bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–05–01
eight papers selected by
Ayesh Seneviratne, Western University



  1. Cell. 2022 Apr 28. pii: S0092-8674(22)00398-1. [Epub ahead of print]185(9): 1455-1470
      Diet as a whole, encompassing food composition, calorie intake, and the length and frequency of fasting periods, affects the time span in which health and functional capacity are maintained. Here, we analyze aging and nutrition studies in simple organisms, rodents, monkeys, and humans to link longevity to conserved growth and metabolic pathways and outline their role in aging and age-related disease. We focus on feasible nutritional strategies shown to delay aging and/or prevent diseases through epidemiological, model organism, clinical, and centenarian studies and underline the need to avoid malnourishment and frailty. These findings are integrated to define a longevity diet based on a multi-pillar approach adjusted for age and health status to optimize lifespan and healthspan in humans.
    DOI:  https://doi.org/10.1016/j.cell.2022.04.002
  2. Immunometabolism. 2022 ;pii: e220008. [Epub ahead of print]4(2):
      Hematopoietic homeostasis depends on the close regulation of hematopoietic stem cell (HSC) activity in the bone marrow. Quiescence and activation in response to stress, among other changes in state, are mediated by shifts in HSC metabolic activity. Although HSC steady-state metabolism is well established, the mechanisms driving HSC activation, proliferation, and differentiation in response to stress remain poorly understood. Here we discuss a study by Mistry et al. that describes a novel metabolic mechanism that fuels HSC activation and expansion. The authors show that to meet their metabolic needs in response to infection, hematopoietic stem and progenitor cells uptake free fatty acids from their microenvironment via CD36 to fuel fatty acid oxidation. These exciting findings suggest that in the context of infection, HSCs undergo a metabolic shift toward fatty acid metabolism that drives emergency hematopoiesis and raise questions about the role of the microenvironment in this process.
    Keywords:  CD36; fatty-acid oxidation; hematopoiesis; hematopoietic stem cells; infection; oxidative phosphorylation
    DOI:  https://doi.org/10.20900/immunometab20220008
  3. Commun Biol. 2022 Apr 28. 5(1): 396
      Aging of hematopoietic stem cells (HSCs) is linked to various blood disorders and malignancies. SIRT1 has been implicated in healthy aging, but its role in HSC aging is poorly understood. Surprisingly, we found that Sirt1 knockout improved the maintenance of quiescence of aging HSCs and their functionality as well as mouse survival in serial bone marrow transplantation (BMT) recipients. The majority of secondary and tertiary BMT recipients of aging wild type donor cells developed B/myeloid mixed phenotype acute leukemia (MPAL), which was markedly inhibited by Sirt1 knockout. SIRT1 inhibition also reduced the growth and survival of human B/myeloid MPAL cells. Sirt1 knockout suppressed global gene activation in old HSCs, prominently the genes regulating protein synthesis and oxidative metabolism, which may involve multiple downstream transcriptional factors. Our results demonstrate an unexpected role of SIRT1 in promoting HSC aging and age-dependent MPAL and suggest SIRT1 may be a new therapeutic target for modulating functions of aging HSCs and treatment of MPAL.
    DOI:  https://doi.org/10.1038/s42003-022-03340-w
  4. Blood. 2022 Apr 25. pii: blood.2021015162. [Epub ahead of print]
      Chronic inflammation with aging ("inflammaging") plays a prominent role in the pathogenesis of myeloid malignancies. Aberrant inflammatory activity impacts many different cells in the marrow, including normal blood and stromal marrow elements and leukemic cells, in unique and distinct ways. Inflammation can promote selective clonal expansion through differential immune-mediated suppression of normal hematopoietic cells and malignant clones. We review these complex roles, how they can be understood by separating cell-intrinsic from extrinsic effects, and how this informs future clinical trials.
    DOI:  https://doi.org/10.1182/blood.2021015162
  5. Annu Rev Cancer Biol. 2021 Mar;5 161-179
      Dietary restriction (DR) is the most successful nutritional intervention for extending lifespan and preserving health in numerous species. Reducing food intake triggers a protective response that shifts energy resources from growth to maintenance and resilience mechanisms. This so-called survival response has been shown to particularly increase life- and health span and decrease DNA damage in DNA repair-deficient mice exhibiting accelerated aging. Accumulation of DNA damage is the main cause of aging, but also of cancer. Moreover, radiotherapies and most chemotherapies are based on damaging DNA, consistent with their ability to induce toxicity and accelerate aging. Since fasting and DR decrease DNA damage and its effects, nutritional preconditioning holds promise for improving (cancer) therapy and preventing short- and long-term side effects of anticancer treatments. This review provides an overview of the link between aging and cancer, highlights important preclinical studies applying such nutritional preconditioning, and summarizes the first clinical trials implementing nutritional preconditioning in cancer treatment.
    Keywords:  DNA damage repair; aging; cancer; chemotherapy; dietary restriction; fasting
    DOI:  https://doi.org/10.1146/annurev-cancerbio-060820-090737
  6. Cancer Lett. 2022 Apr 22. pii: S0304-3835(22)00174-4. [Epub ahead of print] 215691
      Clonal hematopoiesis (CH) is a clonal expansion of single hematopoietic stem cells (HSC) with germline or somatic mutations accumulated in specific genes, which usually leads to clonal dominance via multiple biological pathways and increases the risk of developing hematological malignancies. With the advancement of Next Generation Sequencing (NGS) technology, CH can be widely detected in healthy individuals, many patients complicated with bone marrow failure (BMF), or even in those with myeloproliferative neoplasm (MPN) and therapy-related MDS/AML (t-MDS/AML). Recently, several proof-of-concept studies showed that it is likely to discriminate the CH with high risk developing malignancy through predictive models many years before its onset. Additionally, it has been shown that the CH-related premalignant clones can be abated or eradicated through chemical or genetic measures in animal models, thereby providing an insightful idea for preventing leukemogenesis. However, in despite of these advancements, the clinical implication and early diagnosis of CH for predicting hematological malignancies remain to be more investigated. In this review, we will first review the brief history, risk factors and molecular mechanisms of CH. Then, we will discuss the involved biological process of CH in bone marrow failure diseases, MPN and t-MDS/AML, pointing to its clinical implication. Finally, we will discuss the advancement of early detection of CH at premalignant stage for predicting hematological malignancies, and express perspectives and challenges for early intervention of CH in the future.
    Keywords:  Age-related clonal hematopoiesis (ARCH); Bone marrow failure disease; Clonal hematopoiesis; Clonal hematopoiesis of indeterminate potential (CHIP); Early detection; Hematological malignancy; Myeloproliferative neoplasm; Preventing hematological malignancies; Therapy-related MDS/AML(t-MDS/AML)
    DOI:  https://doi.org/10.1016/j.canlet.2022.215691
  7. Blood Res. 2022 Apr 30. 57(S1): 1-5
      The incidence of hematologic malignancy increases with age; thus, the number of older patients who require intensive chemotherapy is expected to increase with the aging population. In Korea, 61.8%, 59.3%, 47.0%, and 46.7% of newly diagnosed cases of multiple myeloma, myelodysplastic syndrome, myeloproliferative disorder, and non-Hodgkin lymphoma, respectively, occurred in patients aged >65 years in 2018. Health status among older patients, defined by frailty, age-related syndrome of physiological decline and increased vulnerability, is associated with adverse health outcomes. Health status is highly heterogeneous among older patients, and treatment outcomes vary according to frailty and physiologic age rather than chronologic age. Comprehensive geriatric assessment (CGA) is a multidimensional and multidisciplinary diagnostic and treatment process that identifies multiple domains, including functional status, cognition, comorbidities, medications, socioeconomic status, and nutritional status, to develop a coordinated plan to improve treatment-related outcomes and quality of life. Frailty can be assessed with CGA findings, and CGA is considered the "gold standard of care" for frail, older patients. Through CGA, unidentified problems can be assessed, and pre-emptive and non-oncologic interventions can be delivered. CGA is an objective and reliable tool for predicting further treatment-related complications and identifying patients for whom intensive chemotherapy with curative intent is appropriate. CGA should be considered a routine practice before starting treatment planning in older patients diagnosed with hematologic malignancies who require intensive chemotherapy. Further study is needed to allocate individualized treatment plans or multidisciplinary geriatric interventions according to CGA results.
    Keywords:  Frail elderly; Frailty; Geriatric assessment; Hematologic neoplasms; Induction chemotherapy
    DOI:  https://doi.org/10.5045/br.2022.2021218
  8. Elife. 2022 Apr 28. pii: e78693. [Epub ahead of print]11
      A new approach helps to assess the impact of accelerated epigenetic aging on the risk of cancer.
    Keywords:  DNA methylation; Mendelian randomization; cancer; epidemiology; epigenetic age acceleration; epigenetic clocks; genetics; genomics; human; medicine
    DOI:  https://doi.org/10.7554/eLife.78693