI]: 1.18–1.65). Similarly, each standard deviation increase in Visit 2 CRP (OR = 1.24, 95% CI: 1.09–1.40) and Visit 4 CRP (OR = 1.35, 95% CI: 1.19–1.53) was associated with a higher odds of frailty 21 and 15 years later. Participants who maintained elevated CRP (≥3 mg/L) at Visits 2 and 4 or transitioned to a state of elevated CRP during this period were more likely to subsequently meet frailty criteria compared to those who maintained low CRP. These associations were stronger among white, compared to African American, participants ( <i>p</i>-interactions < .038). </p> </div><div class="section"> <a class="named-anchor" id="s4">  </a> <h5 class="section-title" id="d7924266e217">Conclusions</h5> <p id="d7924266e219">Systemic inflammation during midlife may independently promote pathophysiological changes underlying frailty in a subset of the population. </p> </div>

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JAK inhibition alleviates the cellular senescence-associated secretory phenotype and frailty in old age

Ming-ming Xu, Tamara Tchkonia, Husheng Ding … (2015)

Chronic, low grade, sterile inflammation frequently accompanies aging and age-related diseases. Cellular senescence is associated with the production of proinflammatory chemokines, cytokines, and extracellular matrix (ECM) remodeling proteases, which comprise the senescence-associated secretory phenotype (SASP). We found a higher burden of senescent cells in adipose tissue with aging. Senescent human primary preadipocytes as well as human umbilical vein endothelial cells (HUVECs) developed a SASP that could be suppressed by targeting the JAK pathway using RNAi or JAK inhibitors. Conditioned medium (CM) from senescent human preadipocytes induced macrophage migration in vitro and inflammation in healthy adipose tissue and preadipocytes. When the senescent cells from which CM was derived had been treated with JAK inhibitors, the resulting CM was much less proinflammatory. The administration of JAK inhibitor to aged mice for 10 wk alleviated both adipose tissue and systemic inflammation and enhanced physical function. Our findings are consistent with a possible contribution of senescent cells and the SASP to age-related inflammation and frailty. We speculate that SASP inhibition by JAK inhibitors may contribute to alleviating frailty. Targeting the JAK pathway holds promise for treating age-related dysfunction.

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Inflammatory markers in population studies of aging.

Tushar Singh, Anne Newman (2011)

To review findings from major epidemiologic studies regarding risk factors for and consequences of elevated markers of inflammation in older adults. Most large, current epidemiologic studies of older adults have measured serum interleukin-6 (IL-6), C-reactive protein (CRP) and tumor necrosis factor alpha (TNF-alpha) and some studies also include more extensive batteries of measures including soluble receptors. There are few defined risk factors for the modest elevations in inflammatory markers seen with aging. These include visceral adiposity, lower sex steroid hormones, smoking, depression and periodontal disease. Of the markers assessed, IL-6 is most robustly associated with incident disease, disability and mortality. Though correlated with age, the etiology of elevated inflammatory markers remains incompletely defined. Inflammation, especially IL-6 may be a common cause of multiple age-related diseases or a final common pathway by which disease leads to disability and adverse outcomes in older adults. Future research targeting inflammation should examine these pathways. Copyright © 2011. Published by Elsevier B.V.

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Insulin resistance and inflammation as precursors of frailty: the Cardiovascular Health Study.

Caroline Blaum, Steven Moore, Jeremy Walston … (2007)

Our research group has previously shown that the geriatric syndrome of frailty is associated with features of the metabolic syndrome (MetS) on cross-sectional analysis. To test whether MetS and its physiologic determinants-insulin resistance as measured by homeostasis model assessment score (IR-HOMA), increased inflammation and coagulation factor levels, and elevated blood pressure-are associated with incident frailty, we studied a subcohort of participants from the Cardiovascular Health Study observed from 1989/1990 through 1998/1999: 3141 community-dwelling adults, aged 69 to 74 years, without frailty and illnesses that increase inflammation markers or mimic frailty. The association of baseline MetS, IR-HOMA, levels of inflammation and coagulation factors, and systolic blood pressure (SBP) with time to onset of frailty was adjusted for demographic and psychosocial factors and incident events. Our main outcome measure was incident frailty. Metabolic syndrome was not significantly associated with incident frailty (hazard ratio, 1.16 (95% confidence interval [CI], 0.85-1.57). On the other hand, IR-HOMA and C-reactive protein levels were associated with incident frailty: for every standard deviation increment the hazard ratio for frailty was 1.15 (95% CI, 1.02-1.31) and 1.16 (95% CI, 1.02-1.32), respectively. The white blood cell count and factor VIIIc levels had a borderline association. Elevated systolic blood pressure had no association. Similar trends were found for incident prefrailty, a condition that precedes frailty. Two physiologic components of MetS- IR-HOMA and inflammation-are associated with incident frailty. Based on these results, IR-HOMA can be considered part of a larger process that leads to generalized decline.