长寿命和抗癌地下野生啮齿动物Spalax衰老的成纤维细胞和衰老组织中炎症网络的下调。,Aging Cell

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长寿命和抗癌地下野生啮齿动物Spalax衰老的成纤维细胞和衰老组织中炎症网络的下调。
Aging Cell ( IF 8.0 ) Pub Date : 2019-10-11 , DOI: 10.1111/acel.13045
Amani Odeh ₁ , Maria Dronina ₂ , Vered Domankevich ₁ , Imad Shams _{1,

2} , Irena Manov ₂

Affiliation

盲mole鼠（Spalax）是一种野生的，长寿的啮齿动物，已经进化出耐受缺氧和抵抗癌症的机制。以前，与大鼠相比，我们证明了遗传毒性应激后Spalax成纤维细胞具有高DNA修复能力和低DNA损伤。由于衰老相关分泌表型（SASP）的获得是持续性DNA损伤的结果，因此我们研究了Spalax中的细胞衰老是否伴随炎症反应。斯帕克斯成纤维细胞经历复制性衰老（RS）和依托泊苷诱导的衰老（EIS），其表现为衰老相关的β-半乳糖苷酶（SA-β-Gal）活性增加，生长停滞以及p21，p16和p53 mRNA的过表达。然而，与小鼠和人类成纤维细胞不同，RS和EIS Spalax细胞显示出无法检测到或降低的SASP因子的表达：白介素-6（IL6），IL8，IL1α，与生长相关的癌基因α（GROα），SerpinB2和细胞间粘附分子（ICAM-1）。显然，由于Spalax中有效的DNA修复，衰老细胞没有积累SASP激活所需的DNA损伤。相反，Spalax可以在复制性或中度遗传毒性胁迫期间维持DNA完整性，并限制促炎性分泌。但是，暴露于乳腺癌细胞MDA-MB-231的条件培养基中会导致DNA损伤增加，通过核易位激活核因子κB（NF-κB）以及在RS Spalax细胞中表达炎症介质。对衰老的Spalax脑和肠中SASP的评估证实了炎症相关基因的下调。这些发现表明，缓解Spalax细胞衰老和衰老过程中炎症反应的自然机制可以预防与年龄有关的慢性炎症，从而支持健康的衰老和长寿。

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Downregulation of the inflammatory network in senescent fibroblasts and aging tissues of the long-lived and cancer-resistant subterranean wild rodent, Spalax.

The blind mole rat (Spalax) is a wild, long‐lived rodent that has evolved mechanisms to tolerate hypoxia and resist cancer. Previously, we demonstrated high DNA repair capacity and low DNA damage in Spalax fibroblasts following genotoxic stress compared with rats. Since the acquisition of senescence‐associated secretory phenotype (SASP) is a consequence of persistent DNA damage, we investigated whether cellular senescence in Spalax is accompanied by an inflammatory response. Spalax fibroblasts undergo replicative senescence (RS) and etoposide‐induced senescence (EIS), evidenced by an increased activity of senescence‐associated beta‐galactosidase (SA‐β‐Gal), growth arrest, and overexpression of p21, p16, and p53 mRNAs. Yet, unlike mouse and human fibroblasts, RS and EIS Spalax cells showed undetectable or decreased expression of the well‐known SASP factors: interleukin‐6 (IL6), IL8, IL1α, growth‐related oncogene alpha (GROα), SerpinB2, and intercellular adhesion molecule (ICAM‐1). Apparently, due to the efficient DNA repair in Spalax, senescent cells did not accumulate the DNA damage necessary for SASP activation. Conversely, Spalax can maintain DNA integrity during replicative or moderate genotoxic stress and limit pro‐inflammatory secretion. However, exposure to the conditioned medium of breast cancer cells MDA‐MB‐231 resulted in an increase in DNA damage, activation of the nuclear factor κB (NF‐κB) through nuclear translocation, and expression of inflammatory mediators in RS Spalax cells. Evaluation of SASP in aging Spalax brain and intestine confirmed downregulation of inflammatory‐related genes. These findings suggest a natural mechanism for alleviating the inflammatory response during cellular senescence and aging in Spalax, which can prevent age‐related chronic inflammation supporting healthy aging and longevity.

更新日期：2019-10-11

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