bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–10–08
fourteen papers selected by
Ayesh Seneviratne, Western University
  1. Combinatorial interventions in aging.
  2. SIRT2 counteracts primate cardiac aging.
  3. A chloroplast proteostasis factor prevents aggregation of a human disease-related protein.
  4. Metabolic Regulation of Aged Hematopoietic Stem Cells: Key Players and Mechanisms.
  5. Stem-Cell Aging and Pathways to Precancer Evolution.
  6. Mitochondrial Targeted Interventions for Aging.
  7. Blazing a trail for the clinical use of rapamycin as a geroprotecTOR.
  8. Intrinsic capacity: an under-researched concept in geriatrics.
  9. Mitochondria Dictate Function and Fate of HSCs and T Cells.
  10. New treatment opportunities for older patients with acute myeloid leukemia and the increasing importance of frailty assessment - An oncogeriatric perspective.
  11. BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis.
  12. Inflammasome Signaling, Thromboinflammation, and Venous Thromboembolism.
  13. Biomarkers of cellular senescence and risk of death in humans.
  14. Ameliorative effect of black tea extract on the skin of D-galactose-induced aging mice.
  1. Nat Aging. 2023 Oct 02.
    Combinatorial interventions in aging.
    Andrey A Parkhitko, Elizabeth Filine, Marc Tatar.
      Insight on the underlying mechanisms of aging will advance our ability to extend healthspan, treat age-related pathology and improve quality of life. Multiple genetic and pharmacological manipulations extend longevity in different species, yet monotherapy may be relatively inefficient, and we have limited data on the effect of combined interventions. Here we summarize interactions between age-related pathways and discuss strategies to simultaneously retard these in different organisms. In some cases, combined manipulations additively increase their impact on common hallmarks of aging and lifespan, suggesting they quantitatively participate within the same pathway. In other cases, interactions affect different hallmarks, suggesting their joint manipulation may independently maximize their effects on lifespan and healthy aging. While most interaction studies have been conducted with invertebrates and show varying levels of translatability, the conservation of pro-longevity pathways offers an opportunity to identify 'druggable' targets relevant to multiple human age-associated pathologies.
    DOI:  https://doi.org/10.1038/s43587-023-00489-9
  2. Nat Aging. 2023 Oct 02.
    SIRT2 counteracts primate cardiac aging.
    Laura Cox, Michael Olivier.
      
    DOI:  https://doi.org/10.1038/s43587-023-00496-w
  3. Nat Aging. 2023 Oct 02.
    A chloroplast proteostasis factor prevents aggregation of a human disease-related protein.
      
    DOI:  https://doi.org/10.1038/s43587-023-00503-0
  4. Exp Hematol. 2023 Sep 29. pii: S0301-472X(23)01733-2. [Epub ahead of print]
    Metabolic Regulation of Aged Hematopoietic Stem Cells: Key Players and Mechanisms.
    Nazanin Karimnia, James Harris, Shen Y Heazlewood, Benjamin Cao, Susan K Nilsson.
      Aging is accompanied by a gradual decline in the function and regenerative capacity of hematopoietic stem cells (HSCs), which leads to increased susceptibility to blood disorders. Recent studies have highlighted the critical role of metabolic regulation in governing the fate and function of HSCs, and alterations in metabolism play a critical role in the age-related changes observed in HSCs. Metabolic processes including glycolysis, mitochondrial function, nutrient sensing and inflammation, profoundly influence the maintenance, self-renewal and differentiation potential of the HSC pool. This review focuses on the metabolic alterations that occur in HSCs during aging and the systemic factors which contribute to HSC metabolic dysregulation, leading to impaired cellular function and reduced regenerative capacity. We highlight the impact of age-associated changes in oxidative stress, mitochondrial dysfunction, nutrient availability and inflammation on HSC metabolism and function. Targeting metabolic pathways and modulating key regulators of metabolism hold promise for reducing age-related HSC dysregulation, thus maintaining functional potential as a path towards healthy aging. Exploiting these metabolic interventions has the potential to improve hemopoietic recovery, enhance immune function and pave the way for novel therapeutic interventions to combat age-related blood disorders.
    Keywords:  Aging; autophagy; hematopoietic stem cell; metabolism; mitochondria; niche; nutrients
    DOI:  https://doi.org/10.1016/j.exphem.2023.09.006
  5. N Engl J Med. 2023 Oct 05. 389(14): 1310-1319
    Stem-Cell Aging and Pathways to Precancer Evolution.
    Catriona H M Jamieson, Irving L Weissman.
      
    DOI:  https://doi.org/10.1056/NEJMra2304431
  6. Cold Spring Harb Perspect Med. 2023 Oct 03. pii: a041199. [Epub ahead of print]
    Mitochondrial Targeted Interventions for Aging.
    Sophia Z Liu, Ying Ann Chiao, Peter S Rabinovitch, David J Marcinek.
      Changes in mitochondrial function play a critical role in the basic biology of aging and age-related disease. Mitochondria are typically thought of in the context of ATP production and oxidant production. However, it is clear that the mitochondria sit at a nexus of cell signaling where they affect metabolite, redox, and energy status, which influence many factors that contribute to the biology of aging, including stress responses, proteostasis, epigenetics, and inflammation. This has led to growing interest in identifying mitochondrial targeted interventions to delay or reverse age-related decline in function and promote healthy aging. In this review, we discuss the diverse roles of mitochondria in the cell. We then highlight some of the most promising strategies and compounds to target aging mitochondria in preclinical testing. Finally, we review the strategies and compounds that have advanced to clinical trials to test their ability to improve health in older adults.
    DOI:  https://doi.org/10.1101/cshperspect.a041199
  7. Geroscience. 2023 Oct 06.
    Blazing a trail for the clinical use of rapamycin as a geroprotecTOR.
    RAP PAC Investigators
      Treatment with rapamycin, an inhibitor of the mechanistic Target Of Rapamycin Complex One (mTORC1) protein kinase, has been repeatedly demonstrated to extend lifespan and prevent or delay age-related diseases in diverse model systems. Concerns over the risk of potentially serious side effects in humans, including immunosuppression and metabolic disruptions, have cautiously limited the translation of rapamycin and its analogs as a treatment for aging associated conditions. During the last decade, we and others have developed a working model that suggests that while inhibition of mTORC1 promotes healthy aging, many of the negative side effects of rapamycin are associated with "off-target" inhibition of a second mTOR complex, mTORC2. Differences in the kinetics and molecular mechanisms by which rapamycin inhibits mTORC1 and mTORC2 suggest that a therapeutic window for rapamycin could be exploited using intermittent dosing schedules or alternative rapalogs that may enable more selective inhibition of mTORC1. However, the optimal dosing schedules and the long-term efficacy of such interventions in humans are unknown. Here, we highlight ongoing or upcoming clinical trials that will address outstanding questions regarding the safety, pharmacokinetics, pharmacodynamics, and efficacy of rapamycin and rapalogs on several clinically oriented outcomes. Results from these early phase studies will help guide the design of phase 3 clinical trials to determine whether rapamycin can be used safely to inhibit mTORC1 for the treatment and prevention of age-related diseases in humans.
    Keywords:  Aging; Everolimus; Metabolism; Muscle; Sirolimus; mTOR
    DOI:  https://doi.org/10.1007/s11357-023-00935-x
  8. Age Ageing. 2023 Oct 02. pii: afad183. [Epub ahead of print]52(10):
    Intrinsic capacity: an under-researched concept in geriatrics.
    Emiel O Hoogendijk, Elsa Dent, Kaisa Koivunen.
      In 2015, the World Health Organisation (WHO) introduced the concept of intrinsic capacity (IC) as part of a new public health model for healthy ageing. IC refers to the overall combination of an individual's physical and mental capacities, and is promoted as a new positive approach to the health and wellbeing of older adults. However, there is still insufficient evidence that implementing IC leads to better care for older adults. Moreover, the current operationalisations of IC lead to confusion and redundant research. In this commentary, we discuss whether the concept of IC has added value for geriatrics, and describe the main issues related to its conceptualisation, measurement, and application. We argue that there is a need to clarify and validate the concept of IC, including independent evidence regarding its feasibility and acceptance in clinical practice.
    Keywords:  frail older adults; functional assessment; healthy ageing; intrinsic capacity; measurement properties; older people
    DOI:  https://doi.org/10.1093/ageing/afad183
  9. Cancer Immunol Res. 2023 10 04. 11(10): 1303-1313
    Mitochondria Dictate Function and Fate of HSCs and T Cells.
    Yingxi Xu, Yi-Hsuan Chiang, Ping-Chih Ho, Nicola Vannini.
      Hematopoietic stem cells (HSC) and T cells are intimately related, lineage-dependent cell populations that are extensively used as therapeutic products for the treatment of hematologic malignancies and certain types of solid tumors. These cellular therapies can be life-saving treatments; however, their efficacies are often limited by factors influencing their activity and cellular properties. Among these factors is mitochondrial metabolism, which influences the function and fate commitment of both HSCs and T cells. Mitochondria, besides being the "cellular powerhouse," provide metabolic intermediates that are used as substrates for epigenetic modifications and chromatin remodeling, thus, driving cell fate decisions during differentiation. Moreover, mitochondrial fitness and mitochondrial quality control mechanisms are closely related to cellular function, and impairment of these mitochondrial properties associates with cellular dysfunction due to factors such as T-cell exhaustion and aging. Here, we give an overview of the role of mitochondria in shaping the behavior of these lineage-related cell populations. Moreover, we discuss the potential of novel mitochondria-targeting strategies for enhancing HSC- and T cell-based cancer immunotherapies and highlight how design and application of such approaches requires consideration of the metabolic similarities and differences between HSCs and T cells. See related article on p. 1302.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-22-0685
  10. J Geriatr Oncol. 2023 Sep 30. pii: S1879-4068(23)00228-X. [Epub ahead of print] 101631
    New treatment opportunities for older patients with acute myeloid leukemia and the increasing importance of frailty assessment - An oncogeriatric perspective.
    Benno Diekmann, Marjolijn Timmerman, Liesbeth Hempenius, Eric van Roon, Bas Franken, Mels Hoogendoorn.
      With the introduction of targeted chemotherapy drugs, a new age of treatment for acute myeloid leukemia (AML) has begun. The promotion of the azacitidine+venetoclax combination regimen to first line of treatment in patients deemed ineligible for intensive chemotherapy marks the first of many novel combination regimens becoming part of national treatment guidelines. We review recent phase II and III clinical trials and conclude that these novel regimens offer significant increases in response rates, remission rates, and overall survival. The incidence of adverse events, the accrued time toxicity, and the healthcare costs, however, are increasing as well. Compared with clinical trials, older patients in the real world frequently present with an inferior baseline health status, which is associated with an increased risk of experiencing side effects. The key to reaping the maximum benefit of the new agents and their combination regimens therefore lies in sufficient attention being given to a patients' preexisting comorbidities, potential frailty, and quality of life. A systematic collaboration between hemato-oncologists and geriatricians can be a potent first step towards addressing the increased treatment intensity patients with AML experience under the novel regimens. In this narrative review article we provide an overview of recent and ongoing clinical trials, highlight encountered adverse events, discuss frailty assessment options, and outline an oncogeriatic care path for older patients with AML.
    Keywords:  AML; Acute myeloid leukemia; Adverse events; Care path; Frailty; Geriatric assessment; Ivosidenib; Toxicity; Venetoclax
    DOI:  https://doi.org/10.1016/j.jgo.2023.101631
  11. Circulation. 2023 Oct 02.
    BRCC3-Mediated NLRP3 Deubiquitylation Promotes Inflammasome Activation and Atherosclerosis in Tet2 Clonal Hematopoiesis.
    Mustafa Yalcinkaya, Wenli Liu, Leigh-Anne Thomas, Malgorzata Olszewska, Tong Xiao, Sandra Abramowicz, Eirini P Papapetrou, Marit Westerterp, Nan Wang, Ira Tabas, Alan R Tall.
       BACKGROUND: Clonal hematopoiesis (CH) has emerged as an independent risk factor for atherosclerotic cardiovascular disease, with activation of macrophage inflammasomes as a potential underlying mechanism. The NLRP3 (NLR family pyrin domain containing 3) inflammasome has a key role in promoting atherosclerosis in mouse models of Tet2 CH, whereas inhibition of the inflammasome product interleukin-1β appeared to particularly benefit patients with TET2 CH in CANTOS (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events]). TET2 is an epigenetic modifier that decreases promoter methylation. However, the mechanisms underlying macrophage NLRP3 inflammasome activation in TET2 (Tet methylcytosine dioxygenase 2) deficiency and potential links with epigenetic modifications are poorly understood.
    METHODS: We used cholesterol-loaded TET2-deficient murine and embryonic stem cell-derived isogenic human macrophages to evaluate mechanisms of NLRP3 inflammasome activation in vitro and hypercholesterolemic Ldlr-/- mice modeling TET2 CH to assess the role of NLRP3 inflammasome activation in atherosclerosis.
    RESULTS: Tet2 deficiency in murine macrophages acted synergistically with cholesterol loading in cell culture and with hypercholesterolemia in vivo to increase JNK1 (c-Jun N-terminal kinase 1) phosphorylation and NLRP3 inflammasome activation. The mechanism of JNK (c-Jun N-terminal kinase) activation in TET2 deficiency was increased promoter methylation and decreased expression of the JNK-inactivating dual-specificity phosphatase Dusp10. Active Tet1-deadCas9-targeted editing of Dusp10 promoter methylation abolished cholesterol-induced inflammasome activation in Tet2-deficient macrophages. Increased JNK1 signaling led to NLRP3 deubiquitylation and activation by the deubiquitinase BRCC3 (BRCA1/BRCA2-containing complex subunit 3). Accelerated atherosclerosis and neutrophil extracellular trap formation (NETosis) in Tet2 CH mice were reversed by holomycin, a BRCC3 deubiquitinase inhibitor, and also by hematopoietic deficiency of Abro1, an essential scaffolding protein in the BRCC3-containing cytosolic complex. Human TET2-/- macrophages displayed increased JNK1 and NLRP3 inflammasome activation, especially after cholesterol loading, with reversal by holomycin treatment, indicating human relevance.
    CONCLUSIONS: Hypercholesterolemia and TET2 deficiency converge on a common pathway of NLRP3 inflammasome activation mediated by JNK1 activation and BRCC3-mediated NLRP3 deubiquitylation, with potential therapeutic implications for the prevention of cardiovascular disease in TET2 CH.
    Keywords:  atherosclerosis; clonal hematopoiesis; extracellular traps; hypercholesterolemia; inflammasomes; neutrophils; phosphorylation
    DOI:  https://doi.org/10.1161/CIRCULATIONAHA.123.065344
  12. JACC Basic Transl Sci. 2023 Sep;8(9): 1245-1261
    Inflammasome Signaling, Thromboinflammation, and Venous Thromboembolism.
    Nicola Potere, Antonio Abbate, Yogendra Kanthi, Marc Carrier, Stefano Toldo, Ettore Porreca, Marcello Di Nisio.
      Venous thromboembolism (VTE) remains a major health burden despite anticoagulation advances, suggesting incomplete management of pathogenic mechanisms. The NLRP3 (NACHT-, LRR- and pyrin domain-containing protein 3) inflammasome, interleukin (IL)-1, and pyroptosis are emerging contributors to the inflammatory pathogenesis of VTE. Inflammasome pathway activation occurs in patients with VTE. In preclinical models, inflammasome signaling blockade reduces venous thrombogenesis and vascular injury, suggesting that this therapeutic approach may potentially maximize anticoagulation benefits, protecting from VTE occurrence, recurrence, and ensuing post-thrombotic syndrome. The nonselective NLRP3 inhibitor colchicine and the anti-IL-1β agent canakinumab reduce atherothrombosis without increasing bleeding. Rosuvastatin reduces primary venous thrombotic events at least in part through lipid-lowering independent mechanisms, paving the way to targeted anti-inflammatory strategies in VTE. This review outlines recent preclinical and clinical evidence supporting a role for inflammasome pathway activation in venous thrombosis, and discusses the, yet unexplored, therapeutic potential of modulating inflammasome signaling to prevent and manage VTE.
    Keywords:  anti-inflammatory agents; blood coagulation; embolism and thrombosis; inflammation; interleukin-1; post-thrombotic syndrome
    DOI:  https://doi.org/10.1016/j.jacbts.2023.03.017
  13. Aging Cell. 2023 Oct 06. e14006
    Biomarkers of cellular senescence and risk of death in humans.
    Jennifer L St Sauver, Susan A Weston, Elizabeth J Atkinson, Michaela E Mc Gree, Michelle M Mielke, Thomas A White, Amanda A Heeren, Janet E Olson, Walter A Rocca, Allyson K Palmer, Steven R Cummings, Roger A Fielding, Suzette J Bielinski, Nathan K LeBrasseur.
      A robust and heterogenous secretory phenotype is a core feature of most senescent cells. In addition to mediators of age-related pathology, components of the senescence associated secretory phenotype (SASP) have been studied as biomarkers of senescent cell burden and, in turn, biological age. Therefore, we hypothesized that circulating concentrations of candidate senescence biomarkers, including chemokines, cytokines, matrix remodeling proteins, and growth factors, could predict mortality in older adults. We assessed associations between plasma levels of 28 SASP proteins and risk of mortality over a median follow-up of 6.3 years in 1923 patients 65 years of age or older with zero or one chronic condition at baseline. Overall, the five senescence biomarkers most strongly associated with an increased risk of death were GDF15, RAGE, VEGFA, PARC, and MMP2, after adjusting for age, sex, race, and the presence of one chronic condition. The combination of biomarkers and clinical and demographic covariates exhibited a significantly higher c-statistic for risk of death (0.79, 95% confidence interval (CI): 0.76-0.82) than the covariates alone (0.70, CI: 0.67-0.74) (p < 0.001). Collectively, these findings lend further support to biomarkers of cellular senescence as informative predictors of clinically important health outcomes in older adults, including death.
    Keywords:  GDF15; aging; cohort study; inflammation; mortality; senescence-associated secretory phenotype (SASP)
    DOI:  https://doi.org/10.1111/acel.14006
  14. Front Nutr. 2023 ;10 1275199
    Ameliorative effect of black tea extract on the skin of D-galactose-induced aging mice.
    Xiaojie Zheng, Wenbin Deng, Xinzhou Wang, Zufang Wu, Chong Li, Xin Zhang.
      Aging is a universal and irreversible process, and the skin is an important feature that reflects the aging of the organism. Skin aging has been a focus of attention in recent years because it leads to changes in an individual's external features and the loss of many important biological functions. This experiment investigated the improvement effect of black tea extract (BTE) on the skin of aging mice under D-galactose induction. After 6 weeks of administration, the changes in skin bio-chemical indices and tissue structure were compared with the blank and positive control groups. It was observed that BTE increased water and hyaluronic acid (HA) content, decreased malondialdehyde (MDA) content, enhanced superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activities in the skin of aging mice, and improved the structure of aging damaged skin tissues and increased the content of total collagen. The experimental results showed that BTE can play a significant anti-aging effect on the skin, which can be used as a functional food for aging inhibition.
    Keywords:  anti-aging; biochemical index; black tea extract; skin aging; tissue structure
    DOI:  https://doi.org/10.3389/fnut.2023.1275199
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