Wu Shanyun, Wu Yuqi, Chen Jingnan, Zhuang Pan, Zhang Yu, Jiao Jingjing
Department of Endocrinology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, P R China; National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, Zhejiang, P R China.
National Engineering Laboratory of Intelligent Food Technology and Equipment, Zhejiang Key Laboratory for Agro-Food Processing, College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou, Zhejiang, P R China.
J Nutr Biochem. 2023 Feb;112:109202. doi: 10.1016/j.jnutbio.2022.109202. Epub 2022 Nov 6.
The health benefits of n-3 polyunsaturated fatty acids (PUFAs) in multiple age-related diseases are associated with telomere length. Telomerase is intimately related to inflammation and oxidative stress, but whether the underlying function of n-3 PUFAs on telomere maintenance is based on telomerase activation or related mechanisms remains unclear. Herein, we utilized late-generation (G4) telomerase-deficient (Terc) mice to perform a lifelong docosahexaenoic acid (DHA) intervention to determine the potential of DHA in telomere maintenance and health promotion. Unfortunately, DHA failed to prolong mouse longevity in either intrinsic or premature aging. However, intriguingly, lifelong dietary DHA intervention slowed the aging phenotypes and profoundly attenuated telomere attrition in blood leukocytes and multiple tissues, consistent with decreased β-galactosidase activity and other senescence hallmarks with no observed sex differences. Notably, DHA intervention alleviated telomere attrition-induced γ-H2AX accumulation dependent on poly (ADP-ribose) polymerase 1 (PARP1) recruitment, and further regulated mitochondrial dysfunction critically involved in the DNA damage response. Together with the improvement of mitochondria function, the blocked reactive oxygen species (ROS) accumulation and suppression of the nuclear factor-κB (NF-κB)/nucleotide-binding domain-like receptor protein 3 (NLRP3)/caspase-1 pathways partially indicated anti-oxidative and anti-inflammatory effects of DHA. These data revealed a regulatory paradigm involving DHA in the telomere-DNA-mitochondria feedback loop mediated by DNA damage response and inflammation in alleviating senescence, which may hold potential as a translatable intervention in telomere-related diseases during aging.
n-3多不饱和脂肪酸（PUFA）对多种与年龄相关疾病的健康益处与端粒长度有关。端粒酶与炎症和氧化应激密切相关，但n-3多不饱和脂肪酸在端粒维持方面的潜在功能是基于端粒酶激活还是相关机制仍不清楚。在此，我们利用晚期（G4）端粒酶缺陷（Terc）小鼠进行终生二十二碳六烯酸（DHA）干预，以确定DHA在端粒维持和促进健康方面的潜力。不幸的是，DHA未能延长小鼠的内在寿命或早衰寿命。然而，有趣的是，终生饮食DHA干预减缓了衰老表型，并显著减轻了血液白细胞和多个组织中的端粒磨损，这与β-半乳糖苷酶活性降低和其他衰老特征一致，且未观察到性别差异。值得注意的是，DHA干预减轻了端粒磨损诱导的γ-H2AX积累，这依赖于聚（ADP-核糖）聚合酶1（PARP1）的募集，并进一步调节了与DNA损伤反应密切相关的线粒体功能障碍。随着线粒体功能的改善，活性氧（ROS）积累的阻断以及核因子-κB（NF-κB）/核苷酸结合寡聚化结构域样受体蛋白3（NLRP3）/半胱天冬酶-1途径的抑制部分表明了DHA的抗氧化和抗炎作用。这些数据揭示了一种涉及DHA的调节模式，即在由DNA损伤反应和炎症介导的端粒-DNA-线粒体反馈回路中减轻衰老，这可能作为衰老过程中端粒相关疾病的可转化干预措施具有潜力。
