bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–11–19
twelve papers selected by
Ayesh Seneviratne, Western University
  1. Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity.
  2. Calorie restriction reduces biomarkers of cellular senescence in humans.
  3. Targeting the redox system for cardiovascular regeneration in aging.
  4. Insights into senolytic drugs for the treatment of SARS-CoV-2 infection in the brain.
  5. SMPDL3A links cholesterol metabolism to the cGAS-STING pathway.
  6. Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease.
  7. Entropy meets Physiology: should we translate Ageing as Disorder?
  8. Reliable Hallmarks and Biomarkers of Senescent Lymphocytes.
  9. Sphingolipids and HSC fitness: enigma no more.
  10. NAD+ regulates nucleotide metabolism and genomic DNA replication.
  11. Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias.
  12. Senotherapy, cancer, and aging.
  1. Nat Aging. 2023 Nov 13.
    Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity.
    Roberto Ripa, Eugen Ballhysa, Joachim D Steiner, Raymond Laboy, Andrea Annibal, Nadine Hochhard, Christian Latza, Luca Dolfi, Chiara Calabrese, Anna M Meyer, Maria Cristina Polidori, Roman-Ulrich Müller, Adam Antebi.
      Late-life-initiated dietary interventions show limited efficacy in extending longevity or mitigating frailty, yet the underlying causes remain unclear. Here we studied the age-related fasting response of the short-lived killifish Nothobranchius furzeri. Transcriptomic analysis uncovered the existence of a fasting-like transcriptional program in the adipose tissue of old fish that overrides the feeding response, setting the tissue in persistent metabolic quiescence. The fasting-refeeding cycle triggers an inverse oscillatory expression of genes encoding the AMP-activated protein kinase (AMPK) regulatory subunits Prkag1 (γ1) and Prkag2 (γ2) in young individuals. Aging blunts such regulation, resulting in reduced Prkag1 expression. Transgenic fish with sustained AMPKγ1 countered the fasting-like transcriptional program, exhibiting a more youthful feeding and fasting response in older age, improved metabolic health and longevity. Accordingly, Prkag1 expression declines with age in human tissues and is associated with multimorbidity and multidimensional frailty risk. Thus, selective activation of AMPKγ1 prevents metabolic quiescence and preserves healthy aging in vertebrates, offering potential avenues for intervention.
    DOI:  https://doi.org/10.1038/s43587-023-00521-y
  2. Aging Cell. 2023 Nov 14. e14038
    Calorie restriction reduces biomarkers of cellular senescence in humans.
    Zaira Aversa, Thomas A White, Amanda A Heeren, Cassondra A Hulshizer, Dominik Saul, Xu Zhang, Anthony J A Molina, Leanne M Redman, Corby K Martin, Susan B Racette, Kim M Huffman, Manjushri Bhapkar, Sundeep Khosla, Sai Krupa Das, Roger A Fielding, Elizabeth J Atkinson, Nathan K LeBrasseur.
      Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young-to-middle-aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging-related conditions. Using plasma specimens from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA-IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA-sequencing data from a subset of participants, we observed a significant reduction in a senescence-focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.
    Keywords:  CALERIE™; aging; biomarkers; caloric restriction; inflammation; metabolism; senescence-associated secretory phenotype
    DOI:  https://doi.org/10.1111/acel.14038
  3. Aging Cell. 2023 Nov 13. e14020
    Targeting the redox system for cardiovascular regeneration in aging.
    Meret Sarah Allemann, Pratintip Lee, Jürg H Beer, Seyed Soheil Saeedi Saravi.
      Cardiovascular aging presents a formidable challenge, as the aging process can lead to reduced cardiac function and heightened susceptibility to cardiovascular diseases. Consequently, there is an escalating, unmet medical need for innovative and effective cardiovascular regeneration strategies aimed at restoring and rejuvenating aging cardiovascular tissues. Altered redox homeostasis and the accumulation of oxidative damage play a pivotal role in detrimental changes to stem cell function and cellular senescence, hampering regenerative capacity in aged cardiovascular system. A mounting body of evidence underscores the significance of targeting redox machinery to restore stem cell self-renewal and enhance their differentiation potential into youthful cardiovascular lineages. Hence, the redox machinery holds promise as a target for optimizing cardiovascular regenerative therapies. In this context, we delve into the current understanding of redox homeostasis in regulating stem cell function and reprogramming processes that impact the regenerative potential of the cardiovascular system. Furthermore, we offer insights into the recent translational and clinical implications of redox-targeting compounds aimed at enhancing current regenerative therapies for aging cardiovascular tissues.
    Keywords:  cardiovascular aging; cardiovascular regeneration; cellular senescence; redox machinery; stem/progenitor cell
    DOI:  https://doi.org/10.1111/acel.14020
  4. Nat Aging. 2023 Nov 17.
    Insights into senolytic drugs for the treatment of SARS-CoV-2 infection in the brain.
      
    DOI:  https://doi.org/10.1038/s43587-023-00525-8
  5. Immunity. 2023 Nov 14. pii: S1074-7613(23)00455-7. [Epub ahead of print]56(11): 2459-2461
    SMPDL3A links cholesterol metabolism to the cGAS-STING pathway.
    Heegwon Shin, Hachung Chung.
      Liver X receptor (LXR), well known for its role in cholesterol metabolism, also has anti-inflammatory properties. In this issue of Immunity, Hou et al. demonstrate that LXR signaling induces SMPDL3A, a cGAMP-degrading enzyme that restricts cGAS-cGAMP-STING innate immune signaling, providing a mechanistic link between lipid metabolism and inflammation.
    DOI:  https://doi.org/10.1016/j.immuni.2023.10.015
  6. Nat Med. 2023 Nov 16.
    Clonal selection of hematopoietic stem cells after gene therapy for sickle cell disease.
    Michael Spencer Chapman, Alyssa H Cull, Marioara F Ciuculescu, Erica B Esrick, Emily Mitchell, Hyunchul Jung, Laura O'Neill, Kirsty Roberts, Margarete A Fabre, Nicholas Williams, Jyoti Nangalia, Joanne Quinton, James M Fox, Danilo Pellin, Julie Makani, Myriam Armant, David A Williams, Peter J Campbell, David G Kent.
      Gene therapy (GT) provides a potentially curative treatment option for patients with sickle cell disease (SCD); however, the occurrence of myeloid malignancies in GT clinical trials has prompted concern, with several postulated mechanisms. Here, we used whole-genome sequencing to track hematopoietic stem cells (HSCs) from six patients with SCD at pre- and post-GT time points to map the somatic mutation and clonal landscape of gene-modified and unmodified HSCs. Pre-GT, phylogenetic trees were highly polyclonal and mutation burdens per cell were elevated in some, but not all, patients. Post-GT, no clonal expansions were identified among gene-modified or unmodified cells; however, an increased frequency of potential driver mutations associated with myeloid neoplasms or clonal hematopoiesis (DNMT3A- and EZH2-mutated clones in particular) was observed in both genetically modified and unmodified cells, suggesting positive selection of mutant clones during GT. This work sheds light on HSC clonal dynamics and the mutational landscape after GT in SCD, highlighting the enhanced fitness of some HSCs harboring pre-existing driver mutations. Future studies should define the long-term fate of mutant clones, including any contribution to expansions associated with myeloid neoplasms.
    DOI:  https://doi.org/10.1038/s41591-023-02636-6
  7. Stem Cells. 2023 Nov 11. pii: sxad084. [Epub ahead of print]
    Entropy meets Physiology: should we translate Ageing as Disorder?
    Marco Tatullo.
      Ageing is characterized by an alteration of several physiological processes and biological pathways that leads to an incremented susceptibility to age-related diseases and death. Normally, multipotential stem/progenitor cells may contribute to tissues homeostasis, and to minimize the age-depending DNA damages. Scientific research has demonstrated that ageing induces several complex changes affecting even the Mesenchymal Stromal/Stem Cells (MSCs) ability to self-renew, differentiate, and immunomodulate the human tissues, causing further alterations also in the local microenvironment. Cellular senescence can thus be considered as an overall response to several damages. Accordingly, ageing seems to create the proper conditions to decrease the tissues metabolic performance, and the cell-to-cell communication, resulting in a progressive tissue destruction; on the other hand, the MSCs functions appear to be severely reduced. This concise review summarizes the main alterations affecting the MSCs during ageing, and it also explains the role of inflammation as a key-player in the age-related syndromes. The hypothesis is to suggest a parallelism among the thermodynamic concept of "entropy" and biological ageing, speculating that both can increase within irreversible systems and both lead towards an irreversible disorder; so, the question is: should we translate Ageing as Disorder?
    Keywords:  Age-related diseases; Ageing; Cellular Senescence; Mesenchymal Stromal/Stem cells; Regenerative Medicine
    DOI:  https://doi.org/10.1093/stmcls/sxad084
  8. Int J Mol Sci. 2023 Oct 27. pii: 15653. [Epub ahead of print]24(21):
    Reliable Hallmarks and Biomarkers of Senescent Lymphocytes.
    Yuliya S Martyshkina, Valeriy P Tereshchenko, Daria A Bogdanova, Stanislav A Rybtsov.
      The phenomenon of accumulation of senescent adaptive immunity cells in the elderly is attracting attention due to the increasing risk of global epidemics and aging of the global population. Elderly people are predisposed to various infectious and age-related diseases and are at higher risk of vaccination failure. The accumulation of senescent cells increases age-related background inflammation, "Inflammaging", causing lymphocyte exhaustion and cardiovascular, neurodegenerative, autoimmune and cancer diseases. Here, we present a comprehensive contemporary review of the mechanisms and phenotype of senescence in the adaptive immune system. Although modern research has not yet identified specific markers of aging lymphocytes, several sets of markers facilitate the separation of the aging population based on normal memory and exhausted cells for further genetic and functional analysis. The reasons for the higher predisposition of CD8+ T-lymphocytes to senescence compared to the CD4+ population are also discussed. We point out approaches for senescent-lymphocyte-targeting markers using small molecules (senolytics), antibodies and immunization against senescent cells. The suppression of immune senescence is the most relevant area of research aimed at developing anti-aging and anti-cancer therapy for prolonging the lifespan of the global population.
    Keywords:  biomarkers of senescence; immunosenescence; senescent lymphocytes
    DOI:  https://doi.org/10.3390/ijms242115653
  9. Blood. 2023 Nov 16. 142(20): 1674-1676
    Sphingolipids and HSC fitness: enigma no more.
    Stephanie Z Xie.
      
    DOI:  https://doi.org/10.1182/blood.2023022497
  10. Nat Cell Biol. 2023 Nov 13.
    NAD+ regulates nucleotide metabolism and genomic DNA replication.
    Sebastian Howen Nesgaard Munk, Joanna Maria Merchut-Maya, Alba Adelantado Rubio, Arnaldur Hall, George Pappas, Giacomo Milletti, MyungHee Lee, Lea Giørtz Johnsen, Per Guldberg, Jiri Bartek, Apolinar Maya-Mendoza.
      The intricate orchestration of enzymatic activities involving nicotinamide adenine dinucleotide (NAD+) is essential for maintaining metabolic homeostasis and preserving genomic integrity. As a co-enzyme, NAD+ plays a key role in regulating metabolic pathways, such as glycolysis and Kreb's cycle. ADP-ribosyltransferases (PARPs) and sirtuins rely on NAD+ to mediate post-translational modifications of target proteins. The activation of PARP1 in response to DNA breaks leads to rapid depletion of cellular NAD+ compromising cell viability. Therefore, the levels of NAD+ must be tightly regulated. Here we show that exogenous NAD+, but not its precursors, has a direct effect on mitochondrial activity. Short-term incubation with NAD+ boosts Kreb's cycle and the electron transport chain and enhances pyrimidine biosynthesis. Extended incubation with NAD+ results in depletion of pyrimidines, accumulation of purines, activation of the replication stress response and cell cycle arrest. Moreover, a combination of NAD+ and 5-fluorouridine selectively kills cancer cells that rely on de novo pyrimidine synthesis. We propose an integrated model of how NAD+ regulates nucleotide metabolism, with relevance to healthspan, ageing and cancer therapy.
    DOI:  https://doi.org/10.1038/s41556-023-01280-z
  11. Eur Heart J. 2023 Nov 11. pii: ehad670. [Epub ahead of print]
    Clonal haematopoiesis of indeterminate potential predicts incident cardiac arrhythmias.
    Art Schuermans, Caitlyn Vlasschaert, Victor Nauffal, So Mi Jemma Cho, Md Mesbah Uddin, Tetsushi Nakao, Abhishek Niroula, Marcus D R Klarqvist, Lachelle D Weeks, Amy E Lin, Seyedmohammad Saadatagah, Kim Lannery, Megan Wong, Whitney Hornsby, Steven A Lubitz, Christie Ballantyne, Siddhartha Jaiswal, Peter Libby, Benjamin L Ebert, Alexander G Bick, Patrick T Ellinor, Pradeep Natarajan, Michael C Honigberg.
       BACKGROUND AND AIMS: Clonal haematopoiesis of indeterminate potential (CHIP), the age-related expansion of blood cells with preleukemic mutations, is associated with atherosclerotic cardiovascular disease and heart failure. This study aimed to test the association of CHIP with new-onset arrhythmias.
    METHODS: UK Biobank participants without prevalent arrhythmias were included. Co-primary study outcomes were supraventricular arrhythmias, bradyarrhythmias, and ventricular arrhythmias. Secondary outcomes were cardiac arrest, atrial fibrillation, and any arrhythmia. Associations of any CHIP [variant allele fraction (VAF) ≥ 2%], large CHIP (VAF ≥10%), and gene-specific CHIP subtypes with incident arrhythmias were evaluated using multivariable-adjusted Cox regression. Associations of CHIP with myocardial interstitial fibrosis [T1 measured using cardiac magnetic resonance (CMR)] were also tested.
    RESULTS: This study included 410 702 participants [CHIP: n = 13 892 (3.4%); large CHIP: n = 9191 (2.2%)]. Any and large CHIP were associated with multi-variable-adjusted hazard ratios of 1.11 [95% confidence interval (CI) 1.04-1.18; P = .001] and 1.13 (95% CI 1.05-1.22; P = .001) for supraventricular arrhythmias, 1.09 (95% CI 1.01-1.19; P = .031) and 1.13 (95% CI 1.03-1.25; P = .011) for bradyarrhythmias, and 1.16 (95% CI, 1.00-1.34; P = .049) and 1.22 (95% CI 1.03-1.45; P = .021) for ventricular arrhythmias, respectively. Associations were independent of coronary artery disease and heart failure. Associations were also heterogeneous across arrhythmia subtypes and strongest for cardiac arrest. Gene-specific analyses revealed an increased risk of arrhythmias across driver genes other than DNMT3A. Large CHIP was associated with 1.31-fold odds (95% CI 1.07-1.59; P = .009) of being in the top quintile of myocardial fibrosis by CMR.
    CONCLUSIONS: CHIP may represent a novel risk factor for incident arrhythmias, indicating a potential target for modulation towards arrhythmia prevention and treatment.
    Keywords:  Aging; Arrhythmia; Atrial fibrillation; Cardiac arrest; Genomics; Prevention
    DOI:  https://doi.org/10.1093/eurheartj/ehad670
  12. J Geriatr Oncol. 2023 Nov 15. pii: S1879-4068(23)00568-4. [Epub ahead of print] 101671
    Senotherapy, cancer, and aging.
    Lodovico Balducci, Claire Falandry, Silvio Monfardini.
       INTRODUCTION: We aimed to highlight the effects of senotherapy on the prevention and treatment of cancer in older individuals. The aim of senotherapy is to eliminate senescent cells. These cells express the senescence-associated secretory phenotype (SASP). With production of inflammatory cytokines, growth factors, and different type of proteases, the SASP is responsible for aging-associated disability and diseases. All mammalian cells experience senescence. The main agents of aging include fibroblasts and adipose cells. Senescent tumor cells may undergo genomic reprogramming and re-enter cell cycle with a stem cell phenotype.
    MATERIALS AND METHODS: We conducted a Medline search for the following key words: senotherapy, senolysis, senomorphic agents. We provide a narrative review of the finding.
    RESULTS: Different agents may eliminate senescent cells from cell cultures and murine models. These include metformin, rapamycin, desatinib, quercitin, fisetin, ruloxitinib, and BCL2 inhibitors. A randomized controlled study of metformin in 3,000 patients aged 65-79 without glucose intolerance aiming to establish whether senotherapy may prevent or reverse disability and aging associated diseases, including cancer, is ongoing. Senotherapy prolongs the life span and decreases the incidence of cancer in experimental animal models, as well as delays and reverses disability. Senescent tumor cells are found prior to treatment and after chemotherapy and radiation. These elements may be responsible for tumor recurrence and treatment refractoriness.
    DISCUSSION: Senotherapy may have substantial effects on cancer management including decreased incidence and aggressiveness of cancer, improved tolerance of antineoplastic treatment, and prevention of relapse after primary treatment. Senotherapy may ameliorate several complications of cancer chemotherapy.
    Keywords:  Cancer in the older patient; Chemotherapy; Senolysis; Senomorphic therapy; Senotherapy
    DOI:  https://doi.org/10.1016/j.jgo.2023.101671
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