Authorship：Lead author   Language：Japanese   Publisher：(株)診断と治療社  

＜文献概要＞Headline・最長寿齧歯類ハダカデバネズミは老化耐性・がん化耐性を有し,近年,医学研究の観点から注目を集めている.・ハダカデバネズミは化学発がん誘導に対して顕著な抵抗性を示し,炎症誘導性細胞死であるネクロプトーシス誘導能の欠失による炎症抑制が関与していると考えられる.・ハダカデバネズミの老化細胞は種特異的な機構で細胞死を起こし,老化細胞の蓄積抑制に寄与していると考えられる.・ハダカデバネズミの生体内における発がん抑制には,複数の機構による種特異的な組織の炎症抑制が重要な役割を果たしていると考えられる.

Authorship：Lead author   Language：Japanese   Publisher：医歯薬出版(株)  

ハダカデバネズミ(以下,デバ)は,マウスと同程度の大きさでありながら最大寿命が37年もある最長寿齧歯類である.また,デバは加齢に伴う死亡率の上昇が認められておらず,循環機能や生殖能などの生理的機能の加齢による低下も認められていない.さらに,がんやアルツハイマー病などの加齢性疾患への罹患がほとんど確認されていない.つまり,デバは老化およびがんなどの加齢性疾患に対して顕著な抵抗性を示す哺乳類であり,"老化/がん化抑制法"の開発のための新たなモデル動物として注目されている.本種の老化耐性の分子生物学的機構についてはいまだに不明な部分が多いものの,近年の研究により少しずつ明らかになりつつある.本稿では,一般に老化や加齢性疾患との関連が報告されている,DNA損傷に対する修復機構やタンパク質の恒常性,細胞老化についてのデバのこれまでの知見,ならびに最近,筆者らが報告したデバ特有のセロトニン代謝制御が引き起こす老化細胞死による内因性の老化細胞の除去機構について紹介する.(著者抄録)

Language：Japanese   Publisher：(一社)日本認知症学会  

Authorship：Lead author,　Corresponding author   Language：English  

Naked mole-rats (NMRs) have exceptional longevity and are resistant to age-related physiological decline and diseases. Given the role of cellular senescence in aging, we postulated that NMRs possess unidentified species-specific mechanisms to prevent senescent cell accumulation. Here, we show that upon induction of cellular senescence, NMR fibroblasts underwent delayed and progressive cell death that required activation of the INK4a-retinoblastoma protein (RB) pathway (termed "INK4a-RB cell death"), a phenomenon not observed in mouse fibroblasts. Naked mole-rat fibroblasts uniquely accumulated serotonin and were inherently vulnerable to hydrogen peroxide (H2 O2 ). After activation of the INK4a-RB pathway, NMR fibroblasts increased monoamine oxidase levels, leading to serotonin oxidization and H2 O2 production, which resulted in increased intracellular oxidative damage and cell death activation. In the NMR lung, induction of cellular senescence caused delayed, progressive cell death mediated by monoamine oxidase activation, thereby preventing senescent cell accumulation, consistent with in vitro results. The present findings indicate that INK4a-RB cell death likely functions as a natural senolytic mechanism in NMRs, providing an evolutionary rationale for senescent cell removal as a strategy to resist aging.

DOI： 10.15252/embj.2022111133

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

Abstract

In mammalian mitochondria, translation of the AUA codon is supported by 5-formylcytidine (f⁵C) modification in the mitochondrial methionine tRNA anticodon. The 5-formylation is initiated by NSUN3 methylase. Human NSUN3 mutations are associated with mitochondrial diseases. Here we show that Nsun3 is essential for embryonic development in mice with whole-body Nsun3 knockout embryos dying between E10.5 and E12.5. To determine the functions of NSUN3 in adult tissue, we generated heart-specific Nsun3 knockout (Nsun3^HKO) mice. Nsun3^HKO heart mitochondria were enlarged and contained fragmented cristae. Nsun3^HKO resulted in enhanced heart contraction and age-associated mild heart enlargement. In the Nsun3^HKO hearts, mitochondrial mRNAs that encode respiratory complex subunits were not down regulated, but the enzymatic activities of the respiratory complexes decreased, especially in older mice. Our study emphasizes that mitochondrial tRNA anticodon modification is essential for mammalian embryonic development and shows that tissue-specific loss of a single mitochondrial tRNA modification can induce tissue aberration that worsens in later adulthood.

DOI： 10.1038/s42003-023-04680-x

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Other Link： https://www.nature.com/articles/s42003-023-04680-x

Publishing type：Research paper (scientific journal)   Publisher：Annual Reviews  

Naked mole-rats (NMRs, Heterocephalus glaber) are the longest-lived rodents with a maximum life span exceeding 37 years. They exhibit a delayed aging phenotype and resistance to age-related functional decline/diseases. Specifically, they do not display increased mortality with age, maintain several physiological functions until nearly the end of their lifetime, and rarely develop cancer and Alzheimer's disease. NMRs live in a hypoxic environment in underground colonies in East Africa and are highly tolerant of hypoxia. These unique characteristics of NMRs have attracted considerable interest from zoological and biomedical researchers. This review summarizes previous studies of the ecology, hypoxia tolerance, longevity/delayed aging, and cancer resistance of NMRs and discusses possible mechanisms contributing to their healthy aging. In addition, we discuss current issues and future perspectives to fully elucidate the mechanisms underlying delayed aging and resistance to age-related diseases in NMRs.

Expected final online publication date for the Annual Review of Animal Biosciences, Volume 11 is February 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI： 10.1146/annurev-animal-050322-074744

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Authorship：Lead author   Language：Japanese   Publisher：(株)ニュー・サイエンス社  

ハダカデバネズミ(デバ)はその奇妙な外見や,アリやハチのような特殊な社会形態のみならず,近年,医学研究の観点からも注目を集めている。デバはマウスと同程度の体格の小型齧歯類であるが,最大寿命が37年以上と極めて長寿である。しかもその生存期間の8割もの間,老化の兆候を示さず,加齢に伴う死亡率の上昇も認められない。さらに,これまで自発的な腫瘍形成はほとんど確認されていない。つまりデバは,老化およびがんなどの老化関連疾患に対して顕著な抵抗性を示す哺乳類であることから,「老化・がん化抑制法」の開発のための新たなモデル動物になり得ると考えられている。本稿では,老化・がん化耐性齧歯類であるデバの特徴と最近の研究について紹介する。(著者抄録)

Language：English   Publishing type：Research paper (scientific journal)  

Certain mammalian species are resistant to cancer, and a better understanding of how this cancer resistance arises could provide valuable insights for basic cancer research. Recent technological innovations in molecular biology have allowed the study of cancer-resistant mammals, despite the fact that they are not the classical model animals, which are easily studied using genetic approaches. Naked mole-rats (NMRs, Heterocephalus glaber) are the longest-lived rodent, with a maximum lifespan of more than 37 years, and almost never show spontaneous carcinogenesis. NMRs are currently attracting much attention from aging and cancer researchers, and published studies on NMR have continued to increase over the past decade. Cancer development occurs via multiple steps and involves many biological processes. Recent research on the NMR as a model for cancer resistance suggests that they possess various unique carcinogenesis-resistance mechanisms, including efficient DNA repair pathways, cell-autonomous resistance to transformation, and dampened inflammatory response. Here, we summarize the molecular mechanisms of carcinogenesis-resistance in NMR, which have been uncovered over the past two decades, and discuss future perspectives.

DOI： 10.1111/cas.15570

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Paraspeckles are mammalian-specific nuclear bodies built on the long noncoding RNA NEAT1_2. The molecular mechanisms of paraspeckle formation have been mainly studied using human or mouse cells, and it is not known if the same molecular components are involved in the formation of paraspeckles in other mammalian species. We thus investigated the expression pattern of NEAT1_2 in naked mole-rats (nNEAT1_2), which exhibit extreme longevity and lower susceptibility to cancer. In the intestine, nNEAT1_2 is widely expressed along the entire intestinal epithelium, which is different from the expression of mNeat1_2, that is restricted to the cells of the distal tip in mice. Notably, the expression of FUS, a FET family RNA binding protein, essential for the formation of paraspeckles both in humans and mice, was absent in the distal part of the intestinal epithelium in naked mole-rats. Instead, mRNAs of other FET family proteins EWSR1 and TAF15 were expressed in the distal region. Exogenous expression of these proteins in Fus-deficient murine embryonic fibroblast cells rescued the formation of paraspeckles. These observations suggest that nNEAT1_2 recruits different set of RNA binding proteins in a cell type-specific manner during the formation of paraspeckles in different organisms.

DOI： 10.1261/rna.079135.122

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Naked mole-rats (NMRs) have a very low spontaneous carcinogenesis rate, which has prompted studies on the responsible mechanisms to provide clues for human cancer prevention. However, it remains unknown whether and how NMR tissues respond to experimental carcinogenesis induction. Here, we show that NMRs exhibit extraordinary resistance against potent chemical carcinogenesis induction through a dampened inflammatory response. Although carcinogenic insults damaged skin cells of both NMRs and mice, NMR skin showed markedly lower immune cell infiltration. NMRs harbour loss-of-function mutations in RIPK3 and MLKL genes, which are essential for necroptosis, a type of necrotic cell death that activates strong inflammation. In mice, disruption of Ripk3 reduced immune cell infiltration and delayed carcinogenesis. Therefore, necroptosis deficiency may serve as a cancer resistance mechanism via attenuating the inflammatory response in NMRs. Our study sheds light on the importance of a dampened inflammatory response as a non-cell-autonomous cancer resistance mechanism in NMRs.

DOI： 10.1038/s42003-022-03241-y

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Language：English   Publisher：Frontiers in Immunology  

Severe combined immunodeficiency (SCID) is an inborn error of immunity that occurs in approximately 1 in 50,000 births, mainly due to impaired lymphocyte differentiation. Without curative treatment, such as hematopoietic cell transplantation (HCT) or gene therapy, severe infection in the first year of life could make this condition fatal. The results of HCT are poor when patients have active infections, thus requiring early diagnosis before onset of infection. In five cases of SCID diagnosed in Japan, the oral rotavirus vaccine had been administered before diagnosis. In this study, we demonstrated that the rotavirus from their stools was a vaccine-derived strain. In some cases, severe gastroenteritis triggered the diagnosis of SCID. However, newborn screening for SCID is available before the first rotavirus vaccination using assays for the detection of T-cell receptor excision circles (TRECs). Therefore, to improve the prognosis of patients with SCID in Japan, we should establish a screening system of TRECs for newborns throughout Japan.

DOI： 10.3389/fimmu.2022.786375

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Authorship：Lead author   Language：Japanese   Publisher：(株)羊土社  

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Language：Japanese   Publisher：(公社)日本実験動物協会  

Authorship：Lead author   Language：Japanese   Publishing type：Article, review, commentary, editorial, etc. (scientific journal)  

DOI： 10.34433/dt.0000000909

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Language：Japanese   Publisher：医歯薬出版(株)  

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Other Link： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J00060&link_issn=&doc_id=20231107020015&doc_link_id=issn%3D0039-2359%26volume%3D287%26issue%3D5%26spage%3D399&url=http%3A%2F%2Fwww.pieronline.jp%2Fopenurl%3Fissn%3D0039-2359%26volume%3D287%26issue%3D5%26spage%3D399&type=PierOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00005_2.gif

Language：Japanese   Publisher：(一社)日本認知症学会  

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Language：English   Publisher：John Wiley & Sons Australia, Ltd  

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