bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023‒04‒23
24 papers selected by
Ayesh Seneviratne
Western University
  1. Clonal Hematopoiesis: Origins and determinants of evolution.
  2. Obesity induced inflammation exacerbates clonal hematopoiesis.
  3. Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.
  4. Chow diet in mouse aging studies: nothing regular about it.
  5. Epigenetic modifiers as game changers for healthy ageing.
  6. Yo-yoing stem cells defy dogma to maintain hair colour.
  7. DRAG in situ barcoding reveals an increased number of HSPCs contributing to myelopoiesis with age.
  8. How can we modulate aging through nutrition and physical exercise? An epigenetic approach.
  9. CD150-dependent hematopoietic stem cell sensing of Brucella instructs myeloid commitment.
  10. Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan.
  11. Dietary supplementation with NAD +-boosting compounds in humans: Current knowledge and future directions.
  12. Ex vivo expansion of hematopoietic stem cells.
  13. SIRT4 in ageing.
  14. Age-related loss of chromosome Y is associated with levels of sex hormone binding globulin and clonal hematopoiesis defined by TET2, TP53, and CBL mutations.
  15. Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging.
  16. AMPK activation protects against prostate cancer by inducing a catabolic cellular state.
  17. Boosting in the age of Omicron.
  18. Learning the metabolic language of cancer.
  19. Aging microglia.
  20. The role of frailty in advanced HF and cardiac transplantation.
  21. Age-related changes in plasma biomarkers and their association with mortality in COVID-19.
  22. Performance of a modified fracture risk assessment tool (FRAX) for fragility fracture prediction among older veterans living with HIV.
  23. Age-associated inflammation and implications for skeletal muscle responses to exercise.
  24. RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells.
  1. Leuk Res. 2023 Apr 14. pii: S0145-2126(23)00061-9. [Epub ahead of print]129 107076
    Clonal Hematopoiesis: Origins and determinants of evolution.
    Lourdes M Mendez, Mrinal M Patnaik.
      The accrual of somatic mutations is a byproduct of aging. When a clone bearing a somatic genetic alteration, conferring comparative competitive advantage, displays sufficient outgrowth to become detectable amongst an otherwise polyclonal background in the hematopoietic system, this is called clonal hematopoiesis (CH). Somatic genetic alterations observed in CH include point mutations in cancer related genes, mosaic chromosomal alterations or a combination of these. Interestingly, clonal hematopoiesis (CH) can also occur with somatic variants in genes without a known role in cancer and in the absence of a somatic genetic alteration through a process that has been described as 'genetic drift'. Clonal hematopoiesis of indeterminate significance (CHIP), is age-related and defined by the presence of somatic point mutations in cancer related genes, in the absence of cytopenias or a diagnosis of hematologic neoplasm, with a variant allele fraction ≥ 2 %. Remarkably, the increased mortality associated with CHIP is largely due to cardiovascular disease. Subsequently, CHIP has been associated with a myriad of age-related conditions such as Alzheimer's Disease, osteoporosis, CVA and COPD. CHIP is associated with an increased risk of hematologic malignancies, particularly myeloid neoplasms, with the risk rising with increasing clone size and clonal complexity. Mechanisms regulating clonal evolution and progression to hematologic malignancies remain to be defined. However, observations on context specific CH arising in the setting of bone marrow failure states, or on exposure to chemotherapy and radiation therapy, suggest that CH reflects context specific selection pressures and constraint-escape mechanisms.
    Keywords:  CCUS; CHIP; Clonal evolution; Clonal hematopoiesis; Clonal origin; Mosaic chromosomal alterations
    DOI:  https://doi.org/10.1016/j.leukres.2023.107076
  2. J Clin Invest. 2023 Apr 18. pii: e163968. [Epub ahead of print]
    Obesity induced inflammation exacerbates clonal hematopoiesis.
    Santhosh Kumar Pasupuleti, Baskar Ramdas, Sarah S Burns, Lakshmi Reddy Palam, Rahul Kanumuri, Ramesh Kumar, Taruni R Pandhiri, Utpal Dave, Nanda Kumar Yellapu, Xinyu Zhou, Chi Zhang, George E Sandusky, Zhi Yu, Michael C Honigberg, Alexander G Bick, Gabriel K Griffin, Abhishek Niroula, Benjamin L Ebert, Sophie Paczesny, Pradeep Natarajan, Reuben Kapur.
      Characterized by the accumulation of somatic mutations in blood cell lineages, clonal hematopoiesis (CH) of indeterminate potential (CHIP) is frequent in ageing, involves expansion of mutated hematopoietic stem and progenitor cells (HSC/Ps) that leads to an increased risk of hematologic malignancy. However, risk factors that contribute to CHIP-associated CH are poorly understood. Obesity induces a pro-inflammatory state and fatty bone marrow (FBM), which may influence CHIP-associated pathologies. We analyzed exome sequencing and clinical data from 47,466 individuals with validated CHIP in UK Biobank. CHIP was present in 5.8% of the study population and was associated with a significant increase in waist-to-hip ratio (WHR). Mouse models of obesity and CHIP driven by heterozygosity of Tet2, Dnmt3a, Asxl1 and Jak2 resulted in exacerbated expansion of mutant HSC/Ps due in part to excessive inflammation. Our results show that obesity is highly associated with CHIP and a pro-inflammatory state can potentiate progression of CHIP to more significant hematologic neoplasia. Calcium channel blocker, nifedipine or SKF-96365, either alone or in combination with metformin, MCC950 or anakinra (IL-1 receptor antagonist), suppressed the growth of mutant CHIP cells and partially restored normal hematopoiesis. Targeting CHIP mutant cells with these drugs could be a potential therapeutic approach to treat CH and its associated abnormalities in obese individuals.
    Keywords:  Cancer; Hematology; Hematopoietic stem cells; Inflammation
    DOI:  https://doi.org/10.1172/JCI163968
  3. Cancer Drug Resist. 2023 ;6(1): 138-150
    Resistance to energy metabolism - targeted therapy of AML cells residual in the bone marrow microenvironment.
    Yoko Tabe, Marina Konopleva.
      In response to the changing availability of nutrients and oxygen in the bone marrow microenvironment, acute myeloid leukemia (AML) cells continuously adjust their metabolic state. To meet the biochemical demands of their increased proliferation, AML cells strongly depend on mitochondrial oxidative phosphorylation (OXPHOS). Recent data indicate that a subset of AML cells remains quiescent and survives through metabolic activation of fatty acid oxidation (FAO), which causes uncoupling of mitochondrial OXPHOS and facilitates chemoresistance. For targeting these metabolic vulnerabilities of AML cells, inhibitors of OXPHOS and FAO have been developed and investigated for their therapeutic potential. Recent experimental and clinical evidence has revealed that drug-resistant AML cells and leukemic stem cells rewire metabolic pathways through interaction with BM stromal cells, enabling them to acquire resistance against OXPHOS and FAO inhibitors. These acquired resistance mechanisms compensate for the metabolic targeting by inhibitors. Several chemotherapy/targeted therapy regimens in combination with OXPHOS and FAO inhibitors are under development to target these compensatory pathways.
    Keywords:  Bone marrow microenvironment; acute myeloid leukemia; energy metabolism; fatty acid oxidation; mitochondria; oxidative phosphorylation
    DOI:  https://doi.org/10.20517/cdr.2022.133
  4. Geroscience. 2023 Apr 20.
    Chow diet in mouse aging studies: nothing regular about it.
    Jennifer Lee, Chloe Purello, Sarah L Booth, Brian Bennett, Christopher D Wiley, Ron Korstanje.
      Chow diet is used in the majority of rodent studies and, although assumed to be standardized for dietary source and nutritional contents, it varies widely across commercial formulations. Similarly, current approaches to study aging in rodents involve a single-diet formulation across the lifespan and overlook age-specific nutritional requirements, which may have long-term effects on aging processes. Together, these nutrition-based disparities represent major gaps in geroscience research, affecting the interpretation and reproducibility of the studies. This perspective aims to raise awareness on the importance of rodent diet formulation and proposes that geroscientists include detailed descriptions of all experimental diets and feeding protocols. Detailed reporting of diets will enhance rigor and reproducibility of aging rodent studies and lead to more translational outcomes in geroscience research.
    Keywords:  Aging; Chow diet; Dietary source
    DOI:  https://doi.org/10.1007/s11357-023-00775-9
  5. Rejuvenation Res. 2023 Apr 21.
    Epigenetic modifiers as game changers for healthy ageing.
    Shikha Sharma, Ramesh Bhonde.
      Epigenetic alterations during ageing are manifested with altered gene expression linking it to lifespan regulation, genetic instability, and diseases. Diet and epigenetic modifiers exert a profound effect on the lifespan of an organism by modulating the epigenetic marks. However, our understanding of the multifactorial nature of the epigenetic process during ageing and the onset of disease conditions as well as its reversal by epidrugs, diet, or environmental factors is still mystifying. This review covers the key findings in epigenetics related to ageing and age-related diseases. Further, it holds a discussion about the epigenetic clocks and their implications in various age-related disease conditions including cancer. Although, epigenetics is a reversible process how fast the epigenetic alterations can revert to normal is an intriguing question. Therefore, this paper touches on the possibility of utilizing nutrition and MSCs secretome to accelerate the epigenetic reversal and emphasizes the identification of new therapeutic epigenetic modifiers to counter epigenetic alteration during ageing.
    DOI:  https://doi.org/10.1089/rej.2022.0059
  6. Nature. 2023 Apr;616(7958): 666-667
    Yo-yoing stem cells defy dogma to maintain hair colour.
    Carlos Galvan, William E Lowry.
      
    Keywords:  Ageing; Physiology; Stem cells
    DOI:  https://doi.org/10.1038/d41586-023-00918-0
  7. Nat Commun. 2023 04 17. 14(1): 2184
    DRAG in situ barcoding reveals an increased number of HSPCs contributing to myelopoiesis with age.
    Jos Urbanus, Jason Cosgrove, Joost B Beltman, Yuval Elhanati, Rafael A Moral, Cecile Conrad, Jeroen W van Heijst, Emilie Tubeuf, Arno Velds, Lianne Kok, Candice Merle, Jens P Magnusson, Léa Guyonnet, Jonas Frisén, Silvia Fre, Aleksandra M Walczak, Thierry Mora, Heinz Jacobs, Ton N Schumacher, Leïla Perié.
      Ageing is associated with changes in the cellular composition of the immune system. During ageing, hematopoietic stem and progenitor cells (HSPCs) that produce immune cells are thought to decline in their regenerative capacity. However, HSPC function has been mostly assessed using transplantation assays, and it remains unclear how HSPCs age in the native bone marrow niche. To address this issue, we present an in situ single cell lineage tracing technology to quantify the clonal composition and cell production of single cells in their native niche. Our results demonstrate that a pool of HSPCs with unequal output maintains myelopoiesis through overlapping waves of cell production throughout adult life. During ageing, the increased frequency of myeloid cells is explained by greater numbers of HSPCs contributing to myelopoiesis rather than the increased myeloid output of individual HSPCs. Strikingly, the myeloid output of HSPCs remains constant over time despite accumulating significant transcriptomic changes throughout adulthood. Together, these results show that, unlike emergency myelopoiesis post-transplantation, aged HSPCs in their native microenvironment do not functionally decline in their regenerative capacity.
    DOI:  https://doi.org/10.1038/s41467-023-37167-8
  8. Aging (Albany NY). 2023 Apr 20. 15
    How can we modulate aging through nutrition and physical exercise? An epigenetic approach.
    ALFA Score Consortium
      The World Health Organization predicts that by 2050, 2.1 billion people worldwide will be over 60 years old, a drastic increase from only 1 billion in 2019. Considering these numbers, strategies to ensure an extended "healthspan" or healthy longevity are urgently needed. The present study approaches the promotion of healthspan from an epigenetic perspective. Epigenetic phenomena are modifiable in response to an individual's environmental exposures, and therefore link an individual's environment to their gene expression pattern. Epigenetic studies demonstrate that aging is associated with decondensation of the chromatin, leading to an altered heterochromatin structure, which promotes the accumulation of errors. In this review, we describe how aging impacts epigenetics and how nutrition and physical exercise can positively impact the aging process, from an epigenetic point of view. Canonical histones are replaced by histone variants, concomitant with an increase in histone post-translational modifications. A slight increase in DNA methylation at promoters has been observed, which represses transcription of previously active genes, in parallel with global genome hypomethylation. Aging is also associated with deregulation of gene expression - usually provided by non-coding RNAs - leading to both the repression of previously transcribed genes and to the transcription of previously repressed genes. Age-associated epigenetic events are less common in individuals with a healthy lifestyle, including balanced nutrition, caloric restriction and physical exercise. Healthy aging is associated with more tightly condensed chromatin, fewer PTMs and greater regulation by ncRNAs.
    Keywords:  aging; caloric restriction; epigenetics; nutrition; physical exercise
    DOI:  https://doi.org/10.18632/aging.204668
  9. J Exp Med. 2023 Jul 03. pii: e20210567. [Epub ahead of print]220(7):
    CD150-dependent hematopoietic stem cell sensing of Brucella instructs myeloid commitment.
    Lisiena Hysenaj, Bérengère de Laval, Vilma Arce-Gorvel, Mile Bosilkovski, Gabriela González-Espinoza, Guilhaume Debroas, Michael H Sieweke, Sandrine Sarrazin, Jean-Pierre Gorvel.
      So far, hematopoietic stem cells (HSC) are considered the source of mature immune cells, the latter being the only ones capable of mounting an immune response. Recent evidence shows HSC can also directly sense cytokines released upon infection/inflammation and pathogen-associated molecular pattern interaction while keeping a long-term memory of previously encountered signals. Direct sensing of danger signals by HSC induces early myeloid commitment, increases myeloid effector cell numbers, and contributes to an efficient immune response. Here, by using specific genetic tools on both the host and pathogen sides, we show that HSC can directly sense B. abortus pathogenic bacteria within the bone marrow via the interaction of the cell surface protein CD150 with the bacterial outer membrane protein Omp25, inducing efficient functional commitment of HSC to the myeloid lineage. This is the first demonstration of direct recognition of a live pathogen by HSC via CD150, which attests to a very early contribution of HSC to immune response.
    DOI:  https://doi.org/10.1084/jem.20210567
  10. Geroscience. 2023 Apr 22.
    Genetic perturbation of mitochondrial function reveals functional role for specific mitonuclear genes, metabolites, and pathways that regulate lifespan.
    Cheryl Zi Jin Phua, Xiaqing Zhao, Lesly Turcios-Hernandez, Morrigan McKernan, Morteza Abyadeh, Siming Ma, Daniel Promislow, Matt Kaeberlein, Alaattin Kaya.
      Altered mitochondrial function is tightly linked to lifespan regulation, but underlying mechanisms remain unclear. Here, we report the chronological and replicative lifespan variation across 167 yeast knock-out strains, each lacking a single nuclear-coded mitochondrial gene, including 144 genes with human homologs, many associated with diseases. We dissected the signatures of observed lifespan differences by analyzing profiles of each strain's proteome, lipidome, and metabolome under fermentative and respiratory culture conditions, which correspond to the metabolic states of replicative and chronologically aging cells, respectively. Examination of the relationships among extended longevity phenotypes, protein, and metabolite levels revealed that although many of these nuclear-encoded mitochondrial genes carry out different functions, their inhibition attenuates a common mechanism that controls cytosolic ribosomal protein abundance, actin dynamics, and proteasome function to regulate lifespan. The principles of lifespan control learned through this work may be applicable to the regulation of lifespan in more complex organisms, since many aspects of mitochondrial function are highly conserved among eukaryotes.
    Keywords:  Aging; Metabolism; Mitochondrial proteins; Omics; Yeast
    DOI:  https://doi.org/10.1007/s11357-023-00796-4
  11. J Gerontol A Biol Sci Med Sci. 2023 Apr 17. pii: glad106. [Epub ahead of print]
    Dietary supplementation with NAD +-boosting compounds in humans: Current knowledge and future directions.
    Kaitlin A Freeberg, Ce Ann C Udovich, Christopher R Martens, Douglas R Seals, Daniel H Craighead.
      Advancing age and many disease states are associated with declines in nicotinamide adenine dinucleotide (NAD +) levels. Preclinical studies suggest that boosting NAD + abundance with precursor compounds, such as nicotinamide riboside or nicotinamide mononucleotide, has profound effects on physiological function in models of aging and disease. Translation of these compounds for oral supplementation in humans has been increasingly studied within the last ten years; however, the clinical evidence that raising NAD + concentrations can improve physiological function is unclear. The goal of this review was to synthesize the published literature on the effects of chronic oral supplementation with NAD + precursors on healthy aging and age-related chronic diseases. We identified nicotinamide riboside, nicotinamide riboside co-administered with pterostilbene, and nicotinamide mononucleotide as the most common candidates in investigations of NAD +-boosting compounds for improving physiological function in humans. Studies have been performed in generally healthy midlife and older adults, adults with cardiometabolic disease risk factors such as overweight and obesity, and numerous patient populations. Supplementation with these compounds is safe, tolerable, and can increase the abundance of NAD + and related metabolites in multiple tissues. Dosing regimens and study durations vary greatly across interventions, and small sample sizes limit data interpretation of physiological outcomes. Limitations are identified and future research directions are suggested to further our understanding of the potential efficacy of NAD +-boosting compounds for improving physiological function and extending human healthspan.
    Keywords:  Clinical Trials; Nicotinamide Riboside; Nutrition; Physiology; Successful Aging
    DOI:  https://doi.org/10.1093/gerona/glad106
  12. Exp Cell Res. 2023 Apr 13. pii: S0014-4827(23)00146-5. [Epub ahead of print]427(1): 113599
    Ex vivo expansion of hematopoietic stem cells.
    Yuan Wang, Ryohichi Sugimura.
      Hematopoietic stem cells (HSCs) are multipotent progenitor cells that can differentiate into various mature blood cells and immune cells, thus reconstituting hematopoiesis. By taking advantage of the tremendous potential of HSCs, varied hereditary and hematologic diseases are promised to be alleviated or cured. To solve the contradiction between the growing demand for HSCs in disease treatment and the low population of HSCs in both cord blood and bone marrow, ex vivo HSC expansion along with multiple protocols has been investigated for harvesting adequate HSCs over the past two decades. This review surveys the state-of-the-art techniques for ex vivo HSC self-renewal and provides a concise summary of the effects of diverse intrinsic and extrinsic factors on the expansion of HSCs. The remaining challenges and emerging opportunities in the field of HSC expansion are also presented.
    Keywords:  Ex vivo; Expansion; HSC; Small molecules; Transplantation; polymers
    DOI:  https://doi.org/10.1016/j.yexcr.2023.113599
  13. Biogerontology. 2023 Apr 17.
    SIRT4 in ageing.
    Ling He, Qingcheng Liu, Jielong Cheng, Mei Cao, Shuaimei Zhang, Xiaolin Wan, Jian Li, Huaijun Tu.
      Ageing is a phenomenon in which cells, tissues and organs undergo systemic pathological changes as individuals age, leading to the occurrence of ageing-related diseases and the end of life. It is associated with many phenotypes known as ageing characteristics, such as genomic instability, nutritional imbalance, mitochondrial dysfunction, cell senescence, stem cell depletion, and an altered microenvironment. The sirtuin family (SIRT), known as longevity proteins, is thought to delay ageing and prolong life, and mammals, including humans, have seven family members (SIRT1-7). SIRT4 has been studied less among the sirtuin family thus far, but it has been reported that it has important physiological functions in organisms, such as promoting DNA damage repair, participating in the energy metabolism of three substances, inhibiting inflammatory reactions and apoptosis, and regulating mitochondrial function. Recently, some studies have demonstrated the involvement of SIRT4 in age-related processes, but knowledge in this field is still scarce. Therefore, this review aims to analyse the relationship between SIRT4 and ageing characteristics as well as some age-related diseases (e.g., cardiovascular diseases, metabolic diseases, neurodegenerative diseases and cancer).
    Keywords:  Ageing; Ageing-associated diseases; SIRT4; Sirtuins
    DOI:  https://doi.org/10.1007/s10522-023-10022-5
  14. Sci Adv. 2023 Apr 21. 9(16): eade9746
    Age-related loss of chromosome Y is associated with levels of sex hormone binding globulin and clonal hematopoiesis defined by TET2, TP53, and CBL mutations.
    Ahmed A Z Dawoud, William J Tapper, Nicholas C P Cross.
      Mosaic loss of the Y-chromosome (LOY) in peripheral blood leukocytes is the most common somatic alteration in men and linked to wide range of malignant and nonmalignant conditions. LOY is associated with age, smoking, and constitutional genetics. Here, we aimed to assess the relationships between LOY, serum biomarkers, and clonal hematopoiesis (CH). LOY in U.K. Biobank was strongly associated with levels of sex hormone binding globulin (SHBG), a key regulator of testosterone bioavailability. Mendelian randomization suggested a causal effect of SHBG on LOY but there was no evidence for an effect of LOY on SHBG. In contrast, age-related CH defined by somatic driver mutations was not associated with SHBG but was associated with LOY at clonal fractions above 30%. TET2, TP53, and CBL mutations were enriched in LOY cases, but JAK2 V617F was depleted. Our findings thus identify independent relationships between LOY, sex hormone levels, and CH.
    DOI:  https://doi.org/10.1126/sciadv.ade9746
  15. Cell Stem Cell. 2023 Apr 13. pii: S1934-5909(23)00087-5. [Epub ahead of print]
    Exercise reprograms the inflammatory landscape of multiple stem cell compartments during mammalian aging.
    Ling Liu, Soochi Kim, Matthew T Buckley, Jaime M Reyes, Jengmin Kang, Lei Tian, Mingqiang Wang, Alexander Lieu, Michelle Mao, Cristina Rodriguez-Mateo, Heather D Ishak, Mira Jeong, Joseph C Wu, Margaret A Goodell, Anne Brunet, Thomas A Rando.
      Exercise has the ability to rejuvenate stem cells and improve tissue regeneration in aging animals. However, the cellular and molecular changes elicited by exercise have not been systematically studied across a broad range of cell types in stem cell compartments. We subjected young and old mice to aerobic exercise and generated a single-cell transcriptomic atlas of muscle, neural, and hematopoietic stem cells with their niche cells and progeny, complemented by whole transcriptome analysis of single myofibers. We found that exercise ameliorated the upregulation of a number of inflammatory pathways associated with old age and restored aspects of intercellular communication mediated by immune cells within these stem cell compartments. Exercise has a profound impact on the composition and transcriptomic landscape of circulating and tissue-resident immune cells. Our study provides a comprehensive view of the coordinated responses of multiple aged stem cells and niche cells to exercise at the transcriptomic level.
    Keywords:  aging; exercise; hematopoietic stem cells; inflammation; muscle stem cells; myofibers; neural stem cells; scRNA-seq; skeletal muscle; subventricular zone
    DOI:  https://doi.org/10.1016/j.stem.2023.03.016
  16. Cell Rep. 2023 Apr 15. pii: S2211-1247(23)00407-2. [Epub ahead of print]42(4): 112396
    AMPK activation protects against prostate cancer by inducing a catabolic cellular state.
    Lucy Penfold, Angela Woods, Alice E Pollard, Julia Arizanova, Eneko Pascual-Navarro, Phillip J Muckett, Marian H Dore, Alex Montoya, Chad Whilding, Louise Fets, Joao Mokochinski, Theodora A Constantin, Anabel Varela-Carver, Damien A Leach, Charlotte L Bevan, Alexander Yu Nikitin, Zoe Hall, David Carling.
      Emerging evidence indicates that metabolic dysregulation drives prostate cancer (PCa) progression and metastasis. AMP-activated protein kinase (AMPK) is a master regulator of metabolism, although its role in PCa remains unclear. Here, we show that genetic and pharmacological activation of AMPK provides a protective effect on PCa progression in vivo. We show that AMPK activation induces PGC1α expression, leading to catabolic metabolic reprogramming of PCa cells. This catabolic state is characterized by increased mitochondrial gene expression, increased fatty acid oxidation, decreased lipogenic potential, decreased cell proliferation, and decreased cell invasiveness. Together, these changes inhibit PCa disease progression. Additionally, we identify a gene network involved in cell cycle regulation that is inhibited by AMPK activation. Strikingly, we show a correlation between this gene network and PGC1α gene expression in human PCa. Taken together, our findings support the use of AMPK activators for clinical treatment of PCa to improve patient outcome.
    Keywords:  AMPK; CP: Cancer; CP: Metabolism; PGC1α; cell cycle regulation; fatty acid oxidation; high-fat diet; lipogenesis; metabolism; metastasis; mitochondria; prostate cancer
    DOI:  https://doi.org/10.1016/j.celrep.2023.112396
  17. Elife. 2023 Apr 17. pii: e87358. [Epub ahead of print]12
    Boosting in the age of Omicron.
    Alex Sigal.
      A third dose of the inactivated vaccine CoronaVac fails to stimulate the production of neutralizing antibodies which target the Omicron variant.
    Keywords:  COVID-19; epidemiology; global health; human; humoral immunity; immunology; inflammation; vaccine
    DOI:  https://doi.org/10.7554/eLife.87358
  18. Nature. 2023 Apr;616(7958): 670-671
    Learning the metabolic language of cancer.
    Minervo Perez, Jordan L Meier.
      
    Keywords:  Cancer; Cell biology; Metabolism
    DOI:  https://doi.org/10.1038/d41586-023-01024-x
  19. Cell Mol Life Sci. 2023 Apr 21. 80(5): 126
    Aging microglia.
    Ignazio Antignano, Yingxiao Liu, Nina Offermann, Melania Capasso.
      Microglia are the tissue-resident macrophage population of the brain, specialized in supporting the CNS environment and protecting it from endogenous and exogenous insults. Nonetheless, their function declines with age, in ways that remain to be fully elucidated. Given the critical role played by microglia in neurodegenerative diseases, a better understanding of the aging microglia phenotype is an essential prerequisite in designing better preventive and therapeutic strategies. In this review, we discuss the most recent literature on microglia in aging, comparing findings in rodent models and human subjects.
    Keywords:  Aging; Human microglia; Microglia; Neuroinflammation; RNAseq; Senescence
    DOI:  https://doi.org/10.1007/s00018-023-04775-y
  20. Front Cardiovasc Med. 2023 ;10 1082371
    The role of frailty in advanced HF and cardiac transplantation.
    Nicole K Bart, Alice Powell, Peter S Macdonald.
      Frailty is a complex, multi-system condition often associated with multimorbidity. It has become an important prognostic maker across a range of conditions and is particularly relevant in patients with cardiovascular disease. Frailty encompasses a range of domains including, physical, psychological, and social. There are currently a range of validated tools available to measure frailty. It is an especially important measurement in advanced HF, because frailty occurs in up to 50% of HF patients and is potentially reversible with therapies such as mechanical circulatory support and transplantation. Moreover, frailty is dynamic, and therefore serial measurements are important. This review delves into the measurement of frailty, mechanisms, and its role in different cardiovascular cohorts. Understanding frailty will help determine patients that will benefit from therapies, as well as prognosticate outcomes.
    Keywords:  ageing; cardiac disease; frailty; heart failure; robustness; superAging; transplantation
    DOI:  https://doi.org/10.3389/fcvm.2023.1082371
  21. Eur Respir J. 2023 Apr 20. pii: 2300011. [Epub ahead of print]
    Age-related changes in plasma biomarkers and their association with mortality in COVID-19.
    Amsterdam UMC COVID-19 biobank study group
      BACKGROUND: COVID-19-induced mortality occurs predominantly in older patients. Several immunomodulating therapies seem less beneficial in these patients. The biological substrate behind these observations is unknown. The aim of this study was to obtain insight into the association between ageing, the host response, and mortality in patients with COVID-19.METHODS: We determined 43 biomarkers reflective of alterations in four pathophysiological domains: endothelial cell and coagulation activation, inflammation and organ damage, and cytokine and chemokine release. We used mediation analysis to associate ageing-driven alterations in the host response with 30-day mortality. Biomarkers associated with both ageing and mortality were validated in an intensive care unit and external cohort.
    RESULTS: 464 general ward patients with COVID-19 were stratified according to age decades. Increasing age was an independent risk factor for 30-day mortality. Ageing was associated with alterations in each of the host response domains, characterised by greater activation of the endothelium and coagulation system and stronger elevation of inflammation and organ damage markers, which was independent of an increase in age-related comorbidities. Soluble tumor necrosis factor receptor 1, soluble triggering receptor expressed on myeloid cells 1, and soluble thrombomodulin showed the strongest correlation with ageing and explained part of the ageing-driven increase in 30-day mortality (proportion mediated: 13.0%, 12.9% and 12.6%, respectively).
    CONCLUSION: Ageing is associated with a strong and broad modification of the host response to COVID-19, and specific immune changes likely contribute to increased mortality in older patients. These results may provide insight into potential age-specific immunomodulatory targets in COVID-19.
    DOI:  https://doi.org/10.1183/13993003.00011-2023
  22. AIDS. 2023 Apr 06.
    Performance of a modified fracture risk assessment tool (FRAX) for fragility fracture prediction among older veterans living with HIV.
    Julie A Womack, Terrence E Murphy, Linda Leo-Summers, Farah Kidwai-Khan, Melissa Skanderson, Thomas M Gill, Barbara Gulanski, Maria C Rodriguez-Barradas, Michael T Yin, Evelyn Hsieh.
      OBJECTIVE: Fragility fractures (fractures) are a critical outcome for persons aging with HIV (PAH). Research suggests that the fracture risk assessment tool (FRAX) only modestly estimates fracture risk among PAH. We provide an updated evaluation of how well a 'modified FRAX' identifies PAH at risk for fractures in a contemporary HIV cohort.DESIGN: Cohort study.
    METHODS: We used data from the Veterans Aging Cohort Study to evaluate veterans living with HIV, aged 50+ years, for the occurrence of fractures from 1 January 2010 through 31 December 2019. Data from 2009 were used to evaluate the eight FRAX predictors available to us: age, sex, BMI, history of previous fracture, glucocorticoid use, rheumatoid arthritis, alcohol use, and smoking status. These predictor values were then used to estimate participant risk for each of two types of fractures (major osteoporotic and hip) over the subsequent 10 years in strata defined by race/ethnicity using multivariable logistic regression.
    RESULTS: Discrimination for major osteoporotic fracture was modest [Blacks: area under the curve (AUC) 0.62; 95% confidence interval (CI) 0.62, 0.63; Whites: AUC 0.61; 95% CI 0.60, 0.61; Hispanic: AUC 0.63; 95% CI 0.62, 0.65]. For hip fractures, discrimination was modest to good (Blacks: AUC 0.70; 95% CI 0.69, 0.71; Whites: AUC 0.68; 95% CI 0.67, 0.69]. Calibration was good in all models across all racial/ethnic groups.
    CONCLUSION: Our 'modified FRAX' exhibited modest discrimination for predicting major osteoporotic fracture and slightly better discrimination for hip fracture. Future studies should explore whether augmentation of this subset of FRAX predictors results in enhanced prediction of fractures among PAH.
    DOI:  https://doi.org/10.1097/QAD.0000000000003566
  23. Exp Gerontol. 2023 Apr 19. pii: S0531-5565(23)00098-0. [Epub ahead of print] 112177
    Age-associated inflammation and implications for skeletal muscle responses to exercise.
    Hawley E Kunz, Ian R Lanza.
      Aging is associated with profound alterations in skeletal muscle, including loss of muscle mass and function, local inflammation, altered mitochondrial physiology, and attenuated anabolic responses to exercise termed anabolic resistance. "Inflammaging," the chronic, low-grade inflammation associated with aging, may contribute to many of the age-related derangements in skeletal muscle, including its ability to respond to exercise and nutritional stimuli. Inflammation and exercise are closely intertwined in numerous ways. A single bout of muscle-damaging exercise stimulates an acute inflammatory response in the skeletal muscle that is essential for muscle repair and regeneration; however, the chronic systemic and local inflammation associated with aging may impair acute inflammatory and anabolic responses to exercise. In contrast, exercise training is anti-inflammatory, targeting many of the potential root causes of inflammaging. In this review, we discuss the interplay between inflammation and exercise in aging and highlight potential therapeutic targets for improving adaptive responses to exercise in older adults.
    Keywords:  Aging; Exercise; Inflammation; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.exger.2023.112177
  24. Nat Commun. 2023 Apr 21. 14(1): 2290
    RNA binding protein SYNCRIP maintains proteostasis and self-renewal of hematopoietic stem and progenitor cells.
    Florisela Herrejon Chavez, Hanzhi Luo, Paolo Cifani, Alli Pine, Karen L Chu, Suhasini Joshi, Ersilia Barin, Alexandra Schurer, Mandy Chan, Kathryn Chang, Grace Y Q Han, Aspen J Pierson, Michael Xiao, Xuejing Yang, Lindsey M Kuehm, Yuning Hong, Diu T T Nguyen, Gabriela Chiosis, Alex Kentsis, Christina Leslie, Ly P Vu, Michael G Kharas.
      Tissue homeostasis is maintained after stress by engaging and activating the hematopoietic stem and progenitor compartments in the blood. Hematopoietic stem cells (HSCs) are essential for long-term repopulation after secondary transplantation. Here, using a conditional knockout mouse model, we revealed that the RNA-binding protein SYNCRIP is required for maintenance of blood homeostasis especially after regenerative stress due to defects in HSCs and progenitors. Mechanistically, we find that SYNCRIP loss results in a failure to maintain proteome homeostasis that is essential for HSC maintenance. SYNCRIP depletion results in increased protein synthesis, a dysregulated epichaperome, an accumulation of misfolded proteins and induces endoplasmic reticulum stress. Additionally, we find that SYNCRIP is required for translation of CDC42 RHO-GTPase, and loss of SYNCRIP results in defects in polarity, asymmetric segregation, and dilution of unfolded proteins. Forced expression of CDC42 recovers polarity and in vitro replating activities of HSCs. Taken together, we uncovered a post-transcriptional regulatory program that safeguards HSC self-renewal capacity and blood homeostasis.
    DOI:  https://doi.org/10.1038/s41467-023-38001-x
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