bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–08–15
twenty-two papers selected by
Ayesh Seneviratne, University of Toronto
  1. HBO1 Is a Targetable Driver of Leukemia Stem Cell Maintenance.
  2. Interacting evolutionary pressures drive mutation dynamics and health outcomes in aging blood.
  3. The Hematopoietic Bone Marrow Niche Ecosystem.
  4. Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging.
  5. The antagonistic pleiotropy of insulin-like growth factor 1.
  6. CCL2 associated with CD38 expression during ex vivo expansion in human cord blood-derived hematopoietic stem cells.
  7. Stem Cells for Aging-Related Disorders.
  8. Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients.
  9. Prostate Cancer Progression: as a Matter of Fats.
  10. Regulatory T cells promote the stemness of leukemia stem cells through IL10 cytokine-related signaling pathway.
  11. Mining old transcriptomes to predict HSC age.
  12. Age-related changes in the parameters of carbohydrate metabolism and supply of vitamins B1, B2 in residents of two northern regions.
  13. The Potential of Calorie Restriction and Calorie Restriction Mimetics in Delaying Aging: Focus on Experimental Models.
  14. Does physical activity protect older persons with frailty and cognitive impairment from excess all-cause mortality?
  15. The Role of Innate Immunity and Bioactive Lipid Mediators in COVID-19 and Influenza.
  16. Mediterranean Diet Reduces Atherosclerosis Progression in Coronary Heart Disease: An Analysis of the CORDIOPREV Randomized Controlled Trial.
  17. Making machine learning trustworthy.
  18. Disparities in older adult accrual to cancer trials: Analysis from the alliance for clinical trials in oncology (A151736).
  19. Thrifty Hormone Ghrelin: The Secret of Aging Muscularly.
  20. Metabolism and Innate Immunity Meet at the Mitochondria.
  21. The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage.
  22. The evolution of hematopoietic cells under cancer therapy.
  1. Cancer Discov. 2020 Feb;10(2): 172
    HBO1 Is a Targetable Driver of Leukemia Stem Cell Maintenance.
      HBO1 is required for maintenance of leukemia stem cells (LSC) in acute myeloid leukemia (AML).
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2019-190
  2. Nat Commun. 2021 Aug 13. 12(1): 4921
    Interacting evolutionary pressures drive mutation dynamics and health outcomes in aging blood.
    Kimberly Skead, Armande Ang Houle, Sagi Abelson, Mawusse Agbessi, Vanessa Bruat, Boxi Lin, David Soave, Liran Shlush, Stephen Wright, John Dick, Quaid Morris, Philip Awadalla.
      Age-related clonal hematopoiesis (ARCH) is characterized by age-associated accumulation of somatic mutations in hematopoietic stem cells (HSCs) or their pluripotent descendants. HSCs harboring driver mutations will be positively selected and cells carrying these mutations will rise in frequency. While ARCH is a known risk factor for blood malignancies, such as Acute Myeloid Leukemia (AML), why some people who harbor ARCH driver mutations do not progress to AML remains unclear. Here, we model the interaction of positive and negative selection in deeply sequenced blood samples from individuals who subsequently progressed to AML, compared to healthy controls, using deep learning and population genetics. Our modeling allows us to discriminate amongst evolutionary classes with high accuracy and captures signatures of purifying selection in most individuals. Purifying selection, acting on benign or mildly damaging passenger mutations, appears to play a critical role in preventing disease-predisposing clones from rising to dominance and is associated with longer disease-free survival. Through exploring a range of evolutionary models, we show how different classes of selection shape clonal dynamics and health outcomes thus enabling us to better identify individuals at a high risk of malignancy.
    DOI:  https://doi.org/10.1038/s41467-021-25172-8
  3. Front Cell Dev Biol. 2021 ;9 705410
    The Hematopoietic Bone Marrow Niche Ecosystem.
    Julia Fröbel, Theresa Landspersky, Gülce Percin, Christina Schreck, Susann Rahmig, Alessandro Ori, Daniel Nowak, Marieke Essers, Claudia Waskow, Robert A J Oostendorp.
      The bone marrow (BM) microenvironment, also called the BM niche, is essential for the maintenance of fully functional blood cell formation (hematopoiesis) throughout life. Under physiologic conditions the niche protects hematopoietic stem cells (HSCs) from sustained or overstimulation. Acute or chronic stress deregulates hematopoiesis and some of these alterations occur indirectly via the niche. Effects on niche cells include skewing of its cellular composition, specific localization and molecular signals that differentially regulate the function of HSCs and their progeny. Importantly, while acute insults display only transient effects, repeated or chronic insults lead to sustained alterations of the niche, resulting in HSC deregulation. We here describe how changes in BM niche composition (ecosystem) and structure (remodeling) modulate activation of HSCs in situ. Current knowledge has revealed that upon chronic stimulation, BM remodeling is more extensive and otherwise quiescent HSCs may be lost due to diminished cellular maintenance processes, such as autophagy, ER stress response, and DNA repair. Features of aging in the BM ecology may be the consequence of intermittent stress responses, ultimately resulting in the degeneration of the supportive stem cell microenvironment. Both chronic stress and aging impair the functionality of HSCs and increase the overall susceptibility to development of diseases, including malignant transformation. To understand functional degeneration, an important prerequisite is to define distinguishing features of unperturbed niche homeostasis in different settings. A unique setting in this respect is xenotransplantation, in which human cells depend on niche factors produced by other species, some of which we will review. These insights should help to assess deviations from the steady state to actively protect and improve recovery of the niche ecosystem in situ to optimally sustain healthy hematopoiesis in experimental and clinical settings.
    Keywords:  aging; bone marrow; hematopoiesis; leukemia; microenvironment; niche; transplantation; xenograft
    DOI:  https://doi.org/10.3389/fcell.2021.705410
  4. Cell Stem Cell. 2021 Aug 06. pii: S1934-5909(21)00294-0. [Epub ahead of print]
    Hsf1 promotes hematopoietic stem cell fitness and proteostasis in response to ex vivo culture stress and aging.
    Miriama Kruta, Mary Jean Sunshine, Bernadette A Chua, Yunpeng Fu, Ashu Chawla, Christopher H Dillingham, Lorena Hidalgo San Jose, Bijou De Jong, Fanny J Zhou, Robert A J Signer.
      Maintaining proteostasis is key to resisting stress and promoting healthy aging. Proteostasis is necessary to preserve stem cell function, but little is known about the mechanisms that regulate proteostasis during stress in stem cells, and whether disruptions of proteostasis contribute to stem cell aging is largely unexplored. We determined that ex-vivo-cultured mouse and human hematopoietic stem cells (HSCs) rapidly increase protein synthesis. This challenge to HSC proteostasis was associated with nuclear accumulation of Hsf1, and deletion of Hsf1 impaired HSC maintenance ex vivo. Strikingly, supplementing cultures with small molecules that enhance Hsf1 activation partially suppressed protein synthesis, rebalanced proteostasis, and supported retention of HSC serial reconstituting activity. Although Hsf1 was dispensable for young adult HSCs in vivo, Hsf1 deficiency increased protein synthesis and impaired the reconstituting activity of middle-aged HSCs. Hsf1 thus promotes proteostasis and the regenerative activity of HSCs in response to culture stress and aging.
    Keywords:  Hsf1; aging; heat shock response; hematopoiesis; hematopoietic stem cell; protein synthesis; proteostasis; stem cell; stress; translation
    DOI:  https://doi.org/10.1016/j.stem.2021.07.009
  5. Aging Cell. 2021 Aug 07. e13443
    The antagonistic pleiotropy of insulin-like growth factor 1.
    William B Zhang, Kenny Ye, Nir Barzilai, Sofiya Milman.
      While insulin-like growth factor-1 (IGF-1) is a well-established modulator of aging and longevity in model organisms, its role in humans has been controversial. In this study, we used the UK Biobank (n = 440,185) to resolve previous ambiguities in the relationship between serum IGF-1 levels and clinical disease. We examined prospective associations of serum IGF-1 with mortality, dementia, vascular disease, diabetes, osteoporosis, and cancer, finding two generalized patterns: First, IGF-1 interacts with age to modify risk in a manner consistent with antagonistic pleiotropy; younger individuals with high IGF-1 are protected from disease, while older individuals with high IGF-1 are at increased risk for incident disease or death. Second, the association between IGF-1 and risk is generally U-shaped, indicating that both high and low levels of IGF-1 may be detrimental. With the exception of a more uniformly positive relationship between IGF-1 and cancer, these effects were remarkably consistent across a wide range of conditions, providing evidence for a unifying pathway that determines risk for most age-associated diseases. These data suggest that IGF-1 signaling could be harmful in older adults, who may actually benefit from the attenuation of biological growth pathways.
    Keywords:  IGF; clinical outcomes; evolution; human aging
    DOI:  https://doi.org/10.1111/acel.13443
  6. Aging (Albany NY). 2021 Aug 10. null(undefined):
    CCL2 associated with CD38 expression during ex vivo expansion in human cord blood-derived hematopoietic stem cells.
    Chao-Ling Yao, Poyin Huang, Tsai-Chi Liu, Yung-Kai Lin, Ching-Yun Chen, Yi-Ting Lai, Tzu Yun Chin, Tsung-Yu Tseng, Yi-Chiung Hsu.
      To date, different experimental strategies have been developed for the ex vivo expansion of human hematopoietic stem cells (HSCs) for clinical applications. However, differences in the genomic function of expanded HSCs under different culture systems remain unclear. In this study, we compared the gene expression profiles of HSCs in ex vivo expanded serum (10% FBS, fetal bovine serum) and serum-free culture systems and analyzed the molecular functions of differentially expressed genes using microarray chips. We identified 839 differentially expressed genes between the two culture systems. These genes were enriched in the TNF -regulated inflammatory pathway in an FBS culture system. In addition, the mRNA expression of CCL2 (C-C motif chemokine ligand 2), TNF (tumor necrosis factor) and FOS (FBJ murine osteosarcoma viral oncogene homolog) was validated by RT-qPCR. Our data revealed that ex vivo expansion of HSCs using the FBS culture system induces an inflammatory response and high CD38 expression, indicating that this system might activate an inflammatory pathway and induce expression of the cancer marker CD38 during ex vivo expansion of HSCs. This study provides a transcriptional profile and new insights into the genomic functions of HSCs under different expanded cultures.
    Keywords:  CD38; cord blood; hematopoietic stem cells; inflammation; microarray
    DOI:  https://doi.org/10.18632/aging.203398
  7. Stem Cell Rev Rep. 2021 Aug 10.
    Stem Cells for Aging-Related Disorders.
    Mia C Borlongan, Jeffrey Farooq, Nadia Sadanandan, Zhen-Jie Wang, Blaise Cozene, Jea-Young Lee, Gary K Steinberg.
      This review captures recent advances in biological and translational research on stem cells. In particular, we discuss new discoveries and concepts regarding stem cell treatment of aging-related disorders. A myriad of stem cell sources exists, from hematopoietic to mesenchymal and neural cell lineages. We examine current applications of exogenous adult bone marrow-derived stem cells as an effective and safe transplantable cell source, as well as the use of electrical stimulation to promote endogenous neurogenesis for Parkinson's disease. We also explore the potential of transplanting exogenous umbilical cord blood cells and mobilizing host resident stem cells in vascular dementia and aging. In addition, we assess the ability of small molecules to recruit resident stem cells in Alzheimer's disease. Finally, we evaluate mechanisms of action recently implicated in stem cell therapy, such as the role of long non-coding RNAs, G-protein coupled receptor 5, and NeuroD1. Our goal is to provide a synopsis of recent milestones regarding the application of stem cells in aging.
    Keywords:  Aging-related disorders; Regenerative medicine; Stem cells; Transplantation
    DOI:  https://doi.org/10.1007/s12015-021-10222-x
  8. N Engl J Med. 2021 Aug 11.
    Randomized Trial of a Third Dose of mRNA-1273 Vaccine in Transplant Recipients.
    Victoria G Hall, Victor H Ferreira, Terrance Ku, Matthew Ierullo, Beata Majchrzak-Kita, Cecilia Chaparro, Nazia Selzner, Jeffrey Schiff, Michael McDonald, George Tomlinson, Vathany Kulasingam, Deepali Kumar, Atul Humar.
      
    DOI:  https://doi.org/10.1056/NEJMc2111462
  9. Front Oncol. 2021 ;11 719865
    Prostate Cancer Progression: as a Matter of Fats.
    Natalia Scaglia, Yesica Romina Frontini-López, Giorgia Zadra.
      Advanced prostate cancer (PCa) represents the fifth cause of cancer death worldwide. Although survival has improved with second-generation androgen signaling and Parp inhibitors, the benefits are not long-lasting, and new therapeutic approaches are sorely needed. Lipids and their metabolism have recently reached the spotlight with accumulating evidence for their role as promoters of PCa development, progression, and metastasis. As a result, interest in targeting enzymes/transporters involved in lipid metabolism is rapidly growing. Moreover, the use of lipogenic signatures to predict prognosis and resistance to therapy has been recently explored with promising results. Despite the well-known association between obesity with PCa lethality, the underlying mechanistic role of diet/obesity-derived metabolites has only lately been unveiled. Furthermore, the role of lipids as energy source, building blocks, and signaling molecules in cancer cells has now been revisited and expanded in the context of the tumor microenvironment (TME), which is heavily influenced by the external environment and nutrient availability. Here, we describe how lipids, their enzymes, transporters, and modulators can promote PCa development and progression, and we emphasize the role of lipids in shaping TME. In a therapeutic perspective, we describe the ongoing efforts in targeting lipogenic hubs. Finally, we highlight studies supporting dietary modulation in the adjuvant setting with the purpose of achieving greater efficacy of the standard of care and of synthetic lethality. PCa progression is "a matter of fats", and the more we understand about the role of lipids as key players in this process, the better we can develop approaches to counteract their tumor promoter activity while preserving their beneficial properties.
    Keywords:  castration resistance; fatty acids; lipid metabolism; lipidomics; microenvironment; obesity; prostate cancer
    DOI:  https://doi.org/10.3389/fonc.2021.719865
  10. Leukemia. 2021 Aug 11.
    Regulatory T cells promote the stemness of leukemia stem cells through IL10 cytokine-related signaling pathway.
    Yingxi Xu, Junli Mou, Ying Wang, Wei Zhou, Qing Rao, Haiyan Xing, Zheng Tian, Kejing Tang, Min Wang, Jianxiang Wang.
      Regulatory T cells (Tregs) could maintain the characteristics of stem cells and inhibit the differentiation of normal hematopoietic stem/progenitor cells. Recent studies have shown that Tregs, as an important component of acute myeloid leukemia (AML) microenvironments, can help AML cells to evade immune surveillance. However, their function in directly regulating the stemness of AML cells remains elusive. In this study, the increased stemness of AML cells promoted by Tregs was verified in vitro and in vivo. The cytokines released by Tregs were explored, the highly expressed anti-inflammatory cytokine IL10 was found, which could promote the stemness of AML cells through the activation of PI3K/AKT signal pathway. Moreover, disrupting the IL10/IL10R/PI3K/AKT signal in AML/ETO c-kitmut (A/Ec) leukemia mice could prolong the mice survival and reduce the stemness of A/Ec leukemia cells. Finally, it was confirmed in patient samples that the proportion of Tregs to leukemia stem cells (LSCs) was positively correlated, and in CD34+ primary AML cells, the activation of PI3K/AKT was stronger in patients with high Tregs' infiltration. After rhIL10 treatment, primary AML cells showed increased activation of PI3K/AKT signaling. Therefore, blocking the interaction between Tregs and AML cells may be a new approach to target LSCs in AML treatment.
    DOI:  https://doi.org/10.1038/s41375-021-01375-2
  11. Blood. 2021 Aug 12. 138(6): 422-423
    Mining old transcriptomes to predict HSC age.
    Mathilde Poplineau, Estelle Duprez.
      
    DOI:  https://doi.org/10.1182/blood.2021012002
  12. Klin Lab Diagn. 2021 Aug 13. 66(8): 465-471
    Age-related changes in the parameters of carbohydrate metabolism and supply of vitamins B1, B2 in residents of two northern regions.
    O S Vlasova, F A Bichkaeva.
      A great deal of research was being done in studying of the age-related characteristics of carbohydrate metabolism and the provision of vitamins B1, B2 among the population of the Subarctic (SR) and Arctic (AR) regions, differing in the extreme natural and climatic-geographic living conditions. The surveyed population was divided into five age groups: 16-21, 22-35, 36-45, 46-60 and 61-74 years old. The parameters of carbohydrate metabolism (glucose, lactate, pyruvate) were determined in the blood serum, the content of thiamine (thiamin diphosphate effect) and riboflavin - in hemolysates, and the values of the lactate/pyruvate ratio (Lac/Pyr) were calculated. Statistical data processing was performed by nonparametric methods. An increase in glucose levels was found in persons of older age groups. Age-related fluctuations of metabolites of carbohydrate metabolism were manifested by a lower content of lactate and the value of the Lac/Pyr ratio in persons aged 16-21 years. Regardless of the age and region of the survey, there were revealed high lactate concentrations, Lac/Pyr values and reduced pyruvate levels, as well as low glucose levels in group aged 16-21 year in AR. For vitamins B1, B2, no pronounced age-related changes were observed, while the content of riboflavin was higher in persons of SR. Moderate hypovitaminosis of thiamin was detected in 13-20,1% and 6,1-22,7% of cases in SR and AR, pronounced - 8,3-11,6% and 4,6-23,5%, respectively, vitamin B2 deficiency was noted in 19,4-23,9% of persons in the AR and in 33,8-42,9% of persons in the AR. Vitamins in both regions at different age periods contributed to the formation of levels of indicators of carbohydrate metabolism: glucose and pyruvate in SR, lactate in AR.
    Keywords:  age; carbohydrate metabolism; glucose; the Arctic; the North; vitamin B1; vitamin B2
    DOI:  https://doi.org/10.51620/0869-2084-2021-66-8-465-471
  13. Nutrients. 2021 Jul 09. pii: 2346. [Epub ahead of print]13(7):
    The Potential of Calorie Restriction and Calorie Restriction Mimetics in Delaying Aging: Focus on Experimental Models.
    Emiliana Giacomello, Luana Toniolo.
      Aging is a biological process determined by multiple cellular mechanisms, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, that ultimately concur in the functional decline of the individual. The evidence that the old population is steadily increasing and will triplicate in the next 50 years, together with the fact the elderlies are more prone to develop pathologies such as cancer, diabetes, and degenerative disorders, stimulates an important effort in finding specific countermeasures. Calorie restriction (CR) has been demonstrated to modulate nutrient sensing mechanisms, inducing a better metabolic profile, enhanced stress resistance, reduced oxidative stress, and improved inflammatory response. Therefore, CR and CR-mimetics have been suggested as powerful means to slow aging and extend healthy life-span in experimental models and humans. Taking into consideration the difficulties and ethical issues in performing aging research and testing anti-aging interventions in humans, researchers initially need to work with experimental models. The present review reports the major experimental models utilized in the study of CR and CR-mimetics, highlighting their application in the laboratory routine, and their translation to human research.
    Keywords:  aging; calorie restriction; calorie restriction mimetic; experimental models; health-span; life-span; resveratrol
    DOI:  https://doi.org/10.3390/nu13072346
  14. Arch Gerontol Geriatr. 2021 Aug 06. pii: S0167-4943(21)00163-1. [Epub ahead of print]97 104500
    Does physical activity protect older persons with frailty and cognitive impairment from excess all-cause mortality?
    Chia-Lin Li, Yu-Chan Chiu, Yea-Ing L Shyu, Fiona F Stanaway, Hsing-Yi Chang, Yuh-Bin Bai.
       OBJECTIVES: The main aim of this study was to examine how physical activity in combination with physical frailty and cognitive impairment affects risk of mortality in older adults.
    STUDY DESIGN: A national sample of community-dwelling Taiwanese aged 65 years or older (n=2678) was followed for 5 years.
    MAIN OUTCOME MEASURES: Frailty was determined based on the Fatigue, Resistance, Ambulation, Illness, and Loss of weight (FRAIL) scale. The Mini-Mental State Examination was used to assess cognitive impairment. Information on self-reported physical activity was collected at baseline. The study cohort was followed until the date of death or the end of the study period (31 December 2018). Deaths were confirmed by the computerized data files of the National Register of Deaths.
    RESULTS: A total of 417 deaths were recorded after 12415.2 person-years of follow-up. After adjustment for other factors, compared with active participants who were physically robust with normal cognition, inactive participants who were with either frail/pre-frail or cognitively impaired had hazard ratios for mortality of 2.65 (95% CI=[1.88-3.74]) and 3.09 (95% CI=[2.08-4.59]), respectively. Inactive participants with coexisting frailty/pre-frailty and cognitive impairment had the highest hazard ratio for mortality of 3.85 (95% CI=[2.73-5.45]). Being active was associated with a mortality reduction of 31%, 38%, and 42% in physically robust participants with normal cognition, those who were frail/pre-frail only, and those with cognitive impairment only, respectively.
    CONCLUSIONS: Having a physically active life style has beneficial effects on survival in older persons with either frailty/pre-frailty or cognitive impairment.
    Keywords:  Cognitive impairment; Frailty; Mortality; Physical activity; Taiwan
    DOI:  https://doi.org/10.1016/j.archger.2021.104500
  15. Front Physiol. 2021 ;12 688946
    The Role of Innate Immunity and Bioactive Lipid Mediators in COVID-19 and Influenza.
    Sabina Sahanic, Judith Löffler-Ragg, Piotr Tymoszuk, Richard Hilbe, Egon Demetz, Rebecca K Masanetz, Markus Theurl, Johannes Holfeld, Can Gollmann-Tepeköylü, Alexandar Tzankov, Guenter Weiss, Martin Giera, Ivan Tancevski.
      In this review, we discuss spatiotemporal kinetics and inflammatory signatures of innate immune cells specifically found in response to SARS-CoV-2 compared to influenza virus infection. Importantly, we cover the current understanding on the mechanisms by which SARS-CoV-2 may fail to engage a coordinated type I response and instead may lead to exaggerated inflammation and death. This knowledge is central for the understanding of available data on specialized pro-resolving lipid mediators in severe SARS-CoV-2 infection pointing toward inhibited E-series resolvin synthesis in severe cases. By investigating a publicly available RNA-seq database of bronchoalveolar lavage cells from patients affected by COVID-19, we moreover offer insights into the regulation of key enzymes involved in lipid mediator synthesis, critically complementing the current knowledge about the mediator lipidome in severely affected patients. This review finally discusses different potential approaches to sustain the synthesis of 3-PUFA-derived pro-resolving lipid mediators, including resolvins and lipoxins, which may critically aid in the prevention of acute lung injury and death from COVID-19.
    Keywords:  COVID-19; influenza virus; innate immunity; lipid mediator; macrophages and neutrophils; metabololipidomics
    DOI:  https://doi.org/10.3389/fphys.2021.688946
  16. Stroke. 2021 Aug 10. STROKEAHA120033214
    Mediterranean Diet Reduces Atherosclerosis Progression in Coronary Heart Disease: An Analysis of the CORDIOPREV Randomized Controlled Trial.
    Jose Jimenez-Torres, Juan F Alcalá-Diaz, Jose D Torres-Peña, Francisco M Gutierrez-Mariscal, Ana Leon-Acuña, Purificación Gómez-Luna, Carolina Fernández-Gandara, Gracia M Quintana-Navarro, Jose C Fernandez-Garcia, Pablo Perez-Martinez, Jose M Ordovas, Javier Delgado-Lista, Elena M Yubero-Serrano, Jose Lopez-Miranda.
       BACKGROUND AND PURPOSE: Lifestyle and diet affect cardiovascular risk, although there is currently no consensus about the best dietary model for the secondary prevention of cardiovascular disease. The CORDIOPREV study (Coronary Diet Intervention With Olive Oil and Cardiovascular Prevention) is an ongoing prospective, randomized, single-blind, controlled trial in 1002 coronary heart disease patients, whose primary objective is to compare the effect of 2 healthy dietary patterns (low-fat rich in complex carbohydrates versus Mediterranean diet rich in extra virgin olive oil) on the incidence of cardiovascular events. Here, we report the results of one secondary outcome of the CORDIOPREV study. Thus, to evaluate the efficacy of these diets in reducing cardiovascular disease risk. Intima-media thickness of both common carotid arteries (IMT-CC) was ultrasonically assessed bilaterally. IMT-CC is a validated surrogate for the status and future cardiovascular disease risk.
    METHODS: From the total participants, 939 completed IMT-CC evaluation at baseline and were randomized to follow a Mediterranean diet (35% fat, 22% monounsaturated fatty acids, <50% carbohydrates) or a low-fat diet (28% fat, 12% monounsaturated fatty acids, >55% carbohydrates) with IMT-CC measurements at 5 and 7 years. We also analyzed the carotid plaque number and height.
    RESULTS: The Mediterranean diet decreased IMT-CC at 5 years (-0.027±0.008 mm; P<0.001), maintained at 7 years (-0.031±0.008 mm; P<0.001), compared to baseline. The low-fat diet did not modify IMT-CC. IMT-CC and carotid plaquemax height were higher decreased after the Mediterranean diet, compared to the low-fat diet, throughout follow-up. Baseline IMT-CC had the strongest association with the changes in IMT-CC after the dietary intervention.
    CONCLUSIONS: Long-term consumption of a Mediterranean diet rich in extravirgin olive oil, if compared to a low-fat diet, was associated with decreased atherosclerosis progression, as shown by reduced IMT-CC and carotid plaque height. These findings reinforce the clinical benefits of the Mediterranean diet in the context of secondary cardiovascular prevention.
    REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00924937.
    Keywords:  atherosclerosis; cardiovascular disease; diet, Mediterranean; fatty acids; olive oil
    DOI:  https://doi.org/10.1161/STROKEAHA.120.033214
  17. Science. 2021 08 13. 373(6556): 743-744
    Making machine learning trustworthy.
    Birhanu Eshete.
      
    DOI:  https://doi.org/10.1126/science.abi5052
  18. J Geriatr Oncol. 2021 Aug 04. pii: S1879-4068(21)00170-3. [Epub ahead of print]
    Disparities in older adult accrual to cancer trials: Analysis from the alliance for clinical trials in oncology (A151736).
    Noam A VanderWalde, Travis Dockter, Daniel V Wakefield, Daniel Satele, Jeff Sloan, Reshma Jagsi, Stuart M Lichtman, Rachel A Freedman, Jacqueline M Lafky, Hyman Muss, Harvey Jay Cohen, Jennifer Le-Rademacher, Aminah Jatoi.
       BACKGROUND: Older adults are under-represented in cancer clinical trials. However, it remains unclear which types of trials under-enroll aging patients. We aimed to identify associations between trial characteristics and disparate enrollment of older adults onto trials sponsored by the Alliance for Clinical Trials in Oncology (Alliance).
    METHODS: Actual age ≥ 65 percentage and trial data were extracted from the Alliance closed study list. Each trial, based on its cancer type and years of enrollment, was assigned an expected age ≥ 65 percentage extracted from the Surveillance, Epidemiology, and End Results (SEER) US population-based database. Enrollment disparity difference (EDD), the difference between the expected age ≥ 65 percentage and the actual age ≥ 65 percentage, was calculated for each trial. Linear regression determined trial variables associated with larger EDDs and variables with an overall association p-value <0.20 were included in a multivariable fixed-effects linear model.
    RESULTS: The median age of 66,708 patients across 237 trials was 60 years (range 18-102). The average actual age ≥ 65 percentage enrolled per trial was lower than each trial's expected age ≥ 65 percentage average (39% vs. 58%; EDD 19, 95% CI 17.1-21.3%, p < 0.0001). In multivariable analyses, non-genitourinary (GU) cancer types (p < 0.001), trimodality+ trials (estimate 8.78, 95%CI 2.21-15.34, p = 0.009), and phase 2 trials (estimate 4.43 95% CI -0.06-8.91; p = 0.05) were all associated with larger EDDs.
    CONCLUSIONS: Disparate enrollment of older adults is not equal across cancer trials. Future strategies to improve older adult inclusion should focus on trial types associated with the highest disparate enrollment.
    Keywords:  Cancer; Clinical trials; Enrollment; Older adults
    DOI:  https://doi.org/10.1016/j.jgo.2021.07.008
  19. J Aging Sci. 2020 ;pii: 005. [Epub ahead of print]8(Suppl 3):
    Thrifty Hormone Ghrelin: The Secret of Aging Muscularly.
    Yuxiang Sun.
      Sarcopenia is a debilitating muscle-wasting disease that is the major cause of frailty and disability in aging. Ghrelin (aka acylated ghrelin, AG) is a circulating peptide hormone with an unique octanoylation on Ser3. AG induces growth hormone (GH) secretion, increases food intake, and promotes adiposity and insulin resistance via its receptor, Growth Hormone Secretagogue Receptor (GHS-R). Unlike AG, unacylated ghrelin (UAG) is a peptide generated from the same ghrelin gene with amino acid sequence identical to AG but without the octanoylation modification, so UAG does not activate GHS-R. Intriguingly, both AG and UAG have been shown to promote differentiation and fusion of muscle C2C12 cells, regulate metabolic and mitochondrial signaling pathways in myotubes, and attenuate fasting- or denervation-induced muscle atrophy. Furthermore, it has also been shown that ghrelin gene deficiency increases vulnerability to fasting-induced muscle loss in aging mice, and AG and UAG effectively protects against muscle atrophy of aging mice. Because UAG doesn't bind to GHS-R, it doesn't have the undesired side-effects of elevated GH-release and increased obesity as AG. In summary, UAG has an impressive anti-atrophic effect in muscle protecting against muscle atrophy in aging, it has potential to be a unique and superior therapeutic candidate for muscle-wasting diseases such as sarcopenia.
    Keywords:  Aging; GHS-R; Ghrelin; Growth hormone; Sarcopenia
  20. Front Cell Dev Biol. 2021 ;9 720490
    Metabolism and Innate Immunity Meet at the Mitochondria.
    Amir Bahat, Thomas MacVicar, Thomas Langer.
      Mitochondria are master regulators of metabolism and have emerged as key signalling organelles of the innate immune system. Each mitochondrion harbours potent agonists of inflammation, including mitochondrial DNA (mtDNA), which are normally shielded from the rest of the cell and extracellular environment and therefore do not elicit detrimental inflammatory cascades. Mitochondrial damage and dysfunction can lead to the cytosolic and extracellular exposure of mtDNA, which triggers inflammation in a number of diseases including autoimmune neurodegenerative disorders. However, recent research has revealed that the extra-mitochondrial exposure of mtDNA is not solely a negative consequence of mitochondrial damage and pointed to an active role of mitochondria in innate immunity. Metabolic cues including nucleotide imbalance can stimulate the release of mtDNA from mitochondria in order to drive a type I interferon response. Moreover, important effectors of the innate immune response to pathogen infection, such as the mitochondrial antiviral signalling protein (MAVS), are located at the mitochondrial surface and modulated by the cellular metabolic status and mitochondrial dynamics. In this review, we explore how and why metabolism and innate immunity converge at the mitochondria and describe how mitochondria orchestrate innate immune signalling pathways in different metabolic scenarios. Understanding how cellular metabolism and metabolic programming of mitochondria are translated into innate immune responses bears relevance to a broad range of human diseases including cancer.
    Keywords:  CGAS; MAVS; STING; innate immunity; metabolism; mitochondria; mitochondrial DNA
    DOI:  https://doi.org/10.3389/fcell.2021.720490
  21. Cell Metab. 2021 Aug 03. pii: S1550-4131(21)00332-6. [Epub ahead of print]
    The requirement for pyruvate dehydrogenase in leukemogenesis depends on cell lineage.
    Sojeong Jun, Swetha Mahesula, Thomas P Mathews, Misty S Martin-Sandoval, Zhiyu Zhao, Elena Piskounova, Michalis Agathocleous.
      Cancer cells are metabolically similar to their corresponding normal tissues. Differences between cancers and normal tissues may reflect reprogramming during transformation or maintenance of the metabolism of the specific normal cell type that originated the cancer. Here, we compare glucose metabolism in hematopoiesis and leukemia. Thymus T cell progenitors were glucose avid and oxidized more glucose in the tricarboxylic acid cycle through pyruvate dehydrogenase (PDH) as compared with other hematopoietic cells. PDH deletion decreased double-positive T cell progenitor cells but had no effect on hematopoietic stem cells, myeloid progenitors, or other hematopoietic cells. PDH deletion blocked the development of Pten-deficient T cell leukemia, but not the development of a Pten-deficient myeloid neoplasm. Therefore, the requirement for PDH in leukemia reflected the metabolism of the normal cell of origin independently of the driver genetic lesion. PDH was required to prevent pyruvate accumulation and maintain glutathione levels and redox homeostasis.
    Keywords:  T cell leukemia; double-positive thymocytes; glycolysis; hematopoietic stem cells; metabolism; pyruvate dehydrogenase; thymus
    DOI:  https://doi.org/10.1016/j.cmet.2021.07.016
  22. Nat Commun. 2021 08 10. 12(1): 4803
    The evolution of hematopoietic cells under cancer therapy.
    Oriol Pich, Albert Cortes-Bullich, Ferran Muiños, Marta Pratcorona, Abel Gonzalez-Perez, Nuria Lopez-Bigas.
      Chemotherapies may increase mutagenesis of healthy cells and change the selective pressures in tissues, thus influencing their evolution. However, their contributions to the mutation burden and clonal expansions of healthy somatic tissues are not clear. Here, exploiting the mutational footprint of some chemotherapies, we explore their influence on the evolution of hematopoietic cells. Cells of Acute Myeloid Leukemia (AML) secondary to treatment with platinum-based drugs show the mutational footprint of these drugs, indicating that non-malignant blood cells receive chemotherapy mutations. No trace of the 5-fluorouracil (5FU) mutational signature is found in AMLs secondary to exposure to 5FU, suggesting that cells establishing the leukemia could be quiescent during treatment. Using the platinum-based mutational signature as a barcode, we determine that the clonal expansion originating the secondary AMLs begins after the start of the cytotoxic treatment. Its absence in clonal hematopoiesis cases is consistent with the start of the clonal expansion predating the exposure to platinum-based drugs.
    DOI:  https://doi.org/10.1038/s41467-021-24858-3
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