以DNA甲基化老化生物標記探討老化加速與心血管健康之關聯性

Abstract

人類的老化速率受到諸多健康因素影響。老化加速（age acceleration）則是指個體的老化速率更甚於其實際年齡（chronological age）所預期。近年，隨著各種DNA甲基化年齡生物標記研究的蓬勃發展，個體生理年齡（biological age）與表觀遺傳學年齡加速（epigenetic age acceleration）可以透過第一代與第二代表觀遺傳學時鐘（epigenetic clock）估計；藉此探究個體健康與老化加速的關聯性成為可行的研究方向。美國心臟協會在（the American Heart Association）在2010年時以四種臨床數據指標與三種生活型態因素定義心血管健康（cardiovascular health）狀態，並且提出創新的七分制心血管健康分數 （cardiovascular health score）用以評估個體心血管健康的優劣程度。近來，部分研究指出較為理想的心血管健康狀態與減緩老化加速的關聯性。然而多數研究僅針對歐裔族群資料進行探討，缺乏應用亞裔族群資料的研究結果相互驗證。 為了探究老化加速與心血管健康之關聯性，吾人分析臺灣人體生物資料庫（the Taiwan Biobank）中2,474名受試者的DNA甲基化樣本資料，將表觀遺傳學年齡加速數值作為應變數、心血管健康分數作為自變數施行複迴歸分析同時調整性別、喝酒與否，與教育程度，用以探究心血管健康狀態與老化加速間的關聯性。其中，四種表觀遺傳學生物鐘被用以計算老化加速，包含基於Horvath’ clock計算的內源性年齡加速（IEAA）、基於Hannum’s clock計算的HannumEAA年齡加速、基於Levine等人提出的PhenoAge計算的表年齡加速（PhenoEAA），與基於Lu 等人提出的GrimAge計算的GrimEAA年齡加速；前兩者屬第一代表觀遺傳學時鐘，後二者屬第二代表觀遺傳學時鐘。心血管健康分數則是根據美國心臟協會對七個理想心血管健康指標的評分標準計算。七個衡量指標包含：抽煙行為、運動習慣、飲食、身體質量指數（BMI）、空腹血糖、血壓、總膽固醇。 研究結果顯示，基於第二代表觀遺傳年齡計算的老化加速與心血管健康分數呈現顯著負向關聯性 (p ≤ 4.5E-4)。相較之下，第一代表觀遺傳年齡加速與心血管健康分數的關聯性卻未達統計上的顯著。此結果進一步支持過去研究對於第二代表觀遺傳學時鐘較能反應個體生理功能與病理狀態之論述。 總結而言，較理想的心血管健康程度與減緩老化加速之關聯性在第二代表觀遺傳學年齡加速模式中達統計上的顯著。維持各項心血管健康指標在理想的標準有助於減緩生理年齡老化加速。此研究為少數針對亞裔族群年齡加速與心血管健康之關聯性探討的研究。透過相對較大的臺灣人族群DNA甲基化資料樣本數，這個研究能為心血管健康衛教相關政策制定提供參考，亦可在預防醫學領域提供減緩、降低老化相關疾病負擔之洞見。

The human aging rate is affected by several health-related factors. Age acceleration refers to an individual aging faster than the expected aging rate regarding his/her chronological age. Recently, with the vigorous development of DNA methylation (DNAm) aging biomarker, the first- and second-generation epigenetic clocks can be used to evaluate biological age and age acceleration, whereby exploring the association between age acceleration and an individual’s health status becomes a feasible research topic. In 2010, the American Heart Association (AHA) defined cardiovascular health (CVH) from four clinical and three lifestyle factors, along with a novel 7-point CVH measure (CVH score) to evaluate an individual’s CVH status. Although ideal CVH has been shown to be associated with a slower aging rate in a few recent studies, most of them were only conducted with European ancestry data. The association between age acceleration and CVH has not been fully investigated for the Asian population. To investigate the association between age acceleration and CVH, we analyzed 2,474 subjects’ DNAm data from the Taiwan Biobank (TWB) and performed multiple linear regression analysis by treating epigenetic age acceleration (EAA) as the response variable, CVH score as the primary explanatory variable while adjusting for sex, drinking, and education level. Four measures of EAA calculated from the corresponding epigenetic clocks were applied to evaluate subjects’ age acceleration, including IEAA based on Horvath’s clock, HannumEAA based on Hannum’s clock, PhenoEAA based on Levine’s PhenoAge, and GrimEAA based on Lu’s GrimAge. Among the four clocks, Horvath’s and Hannum’s clocks were categorized as first-generation epigenetic clocks, whereas Levine’s PhenoAge and Lu’s GrimAge were categorized as the second-generation clocks. CVH score was calculated according to the AHA’s definition with the ideal criteria for seven CVH components, including smoking behavior, physical activity habit, diet, body mass index (BMI), fasting glucose, total cholesterol, and blood pressure levels. The results showed that CVH was negatively associated with both PhenoEAA and GrimEAA (p ≤ 4.5E-4), which were calculated from the second-generation epigenetic clocks. In contrast, associations between age acceleration and CVH were not significant for the EAA calculated from the first-generation clocks (i.e., IEAA and HannumEAA). These results further validated the conclusion of several previous studies that second-generation epigenetic clocks reflect an individual’s physiological and pathological conditions better than first-generation epigenetic clocks. In summary, an ideal CVH is significantly associated with a lower age acceleration when assessing the second-generation EAA. Maintaining each CVH component in the ideal status may help slow down the aging rate. This is one of the first studies exploring the association between CVH and age acceleration based on the Asian population. Benefiting from the relatively large sample size of the DNAm data from the Taiwanese population, this study provides a reference for policy-making in cardiovascular health education. It also offers insights into reducing the disease burden of aging-related disorders in preventive medicine.