bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–09–11
nine papers selected by
Ayesh Seneviratne, Western University
  1. Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Disease.
  2. Looking at IGF-1 through the hourglass.
  3. Regulation of metabolic health by dietary histidine in mice.
  4. Clinical Significance of Clonal Hematopoiesis in the Setting of Autologous Stem Cell Transplantation for Lymphoma.
  5. [Exploring new molecules that regulate hematopoietic stem cells and early stages of lymphoid hematopoiesis: the functional significance of ESAM and SATB1].
  6. Circadian cardiac NAD+ metabolism, from transcriptional regulation to healthy aging.
  7. Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity.
  8. Pharmaceutical interventions to slow human aging. Are we ready for cocktails?
  9. The world's reservoirs are ageing - and belching out more methane.
  1. Transl Res. 2022 Sep 03. pii: S1931-5244(22)00200-6. [Epub ahead of print]
    Clonal Hematopoiesis of Indeterminate Potential and Cardiovascular Disease.
    Seyedmohammad Saadatagah, Christie M Ballantyne.
      Age is the most important risk factor for cardiovascular disease and appears to be more than a marker of cumulative exposure to other risk factors such as dyslipidemia and hypertension. With aging, genetic mutations occur that are not present in our germline DNA, observed as somatic mosaicism. Hematopoietic stem cells have an increased chance of developing mosaicism because they are highly proliferative, and mutations with survival benefits can establish clonal populations. Age-related clonal hematopoiesis resulting from somatic mutations was first described ∼25 years ago. The subset of clonal hematopoiesis in which a driver mutation with variant allele frequency of at least 2% occurs in a gene implicated in hematologic malignancies but in the absence of known hematologic malignancy or other clonal disorder is termed clonal hematopoiesis of indeterminate potential (CHIP). Large-scale exome-sequencing projects have recently enabled the study of CHIP frequency, gene-specific analyses, and longitudinal clinical consequences of CHIP, including an observed increased risk for cardiovascular disease. Animal models provide insight into the mechanisms by which CHIP increases cardiovascular disease risk, and combined animal, clinical, and epidemiological data suggest therapeutic implications for CHIP in cardiovascular disease prevention.
    Keywords:  ASCVD, atherosclerotic cardiovascular disease; BM, bone marrow; CANTOS, Canakinumab Anti-inflammatory Thrombosis Outcomes Study; CHD, coronary heart disease; CHIP, clonal hematopoiesis of indeterminate potential; CI, confidence interval; Cardiovascular disease; FUSION, Finland–United States Investigation of NIDDM Genetics; Genetics; HR, hazard ratio; HSC, hematopoietic stem cell; LDL, low-density lipoprotein; MGBB, Mass General Brigham Biobank; NLRP3, nucleotide-binding oligomerization domain–like receptor family pyrin domain containing–3; OR, odds ratio; PAD, peripheral artery disease; UKBB, UK Biobank; VAF, variant allele frequency. Non-peer-reviewed references are indicated as (#)(P), preprint and (#)(A), abstract; clonal hematopoiesis of indeterminate potential; interleukin, IL; mutation Abbreviations: AIM2, absent in melanoma–2
    DOI:  https://doi.org/10.1016/j.trsl.2022.08.013
  2. Aging (Albany NY). 2022 Aug 25. 14(16): 6379-6380
    Looking at IGF-1 through the hourglass.
    William B Zhang, Sofiya Milman.
      
    Keywords:  IGF-1; aging; growth hormone; morbidity; mortality
    DOI:  https://doi.org/10.18632/aging.204257
  3. J Physiol. 2022 Sep 09.
    Regulation of metabolic health by dietary histidine in mice.
    Victoria Flores, Alexandra B Spicer, Michelle Sonsalla, Nicole E Richardson, Deyang Yu, Grace E Sheridan, Michaela E Trautman, Reji Babygirija, Eunhae P Cheng, Jennifer M Rojas, Shany E Yang, Matthew H Wakai, Ryan Hubbell, Ildiko Kasza, Jay L Tomasiewicz, Cara L Green, Claudia Dantoin, Caroline M Alexander, Joseph A Baur, Kristen C Malecki, Dudley W Lamming.
       KEY POINTS: Protein restriction (PR) promotes metabolic health in rodents and humans and extends rodent lifespan. Restriction of specific individual essential amino acids can recapitulate the benefits of PR. Reduced histidine promotes leanness and increased energy expenditure in male mice. Reduced histidine does not extend the lifespan of mice when begun in mid-life. Dietary levels of histidine are positively associated with BMI in humans.
    ABSTRACT: Low protein (LP) diets are associated with a decreased risk of diabetes in humans, and promote leanness and glycemic control in both rodents and humans. While the effects of an LP diet on glycemic control are mediated by reduced levels of the branched-chain amino acids, we have observed that reducing dietary levels of the other six essential amino acids leads to changes in body composition. Here, we find that dietary histidine plays a key role in the response to a LP diet in male C57BL/6J mice. Specifically reducing dietary levels of histidine by 67% reduces the weight gain of young, lean male mice, reducing both adipose and lean mass without altering glucose metabolism, and rapidly reverses diet-induced obesity and hepatic steatosis in diet-induced obese male mice, increasing insulin sensitivity. This normalization of metabolic health was associated not with caloric restriction or increased activity, but with increased energy expenditure. Surprisingly, the effects of histidine restriction do not require the energy balance hormone Fgf21. Histidine restriction started in mid-life promoted leanness and glucose tolerance in aged males but not females, but did not affect frailty or lifespan in either sex. Finally, we demonstrate that variation in dietary histidine levels helps to explain body mass index differences in humans. Overall, our findings demonstrate that dietary histidine is a key regulator of weight and body composition in male mice and in humans, and suggest that reducing dietary histidine may be a translatable option for the treatment of obesity. Abstract figure legend Lower dietary levels of the essential amino acid histidine reduces adiposity and hepatic steatosis in mice, and is associated with reduced body mass index in humans. This article is protected by copyright. All rights reserved.
    Keywords:  BMI; FGF21; amino acids; body composition; histidine; protein restriction
    DOI:  https://doi.org/10.1113/JP283261
  4. Am J Hematol. 2022 Sep 10.
    Clinical Significance of Clonal Hematopoiesis in the Setting of Autologous Stem Cell Transplantation for Lymphoma.
    Tracy Lackraj, Sharon Ben Barouch, Jessie J F Medeiros, Stephanie Pedersen, Arnavaz Danesh, Mehran Bakhtiari, Michael Hong, Kit Tong, Jesse Joynt, Andrea Arruda, Mark D Minden, John Kuruvilla, Sita Bhella, Vishal Kukreti, Michael Crump, Anca Prica, Christine Chen, Yangqing Deng, Wei Xu, Trevor J Pugh, Armand Keating, John E Dick, Sagi Abelson, Robert Kridel.
      Autologous stem cell transplantation (ASCT) remains a key therapeutic strategy for treating patients with relapsed or refractory non-Hodgkin and Hodgkin lymphoma. Clonal hematopoiesis (CH) has been proposed as a major contributor not only to the development of therapy-related myeloid neoplasms but also to inferior overall survival in patients who had undergone ASCT. Herein, we aimed to investigate the prognostic implications of CH after ASCT in a cohort of 420 lymphoma patients using ultra-deep, highly sensitive error-correction sequencing. CH was identified in the stem cell product samples of 181 patients (43.1%) and was most common in those with T-cell lymphoma (72.2%). The presence of CH was associated with a longer time to neutrophil and platelet recovery. Moreover, patients with evidence of CH had inferior 5-year OS from the time of first relapse (39.4% vs. 45.8%, P=0.043) and from the time of ASCT (51.8% vs. 59.3%, P=0.018). The adverse prognostic impact of CH was not due to therapy-related myeloid neoplasms, the incidence of which was low in our cohort (10-year cumulative incidence of 3.3% vs. 3.0% in those with and without CH, P=0.445). In terms of specific gene mutations, adverse OS was mostly associated with PPM1D mutations (hazard ratio (HR) 1.74, 95% confidence interval (CI) 1.13-2.67, P=0.011). In summary, we found that CH is associated with an increased risk of non-lymphoma-related death after ASCT, which suggests that lymphoma survivors with CH may need intensified surveillance strategies to prevent and treat late complications. This article is protected by copyright. All rights reserved.
    DOI:  https://doi.org/10.1002/ajh.26726
  5. Rinsho Ketsueki. 2022 ;63(8): 906-917
    [Exploring new molecules that regulate hematopoietic stem cells and early stages of lymphoid hematopoiesis: the functional significance of ESAM and SATB1].
    Takafumi Yokota.
      Hematopoietic stem cells (HSCs) possess multilineage differentiation capability, which sustains the production of blood and immune cells throughout life. However, the precise mechanisms by which HSCs initiate differentiation toward a particular lineage and the factors that attenuate their lymphopoietic potential with aging are yet to be elucidated. Our group has investigated this issue for over two decades. We initially developed a method for segregating early lymphoid progenitors from HSCs and identified two molecules: endothelial cell-selective adhesion molecule (ESAM), highly expressed in HSCs, and special AT-rich sequence binding protein 1 (SATB1), expressed in early lymphoid progenitors. ESAM marks HSCs across species, including humans. In addition to its significance in stress-induced hematopoiesis, ESAM is also useful in identifying features of human acute myeloid leukemia stem cells. Further, we determined the role of SATB1 in the early HSC differentiation processes toward the lymphoid lineage. Remarkably, SATB1 expression in HSCs significantly decreased with aging, whereas its exogenous induction in aged HSCs rejuvenated their lymphopoietic potential. Furthermore, SATB1-expressing HSCs demonstrated robust lymphopoietic and long-term reconstituting capability, whereas HSCs without SATB1 skewed toward the myeloid lineage. Thus, our continuing research has revealed the significance of ESAM and SATB1 in the fundamental biology of HSCs.
    Keywords:  Chromatin remodeling protein; Differential regulation; Endothelial lineage-related surface protein; Hematopoietic stem cells
    DOI:  https://doi.org/10.11406/rinketsu.63.906
  6. Am J Physiol Cell Physiol. 2022 Sep 05.
    Circadian cardiac NAD+ metabolism, from transcriptional regulation to healthy aging.
    Bryce J Carpenter, Pieterjan Dierickx.
      Nicotinamide adenine dinucleotide (NAD+) is a critical redox factor and coenzyme with rhythmic availability, and reduced NAD+ levels are a common factor of many disease states, including risk factors associated with aging. Recent studies have expanded on the role of circadian rhythms and the core clock factors that maintain them in the regulation of NAD+ levels in the heart. This has revealed that NAD+ pools and their use are tightly linked to cardiac function, but also heart failure. The convergence of these fields, namely, clock regulation, heart disease, and NAD+ metabolism present a complex network ripe with potential scientific and clinical discoveries, given the growing number of animal models, recently developed technology, and opportunity for safe and accessible precursor supplementation. This review seeks to briefly present known information on circadian rhythms in the heart, connect that research to our understanding of cardiac NAD+ metabolism, and finally discuss potential future experiments to better understand interventional opportunities in cardiovascular health regarding these subjects.
    Keywords:  Cardiovascular Health; Circadian Rhythms; NAD+ Metabolism
    DOI:  https://doi.org/10.1152/ajpcell.00239.2022
  7. Nat Commun. 2022 Sep 03. 13(1): 5187
    Taz protects hematopoietic stem cells from an aging-dependent decrease in PU.1 activity.
    Kyung Mok Kim, Anna Mura-Meszaros, Marie Tollot, Murali Shyam Krishnan, Marco Gründl, Laura Neubert, Marco Groth, Alejo Rodriguez-Fraticelli, Arthur Flohr Svendsen, Stefano Campaner, Nico Andreas, Thomas Kamradt, Steve Hoffmann, Fernando D Camargo, Florian H Heidel, Leonid V Bystrykh, Gerald de Haan, Björn von Eyss.
      Specific functions of the immune system are essential to protect us from infections caused by pathogens such as viruses and bacteria. However, as we age, the immune system shows a functional decline that can be attributed in large part to age-associated defects in hematopoietic stem cells (HSCs)-the cells at the apex of the immune cell hierarchy. Here, we find that the Hippo pathway coactivator TAZ is potently induced in old HSCs and protects these cells from functional decline. We identify Clca3a1 as a TAZ-induced gene that allows us to trace TAZ activity in vivo. Using CLCA3A1 as a marker, we can isolate "young-like" HSCs from old mice. Mechanistically, Taz acts as coactivator of PU.1 and to some extent counteracts the gradual loss of PU.1 expression during HSC aging. Our work thus uncovers an essential role for Taz in a previously undescribed fail-safe mechanism in aging HSCs.
    DOI:  https://doi.org/10.1038/s41467-022-32970-1
  8. Aging Pathobiol Ther. 2022 ;4(2): 51-52
    Pharmaceutical interventions to slow human aging. Are we ready for cocktails?
    Manuela Rosenfeld, Warren Ladiges.
      Slowing human aging with pharmaceuticals is now recognized as a feasible strategy. However, the design of clinical trials is still focused on single drug approaches. The process of aging has multiple pathways, which no current drug has been shown to effectively target. Therefore, it is of interest to study combinations, or cocktails, of drugs. A recently published article reported that a drug cocktail of rapamycin, acarbose and phenylbutyrate slowed aging in middle-aged mice treated for three months. The impact of this report is discussed, with the implications for determining endpoints in humans for testing drug cocktails as well as testing other drug combinations.
    Keywords:  Healthy aging; acarbose; aging mice; drug cocktail; phenylbutyrate; rapamycin
    DOI:  https://doi.org/10.31491/apt.2022.06.086
  9. Nature. 2022 Sep 06.
    The world's reservoirs are ageing - and belching out more methane.
      
    Keywords:  Climate change
    DOI:  https://doi.org/10.1038/d41586-022-02840-3
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