Laboratory of Epidemiology and Population Sciences, National Institute On Aging, National Institutes of Health, Baltimore, MD, USA.
Laboratory of Genetics and Genomics, National Institute On Aging, National Institutes of Health, Baltimore, MD, USA.
BMC Geriatr. 2022 Aug 9;22(1):651. doi: 10.1186/s12877-022-03326-7.
Frailty is a clinical syndrome described as reduced physiological reserve and increased vulnerability. Typically examined in older adults, recent work shows frailty occurs in middle-aged individuals and is associated with increased mortality. Previous investigation of global transcriptome changes in a middle-aged cohort from the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study demonstrated inflammatory genes and pathways were significantly altered by frailty status and race. Transcriptome differences in frailty by sex remain unclear. We sought to discover novel genes and pathways associated with sex and frailty in a diverse middle-aged cohort using RNA-Sequencing.
Differential gene expression and pathway analyses were performed in peripheral blood mononuclear cells for 1) frail females (FRAF, n = 4) vs non-frail females (NORF, n = 4), 2) frail males (FRAM, n = 4) vs non-frail males (NORM, n = 4), 3) FRAM vs FRAF, and 4) NORM vs NORF. We evaluated exclusive significant genes and pathways, as well as overlaps, between the comparison groups.
Over 80% of the significant genes exclusive to FRAF vs NORF, FRAM vs NORM, and FRAM vs FRAF, respectively, were novel and associated with various biological functions. Pathways exclusive to FRAF vs NORF were associated with reduced inflammation, while FRAM vs NORM exclusive pathways were related to aberrant musculoskeletal physiology. Pathways exclusive to FRAM vs FRAF were associated with reduced cell cycle regulation and activated catabolism and Coronavirus pathogenesis.
Our results indicate sex-specific transcriptional changes occur in middle-aged frailty, enhancing knowledge on frailty progression and potential therapeutic targets to prevent frailty.
衰弱是一种临床综合征，表现为生理储备减少和脆弱性增加。衰弱通常在老年人中进行检查，但最近的研究表明，衰弱也发生在中年人群中，并与死亡率增加有关。之前对来自多样性跨越生命跨度的邻里健康老龄化研究（HANDLS）中年队列的全球转录组变化的研究表明，炎症基因和途径因衰弱状态和种族而发生显著改变。性别对衰弱的转录组差异仍不清楚。我们使用 RNA 测序，在一个多样化的中年队列中，试图发现与性别和衰弱相关的新基因和途径。
对 1）衰弱女性（FRAF，n=4）与非衰弱女性（NORF，n=4）、2）衰弱男性（FRAM，n=4）与非衰弱男性（NORM，n=4）、3）FRAM 与 FRAF 以及 4）NORM 与 NORF 的外周血单核细胞进行差异基因表达和途径分析。我们评估了比较组之间的独特显著基因和途径，以及重叠。
FRAF 与 NORF、FRAM 与 NORM 以及 FRAM 与 FRAF 分别有超过 80%的独特显著基因是新的，与各种生物学功能相关。FRAF 与 NORF 之间的独特途径与炎症减少有关，而 FRAM 与 NORM 之间的独特途径与异常的肌肉骨骼生理学有关。FRAM 与 FRAF 之间的独特途径与细胞周期调节减少和分解代谢激活以及冠状病毒发病机制有关。
我们的结果表明，中年衰弱时发生性别特异性转录变化，增强了对衰弱进展和预防衰弱的潜在治疗靶点的认识。
