端粒长度介导老年人膳食n-3 PUFAs摄入量与认知功能之间的关联性：一项横断面研究

Telomere length mediates the association between dietary n-3 PUFAs intake and cognitive function： A cross-sectional study

摘要

目的 本研究旨在探讨老年人膳食n-3多不饱和脂肪酸（n-3 polyunsaturated fatty acids,n-3 PUFAs）摄入量与认知功能之间的关联,并探索白细胞端粒长度的中介作用。方法 利用1999—2002年美国国家健康与营养调查（National Health and Nutrition Examination Survey,NHANES）数据库开展横断面研究,最终分析了2 228例符合纳入标准的参与者,通过24 h膳食回忆访谈评估n-3 PUFAs摄入量,采用定量聚合酶链反应量化白细胞端粒长度,借助韦氏成人智力量表Ⅲ数字符号替换测试测定认知功能。运用多元线性回归模型和亚组模型分析膳食n-3 PUFAs摄入量、白细胞端粒长度与认知功能之间的关联性,限制性立方样条分析膳食n-3 PUFAs摄入量与认知功能、白细胞端粒长度的剂量-反应关系,建立中介模型分析白细胞端粒长度在其中的中介作用。结果 多元线性回归结果显示膳食n-3 PUFAs摄入量（P<0.001）与白细胞端粒长度（P=0.044）是认知功能的影响因素。限制性立方样条模型分析显示膳食n-3 PUFAs摄入量与认知功能呈显著非线性正相关（P<0.001）;白细胞端粒长度与认知功能未检测到显著非线性趋势（P=0.516）。亚组分析显示,膳食n-3 PUFAs与认知功能的正向关联在年龄（P<0.001）、性别（P>0.05）等亚组中均显著且无交互作用;与白细胞端粒长度的关联仅在饮酒史（是）、无高血压亚组中显著,各分层变量无交互作用（P>0.05）。中介模型显示,白细胞端粒长度在膳食n-3 PUFAs摄入量与认知功能之间起部分中介作用,贡献率为1.400%。结论 白细胞端粒长度介导了老年人膳食n-3 PUFAs摄入与认知功能之间的关联性。

Abstract

Objective To investigate the association between dietary intake of n-3 polyunsaturated fatty acids （n-3 PUFAs） and cognitive function in elderly individuals, and to explore the mediating role of leukocyte telomere length. Methods A cross-sectional study was conducted using data from the 1999—2002 National Health and Nutrition Examination Survey （NHANES）. Finally, 2 228 participants who met the inclusion criteria were analyzed. A 24-hour dietary recall interview was used to evaluate the dietary intake of n-3 PUFAs. Quantitative polymerase chain reaction （qPCR） was used to quantify leukocyte telomere length. The Wechsler Adult Intelligence Scale-Ⅲ Digit Symbol Substitution Test was used to measure cognitive function. Mutiple linear regression models and subgroup models were used to analyze the association of dietary intake of n-3 PUFAs and leukocyte telomere length with cognitive function. Restricted cubic spline analysis was used to examine the dose-response relationship of dietary intake of n-3 PUFAs with cognitive function and leukocyte telomere length. A mediation model was established to analyze the mediating role of leukocyte telomere length in this relationship. Results The multiple linear regression results showed that dietary n-3 PUFAs intake （P<0.001） and leukocyte telomere length （P=0.044） were influencing factors of cognitive function. Restricted cubic spline model analysis revealed that dietary intake of n-3 PUFAs showed a significant nonlinear positive correlation with cognitive function （P<0.001）, but no significant nonlinear trend was detected between leukocyte telomere length and cognitive function （P=0.516）. Subgroup analysis revealed that the positive association between dietary n-3 PUFAs and cognitive function remained significant across all subgroups stratified by age and gender, with no significant interaction （P<0.001, P>0.050）. The association with leukocyte telomere length was significant only in subgroups with a history of alcohol consumption and without hypertension, with no significant interactions across stratification variables （P>0.050）. The mediation model indicated that leukocyte telomere length partially mediated the relationship between dietary intake of n-3 PUFAs and cognitive function, with a contribution rate of 1.400%. Conclusion The findings indicate that leukocyte telomere length mediates the association between dietary intake of n-3 PUFAs and cognitive function in elderly individuals.

关键词

脂肪酸类,ω3 / 白细胞端粒长度 / 认知功能

Key words

fatty acids,omega-3 / leukocyte telomere length / cognitive function

[1] Hu Q,Zhou X,Xiao Z,et al.White matter injury,plasma alzheimer's disease,and neurodegenerative biomarkers on cognitive decline in community-dwelling older adults: A 10-year longitudinal study[J]. Alzheimers Dement,2025,21(2):e14594.
[2] Niu Q,Li D,Zhang J,et al.The new perspective of Alzheimer's disease research: Mechanism and therapeutic strategy of neuronal senescence[J].Ageing Res Rev,2024,102:102593.
[3] Chen D,Guo Y,Zhang M,et al.Exercise alleviates cognitive decline of natural aging rats by upregulating notch-mediated autophagy signaling[J]. Brain Res,2025,1850:149398.
[4] Calderon Martinez E,Zachariah Saji S,Salazar Ore JV,et al.The effects of omega-3,DHA,EPA,Souvenaid® in Alzheimer's disease: A systematic review and meta-analysis[J]. Neuropsychopharmacology Rep,2024,44(3):545-556.
[5] Ali Z,Al-Ghouti MA,Abou-Saleh H,et al.Unraveling the omega-3 puzzle: Navigating challenges and innovations for bone health and healthy aging[J]. Mar Drugs,2024,22(10):446.
[6] Yang L,Zhao F,Sun Y,et al.N-3 polyunsaturated fatty acids in elderly with mild cognitive impairment: A systemic review and meta-analysis[J].J Alzheimers Dis,2024,99(s1):s81-s95.
[7] Tian J,Zhang Y,Zhao X.The effects and mechanisms of n-3 and n-6 polyunsaturated fatty acids in the central nervous system[J].Cell Mol Neurobiol,2025,45(1):25.
[8] Lin G,Tang J,Zeng Y,et al.Association of serum n-3 and n-6 docosapentaenoic acids with cognitive performance in elderly adults: National Health and Nutrition Examination Survey 2011-2014[J].J Nutr Biochem,2025,135:109773.
[9] Hong Y,Wang Y,Shu W,et al.Mapping the immune-genetic architecture of aging: A single-cell causal framework for biomarker discovery and therapeutic targeting[J]. Ageing Res Rev,2025,111:102835.
[10] Wu Z,Qu J,Liu G H.Roles of chromatin and genome instability in cellular senescence and their relevance to ageing and related diseases[J].Nat Rev Mol Cell Biol,2024,25(12):979-1000.
[11] Suh SW,Lim E,Burm S,et al.The influence of n-3 polyunsaturated fatty acids on cognitive function in individuals without dementia: A systematic review and dose-response meta-analysis[J]. BMC Med,2024,22(1):109.
[12] Tseng P,Zeng B,Suen M,et al.Efficacy and acceptability of anti-inflammatory eicosapentaenoic acid for cognitive function in alzheimer's dementia: A network meta-analysis of randomized,placebo-controlled trials with omega-3 fatty acids and FDA-approved pharmacotherapy[J]. Brain Behav Immun,2023,111:352-364.
[13] Rossiello F,Jurk D,Passos JF,et al.Telomere dysfunction in ageing and age-related diseases[J]. Nat Cell Biol,2022,24(2):135-147.
[14] Maldonado E,Morales-Pison S,Urbina F,et al.Aging hallmarks and the role of oxidative stress[J]. Antioxidants,2023,12(3):651.
[15] Diukov Y,Bachinskaya N,Dzobak A,et al.Association of telomere length with cognitive impairment[J]. J Mol Neurosci,2023,73(7/8):448-455.
[16] Rodriguez-Fernandez B,Sanchez-Benavides G,Genius P,et al.Association between telomere length and cognitive function among cognitively unimpaired individuals at risk of alzheimer's disease[J]. Neurobiol Aging,2024,141:140-150.
[17] Gao S,Rohr JK,de Vivo I,et al. Telomere length,health,and mortality in a cohort of older black south african adults[J]. J Gerontol A Biol Sci Med Sci,2023,78(11):1983-1990.
[18] Chen C,Yang K,Nan H,et al.Associations of telomere length and change with cognitive decline were modified by sex and race: The REGARDS study[J]. Am J Alzheimers Dis Other Demen,2023,38:15333175231175797.
[19] Wu Y,Zhang Y,Jiao J.The relationship between n-3 polyunsaturated fatty acids and telomere: A review on proposed nutritional treatment against metabolic syndrome and potential signaling pathways[J]. Crit Rev Food Sci Nutr,2024,64(14):4457-4476.
[20] Chen J,Wu S,Wu Y,et al.Long-term dietary DHA intervention prevents telomere attrition and lipid disturbance in telomerase-deficient male mice[J]. Eur J Nutr,2023,62(4):1867-1878.
[21] Wu S,Wu Y,Chen J,et al.Lifelong docosahexaenoic acid intervention ameliorates aging in the telomere-DNA-mitochondria axis in telomerase-deficient mice[J]. J Nutr Biochem,2023,112:109202.
[22] Polom J,Boccardi V.Employing nutrition to delay aging: A plant-based telomere-friendly dietary revolution[J]. Nutrients,2025,17(12):2004.
[23] Lucke-Wold B,Zasler ND,Ruchika F,et al.Supplement and nutraceutical therapy in traumatic brain injury[J]. Nutr Neurosci,2025,28(6):709-743.
[24] Medoro A,Saso L,Scapagnini G,et al.NRF2 signaling pathway and telomere length in aging and age-related diseases[J]. Mol Cell Biochem,2024,479(10):2597-2613.
[25] Ji S,Xiong M,Chen H,et al.Cellular rejuvenation: Molecular mechanisms and potential therapeutic interventions for diseases[J]. Signal Transduct Target Ther,2023,8(1):116.
[26] Crous-Bou M,Lázaro I,Nadal-Zaragoza N,et al.Fatty acids and telomere length[J]. Curr Opin Clin Nutr Metab Care,2025,28(2):86-90.
[27] Wang Y,Kuca K,You L,et al.The role of cellular senescence in neurodegenerative diseases[J].Arch Toxicol,2024,98(8):2393-2408.
[28] Armstrong E,Boonekamp J.Does oxidative stress shorten telomeres in vivo? A Meta-analysis[J]. Ageing Res Rev,2023,85:101854.
[29] Jinesh S,Özüpek B,Aditi P.Premature aging and metabolic diseases: The impact of telomere attrition[J]. Front Aging,2025,6:1541127.
[30] Chatelin M,Drobniak SM,Szulkin M.The association between stressors and telomeres in non-human vertebrates: A Meta-analysis[J]. Ecol Lett,2020,23(2):381-398.
[31] Grytten E,Laupsa-Borge J,Cetin K,et al.Inflammatory markers after supplementation with marine n-3 or plant n-6 PUFAs: A randomized double-blind crossover study[J]. J Lipid Res,2025,66(4):100770.
[32] Wu S,Wu Y,Chen J,et al.Lifelong docosahexaenoic acid intervention ameliorates aging in the telomere-DNA-mitochondria axis in telomerase-deficient mice[J]. J Nutr Biochem,2023,112:109202.
[33] Assalve G,Lunetti P,Rocca MS,et al.Exploring the link between telomeres and mitochondria: Mechanisms and implications in different cell types[J]. Int J Mol Sci,2025,26(3):993.
[34] Holmannova D,Borsky P,Parova H,et al.Non-genomic hallmarks of aging-the review[J]. Int J Mol Sci,2023,24(20):15468.
[35] Lin J,Epel E.Stress and telomere shortening:Insights from cellular mechanisms[J]. Ageing Res Rev,2022,73:101507.

基金资助

国家自然科学基金项目（82204011）; 河北省自然科学基金项目（H2024206447）