α-Terpineol Induces Shelterin Components TRF1 and TRF2 to Mitigate Senescence and Telomere Integrity Loss via A Telomerase-Independent Pathway.

IF 6 2区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Antioxidants Pub Date : 2024-10-17 DOI:10.3390/antiox13101258
Marianna Kapetanou, Sophia Athanasopoulou, Andreas Goutas, Dimitra Makatsori, Varvara Trachana, Efstathios Gonos
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Abstract

Cellular senescence is a hallmark of aging characterized by irreversible growth arrest and functional decline. Progressive telomeric DNA shortening in dividing somatic cells, programmed during development, leads to critically short telomeres that trigger replicative senescence and thereby contribute to aging. Therefore, protecting telomeres from DNA damage is essential in order to avoid entry into senescence and organismal aging. In several organisms, including mammals, telomeres are protected by a protein complex named shelterin that prevents DNA damage at the chromosome ends through the specific function of its subunits. Here, we reveal that the nuclear protein levels of shelterin components TRF1 and TRF2 decline in fibroblasts reaching senescence. Notably, we identify α-terpineol as an activator that effectively enhances TRF1 and TRF2 levels in a telomerase-independent manner, counteracting the senescence-associated decline in these crucial proteins. Moreover, α-terpineol ameliorates the cells' response to oxidative DNA damage, particularly at the telomeric regions, thus preserving telomere length and delaying senescence. More importantly, our findings reveal the significance of the PI3K/AKT pathway in the regulation of shelterin components responsible for preserving telomere integrity. In conclusion, this study deepens our understanding of the molecular pathways involved in senescence-associated telomere dysfunction and highlights the potential of shelterin components to serve as targets of therapeutic interventions, aimed at promoting healthy aging and combating age-related diseases.

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α-松油醇通过端粒酶依赖性途径诱导保护素成分TRF1和TRF2减轻衰老和端粒完整性损失
细胞衰老是衰老的一个标志,其特征是不可逆转的生长停滞和功能衰退。在发育过程中,分裂的体细胞中端粒DNA会逐渐缩短,导致端粒极短,引发复制衰老,从而导致衰老。因此,为了避免进入衰老和机体老化,保护端粒免受DNA损伤至关重要。在包括哺乳动物在内的一些生物体中,端粒受到一种名为 "保护蛋白"(shelterin)的蛋白质复合物的保护,该复合物通过其亚基的特定功能防止染色体末端的DNA损伤。在这里,我们揭示了在进入衰老期的成纤维细胞中,保护蛋白成分TRF1和TRF2的核蛋白水平会下降。值得注意的是,我们发现α-松油醇是一种激活剂,能以端粒酶无关的方式有效提高TRF1和TRF2的水平,从而抵消衰老相关的这些关键蛋白水平的下降。此外,α-松油醇还能改善细胞对氧化DNA损伤的反应,尤其是在端粒区域,从而保持端粒长度并延缓衰老。更重要的是,我们的研究结果揭示了 PI3K/AKT 通路在调控负责维护端粒完整性的保护蛋白成分中的重要作用。总之,这项研究加深了我们对参与衰老相关端粒功能障碍的分子途径的理解,并强调了保护蛋白成分作为治疗干预靶点的潜力,旨在促进健康衰老和防治与年龄相关的疾病。
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来源期刊
Antioxidants
Antioxidants Biochemistry, Genetics and Molecular Biology-Physiology
CiteScore
10.60
自引率
11.40%
发文量
2123
审稿时长
16.3 days
期刊介绍: Antioxidants (ISSN 2076-3921), provides an advanced forum for studies related to the science and technology of antioxidants. It publishes research papers, reviews and communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced. Electronic files and software regarding the full details of the calculation or experimental procedure, if unable to be published in a normal way, can be deposited as supplementary electronic material.
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