Mitochondrial blood-based biomarker is related to cardiorespiratory fitness and aging in a sex-dependent manner

IF 6.8 Q1 CLINICAL NEUROLOGY

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Pub Date : 2025-10-07 DOI:10.1002/trc2.70163

Riley E. Kemna, Amanda Szabo-Reed, Hana D. Mayfield, Paul J. Kueck, Jenae Pennington, Casey S. John, Brittany M. Hauger, Heather M. Wilkins, Eric D. Vidoni, Jill K. Morris

{"title":"Mitochondrial blood-based biomarker is related to cardiorespiratory fitness and aging in a sex-dependent manner","authors":"Riley E. Kemna, Amanda Szabo-Reed, Hana D. Mayfield, Paul J. Kueck, Jenae Pennington, Casey S. John, Brittany M. Hauger, Heather M. Wilkins, Eric D. Vidoni, Jill K. Morris","doi":"10.1002/trc2.70163","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> INTRODUCTION</h3>\n \n <p>A sedentary lifestyle increases the risk for Alzheimer's disease (AD), whereas exercise has been shown to benefit brain health. Physiological factors, such as female sex, are linked to lower cardiorespiratory fitness and can increase the risk of AD, which might impact exercise benefits to the brain. Exploring cellular mechanisms underlying fitness in older adults is essential to understanding exercise and AD risk and how sex might impact this interaction.</p>\n </section>\n \n <section>\n \n <h3> METHODS</h3>\n \n <p>We collected blood from 34 cognitively healthy older adults (age 65+, 18 male, 16 female) enrolled in the COMbined Exercise Trial (COMET; NCT04848038). Subjects underwent a blood draw and clinical assessments for cardiorespiratory fitness and body composition. Blood was collected in ACD tubes, and lymphocytes were isolated. Fluorescent stains used were MitoTracker, Annexin V, MitoSOX, TMRE (tetramethylrhodamine ethyl ester), and Hoechst, analyzed by flow cytometry, and used to calculate a composite mitochondrial function index (MFI).</p>\n </section>\n \n <section>\n \n <h3> RESULTS</h3>\n \n <p>As expected, males had higher lean mass and VO<sub>2peak</sub> than females (<i>p</i> = 0.01), but groups did not differ in body mass index (<i>p</i> = 0.51). Males had a higher MFI compared to females (<i>p</i> = 0.01). Within each sex, we observed unique metabolic relationships. In males, there was an age-associated decline in MFI (<i>R</i><sup>2</sup> = 0.382, <i>p</i> = 0.01). In females, our systemic measure of mitochondrial superoxides had a negative relationship with lean mass (<i>R</i><sup>2</sup> = 0.648, <i>p</i> < 0.01) and oxygen uptake efficiency slope (OUES) (<i>R</i><sup>2</sup> = 0.271, <i>p</i> = 0.04).</p>\n </section>\n \n <section>\n \n <h3> DISCUSSION</h3>\n \n <p>We combined an MFI with measures related to fitness in a cognitively healthy older adult population. We explored physiological factors that impact cardiorespiratory fitness, such as sex. We observed relationships between mitochondrial superoxides and OUES and lean mass in females, whereas males had higher MFI overall. Sex-dependent differences in mitochondrial function and superoxide might be an underlying factor of variable cardiorespiratory fitness between sexes and could help explain differences in AD risk.</p>\n </section>\n \n <section>\n \n <h3> Highlights</h3>\n \n <div>\n <ul>\n \n <li>Mitochondrial blood-biomarker shows sex-dependent relationships in aging.</li>\n \n <li>Mitochondrial function index is higher in older adult males.</li>\n \n <li>Mitochondrial function index declines with age in males.</li>\n \n <li>Mitochondrial reactive oxygen species (ROS) are negatively associated with fitness in females.</li>\n \n <li>Mitochondrial ROS are negatively associated with lean mass in females.</li>\n </ul>\n </div>\n </section>\n </div>","PeriodicalId":53225,"journal":{"name":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","volume":"11 4","pages":""},"PeriodicalIF":6.8000,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://alz-journals.onlinelibrary.wiley.com/doi/epdf/10.1002/trc2.70163","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Alzheimer''s and Dementia: Translational Research and Clinical Interventions","FirstCategoryId":"1085","ListUrlMain":"https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/trc2.70163","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

INTRODUCTION

A sedentary lifestyle increases the risk for Alzheimer's disease (AD), whereas exercise has been shown to benefit brain health. Physiological factors, such as female sex, are linked to lower cardiorespiratory fitness and can increase the risk of AD, which might impact exercise benefits to the brain. Exploring cellular mechanisms underlying fitness in older adults is essential to understanding exercise and AD risk and how sex might impact this interaction.

METHODS

We collected blood from 34 cognitively healthy older adults (age 65+, 18 male, 16 female) enrolled in the COMbined Exercise Trial (COMET; NCT04848038). Subjects underwent a blood draw and clinical assessments for cardiorespiratory fitness and body composition. Blood was collected in ACD tubes, and lymphocytes were isolated. Fluorescent stains used were MitoTracker, Annexin V, MitoSOX, TMRE (tetramethylrhodamine ethyl ester), and Hoechst, analyzed by flow cytometry, and used to calculate a composite mitochondrial function index (MFI).

RESULTS

As expected, males had higher lean mass and VO_2peak than females (p = 0.01), but groups did not differ in body mass index (p = 0.51). Males had a higher MFI compared to females (p = 0.01). Within each sex, we observed unique metabolic relationships. In males, there was an age-associated decline in MFI (R² = 0.382, p = 0.01). In females, our systemic measure of mitochondrial superoxides had a negative relationship with lean mass (R² = 0.648, p < 0.01) and oxygen uptake efficiency slope (OUES) (R² = 0.271, p = 0.04).

DISCUSSION

We combined an MFI with measures related to fitness in a cognitively healthy older adult population. We explored physiological factors that impact cardiorespiratory fitness, such as sex. We observed relationships between mitochondrial superoxides and OUES and lean mass in females, whereas males had higher MFI overall. Sex-dependent differences in mitochondrial function and superoxide might be an underlying factor of variable cardiorespiratory fitness between sexes and could help explain differences in AD risk.

Highlights

Mitochondrial blood-biomarker shows sex-dependent relationships in aging.
Mitochondrial function index is higher in older adult males.
Mitochondrial function index declines with age in males.
Mitochondrial reactive oxygen species (ROS) are negatively associated with fitness in females.
Mitochondrial ROS are negatively associated with lean mass in females.

Abstract Image

查看原文本刊更多论文

线粒体血液生物标志物与心肺健康和衰老以性别依赖的方式相关

久坐不动的生活方式会增加患阿尔茨海默病（AD）的风险，而运动已被证明有益于大脑健康。生理因素，如女性，与较低的心肺健康有关，并可能增加患阿尔茨海默病的风险，这可能会影响锻炼对大脑的好处。探索老年人健康的细胞机制对于理解运动和AD风险以及性别如何影响这种相互作用至关重要。方法：我们收集了34名参加联合运动试验（COMET; NCT04848038）的认知健康老年人（65岁以上，18名男性，16名女性）的血液。受试者接受了抽血和心肺健康和身体成分的临床评估。ACD管采血，分离淋巴细胞。使用的荧光染色剂为MitoTracker、Annexin V、MitoSOX、TMRE（四甲基罗丹明乙酯）和Hoechst，流式细胞术分析，并用于计算复合线粒体功能指数（MFI）。结果男性的瘦体重和vo2峰值均高于女性（p = 0.01），而体重指数各组间差异无统计学意义（p = 0.51）。男性的MFI高于女性（p = 0.01）。在每个性别中，我们观察到独特的代谢关系。在男性中，MFI与年龄相关（R2 = 0.382, p = 0.01）。在女性中，我们的线粒体超氧化物的全身测量与瘦质量（R2 = 0.648, p < 0.01）和氧吸收效率斜率（OUES）呈负相关（R2 = 0.271, p = 0.04）。我们将MFI与认知健康的老年人群的健康相关测量相结合。我们探索了影响心肺健康的生理因素，如性别。我们观察到线粒体超氧化物与女性OUES和瘦质量之间的关系，而男性总体上具有更高的MFI。线粒体功能和超氧化物的性别依赖性差异可能是两性之间心肺适应性变化的潜在因素，并有助于解释AD风险的差异。线粒体血液生物标志物在衰老过程中显示性别依赖关系。老年成年男性线粒体功能指数较高。男性线粒体功能指数随年龄增长而下降。线粒体活性氧（ROS）与女性的适应性呈负相关。线粒体ROS与女性瘦体重呈负相关。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Alzheimer''s and Dementia: Translational Research and Clinical Interventions Medicine-Psychiatry and Mental Health

CiteScore

10.10

自引率

2.10%

发文量

134

审稿时长

10 weeks

期刊介绍： Alzheimer''s & Dementia: Translational Research & Clinical Interventions (TRCI) is a peer-reviewed, open access,journal from the Alzheimer''s Association®. The journal seeks to bridge the full scope of explorations between basic research on drug discovery and clinical studies, validating putative therapies for aging-related chronic brain conditions that affect cognition, motor functions, and other behavioral or clinical symptoms associated with all forms dementia and Alzheimer''s disease. The journal will publish findings from diverse domains of research and disciplines to accelerate the conversion of abstract facts into practical knowledge: specifically, to translate what is learned at the bench into bedside applications. The journal seeks to publish articles that go beyond a singular emphasis on either basic drug discovery research or clinical research. Rather, an important theme of articles will be the linkages between and among the various discrete steps in the complex continuum of therapy development. For rapid communication among a multidisciplinary research audience involving the range of therapeutic interventions, TRCI will consider only original contributions that include feature length research articles, systematic reviews, meta-analyses, brief reports, narrative reviews, commentaries, letters, perspectives, and research news that would advance wide range of interventions to ameliorate symptoms or alter the progression of chronic neurocognitive disorders such as dementia and Alzheimer''s disease. The journal will publish on topics related to medicine, geriatrics, neuroscience, neurophysiology, neurology, psychiatry, clinical psychology, bioinformatics, pharmaco-genetics, regulatory issues, health economics, pharmacoeconomics, and public health policy as these apply to preclinical and clinical research on therapeutics.