Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
Center On Aging and Health, Johns Hopkins University, Baltimore, MD, USA.
Geroscience. 2024 Oct;46(5):5247-5265. doi: 10.1007/s11357-024-01219-8. Epub 2024 Jun 10.
Physical frailty is a syndrome that typically manifests in later life, although the pathogenic process causing physical frailty likely begins decades earlier. To date, few studies have examined the biological signatures in mid-life associated with physical frailty later in life. Among 4,189 middle-aged participants (57.8 ± 5.0 years, 55.8% women) from the Atherosclerosis Risk in Community (ARIC) study, we evaluated the associations of 4,955 plasma proteins (log 2-transformed and standardized) measured using the SomaScan platform with their frailty status approximately 20 years later. Using multinomial logistic regression models adjusting for demographics, health behaviors, kidney function, total cholesterol, and comorbidities, 12 and 221 proteins were associated with prefrailty and frailty in later life, respectively (FDR p < 0.05). Top frailty-associated proteins included neurocan core protein (NCAN, OR = 0.66), fatty acid-binding protein heart (FABP3, OR = 1.62) and adipocyte (FABP4, OR = 1.65), as well proteins involved in the contactin-1 (CNTN1), toll-like receptor 5 (TLR5), and neurogenic locus notch homolog protein 1 (NOTCH1) signaling pathway relevant to skeletal muscle regeneration, myelination, and inflammation. Pathway analyses suggest midlife dysregulation of inflammation, metabolism, extracellular matrix, angiogenesis, and lysosomal autophagy among those at risk for late-life frailty. After further adjusting for midlife body mass index (BMI) - an established frailty risk factor - only CNTN1 (OR = 0.75) remained significantly associated with frailty. Post-hoc analyses demonstrated that the top 41 midlife frailty-associated proteins mediate 32% of the association between mid-life BMI and late-life frailty. Our findings provide new insights into frailty etiology earlier in the life course, enhancing the potential for prevention.
身体虚弱是一种综合征，通常在晚年表现出来，尽管导致身体虚弱的发病过程可能早在几十年前就开始了。迄今为止，很少有研究探讨中年时期与晚年身体虚弱相关的生物学特征。在动脉粥样硬化风险社区（ARIC）研究的 4189 名中年参与者（57.8±5.0 岁，55.8%为女性）中，我们评估了使用 SomaScan 平台测量的 4955 种血浆蛋白（对数 2 转换和标准化）与大约 20 年后的虚弱状态之间的关联。使用调整人口统计学、健康行为、肾功能、总胆固醇和合并症的多项逻辑回归模型，12 种和 221 种蛋白质分别与晚年的虚弱前期和虚弱状态相关（FDR p<0.05）。与虚弱相关的主要蛋白质包括神经粘蛋白核心蛋白（NCAN，OR=0.66）、脂肪酸结合蛋白心脏（FABP3，OR=1.62）和脂肪细胞（FABP4，OR=1.65），以及与骨骼肌肉再生、髓鞘形成和炎症相关的接触蛋白-1（CNTN1）、 toll 样受体 5（TLR5）和神经源性巢蛋白 1（NOTCH1）信号通路相关的蛋白质。通路分析表明，在有晚年虚弱风险的人群中，中年时期的炎症、代谢、细胞外基质、血管生成和溶酶体自噬失调。在进一步调整中年时期体重指数（BMI）后 - 这是一个已确立的虚弱危险因素 - 只有 CNTN1（OR=0.75）与虚弱仍然显著相关。事后分析表明，中年时期与虚弱相关的前 41 种蛋白质介导了中年 BMI 与晚年虚弱之间 32%的关联。我们的研究结果为生命早期的虚弱病因学提供了新的见解，增强了预防的潜力。
