Gomez Maria, Al Mahri Saeed, Abdullah Mashan, Malik Shuja Shafi, Yezli Saber, Yassin Yara, Khan Anas, Lehe Cynthia, Mohammad Sameer, Hoehndorf Robert, Bouchama Abderrezak
Computational Bioscience Research Center (CBRC) Division, King Abdullah University of Science and Technology, Thuwal, Saudi Arabia.
Experimental Medicine Department, King Abdullah International Medical Research Center, King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
Physiol Genomics. 2025 Feb 1;57(2):65-79. doi: 10.1152/physiolgenomics.00053.2024. Epub 2024 Dec 24.
This study investigates the molecular responses to heatstroke in young and old patients by comparing whole-genome transcriptomes between age groups. We analyzed transcriptomic profiles from patients categorized into two age-defined cohorts: young (mean age = 44.9 ± 6 yr) and old (mean age = 66.1 ± 4 yr). Control subjects, exposed to similar environmental heat conditions but without developing heatstroke, were also included in the analysis to provide a baseline for comparison. Despite uniform heatstroke severity at admission, as indicated by core body temperature, consciousness level, and organ damage markers, notable gene expression differences emerged. Old patients showed 37% fewer differentially expressed genes compared with young patients at admission, with a shift toward gene upregulation, deviating from the usual downregulation seen in heat stress responses. Both age groups exhibited increased heat shock protein gene expression, activated the heat stress, and unfolded protein responses indicating comparable proteotoxic stress. Nonetheless, age-specific differences were evident in critical regulatory pathways like Sirtuin, mTOR, and p53 signaling, along with key pathways related to proteostasis, energy metabolism, oxidative stress, and immune responses. Following cooling, older adults exhibited a decline in the heat stress response and a cessation of the unfolded protein response, in contrast to the sustained responses seen in younger individuals. This pattern suggests an age-related adaptability or a diminished protective response capacity with aging. These findings provide insights into the biological mechanisms that may contribute to age-specific vulnerabilities to heat. Our study reveals distinct molecular responses to heatstroke across age groups, with older adults showing fewer differentially expressed genes and an atypical pattern of gene upregulation, contrasting with the downregulation in usual heat stress responses. It also uncovers a reduced heat stress response and an abbreviated unfolded protein response in older adults, likely impairing their cellular repair mechanisms. This contributes to increased vulnerability during severe heat waves, underscoring the urgent need for age-specific interventions.
本研究通过比较不同年龄组之间的全基因组转录组，调查年轻和老年患者对中暑的分子反应。我们分析了分为两个年龄定义队列的患者的转录组概况：年轻组（平均年龄 = 44.9 ± 6岁）和老年组（平均年龄 = 66.1 ± 4岁）。分析中还纳入了暴露于相似环境热条件但未发生中暑的对照受试者，以提供比较基线。尽管入院时中暑严重程度一致，如核心体温、意识水平和器官损伤标志物所示，但仍出现了显著的基因表达差异。与年轻患者相比，老年患者入院时差异表达基因少37%，且基因表达向上调转变，这与热应激反应中常见的下调不同。两个年龄组均表现出热休克蛋白基因表达增加，激活了热应激和未折叠蛋白反应，表明存在相当的蛋白质毒性应激。然而，在关键调节途径如沉默调节蛋白、mTOR和p53信号通路以及与蛋白质稳态、能量代谢、氧化应激和免疫反应相关的关键途径中，年龄特异性差异明显。降温后，老年人的热应激反应下降，未折叠蛋白反应停止，而年轻个体则表现出持续反应。这种模式表明与年龄相关的适应性或随着年龄增长保护反应能力下降。这些发现为可能导致年龄特异性热易感性的生物学机制提供了见解。我们的研究揭示了不同年龄组对中暑的独特分子反应，老年人差异表达基因较少且基因上调模式不典型，与通常热应激反应中的下调形成对比。研究还发现老年人的热应激反应降低且未折叠蛋白反应缩短，这可能损害其细胞修复机制。这导致在严重热浪期间易感性增加，突出了针对不同年龄的干预措施的迫切需求。
