bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒08‒08
twenty-two papers selected by
Ayesh Seneviratne
University of Toronto
  1. Senescence and aging of solid organs? Blame the immune system!
  2. The role of caloric intake in the association of high salt intake with high blood pressure.
  3. Self-rated health trajectory and frailty among community-dwelling older adults: evidence from the Taiwan Longitudinal Study on Aging (TLSA).
  4. TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate.
  5. Ending on a sour note: Lipids orchestrate ferroptosis in cancer.
  6. Clonal hematopoiesis and myeloid malignancies: clonal dynamics and clinical implications.
  7. Hematopoietic stem cells in wound healing response.
  8. Role of Melatonin in Angiotensin and Aging.
  9. Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies.
  10. Infection makes micro-CHIPs into macro-CHIPs.
  11. Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging.
  12. Targeting leukemia-specific dependence on the de novo purine synthesis pathway.
  13. Premature Aging in Chronic Kidney Disease: The Outcome of Persistent Inflammation beyond the Bounds.
  14. Genetic insights into biological mechanisms governing human ovarian ageing.
  15. Surviving Covid-19 with Heparin?
  16. Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty.
  17. The effects of the Dietary Approaches to Stop Hypertension (DASH) diet on metabolic risk factors in patients with chronic disease: A systematic review and meta-analysis of randomized controlled trials.
  18. Understanding the "SMART" features of hematopoietic stem cells and beyond.
  19. Recent trends and increasing differences in life expectancy present opportunities for multidisciplinary research on aging.
  20. Lipid regulation of NLRP3 inflammasome activity through organelle stress.
  21. The life in a gradient: calcium, the lncRNA SPRR2C and mir542/mir196a meet in the epidermis to regulate the aging process.
  22. Traditional Chinese Medicine and Western Medicine Share Similar Philosophical Approaches to Fight COVID-19.
  1. Am J Transplant. 2021 Aug;21(8): 2627
    Senescence and aging of solid organs? Blame the immune system!
    Xian C Li.
      
    DOI:  https://doi.org/10.1111/ajt.16040
  2. Sci Rep. 2021 Aug 04. 11(1): 15803
    The role of caloric intake in the association of high salt intake with high blood pressure.
    Naftali Stern, Assaf Buch, Rebecca Goldsmith, Lesley Nitsan, Miri Margaliot, Ronit Endevelt, Yonit Marcus, Gabi Shefer, Itamar Grotto.
      Since current recommendations call for a substantial reduction in overall sodium consumption, we tested whether or not these recommendations are implemented in common large subpopulations such as those with abnormal weight or hypertension in the current high sodium, high-calorie nutritional environment. In a national representative cross-sectional survey of the community-dwelling subjects aged 25-65 years conducted in Israel between 2015 and 2017, 582 randomly selected subjects completed health and dietary questionnaires, underwent blood pressure and anthropometric measurements and collected 24-h urine specimens, to assess dietary sodium intake. Overall mean 24-h sodium excretion was 3834 mg, more than double the recommended upper intake for adults < 1500 mg/day. Sodium excretion was directly related to caloric intake and blood pressure and linked to the presence of hypertension and overweight/obesity. The highest sodium excretion was seen in overweight/obese hypertensive subjects. This recent national survey shows a high consumption of sodium in the Israeli population and a dose-response association between caloric intake and urinary sodium excretion, independent of BMI and hypertension. Nevertheless, overweight/obese subjects with hypertension consume (excrete) more sodium than other BMI/ blood pressure-related phenotypes and may thus comprise a target subpopulation for future efforts to reduce sodium intake.
    DOI:  https://doi.org/10.1038/s41598-021-95216-y
  3. BMJ Open. 2021 Aug 06. 11(8): e049795
    Self-rated health trajectory and frailty among community-dwelling older adults: evidence from the Taiwan Longitudinal Study on Aging (TLSA).
    Wei-Min Chu, Hsin-En Ho, Chih-Jung Yeh, Yu-Han Hsiao, Pi-Shan Hsu, Shu-Hsin Lee, Meng-Chih Lee.
      OBJECTIVES: Self-rated health (SRH) is an assessment and predictor of health based on an individual's general condition; however, evidence of the value of SRH for predicting frailty remains scarce for older Asian adults. This study aimed to evaluate the relationship between SRH score trajectory and frailty among older individuals in Taiwan.DESIGN: An 8-year retrospective cohort study.
    SETTING: Data were retrieved from the Taiwan Longitudinal Study on Aging from 1999 to 2007.
    PARTICIPANTS: Respondents aged 53-69 years old who were not frail or disabled in 1999 (n=1956).
    PRIMARY AND SECONDARY OUTCOME MEASURES: Frailty was defined using the Fried criteria. The group-based trajectory modelling technique was used to estimate SRH trajectories. Logistic regression analysis was used to examine the associations between changes in SRH and frailty.
    RESULTS: Four SRH trajectory classes were identified across the 8-year follow-up: 232 participants (11.9%) were classified into the constantly poor SRH group, 1123 (57.4%) into the constantly fair SRH group, 335 (17.1%) into the constantly good SRH group and 266 (13.6%) into the good-to-fair SRH group. After adjusting for gender, age, level of education, income, social participation, health behaviours and major comorbidities, it was found that age, poor income satisfaction, without job and constantly poor SRH were associated with increased risk of frailty, while constantly good SRH (OR 0.04, 95% CI (0.01 to 0.32)) and good-to-fair SRH (OR 0.19, 95% CI (0.06 to 0.63)) were associated with reduced risks of frailty.
    CONCLUSIONS: Constantly poor SRH was associated with an increased risk of frailty in older age. SRH in older adults should be recognised as a predictive tool for future frailty. Diet and exercise interventions may help to prevent frailty among high-risk older individuals with constantly low SRH.
    Keywords:  epidemiology; geriatric medicine; public health
    DOI:  https://doi.org/10.1136/bmjopen-2021-049795
  4. Cell Stem Cell. 2021 Jul 28. pii: S1934-5909(21)00288-5. [Epub ahead of print]
    TFEB-mediated endolysosomal activity controls human hematopoietic stem cell fate.
    Laura García-Prat, Kerstin B Kaufmann, Florin Schneiter, Veronique Voisin, Alex Murison, Jocelyn Chen, Michelle Chan-Seng-Yue, Olga I Gan, Jessica L McLeod, Sabrina A Smith, Michelle C Shoong, Darrien Parris, Kristele Pan, Andy G X Zeng, Gabriela Krivdova, Kinam Gupta, Shin-Ichiro Takayanagi, Elvin Wagenblast, Weijia Wang, Mathieu Lupien, Timm Schroeder, Stephanie Z Xie, John E Dick.
      It is critical to understand how human quiescent long-term hematopoietic stem cells (LT-HSCs) sense demand from daily and stress-mediated cues and then transition into bioenergetically active progeny to differentiate and meet these cellular needs. However, the demand-adapted regulatory circuits of these early steps of hematopoiesis are largely unknown. Here we show that lysosomes, sophisticated nutrient-sensing and signaling centers, are regulated dichotomously by transcription factor EB (TFEB) and MYC to balance catabolic and anabolic processes required for activating LT-HSCs and guiding their lineage fate. TFEB-mediated induction of the endolysosomal pathway causes membrane receptor degradation, limiting LT-HSC metabolic and mitogenic activation, promoting quiescence and self-renewal, and governing erythroid-myeloid commitment. In contrast, MYC engages biosynthetic processes while repressing lysosomal catabolism, driving LT-HSC activation. Our study identifies TFEB-mediated control of lysosomal activity as a central regulatory hub for proper and coordinated stem cell fate determination.
    Keywords:  MYC; TFEB; TfR1; anabolism; endocytosis; erythropoiesis; long-term HSC; lysosomes; myelopoiesis; self-renewal
    DOI:  https://doi.org/10.1016/j.stem.2021.07.003
  5. Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00327-2. [Epub ahead of print]33(8): 1507-1509
    Ending on a sour note: Lipids orchestrate ferroptosis in cancer.
    Mike Lange, James A Olzmann.
      Lipid metabolism is altered in the acidic tumor microenvironment. Here, the authors show that polyunsaturated fatty acid supplementation, together with concomitant inhibition of lipid droplet biogenesis, induces ferroptosis in acidic cancer cells. These findings highlight the potential to exploit cancer dependence on exogenous lipids as a therapeutic vulnerability.
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.011
  6. Curr Opin Hematol. 2021 Aug 02.
    Clonal hematopoiesis and myeloid malignancies: clonal dynamics and clinical implications.
    Chiara Elena, Anna Gallì, Elisa Bono, Gabriele Todisco, Luca Malcovati.
      PURPOSE OF REVIEW: Clinical and experimental studies have uncovered relevant clinical implications of clonal hematopoiesis. However, the true magnitude of this process, clonal dynamics over time and mechanisms of progression into overt malignancy remain to be largely elucidated. In this article, the consequences of clonal hematopoiesis, its significance in the context of cytopenia, and its implications in the clinical management of patients with myeloid malignancies are reviewed and discussed.RECENT FINDINGS: Clonal hematopoiesis has been associated with higher risk of hematologic cancers, as well as of death from cardiovascular causes. Clonal hematopoiesis has been proven clinically relevant in the context of disorders characterized by peripheral blood cytopenia, including aplastic anemia, hypoplastic myelodysplastic syndrome, cytopenia of undetermined significance, as well as unexplained anemia of the elderly.
    SUMMARY: . The available evidence has been proving the utility of somatic mutational analysis in patients with unexplained cytopenia, as well as in those receiving a diagnosis of myeloid neoplasm, enabling more accurate diagnosis, risk assessment, effective therapeutic strategies and residual disease monitoring. The access to a minimally invasive assessment is paving the way for screening programs of clonal hematopoiesis in individuals with absent or mild hematologic phenotype, as well as for therapeutic targeting of preleukemia cells.
    DOI:  https://doi.org/10.1097/MOH.0000000000000675
  7. Adv Wound Care (New Rochelle). 2021 Aug 06.
    Hematopoietic stem cells in wound healing response.
    Norifumi Urao, Jinghua Liu, Kentaro Takahashi, Gayathri Ganesh.
      SIGNIFICANCE: Emerging evidence has shown a link between the status of hematopoietic stem cells (HSCs) and wound healing responses. Thus, better understanding HSCs will contribute to further advances in wound healing research. Recent Advances: Myeloid cells such as neutrophils and monocyte-derived macrophages are critical players in the process of wound healing. HSCs actively respond to wound injury and other tissue insults including infection and produce the effector myeloid cells, and a failing of the HSC response can result in impaired wound healing. Technological advances such as transcriptome at single-cell resolution, epigenetics, three-dimensional imaging, transgenic animals, and animal models, have provided novel concepts of myeloid generation (myelopoiesis) from HSCs, and have revealed cell-intrinsic and -extrinsic mechanisms that can impact HSC functions in the context of health conditions.CRITICAL ISSUES: The newer concepts include - the programmed cellular fate at a differentiation stage that is used to be considered as the multilineage, the signaling pathways that can activate HSCs directly and indirectly, the mechanisms that can deteriorate HSCs, the roles and remodeling of the surrounding environment for HSCs and their progenitors (the niche).
    FUTURE DIRECTIONS: The researches on HSCs, which produces blood cells, should contribute to the development of blood biomarkers predicting a risk of chronic wounds, which may transform clinical practice of wound care with precision medicine for patients at high risk of poor healing.
    DOI:  https://doi.org/10.1089/wound.2021.0065
  8. Molecules. 2021 Jul 31. pii: 4666. [Epub ahead of print]26(15):
    Role of Melatonin in Angiotensin and Aging.
    Ahmet Ozer Sehirli, Serkan Sayıner, Ugochukwu Chukwunyere, Nedime Serakinci.
      The cellular utilization of oxygen leads to the generation of free radicals in organisms. The accumulation of these free radicals contributes significantly to aging and several age-related diseases. Angiotensin II can contribute to DNA damage through oxidative stress by activating the NAD(P)H oxidase pathway, which in turn results in the production of reactive oxygen species. This radical oxygen-containing molecule has been linked to aging and several age-related disorders, including renal damage. Considering the role of angiotensin in aging, melatonin might relieve angiotensin-II-induced stress by enhancing the mitochondrial calcium uptake 1 pathway, which is crucial in preventing the mitochondrial calcium overload that may trigger increased production of reactive oxygen species and oxidative stress. This review highlights the role and importance of melatonin together with angiotensin in aging and age-related diseases.
    Keywords:  aging; angiotensin; inflammation; melatonin; oxidative stress
    DOI:  https://doi.org/10.3390/molecules26154666
  9. Dev Cell. 2021 Aug 02. pii: S1534-5807(21)00592-X. [Epub ahead of print]
    Chromosomal instability accelerates the evolution of resistance to anti-cancer therapies.
    Devon A Lukow, Erin L Sausville, Pavit Suri, Narendra Kumar Chunduri, Angela Wieland, Justin Leu, Joan C Smith, Vishruth Girish, Ankith A Kumar, Jude Kendall, Zihua Wang, Zuzana Storchova, Jason M Sheltzer.
      Aneuploidy is a ubiquitous feature of human tumors, but the acquisition of aneuploidy typically antagonizes cellular fitness. To investigate how aneuploidy could contribute to tumor growth, we triggered periods of chromosomal instability (CIN) in human cells and then exposed them to different culture environments. We discovered that transient CIN reproducibly accelerates the acquisition of resistance to anti-cancer therapies. Single-cell sequencing revealed that these resistant populations develop recurrent aneuploidies, and independently deriving one chromosome-loss event that was frequently observed in paclitaxel-resistant cells was sufficient to decrease paclitaxel sensitivity. Finally, we demonstrated that intrinsic levels of CIN correlate with poor responses to numerous therapies in human tumors. Our results show that, although CIN generally decreases cancer cell fitness, it also provides phenotypic plasticity to cancer cells that can allow them to adapt to diverse stressful environments. Moreover, our findings suggest that aneuploidy may function as an under-explored cause of therapy failure.
    Keywords:  CIN; aneuploidy; cancer; drug resistance; evolution
    DOI:  https://doi.org/10.1016/j.devcel.2021.07.009
  10. Cell Stem Cell. 2021 Aug 05. pii: S1934-5909(21)00291-5. [Epub ahead of print]28(8): 1335-1336
    Infection makes micro-CHIPs into macro-CHIPs.
    Jayakrishnan Gopakumar, Siddhartha Jaiswal.
      In this issue of Cell Stem Cell, Hormaechea-Agulla et al. (2021) demonstrate that IFNγ signaling following an infection in mice provides a selective pressure that drives growth of Dnmt3a-/- hematopoietic stem cells. This clonal expansion is mediated by global methylation changes that lead to an increased self-renewing capacity.
    DOI:  https://doi.org/10.1016/j.stem.2021.07.006
  11. Int J Mol Sci. 2021 Jul 26. pii: 7958. [Epub ahead of print]22(15):
    Common Muscle Metabolic Signatures Highlight Arginine and Lysine Metabolism as Potential Therapeutic Targets to Combat Unhealthy Aging.
    Janina Tokarz, Gabriele Möller, Anna Artati, Simone Huber, Anja Zeigerer, Bert Blaauw, Jerzy Adamski, Kenneth Allen Dyar.
      Biological aging research is expected to reveal modifiable molecular mechanisms that can be harnessed to slow or possibly reverse unhealthy trajectories. However, there is first an urgent need to define consensus molecular markers of healthy and unhealthy aging. Established aging hallmarks are all linked to metabolism, and a 'rewired' metabolic circuitry has been shown to accelerate or delay biological aging. To identify metabolic signatures distinguishing healthy from unhealthy aging trajectories, we performed nontargeted metabolomics on skeletal muscles from 2-month-old and 21-month-old mice, and after dietary and lifestyle interventions known to impact biological aging. We hypothesized that common metabolic signatures would highlight specific pathways and processes promoting healthy aging, while revealing the molecular underpinnings of unhealthy aging. Here, we report 50 metabolites that commonly distinguished aging trajectories in all cohorts, including 18 commonly reduced under unhealthy aging and 32 increased. We stratified these metabolites according to known relationships with various aging hallmarks and found the greatest associations with oxidative stress and nutrient sensing. Collectively, our data suggest interventions aimed at maintaining skeletal muscle arginine and lysine may be useful therapeutic strategies to minimize biological aging and maintain skeletal muscle health, function, and regenerative capacity in old age.
    Keywords:  aging; diet; exercise; lifestyle; metabolic signatures; metabolomics; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms22157958
  12. Leukemia. 2021 Aug 03.
    Targeting leukemia-specific dependence on the de novo purine synthesis pathway.
    Takuji Yamauchi, Kohta Miyawaki, Yuichiro Semba, Masatomo Takahashi, Yoshihiro Izumi, Jumpei Nogami, Fumihiko Nakao, Takeshi Sugio, Kensuke Sasaki, Luca Pinello, Daniel E Bauer, Takeshi Bamba, Koichi Akashi, Takahiro Maeda.
      Acute myeloid leukemia (AML) is a devastating disease, and clinical outcomes are still far from satisfactory. Here, to identify novel targets for AML therapy, we performed a genome-wide CRISPR/Cas9 screen using AML cell lines, followed by a second screen in vivo. We show that PAICS, an enzyme involved in de novo purine biosynthesis, is a potential target for AML therapy. AML cells expressing shRNA-PAICS exhibited a proliferative disadvantage, indicating a toxic effect of shRNA-PAICS. Treatment of human AML cells with a PAICS inhibitor suppressed their proliferation by inhibiting DNA synthesis and promoting apoptosis and had anti-leukemic effects in AML PDX models. Furthermore, CRISPR/Cas9 screens using AML cells in the presence of the inhibitor revealed genes mediating resistance or synthetic lethal to PAICS inhibition. Our findings identify PAICS as a novel therapeutic target for AML and further define components of de novo purine synthesis pathway and its downstream effectors essential for AML cell survival.
    DOI:  https://doi.org/10.1038/s41375-021-01369-0
  13. Int J Environ Res Public Health. 2021 Jul 29. pii: 8044. [Epub ahead of print]18(15):
    Premature Aging in Chronic Kidney Disease: The Outcome of Persistent Inflammation beyond the Bounds.
    Andrea Figuer, Guillermo Bodega, Patricia Tato, Gemma Valera, Nadia Serroukh, Noemi Ceprian, Patricia de Sequera, Enrique Morales, Julia Carracedo, Rafael Ramírez, Matilde Alique.
      Over the last hundred years, life expectancy in developed countries has increased because of healthier living habits and the treatment of chronic pathologies causing premature aging. Aging is an inexorable, time-dependent, multifactorial process characterized by a series of progressive and irreversible physiological changes associated with loss of functional, psychological, and social capabilities. Numerous factors, such as oxidative stress, inflammation, and cellular senescence, and an irreversible geriatric syndrome known as frailty, contribute to human body deterioration in aging. The speed of aging may differ between individuals depending on the presence or absence of multiple factors (genetic and/or environment) and the subsequent misbalance of homeostasis, together with the increase of frailty, which also plays a key role in developing chronic diseases. In addition, pathological circumstances have been reported to precipitate or accelerate the aging process. This review investigated the mechanisms involved in the developing pathologies, particularly chronic kidney disease, associated with aging.
    Keywords:  aging; cellular senescence; chronic kidney disease; elderly; frailty; oxidative stress
    DOI:  https://doi.org/10.3390/ijerph18158044
  14. Nature. 2021 Aug 04.
    Genetic insights into biological mechanisms governing human ovarian ageing.
    Katherine S Ruth, Felix R Day, Jazib Hussain, Ana Martínez-Marchal, Catherine E Aiken, Ajuna Azad, Deborah J Thompson, Lucie Knoblochova, Hironori Abe, Jane L Tarry-Adkins, Javier Martin Gonzalez, Pierre Fontanillas, Annique Claringbould, Olivier B Bakker, Patrick Sulem, Robin G Walters, Chikashi Terao, Sandra Turon, Momoko Horikoshi, Kuang Lin, N Charlotte Onland-Moret, Aditya Sankar, Emil Peter Thrane Hertz, Pascal N Timshel, Vallari Shukla, Rehannah Borup, Kristina W Olsen, Paula Aguilera, Mònica Ferrer-Roda, Yan Huang, Stasa Stankovic, Paul R H J Timmers, Thomas U Ahearn, Behrooz Z Alizadeh, Elnaz Naderi, Irene L Andrulis, Alice M Arnold, Kristan J Aronson, Annelie Augustinsson, Stefania Bandinelli, Caterina M Barbieri, Robin N Beaumont, Heiko Becher, Matthias W Beckmann, Stefania Benonisdottir, Sven Bergmann, Murielle Bochud, Eric Boerwinkle, Stig E Bojesen, Manjeet K Bolla, Dorret I Boomsma, Nicholas Bowker, Jennifer A Brody, Linda Broer, Julie E Buring, Archie Campbell, Harry Campbell, Jose E Castelao, Eulalia Catamo, Stephen J Chanock, Georgia Chenevix-Trench, Marina Ciullo, Tanguy Corre, Fergus J Couch, Angela Cox, Laura Crisponi, Simon S Cross, Francesco Cucca, Kamila Czene, George Davey Smith, Eco J C N de Geus, Renée de Mutsert, Immaculata De Vivo, Ellen W Demerath, Joe Dennis, Alison M Dunning, Miriam Dwek, Mikael Eriksson, Tõnu Esko, Peter A Fasching, Jessica D Faul, Luigi Ferrucci, Nora Franceschini, Timothy M Frayling, Manuela Gago-Dominguez, Massimo Mezzavilla, Montserrat García-Closas, Christian Gieger, Graham G Giles, Harald Grallert, Daniel F Gudbjartsson, Vilmundur Gudnason, Pascal Guénel, Christopher A Haiman, Niclas Håkansson, Per Hall, Caroline Hayward, Chunyan He, Wei He, Gerardo Heiss, Miya K Høffding, John L Hopper, Jouke J Hottenga, Frank Hu, David Hunter, Mohammad A Ikram, Rebecca D Jackson, Micaella D R Joaquim, Esther M John, Peter K Joshi, David Karasik, Sharon L R Kardia, Christiana Kartsonaki, Robert Karlsson, Cari M Kitahara, Ivana Kolcic, Charles Kooperberg, Peter Kraft, Allison W Kurian, Zoltan Kutalik, Martina La Bianca, Genevieve LaChance, Claudia Langenberg, Lenore J Launer, Joop S E Laven, Deborah A Lawlor, Loic Le Marchand, Jingmei Li, Annika Lindblom, Sara Lindstrom, Tricia Lindstrom, Martha Linet, YongMei Liu, Simin Liu, Jian'an Luan, Reedik Mägi, Patrik K E Magnusson, Massimo Mangino, Arto Mannermaa, Brumat Marco, Jonathan Marten, Nicholas G Martin, Hamdi Mbarek, Barbara McKnight, Sarah E Medland, Christa Meisinger, Thomas Meitinger, Cristina Menni, Andres Metspalu, Lili Milani, Roger L Milne, Grant W Montgomery, Dennis O Mook-Kanamori, Antonella Mulas, Anna M Mulligan, Alison Murray, Mike A Nalls, Anne Newman, Raymond Noordam, Teresa Nutile, Dale R Nyholt, Andrew F Olshan, Håkan Olsson, Jodie N Painter, Alpa V Patel, Nancy L Pedersen, Natalia Perjakova, Annette Peters, Ulrike Peters, Paul D P Pharoah, Ozren Polasek, Eleonora Porcu, Bruce M Psaty, Iffat Rahman, Gad Rennert, Hedy S Rennert, Paul M Ridker, Susan M Ring, Antonietta Robino, Lynda M Rose, Frits R Rosendaal, Jacques Rossouw, Igor Rudan, Rico Rueedi, Daniela Ruggiero, Cinzia F Sala, Emmanouil Saloustros, Dale P Sandler, Serena Sanna, Elinor J Sawyer, Chloé Sarnowski, David Schlessinger, Marjanka K Schmidt, Minouk J Schoemaker, Katharina E Schraut, Christopher Scott, Saleh Shekari, Amruta Shrikhande, Albert V Smith, Blair H Smith, Jennifer A Smith, Rossella Sorice, Melissa C Southey, Tim D Spector, John J Spinelli, Meir Stampfer, Doris Stöckl, Joyce B J van Meurs, Konstantin Strauch, Unnur Styrkarsdottir, Anthony J Swerdlow, Toshiko Tanaka, Lauren R Teras, Alexander Teumer, Unnur Þorsteinsdottir, Nicholas J Timpson, Daniela Toniolo, Michela Traglia, Melissa A Troester, Thérèse Truong, Jessica Tyrrell, André G Uitterlinden, Sheila Ulivi, Celine M Vachon, Veronique Vitart, Uwe Völker, Peter Vollenweider, Henry Völzke, Qin Wang, Nicholas J Wareham, Clarice R Weinberg, David R Weir, Amber N Wilcox, Ko Willems van Dijk, Gonneke Willemsen, James F Wilson, Bruce H R Wolffenbuttel, Alicja Wolk, Andrew R Wood, Wei Zhao, Marek Zygmunt, , , , , , , , , Zhengming Chen, Liming Li, Lude Franke, Stephen Burgess, Patrick Deelen, Tune H Pers, Marie Louise Grøndahl, Claus Yding Andersen, Anna Pujol, Andres J Lopez-Contreras, Jeremy A Daniel, Kari Stefansson, Jenny Chang-Claude, Yvonne T van der Schouw, Kathryn L Lunetta, Daniel I Chasman, Douglas F Easton, Jenny A Visser, Susan E Ozanne, Satoshi H Namekawa, Petr Solc, Joanne M Murabito, Ken K Ong, Eva R Hoffmann, Anna Murray, Ignasi Roig, John R B Perry.
      Reproductive longevity is essential for fertility and influences healthy ageing in women1,2, but insights into its underlying biological mechanisms and treatments to preserve it are limited. Here we identify 290 genetic determinants of ovarian ageing, assessed using normal variation in age at natural menopause (ANM) in about 200,000 women of European ancestry. These common alleles were associated with clinical extremes of ANM; women in the top 1% of genetic susceptibility have an equivalent risk of premature ovarian insufficiency to those carrying monogenic FMR1 premutations3. The identified loci implicate a broad range of DNA damage response (DDR) processes and include loss-of-function variants in key DDR-associated genes. Integration with experimental models demonstrates that these DDR processes act across the life-course to shape the ovarian reserve and its rate of depletion. Furthermore, we demonstrate that experimental manipulation of DDR pathways highlighted by human genetics increases fertility and extends reproductive life in mice. Causal inference analyses using the identified genetic variants indicate that extending reproductive life in women improves bone health and reduces risk of type 2 diabetes, but increases the risk of hormone-sensitive cancers. These findings provide insight into the mechanisms that govern ovarian ageing, when they act, and how they might be targeted by therapeutic approaches to extend fertility and prevent disease.
    DOI:  https://doi.org/10.1038/s41586-021-03779-7
  15. N Engl J Med. 2021 Aug 04.
    Surviving Covid-19 with Heparin?
    Hugo Ten Cate.
      
    DOI:  https://doi.org/10.1056/NEJMe2111151
  16. Exp Gerontol. 2021 Aug 03. pii: S0531-5565(21)00290-4. [Epub ahead of print] 111508
    Mitophagy: At the heart of mitochondrial quality control in cardiac aging and frailty.
    Anna Picca, Riccardo Calvani, Hélio José Coelho-Júnior, Emanuele Marzetti.
      Cardiovascular disease is highly prevalent among older adults and poses a huge burden on morbidity, disability, and mortality. The age-related increased vulnerability of the cardiovascular system towards stressors is as a pathophysiological trait of cardiovascular disease. This has been associated with a progressive deterioration of blood vessels and decline in heart function during aging. Cardiomyocytes rely mostly on oxidative metabolism for deploying their activities and mitochondrial metabolism is crucial to this purpose. Dysmorphic, inefficient, and oxidant-producing mitochondria have been identified in aged cardiomyocytes in the setting of cardiac structural and functional alterations. These aberrant organelles are thought to arise from inefficient mitochondrial quality control, which has therefore been place in the spotlight as a relevant mechanism of cardiac aging. As a result of alterations in mitochondrial quality control and imbalanced oxidant defense, mitochondrial damage accumulates and contributes to cardiac frailty. Herein, we discuss the contribution of defective mitochondrial quality control pathways to cardiac frailty. Emerging findings pointing towards the exploitation of these pathways as therapeutic targets against cardiac aging and cardiovascular disease will also be illustrated.
    Keywords:  Autophagy; Cardioprotection; Extracellular vesicles; Mitochondrial derived vesicles; Mitochondrial quality control; Therapeutics
    DOI:  https://doi.org/10.1016/j.exger.2021.111508
  17. Nutr Metab Cardiovasc Dis. 2021 Jun 10. pii: S0939-4753(21)00253-2. [Epub ahead of print]
    The effects of the Dietary Approaches to Stop Hypertension (DASH) diet on metabolic risk factors in patients with chronic disease: A systematic review and meta-analysis of randomized controlled trials.
    Abolfazl Lari, Mohammad H Sohouli, Somaye Fatahi, Henrique S Cerqueira, Heitor O Santos, Behnaz Pourrajab, Mahshid Rezaei, Solaleh Saneie, Seyedeh T Rahideh.
      AIMS: The DASH diet was designed for helping control of blood pressure but, fortunately, it can also be prescribed for many other chronic conditions. The current study intended to assess the potential effects of DASH diet on metabolic risk factors in patients with chronic disease.DATA SYNTHESIS: We carried out a systematic literature search for RCTs from inception until July 2020. A total of 54 clinical trials were included in the final analysis. Compared to control groups, a significant lower effect of the DASH diet was noted for body weight (-1.59 kg; p < 0.001), BMI (-0.64 kg/m2; p < 0.001), and WC (-1.93 cm; p < 0.001) as well as for SBP (-3.94 mmHg; p < 0.001) and DBP (-2.44 mmHg; P < 0.001). The DASH diet significantly decreased TC (-5.12 mg/dl; p = 0.008) and LDL-C levels (-3.53 mg/dl; p = 0.041), but not HDL-C (0.30 mg/dl; p = 0.510), TG (-4.22 mg/dl; p = 0.067), and VLDL-C (-2.16 mg/dl; p = 0.062). No significant effect of the DASH diet was noted for blood glucose (-0.38 mg/dl; p = 0.216), insulin (-0.03 μIU/mL; p = 0.817), HOMA-IR (-0.15; p = 0.132), and CRP (-0.33 mg/l; p = 0.173).
    CONCLUSIONS: The DASH diet is a feasible approach to weight loss and to control blood pressure and hypercholesterolemia.
    Keywords:  Cardiovascular disease; DASH diet; Hypertension; Metabolic syndrome; Obesity; Weight loss
    DOI:  https://doi.org/10.1016/j.numecd.2021.05.030
  18. Sci China Life Sci. 2021 Jul 30.
    Understanding the "SMART" features of hematopoietic stem cells and beyond.
    Shiru Yuan, Guohuan Sun, Yawen Zhang, Fang Dong, Hui Cheng, Tao Cheng.
      Since the huge success of bone marrow transplantation technology in clinical practice, hematopoietic stem cells (HSCs) have become the gold standard for defining the properties of adult stem cells (ASCs). Here, we describe the "self-renewal, multi-lineage differentiation, apoptosis, rest, and trafficking" or "SMART" model, which has been developed based on data derived from studies of HSCs as the most well-characterized stem cell type. Given the potential therapeutic applications of ASCs, we delineate the key characteristics of HSCs using this model and speculate on the physiological relevance of stem cells identified in other tissues. Great strides are being made in understanding the biology of ASCs, and efforts are now underway to develop safe and effective ASC-based therapies in this emerging area.
    Keywords:  adult stem cells; hematopoietic stem cells; stem cell biology
    DOI:  https://doi.org/10.1007/s11427-021-1961-1
  19. Nat Aging. 2021 Jan;1(1): 12-13
    Recent trends and increasing differences in life expectancy present opportunities for multidisciplinary research on aging.
    Eileen M Crimmins.
      The increase in multidisciplinary research in the field of aging has many benefits and should be further applied to better understand and possibly reverse the stalled increase in life expectancy as well as growing social inequalities in life expectancy in many countries.
    DOI:  https://doi.org/10.1038/s43587-020-00016-0
  20. Trends Immunol. 2021 Jul 29. pii: S1471-4906(21)00140-X. [Epub ahead of print]
    Lipid regulation of NLRP3 inflammasome activity through organelle stress.
    Jonathan J Liang, Iain D C Fraser, Clare E Bryant.
      Inflammation driven by the NLRP3 inflammasome in macrophages is an important contributor to chronic metabolic diseases that affect growing numbers of individuals. Many of these diseases involve the pathologic accumulation of endogenous lipids or their oxidation products, which can activate NLRP3. Other endogenous lipids, however, can inhibit the activation of NLRP3. The intracellular mechanisms by which these lipids modulate NLRP3 activity are now being identified. This review discusses emerging evidence suggesting that organelle stress, particularly involving mitochondria, lysosomes, and the endoplasmic reticulum, may be key in lipid-induced modification of NLRP3 inflammasome activity.
    Keywords:  NLRP3; inflammasome; lipids; macrophages
    DOI:  https://doi.org/10.1016/j.it.2021.07.005
  21. Aging (Albany NY). 2021 Aug 02. 13(undefined):
    The life in a gradient: calcium, the lncRNA SPRR2C and mir542/mir196a meet in the epidermis to regulate the aging process.
    Sven Breunig, Veronika Wallner, Katharina Kobler, Herbert Wimmer, Peter Steinbacher, Maria Karolin Streubel, Johannes Bischof, Jutta Duschl, Claudia Neuhofer, Wolfgang Gruber, Fritz Aberger, Michael Breitenbach, Elisabeth Russe, Gottfried Wechselberger, Albert Duranton, Klaus Richter, Mark Rinnerthaler.
      The turnover of the epidermis beginning with the progenitor cells in the basal layer to the fully differentiated corneocytes is tightly regulated by calcium. Calcium more than anything else promotes the differentiation of keratinocytes which implies the need for a calcium gradient with low concentrations in the stratum basale and high concentrations in the stratum granulosum. One of the hallmarks of skin aging is a collapse of this gradient that has a direct impact on the epidermal fitness. The rise of calcium in the stratum basale reduces cell proliferation, whereas the drop of calcium in the stratum granulosum leads to a changed composition of the cornified envelope. We showed that keratinocytes respond to the calcium induced block of cell division by a large increase of the expression of several miRNAs (hsa-mir542-5p, hsa-mir125a, hsa-mir135a-5p, hsa-mir196a-5p, hsa-mir491-5p and hsa-mir552-5p). The pitfall of this rescue mechanism is a dramatic change in gene expression which causes a further impairment of the epidermal barrier. This effect is attenuated by a pseudogene (SPRR2C) that gives rise to a lncRNA. SPRR2C specifically resides in the stratum granulosum/corneum thus acting as a sponge for miRNAs.
    Keywords:  epidermal barrier; lncRNA; miRNA; pseudogene; skin aging
    DOI:  https://doi.org/10.18632/aging.203385
  22. Aging Dis. 2021 Aug;12(5): 1162-1168
    Traditional Chinese Medicine and Western Medicine Share Similar Philosophical Approaches to Fight COVID-19.
    Fangfang Zhao, Zhenhong Yang, Ningqun Wang, Kunlin Jin, Yumin Luo.
      Though disciplines in the same field, modern medicine (Western medicine) and traditional medicine (Traditional Chinese medicine, TCM) have been viewed as two distinct and divergent fields of medicine and thus differ greatly in their ways of diagnosing, treating, and preventing disease. In brief, Western medicine is primarily an evidence (laboratory)-based science, whereas TCM is more of a healing art based on the theory of Yin and Yang and the five elements in the human body. Therefore, whether TCM and Western medicine could use similar philosophical approaches to treat disease remains unclear. It is well-known that vitamin D enhances immune function and reduces the spread of some viruses. Indeed, recent evidence shows that the blood calcium level is strongly associated with COVID-19 severity, and vitamin D supplementation has shown favorable effects in viral infections. According to TCM theory, the pathogenesis of COVID-19 is closely associated with cold-dampness, an etiological factor in TCM. Cold-dampness could be attenuated by sun exposure and Wenyang herbs, both of which can restore the vitamin D level in the blood in Western medicine. Therefore, TCM and Western medicine could share similar philosophical methods to fight COVID-19 and understanding their philosophical theories could achieve the maximum benefits for treatment of COVID-19 and other diseases.
    Keywords:  COVID-19; Traditional Chinese medicine; Western medicine; calcium; cold-dampness; vitamin D
    DOI:  https://doi.org/10.14336/AD.2021.0512
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