環境溫度與老化相關分子生物標記之關聯性：以臺灣社區族群為研究對象

Abstract

在氣候變遷的影響下，環境溫度持續上升，其中戶外工作者與農業工作者所承受之熱暴露負擔尤重，然而累積性熱暴露與分子層次老化之間的關聯，目前仍缺乏明確證據。本研究目的在於探討環境熱暴露與四項老化生物標記之關聯性，包括端粒長度（telomere length）、粒線體DNA套數（mitochondrial DNA copy number, mtDNA-CN）、粒線體DNA缺失比例（mtDNA deletion ratio），以及生長分化因子15（growth differentiation factor 15, GDF-15），研究對象為臺灣社區族群。本研究採社區為基礎之橫斷面研究設計，自2022年7月至2024年12月，於臺中、嘉義、彰化、南投及雲林等縣市共收案127位成人，其中69.3%為農業工作者。橫斷面熱暴露於受試者健檢時測量，包括環境溫度、室內與室外濕球黑球溫度（wet-bulb globe temperature, WBGT），以及日照下與從事體力勞動時之熱指數（heat index, HI）；居住地每日溫度、相對濕度（relative humidity, RH）、熱指數與日夜溫差（diurnal temperature range, DTR），則採用87個氣象測站之觀測資料，以泛克利金空間內插法（universal kriging）重建受試者採樣日前365天之延遲期間暴露。端粒長度以單色多重定量聚合酶連鎖反應（monochrome multiplex qPCR）測定，粒線體DNA套數與缺失比例以qPCR測定，血漿GDF-15則以酵素連結免疫吸附法（enzyme-linked immunosorbent assay, ELISA）測定；統計分析採多元線性迴歸與分布式延遲非線性模式（distributed lag non-linear models, DLNMs），並校正年齡與性別，暴露時間窗涵蓋7至365天。結果顯示，實際年齡與端粒長度、粒線體DNA套數及GDF-15均呈顯著相關；相較於非農業工作者，農業工作者之端粒較短、粒線體DNA套數較低，且GDF-15濃度較高。於DLNMs分析中，較高之平均熱指數HI(mean)與最低熱指數HI(min)於21天及30天暴露時間窗與端粒縮短有關，較高之相對濕度亦於180天暴露時間窗與端粒縮短有關；反之，最低溫度T(min)與熱指數之日夜溫差DTR(HI)則與端粒長度呈正相關。GDF-15隨21天之最高溫度上升58.9%、隨30天之平均熱指數上升14.3%，其中又以累積相對濕度於180天（上升441.7%）及365天（上升912.8%）之效應最為顯著。粒線體相關指標之結果則較不一致：粒線體DNA套數隨最低溫度與相對濕度而上升，而缺失比例於365天暴露時間窗隨平均熱指數上升、隨日夜溫差下降。本研究結果顯示，累積性環境熱與濕度暴露與分子老化之關聯，主要呈現於中長期暴露時間窗而非急性暴露，且粒線體之反應可能反映代償性適應機制，可作為未來保障高齡化戶外工作族群健康之公共衛生介入依據。

Rising ambient temperatures under climate change disproportionately affect outdoor and agricultural workers, yet how cumulative heat exposure relates to molecular aging remains poorly characterized. This study examined the association between ambient heat exposure and four biomarkers of biological aging: telomere length, mitochondrial DNA copy number (mtDNA-CN), mtDNA deletion ratio, and growth differentiation factor 15 (GDF-15) in a community-based population in Taiwan. From July 2022 to December 2024, 127 adults were enrolled from Taichung, Chiayi, Changhua, Nantou, and Yunlin counties, of whom 69.3% were agricultural workers. Cross-sectional heat exposure, including ambient temperature, indoor and outdoor wet-bulb globe temperature, and heat index under direct sunlight and under physical labor, was measured at clinic visits, while daily residential temperature, relative humidity (RH), heat index (HI), and diurnal temperature range (DTR) were reconstructed over a 365-day lag period using universal kriging of data from 87 weather monitoring stations. Relative telomere length was measured by monochrome multiplex qPCR, mtDNA-CN and deletion ratio by qPCR, and plasma GDF-15 by ELISA. Multiple linear regression and distributed lag non-linear models (DLNMs), adjusted for age and sex, were fitted across exposure windows of 7 to 365 days. Chronological age was significantly correlated with telomere length, mtDNA-CN, and GDF-15, and farmers exhibited shorter telomeres, lower mtDNA-CN, and higher GDF-15 than non-farmers. In the DLNMs, higher HI(mean) and HI(min) were associated with telomere attrition at the 21- and 30-day windows, and higher RH with shorter telomeres at 180 days, whereas minimum temperature and DTR(HI) were positively associated with telomere length. GDF-15 increased with maximum temperature at 21 days (58.9%) and HI(mean) at 30 days (14.3%), with the largest increases observed for cumulative RH at 180 days (441.7%) and 365 days (912.8%). Mitochondrial measures were less consistent: mtDNA-CN rose with minimum temperature and RH, while the deletion ratio increased with HI(mean) and decreased with DTR over 365 days. These findings indicate that cumulative ambient heat and humidity exposure are associated with molecular aging over medium- to long-term windows rather than acutely, and that mitochondrial responses may reflect compensatory adaptation.