bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2024‒04‒21
seven papers selected by
Ayesh Seneviratne, Western University
  1. FOXP1 is a gatekeeper of cellular senescence with ovarian aging.
  2. Epigenetics of hematopoietic stem cell aging.
  3. Aging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function.
  4. The impact of obesity-induced inflammation on clonal hematopoiesis.
  5. The intersection of frailty and metabolism.
  6. Repetitive element transcript accumulation is associated with inflammaging in humans.
  7. Biological Clocks: Why We Need Them, Why We Cannot Trust Them, How They Might Be Improved.
  1. Nat Aging. 2024 Apr;4(4): 451-452
    FOXP1 is a gatekeeper of cellular senescence with ovarian aging.
      
    DOI:  https://doi.org/10.1038/s43587-024-00608-0
  2. Curr Opin Hematol. 2024 Apr 15.
    Epigenetics of hematopoietic stem cell aging.
    Takako Yokomizo, Motohiko Oshima, Atsushi Iwama.
      PURPOSE OF REVIEW: The development of new antiaging medicines is of great interest to the current elderly and aging population. Aging of the hematopoietic system is attributed to the aging of hematopoietic stem cells (HSCs), and epigenetic alterations are the key effectors driving HSC aging. Understanding the epigenetics of HSC aging holds promise of providing new insights for combating HSC aging and age-related hematological malignancies.RECENT FINDINGS: Aging is characterized by the progressive loss of physiological integrity, leading to impaired function and increased vulnerability to death. During aging, the HSCs undergo both quantitative and qualitative changes. These functional changes in HSCs cause dysregulated hematopoiesis, resulting in anemia, immune dysfunction, and an increased risk of hematological malignancies. Various cell-intrinsic and cell-extrinsic effectors influencing HSC aging have also been identified. Epigenetic alterations are one such mechanism.
    SUMMARY: Cumulative epigenetic alterations in aged HSCs affect their fate, leading to aberrant self-renewal, differentiation, and function of aged HSCs. In turn, these factors provide an opportunity for aged HSCs to expand by modulating their self-renewal and differentiation balance, thereby contributing to the development of hematological malignancies.
    DOI:  https://doi.org/10.1097/MOH.0000000000000818
  3. Nat Aging. 2024 Apr;4(4): 510-526
    Aging-induced MCPH1 translocation activates necroptosis and impairs hematopoietic stem cell function.
    Hanqing He, Yuqian Wang, Baixue Tang, Qiongye Dong, Chou Wu, Wanling Sun, Jianwei Wang.
      DNA damage contributes to the aging of hematopoietic stem cells (HSCs), yet the underlying molecular mechanisms are not fully understood. In this study, we identified a heterogeneous functional role of microcephalin (MCPH1) in the nucleus and cytoplasm of mouse HSCs. In the nucleus, MCPH1 maintains genomic stability, whereas in the cytoplasm, it prevents necroptosis by binding with p-RIPK3. Aging triggers MCPH1 translocation from cytosol to nucleus, reducing its cytoplasmic retention and leading to the activation of necroptosis and deterioration of HSC function. Mechanistically, we found that KAT7-mediated lysine acetylation within the NLS motif of MCPH1 in response to DNA damage facilitates its nuclear translocation. Targeted mutation of these lysines inhibits MCPH1 translocation and, consequently, compromises necroptosis. The dysfunction of necroptosis signaling, in turn, improves the function of aged HSCs. In summary, our findings demonstrate that DNA damage-induced redistribution of MCPH1 promotes HSC aging and could have broader implications for aging and aging-related diseases.
    DOI:  https://doi.org/10.1038/s43587-024-00609-z
  4. Curr Opin Hematol. 2024 Apr 22.
    The impact of obesity-induced inflammation on clonal hematopoiesis.
    Santhosh Kumar Pasupuleti, Reuben Kapur.
      PURPOSE OF REVIEW: This review meticulously delves into existing literature and recent findings to elucidate the intricate link between obesity and clonal hematopoiesis of indeterminate potential (CHIP) associated clonal hematopoiesis. It aims to enhance our comprehension of this multifaceted association, offering insights into potential avenues for future research and therapeutic interventions.RECENT FINDINGS: Recent insights reveal that mutations in CHIP-associated genes are not limited to symptomatic patients but are also present in asymptomatic individuals. This section focuses on the impact of obesity-induced inflammation and fatty bone marrow (FBM) on the development of CHIP-associated diseases. Common comorbidities such as obesity, diabetes, and infection, fostering pro-inflammatory environments, play a pivotal role in the acceleration of these pathologies. Our research underscores a notable association between CHIP and an increased waist-to-hip ratio (WHR), emphasizing the link between obesity and myeloid leukemia. Recent studies highlight a strong correlation between obesity and myeloid leukemias in both children and adults, with increased risks and poorer survival outcomes in overweight individuals.
    SUMMARY: We discuss recent insights into how CHIP-associated pathologies respond to obesity-induced inflammation, offering implications for future studies in the intricate field of clonal hematopoiesis.
    DOI:  https://doi.org/10.1097/MOH.0000000000000819
  5. Cell Metab. 2024 Apr 05. pii: S1550-4131(24)00091-3. [Epub ahead of print]
    The intersection of frailty and metabolism.
    Manish Mishra, Judy Wu, Alice E Kane, Susan E Howlett.
      On average, aging is associated with unfavorable changes in cellular metabolism, which are the processes involved in the storage and expenditure of energy. However, metabolic dysregulation may not occur to the same extent in all older individuals as people age at different rates. Those who are aging rapidly are at increased risk of adverse health outcomes and are said to be "frail." Here, we explore the links between frailty and metabolism, including metabolic contributors and consequences of frailty. We examine how metabolic diseases may modify the degree of frailty in old age and suggest that frailty may predispose toward metabolic disease. Metabolic interventions that can mitigate the degree of frailty in people are reviewed. New treatment strategies developed in animal models that are poised for translation to humans are also considered. We suggest that maintaining a youthful metabolism into older age may be protective against frailty.
    Keywords:  frailty index; frailty phenotype; metabolic dysregulation; metabolic syndrome; mouse models; protein restriction
    DOI:  https://doi.org/10.1016/j.cmet.2024.03.012
  6. Geroscience. 2024 Apr 20.
    Repetitive element transcript accumulation is associated with inflammaging in humans.
    Meghan E Smith, Devin Wahl, Alyssa N Cavalier, Gabriella T McWilliams, Matthew J Rossman, Gregory R Giordano, Angela D Bryan, Douglas R Seals, Thomas J LaRocca.
      Chronic, low-grade inflammation increases with aging, contributing to functional declines and diseases that reduce healthspan. Growing evidence suggests that transcripts from repetitive elements (RE) in the genome contribute to this "inflammaging" by stimulating innate immune activation, but evidence of RE-associated inflammation with aging in humans is limited. Here, we present transcriptomic and clinical data showing that RE transcript levels are positively related to gene expression of innate immune sensors, and to serum interleukin 6 (a marker of systemic inflammation), in a large group of middle-aged and older adults. We also: (1) use transcriptomics and whole-genome bisulfite (methylation) sequencing to show that many RE may be hypomethylated with aging, and that aerobic exercise, a healthspan-extending intervention, reduces RE transcript levels and increases RE methylation in older adults; and (2) extend our findings in a secondary dataset demonstrating age-related changes in RE chromatin accessibility. Collectively, our data support the idea that age-related RE transcript accumulation may play a role in inflammaging in humans, and that RE dysregulation with aging may be due in part to upstream epigenetic changes.
    Keywords:  Aging; Exercise; Inflammation; Transcriptomics
    DOI:  https://doi.org/10.1007/s11357-024-01126-y
  7. Biochemistry (Mosc). 2024 Feb;89(2): 356-366
    Biological Clocks: Why We Need Them, Why We Cannot Trust Them, How They Might Be Improved.
    Josh Mitteldorf.
      Late in life, the body is at war with itself. There is a program of self-destruction (phenoptosis) implemented via epigenetic and other changes. I refer to these as type (1) epigenetic changes. But the body retains a deep instinct for survival, and other epigenetic changes unfold in response to a perception of accumulated damage (type (2)). In the past decade, epigenetic clocks have promised to accelerate the search for anti-aging interventions by permitting prompt, reliable, and convenient measurement of their effects on lifespan without having to wait for trial results on mortality and morbidity. However, extant clocks do not distinguish between type (1) and type (2). Reversing type (1) changes extends lifespan, but reversing type (2) shortens lifespan. This is why all extant epigenetic clocks may be misleading. Separation of type (1) and type (2) epigenetic changes will lead to more reliable clock algorithms, but this cannot be done with statistics alone. New experiments are proposed. Epigenetic changes are the means by which the body implements phenoptosis, but they do not embody a clock mechanism, so they cannot be the body's primary timekeeper. The timekeeping mechanism is not yet understood, though there are hints that it may be (partially) located in the hypothalamus. For the future, we expect that the most fundamental measurement of biological age will observe this clock directly, and the most profound anti-aging interventions will manipulate it.
    Keywords:  aging clocks; epigenetic clocks; methylation clocks; phenoptosis; programmed aging
    DOI:  https://doi.org/10.1134/S0006297924020135
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