bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–03–19
twelve papers selected by
Ayesh Seneviratne, Western University



  1. Ageing Res Rev. 2023 Mar 09. pii: S1568-1637(23)00067-3. [Epub ahead of print] 101908
      The hallmarks of aging constitute an interconnected network of basic mechanisms that modulate aging and can be modulated by lifestyle factors, including dietary strategies. This narrative review aimed to summarize the evidence on promoting dietary restriction or adherence to specific dietary patterns on cellular hallmarks of aging. Studies with preclinical models or humans were considered. Dietary restriction (DR), usually operationalized as a reduction in caloric intake, is the main strategy applied to study the axis diet-hallmarks of aging. DR has been shown to modulate mainly genomic instability, loss of proteostasis, deregulating nutrient sensing, cellular senescence, and altered intercellular communication. Much less evidence exists on the role of dietary patterns, with most of the studies evaluating the Mediterranean Diet and other similar plant-based diets, and the ketogenic diet. Potential benefits are described in genomic instability, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, and altered intercellular communication. Given the predominant place of food in human life, it is imperative to determine the impact of nutritional strategies on the modulation of lifespan and health span, considering applicability, long-term adherence, and side effects.
    Keywords:  caloric restriction; dietary patterns; fasting; food intake; hallmarks of aging
    DOI:  https://doi.org/10.1016/j.arr.2023.101908
  2. Haematologica. 2023 Mar 16.
      Hematopoietic stem cells (HSCs) maintain lifetime whole blood hematopoiesis through self-renewal and differentiation. To sustain HSC stemness, most HSCs reside in a quiescence state, which is affected by diverse cellular stress and intracellular signal transduction. How HSCs accommodate those challenges to preserve lifetime capacity remains elusive. Here we show that Pax transactivation domain-interacting protein (PTIP) is required for preserving hematopoietic stem cell quiescence via regulating lysosomal activity. Using a genetic knockout mouse model to specifically delete Ptip in HSCs, we find that loss of Ptip promotes HSCs exiting quiescence, and results in functional exhaustion of HSCs. Mechanistically, Ptip loss increases lysosomal degradative activity of HSCs. Restraining lysosomal activity restores the quiescence and repopulation potency of Ptip-/- HSCs. Additionally, PTIP interacts with SMAD2/3 and mediates TGFβ signaling-induced HSC quiescence. Overall, our work uncovers a key role of PTIP in sustaining HSC quiescence via regulating lysosomal activity.
    DOI:  https://doi.org/10.3324/haematol.2022.282224
  3. Surg Obes Relat Dis. 2023 Feb 07. pii: S1550-7289(23)00068-0. [Epub ahead of print]
      Obesity and associated metabolic dysfunction are on the rise in the United States and around the world. Metabolic dysfunction often leads to chronic disease, including cancer. Recent evidence suggests that weight loss among individuals with obesity may decrease cancer risk. Metabolic and bariatric surgery (MBS) leads to greater maximum and sustained weight loss than nonsurgical dietary strategies and demonstrates the most convincing evidence that weight loss lowers cancer risk. Caloric restriction diets combined with GLP-1 receptor agonists demonstrate weight loss intermediate between MBS and other nonsurgical diet strategies so long as individuals consistently take the medication. Weight regain after initial loss is a major problem with all weight loss strategies. To better prevent cancer in individuals with obesity, we need to individualize weight loss strategies, determining what strategy works for a given individual and how to implement it. We need to learn (1) what an individual's impediments to initial and sustained weight loss are; (2) what the optimal weight loss strategy, be it diet modification, diet modification + medication, or MBS followed by diet modification, is; (3) how exercise(s) should be incorporated into weight loss strategies; (4) where medications fit into the treatment strategy of individuals with obesity; and (5) what the mechanisms driving the influence of MBS on cancer risk are. We also need to (6) explore expanding the eligibility of MBS to individuals with a body mass index <35 kg/m2. Answers to these questions require a better understanding of how MBS impacts cancer risk, including in which groups (women versus men, which racial and ethnic groups, which cancers, which MBS procedure) MBS works best to reduce risk. The National Cancer Institute, through new funding opportunities, hopes to advance our understanding of how obesity drives cancer risk and how individuals with obesity can prevent cancer development and, among those with cancer, prevent disease recurrence.
    Keywords:  Bariatric surgery; Cancer prevention; Metabolic surgery; Obesity
    DOI:  https://doi.org/10.1016/j.soard.2023.01.029
  4. EBioMedicine. 2023 Mar;pii: S2352-3964(23)00093-2. [Epub ahead of print]89 104528
      
    DOI:  https://doi.org/10.1016/j.ebiom.2023.104528
  5. Curr Oncol Rep. 2023 Mar 16.
       PURPOSE OF REVIEW: This article summarizes the current knowledge about clonal hematopoiesis of indeterminate potential (CHIP), its association with cardiovascular disease (CVD), and other outcomes, pathogenesis, postulated mechanisms of various pathologies, current knowledge gaps, possible targets of intervention, and therapeutic implications.
    RECENT FINDINGS: Recently, a common age-related hematological entity known as CHIP has been identified as the independent risk factor for CVD. CHIP is defined as the presence of clonally expanded blood cells involving leukemogenic mutations without the evidence of malignancy. CHIP is known to increase the inflammatory state which in turn is thought to be responsible for increased risk of CVD. Apart from CVD and malignancy, CHIP is also associated with pulmonary embolism, COPD, CKD, stroke, altered metabolism, obesity, liver disease, and increased all-cause mortality. At the same time surprisingly, CHIP is found to have positive outcomes in bone marrow transplant patients and similar reciprocal association with Alzheimer's disease. The risk of CVD and cancer increases with the advancing age, and these two are the leading causes of death in the USA. CHIP is an independent risk factor for CVD development. Most patients with CHIP have somatic clonal mutations in epigenetic regulators, DNA repair genes, or regulatory tyrosine kinases without evidence of overt hematological malignancy. CHIP portends increased risk for leukemia development and carries twofold increased risk of CVD including CAD, MI, and poor prognosis in heart failure. CHIP is associated with various other pathologies making CHIP an area of active research interest in recent years. Current research efforts aim to bridge many knowledge gaps in understanding of CHIP that still exist.
    Keywords:  ASXL1; CHIP; Cardiovascular disease; Clonal hematopoiesis of indeterminate potential; DNMT3A; JAK2; Somatic mutations; TET2
    DOI:  https://doi.org/10.1007/s11912-023-01382-9
  6. Curr Oncol Rep. 2023 Mar 15.
       PURPOSE OF REVIEW: Clonal hematopoiesis (CH) refers to the expansion of hematopoietic stem cell clones and their cellular progeny due to somatic mutations, mosaic chromosomal alterations (mCAs), or copy number variants which naturally accumulate with age. CH has been linked to increased risk of blood cancers, but CH has also been linked to adverse cardiovascular outcomes.
    RECENT FINDINGS: A combination of clinical outcome studies and mouse models have offered strong evidence that CH mutations either correlate with or cause atherosclerosis, diabetes mellitus, chronic kidney disease, heart failure, pulmonary hypertension, aortic aneurysm, myocardial infarction, stroke, aortic stenosis, poor outcomes following transcatheter aortic valve replacement (TAVR) or orthotopic heart transplant, death or need of renal replacement therapy secondary to cardiogenic shock, death from cardiovascular causes at large, and enhance anthracycline cardiac toxicity. Mechanistically, some adverse outcomes are caused by macrophage secretion of IL-1β and IL-6, neutrophil invasion of injured myocardium, and T-cell skewing towards inflammatory phenotypes. CH mutations lead to harmful inflammation and arterial wall invasion by bone marrow-derived cells resulting in poor cardiovascular health and outcomes. Blockade of IL-1β or JAK2 signaling are potential avenues for preventing CH-caused cardiovascular morbidity and mortality.
    Keywords:  CHIP; Cardio-oncology; Clonal hematopoiesis; TET2; Therapy-related cardiac toxicity
    DOI:  https://doi.org/10.1007/s11912-023-01398-1
  7. Cell Rep. 2023 Mar 10. pii: S2211-1247(23)00250-4. [Epub ahead of print]42(3): 112239
      It is widely believed that hematopoiesis after birth is established by hematopoietic stem cells (HSCs) in the bone marrow and that HSC-independent hematopoiesis is limited only to primitive erythro-myeloid cells and tissue-resident innate immune cells arising in the embryo. Here, surprisingly, we find that significant percentages of lymphocytes are not derived from HSCs, even in 1-year-old mice. Instead, multiple waves of hematopoiesis occur from embryonic day 7.5 (E7.5) to E11.5 endothelial cells, which simultaneously produce HSCs and lymphoid progenitors that constitute many layers of adaptive T and B lymphocytes in adult mice. Additionally, HSC lineage tracing reveals that the contribution of fetal liver HSCs to peritoneal B-1a cells is minimal and that the majority of B-1a cells are HSC independent. Our discovery of extensive HSC-independent lymphocytes in adult mice attests to the complex blood developmental dynamics spanning the embryo-to-adult transition and challenges the paradigm of HSCs exclusively underpinning the postnatal immune system.
    Keywords:  AGM region; B-1a cells; CP: Developmental biology; HSC precursors; HSC-independent hematopoiesis; adaptive immune lymphocytes; hemogenic endothelial cells; lineage tracing mouse models; mouse embryo; multi-potent progenitors
    DOI:  https://doi.org/10.1016/j.celrep.2023.112239
  8. Front Immunol. 2023 ;14 1132653
      Aging is associated with an increased incidence of autoimmune diseases, despite the progressive decline of immune responses (immunosenescence). This apparent paradox can be explained by the age-related chronic low-grade systemic inflammation (inflammaging) and progressive dysregulation of innate signaling. During cellular aging, there is an accumulation of damaged DNA in the cell's cytoplasm, which serves as ubiquitous danger-associated molecule, promptly recognized by DNA sensors. For instance, the free cytoplasmic DNA can be recognized, by DNA-sensing molecules like cGAS-STING (cyclic GMP-AMP synthase linked to a stimulator of interferon genes), triggering transcriptional factors involved in the secretion of pro-inflammatory mediators. However, the contribution of this pathway to the aging immune system remains largely unknown. Here, we highlight recent advances in understanding the biology of the cGAS-STING pathway, its influence on the senescence-associated secretory phenotype (SASP), and its modulation of the immune system during sterile inflammation. We propose that this important stress sensor of DNA damage is also a trigger of immunosenescence and inflammaging.
    Keywords:  NF-κB; SASP; aging; cGAS; immunosenescence; inflammaging; senescence
    DOI:  https://doi.org/10.3389/fimmu.2023.1132653