Cellular senescence induction leads to progressive cell death via the INK4a-RB pathway in naked mole-rats.

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.

Carcinogenesis resistance in the longest-lived rodent, the naked mole-rat.

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.

Returning long-range PM2.5 transport into the leeward of East Asia in 2021 after Chinese economic recovery from the COVID-19 pandemic.

Changes in the aerosol composition of sulfate (SO42-) and nitrate (NO3-) from 2012 to 2019 have been captured as a paradigm shift in the region downwind of China. Specifically, SO42- dramatically decreased and NO3- dramatically increased over downwind locations such as western Japan due to the faster reduction of SO2 emissions than NOx emissions and the almost constant trend of NH3 emissions from China. Emissions from China sharply decreased during COVID-19 lockdowns in February-March 2020, after which China's economic situation seemed to recover going into 2021. Given this substantial change in Chinese emissions, it is necessary to clarify the impact of long-range PM2.5 transport into the leeward of East Asia. In this study, ground-based aerosol compositions observed at three sites in western Japan were analysed. The concentrations of PM2.5, SO42- and NO3- decreased in 2020 (during COVID-19) compared with 2018-2019 (before COVID-19). In 2021 (after COVID-19), PM2.5 and NO3- increased and SO42- was unchanged. This suggests the returning long-range PM2.5 transport in 2021. From numerical simulations, the status of Chinese emissions during COVID-19 did not explain this returning impact in 2021. This study shows that the status of Chinese emissions in 2021 recovered to that before COVID-19.

Resistance to chemical carcinogenesis induction via a dampened inflammatory response in naked mole-rats.

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.

Isolation and characterization of neural stem/progenitor cells in the subventricular zone of the naked mole-rat brain.

BACKGROUND: The naked mole-rat (NMR) is the longest-lived rodent with a maximum lifespan of more than 37 years and shows a negligible senescence phenotype, suggesting that tissue stem cells of NMRs are highly capable of maintaining homeostasis. However, the properties of NMR tissue stem cells, including neural stem cells (NSCs), are largely unclear. METHODS: Neural stem/progenitor cells (NS/PCs) were isolated from the subventricular zone of the neonate NMR brain (NMR-NS/PCs) and cultured in neurosphere and adherent culture conditions. Expression of NSC markers and markers of neurons, astrocytes, and oligodendrocytes was analyzed by immunocytochemistry. In adherent culture conditions, the proliferation rate and cell cycle of NMR-NS/PCs were assessed and compared with those of NS/PCs from mice (mouse-NS/PCs). The DNA damage response to γ-irradiation was analyzed by immunocytochemistry and reverse transcription-quantitative PCR. RESULTS: NMR-NS/PCs expressed several NSC markers and differentiated into neurons, astrocytes, and oligodendrocytes. NMR-NS/PCs proliferated markedly slower than mouse-NS/PCs, and a higher percentage of NMR-NS/PCs than mouse-NS/PCs was in G0/G1 phase. Notably, upon γ-irradiation, NMR-NS/PCs exhibited a faster initiation of the DNA damage response and were less prone to dying than mouse-NS/PCs. CONCLUSIONS: NMR-NS/PCs were successfully isolated and cultured. The slow proliferation of NMR-NS/PCs and their resistance to DNA damage may help to prevent stem cell exhaustion in the brain during the long lifespan of NMRs. Our findings provide novel insights into the mechanism underlying delayed aging of NMRs. Further analysis of NMR tissue stem cells may lead to the development of new strategies that can prevent aging in humans.

Association of Protein and Endotoxin in Outdoor Air with Emergency Department Visits for Children and Adults with Asthma in Fukuoka, Japan.

We examined the association of biological components in airborne particles, i.e., proteins and endotoxins, in outdoor air with asthma exacerbation in the Fukuoka metropolitan area, Fukuoka, Japan. Data on emergency department (ED) visits for asthma in children (age, 0-14 years) and adults (age, 15-64 years) were collected at a medical center from December 2014 to November 2015. One hundred eighty-one children and 143 adults visited the ED for asthma, and the weekly number of ED visits in children increased in autumn, i.e., September (second week) to November (first week). Fine (aerodynamic diameter ≤2.5 µm) and coarse (≥2.5 µm) particles were collected for 3 or 4 weeks per month, and protein and endotoxin concentrations were analyzed. Protein was largely prevalent in fine particles (0.34-7.33 µg/m3), and concentrations were high in April, May, June, and October. In contrast, endotoxin was mainly included in coarse particles (0.0010-0.0246 EU/m3), and concentrations were high in September (third week), October (first, second, and fourth weeks), February (fourth week), and July (first week). The results of a Poisson regression analysis indicated that endotoxin (in fine and coarse particles alike) was a significant factor for ED visits related to asthma in children, even after adjusting for meteorological factors, i.e., temperature, relative humidity, and wind speed. However, there was no association between environmental factors and ED visits for asthma in adults. These results suggest that endotoxin in outdoor air is significantly associated with an increased risk of asthma exacerbation in children.

Paradigm shift in aerosol chemical composition over regions downwind of China.

A rapid decrease in PM2.5 concentrations in China has been observed in response to the enactment of strong emission control policies. From 2012 to 2017, total emissions of SO2 and NOx from China decreased by approximately 63% and 24%, respectively. Simultaneously, decreases in the PM2.5 concentration in Japan have been observed since 2014, and the proportion of stations that satisfy the PM2.5 environmental standard (daily, 35 µg/m3; annual average, 15 µg/m3) increased from 37.8% in fiscal year (FY) 2014 (April 2014 to March 2015) to 89.9% in FY 2017. However, the quantitative relationship between the PM2.5 improvement in China and the PM2.5 concentration in downwind regions is not well understood. Here, we (1) quantitatively evaluate the impacts of Chinese environmental improvements on downwind areas using source/receptor analysis with a chemical transport model, and (2) show that these rapid emissions reductions improved PM2.5 concentrations both in China and its downwind regions, but the difference between SO2 and NOx reduction rates led to greater production of nitrates (e.g., NH4NO3) due to a chemical imbalance in the ammonia-nitric acid-sulfuric acid-water system. Observations from a clean remote island in western Japan and numerical modeling confirmed this paradigm shift.