bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–12–04
ten papers selected by
Ayesh Seneviratne, Western University
  1. Clonal Hematopoiesis and Its Impact on Human Health.
  2. Cellular enlargement - A new hallmark of aging?
  3. Cardiac PI3K p110α attenuation delays aging and extends lifespan.
  4. TNF Receptors Choose HSC Fate in Supporting Dnmt3a-Mutant Clonal Hematopoiesis.
  5. Understanding how comprehensive geriatric assessment works: the importance of varied methodological approaches.
  6. CHIP Happens: Clonal hematopoiesis of indeterminate potential and its relationship to solid tumors.
  7. Frailty in older people living with HIV: current status and clinical management.
  8. Special Issue: Circadian Rhythms and Age Related Disorder: How Does Aging Impact Mammalian Circadian Organization?
  9. Role of Bcl-2 inhibition in Myelodysplastic Syndromes.
  10. Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer's disease.
  1. Annu Rev Med. 2022 Nov 30.
    Clonal Hematopoiesis and Its Impact on Human Health.
    Herra Ahmad, Nikolaus Jahn, Siddhartha Jaiswal.
      Aging is associated with increased mutational burden in every tissue studied. Occasionally, fitness-increasing mutations will arise, leading to stem cell clonal expansion. This process occurs in several tissues but has been best studied in blood. Clonal hematopoiesis is associated with an increased risk of blood cancers, such as acute myeloid leukemia, which result if additional cooperating mutations occur. Surprisingly, it is also associated with an increased risk of nonmalignant diseases, such as atherosclerotic cardiovascular disease. This may be due to enhanced inflammation in mutated innate immune cells, which could be targeted clinically with anti-inflammatory drugs. Recent studies have uncovered other factors that predict poor outcomes in patients with clonal hematopoiesis, such as size of the mutant clone, mutated driver genes, and epigenetic aging. Though clonality is inevitable and largely a function of time, recent work has shown that inherited genetic variation can also influence this process. Clonal hematopoiesis provides a paradigm for understanding how age-related changes in tissue stem cell composition and function influence human health. Expected final online publication date for the Annual Review of Medicine, Volume 74 is January 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
    DOI:  https://doi.org/10.1146/annurev-med-042921-112347
  2. Front Cell Dev Biol. 2022 ;10 1036602
    Cellular enlargement - A new hallmark of aging?
    Daniel M Davies, Kim van den Handel, Soham Bharadwaj, Jette Lengefeld.
      Years of important research has revealed that cells heavily invest in regulating their size. Nevertheless, it has remained unclear why accurate size control is so important. Our recent study using hematopoietic stem cells (HSCs) in vivo indicates that cellular enlargement is causally associated with aging. Here, we present an overview of these findings and their implications. Furthermore, we performed a broad literature analysis to evaluate the potential of cellular enlargement as a new aging hallmark and to examine its connection to previously described aging hallmarks. Finally, we highlight interesting work presenting a correlation between cell size and age-related diseases. Taken together, we found mounting evidence linking cellular enlargement to aging and age-related diseases. Therefore, we encourage researchers from seemingly unrelated areas to take a fresh look at their data from the perspective of cell size.
    Keywords:  Cellular enlargement; aging-related diseases; cell size physiology; hallmarks of aging; stem cells
    DOI:  https://doi.org/10.3389/fcell.2022.1036602
  3. Cell Stress. 2022 Aug;6(8): 72-75
    Cardiac PI3K p110α attenuation delays aging and extends lifespan.
    Mahmoud Abdellatif, Tobias Eisenberg, Alexander Martin Heberle, Kathrin Thedieck, Guido Kroemer, Simon Sedej.
      Phosphoinositide 3-kinase (PI3K) is a key component of the insulin signaling pathway that controls cellular me-tabolism and growth. Loss-of-function mutations in PI3K signaling and other downstream effectors of the insulin signaling pathway extend the lifespan of various model organisms. However, the pro-longevity effect appears to be sex-specific and young mice with reduced PI3K signaling have increased risk of cardiac disease. Hence, it remains elusive as to whether PI3K inhibition is a valid strategy to delay aging and extend healthspan in humans. We recently demonstrated that reduced PI3K activity in cardiomyocytes delays cardiac growth, causing subnormal contractility and cardiopulmonary functional capacity, as well as increased risk of mortality at young age. In stark contrast, in aged mice, experi-mental attenuation of PI3K signaling reduced the age-dependent decline in cardiac function and extended maximal lifespan, suggesting a biphasic effect of PI3K on cardiac health and survival. The cardiac anti-aging effects of reduced PI3K activity coincided with enhanced oxida-tive phosphorylation and required increased autophagic flux. In humans, explanted failing hearts showed in-creased PI3K signaling, as indicated by increased phos-phorylation of the serine/threonine-protein kinase AKT. Hence, late-life cardiac-specific targeting of PI3K might have a therapeutic potential in cardiac aging and related diseases.
    Keywords:  IGF1; PI3K; aging; autophagy; cardiomyopathy; heart failure; insulin signaling; mitochondrial dysfunction
    DOI:  https://doi.org/10.15698/cst2022.08.270
  4. Cancer Discov. 2022 Dec 02. 12(12): 2724-2726
    TNF Receptors Choose HSC Fate in Supporting Dnmt3a-Mutant Clonal Hematopoiesis.
    Katia E Niño, Eric M Pietras.
       SUMMARY: TNFα receptor signaling distinctly promotes self-renewal and lymphoid differentiation in Dnmt3a-mutant hematopoietic stem cells, contributing to clonal hematopoiesis of indeterminate potential. See related article by SanMiguel et al., p. 2763 (3).
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1022
  5. Aging Clin Exp Res. 2022 Nov 30.
    Understanding how comprehensive geriatric assessment works: the importance of varied methodological approaches.
    Sarah T Fox, Monika Janda, Ruth Hubbard.
      Comprehensive geriatric assessment (CGA) is the gold standard model of care for older adults with frailty. However, despite a large number of published clinical trials, there remain many unanswered questions about how CGA works in different circumstances. This uncertainty stems from CGA being a deeply complex intervention that is heavily modified by context. This review describes recent and novel methodological approaches that explore the active ingredients of CGA and their interaction with context. Future research should continue to embrace broad methodologies that can help us better understand this intervention, in such a way that it can be implemented with fidelity and associated with positive outcomes for older adults.
    Keywords:  Complex systems; Healthcare research; Older adult
    DOI:  https://doi.org/10.1007/s40520-022-02305-7
  6. Clin Cancer Res. 2022 Dec 01. pii: CCR-22-2598. [Epub ahead of print]
    CHIP Happens: Clonal hematopoiesis of indeterminate potential and its relationship to solid tumors.
    Sarah C Reed, Sarah Croessmann, Ben Ho Park.
      Clonal hematopoiesis of indeterminate potential (CHIP) is characterized by the expansion of hematopoietic cells harboring leukemia-associated somatic mutations in otherwise healthy people and occurs in at least 10% of adults over 70. It is well established that people with CHIP have increased rates of hematologic malignancy, increased risk of cardiovascular disease (CVD), and worse all-cause mortality compared to those without CHIP. Despite recent advancements in understanding CHIP as it relates to these known outcomes, much remains to be learned about the development and role of CHIP in other disease states. Emerging research has identified high rates of CHIP in patients with solid tumors, driven in part by oncologic therapy, and revealed associations between CHIP and differential outcomes in both solid tumors and other diseases. Recent studies have demonstrated that CHIP can contribute to dysregulated inflammatory signaling in multiple contexts, underscoring the importance of interrogating how CHIP might alter tumor immunology. Here, we review the role of CHIP mutations in clonal expansion of hematopoietic cells, explore the relationship between CHIP and solid tumors, and discuss the potential roles of CHIP in inflammation and solid tumor biology.
    DOI:  https://doi.org/10.1158/1078-0432.CCR-22-2598
  7. BMC Geriatr. 2022 Nov 30. 22(1): 919
    Frailty in older people living with HIV: current status and clinical management.
    D Scott Kehler, Jovana Milic, Giovanni Guaraldi, Tamas Fulop, Julian Falutz.
      This paper will update care providers on the clinical and scientific aspects of frailty which affects an increasing proportion of older people living with HIV (PLWH). The successful use of combination antiretroviral therapy has improved long-term survival in PLWH. This has increased the proportion of PLWH older than 50 to more than 50% of the HIV population. Concurrently, there has been an increase in the premature development of age-related comorbidities as well as geriatric syndromes, especially frailty, which affects an important minority of older PLWH. As the number of frail older PLWH increases, this will have an important impact on their health care delivery. Frailty negatively affects a PLWH's clinical status, and increases their risk of adverse outcomes, impacting quality of life and health-span. The biologic constructs underlying the development of frailty integrate interrelated pathways which are affected by the process of aging and those factors which accelerate aging. The negative impact of sarcopenia in maintaining musculoskeletal integrity and thereby functional status may represent a bidirectional interaction with frailty in PLWH. Furthermore, there is a growing body of literature that frailty states may be transitional. The recognition and management of related risk factors will help to mitigate the development of frailty. The application of interdisciplinary geriatric management principles to the care of older PLWH allows reliable screening and care practices for frailty. Insight into frailty, increasingly recognized as an important marker of biologic age, will help to understand the diversity of clinical status occurring in PLWH, which therefore represents a fundamentally new and important aspect to be evaluated in their health care.
    Keywords:  Frailty; HIV; Pathophysiology; Resilience; Sarcopenia; Transitions
    DOI:  https://doi.org/10.1186/s12877-022-03477-7
  8. Adv Biol (Weinh). 2022 Nov 30. e2200219
    Special Issue: Circadian Rhythms and Age Related Disorder: How Does Aging Impact Mammalian Circadian Organization?
    Wei Xu, Xiaodong Li.
      Aging significantly impacts circadian timing in mammals. The amplitude and precision of behavioral, endocrine, and metabolic rhythms decline with age. This is accompanied with an age-related decline in the amplitude of central pacemaker output, although the molecular clock in the suprachiasmatic nucleus exhibit robust oscillation. Peripheral clocks also exhibit robust oscillation during aging, when extensive reprogramming of other genes' expression rhythms occurs in peripheral tissues. The age-related dissociation between the molecular clock and downstream rhythms in both central and peripheral tissues indicates that mechanisms other than the molecular clock are involved in mediating the impact the aging on circadian organization. In this article, findings are reviewed on the impact of aging on circadian timing functions, and the potential role of increased inflammatory response in age-related changes in circadian organization is highlighted.
    Keywords:  aging; circadian rhythms; inflammatory response; mammalian; peripheral clock; suprachiasmatic nucleus
    DOI:  https://doi.org/10.1002/adbi.202200219
  9. Int J Cancer. 2022 Nov 28.
    Role of Bcl-2 inhibition in Myelodysplastic Syndromes.
    Sabine Blum, Gerasimos Tsilimidos, Helena Bresser, Michael Lübbert.
      Myelodysplasic Syndromes (MDS) are diseases occurring mainly in the elderly population. Although hematopoietic stem cell transplantation is the only hope for cure, a majority of the patients suffering from MDS are too old or frail for intensive treatment regimens such as intensive chemotherapy and transplantation. The gold standard for those patients is currently treatment with hypomethylating agents, although real life data could not reproduce the overall survival rates reported for the pivotal azacitidine phase III study. MDS treatment is often inspired by treatment for acute myeloid leukemia (AML). The new gold standard for elderly and frail patients not able to undergo intensive treatment regimens in AML is the combination of hypomethylating agents with venetoclax, a BCL-2 inhibitor that also showed excellent treatment outcomes in other hematological malignancies. In this review, we explain the rationale for the use of venetoclax in hematological malignancies, study outcomes available so far and the current knowledge of its use in MDS. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ijc.34377
  10. Cell Stem Cell. 2022 Dec 01. pii: S1934-5909(22)00457-X. [Epub ahead of print]29(12): 1637-1652.e6
    Increased post-mitotic senescence in aged human neurons is a pathological feature of Alzheimer's disease.
    Joseph R Herdy, Larissa Traxler, Ravi K Agarwal, Lukas Karbacher, Johannes C M Schlachetzki, Lena Boehnke, Dina Zangwill, Doug Galasko, Christopher K Glass, Jerome Mertens, Fred H Gage.
      The concept of senescence as a phenomenon limited to proliferating cells has been challenged by growing evidence of senescence-like features in terminally differentiated cells, including neurons. The persistence of senescent cells late in life is associated with tissue dysfunction and increased risk of age-related disease. We found that Alzheimer's disease (AD) brains have significantly higher proportions of neurons that express senescence markers, and their distribution indicates bystander effects. AD patient-derived directly induced neurons (iNs) exhibit strong transcriptomic, epigenetic, and molecular biomarker signatures, indicating a specific human neuronal senescence-like state. AD iN single-cell transcriptomics revealed that senescent-like neurons face oncogenic challenges and metabolic dysfunction as well as display a pro-inflammatory signature. Integrative profiling of the inflammatory secretome of AD iNs and patient cerebral spinal fluid revealed a neuronal senescence-associated secretory phenotype that could trigger astrogliosis in human astrocytes. Finally, we show that targeting senescence-like neurons with senotherapeutics could be a strategy for preventing or treating AD.
    Keywords:  Alzheimer’s disease; SASP; aging; induced neurons (iNs); inflammation; senescence; senolytics
    DOI:  https://doi.org/10.1016/j.stem.2022.11.010
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