bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–06–05
nine papers selected by
Ayesh Seneviratne, Western University
  1. Somatic Mutations and Clonal Hematopoiesis as Drivers of Age-Related Cardiovascular Risk.
  2. NAD+ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities.
  3. Metrics for rat blood aging.
  4. Nutritional quality of calorie restricted diets in the CALERIE™ 1 trial.
  5. Blood's life history traced through genomic scars.
  6. The longitudinal dynamics and natural history of clonal haematopoiesis.
  7. Association of Diet Quality With Longevity and Successful Aging in Israeli Adults 65 Years or Older.
  8. Clonal dynamics of haematopoiesis across the human lifespan.
  9. Inflammatory Microenvironment Accelerates Bone Marrow Mesenchymal Stem Cell Aging.
  1. Curr Cardiol Rep. 2022 Jun 03.
    Somatic Mutations and Clonal Hematopoiesis as Drivers of Age-Related Cardiovascular Risk.
    Bernhard Haring, Stephanie Wissel, JoAnn E Manson.
       PURPOSE OF REVIEW: Clonal hematopoiesis of indeterminate potential (CHIP) has been identified as a novel cardiovascular risk factor. Here we review the relationship of lifestyle and environmental risk factors predisposing to somatic mutations and CHIP and provide an overview on age-related cardiovascular outcomes.
    RECENT FINDINGS: CHIP has been associated with accelerated atherosclerosis and cardiovascular disease in both epidemiological and experimental studies. The most commonly mutated candidate driver genes are DNMT3A, TET2, JAK2, and ASXL1. The underlying mechanisms appear predominantly related to inflammatory pathways. Although age is the dominant risk factor for developing CHIP, emerging evidence suggests that other factors such as smoking, obesity/type 2 diabetes, or an unhealthy diet play a role in the occurrence of somatic mutations. Evidence suggests a strong link between vascular risk factors, somatic hematopoietic mutations, and age-related cardiovascular disease. Further studies on CHIP biology are required to identify targeted interventions for risk reduction in patients with CHIP and inform the utility of screening strategies.
    Keywords:  Age-related cardiovascular risk; Clonal hematopoiesis of indeterminate potential; Preventive cardiology; Somatic mutations
    DOI:  https://doi.org/10.1007/s11886-022-01724-2
  2. J Lipid Atheroscler. 2022 May;11(2): 111-132
    NAD+ and Vascular Dysfunction: From Mechanisms to Therapeutic Opportunities.
    Mahmoud Abdellatif, Heiko Bugger, Guido Kroemer, Simon Sedej.
      Nicotinamide adenine dinucleotide (NAD+) is an essential and pleiotropic coenzyme involved not only in cellular energy metabolism, but also in cell signaling, epigenetic regulation, and post-translational protein modifications. Vascular disease risk factors are associated with aberrant NAD+ metabolism. Conversely, the therapeutic increase of NAD+ levels through the administration of NAD+ precursors or inhibitors of NAD+-consuming enzymes reduces chronic low-grade inflammation, reactivates autophagy and mitochondrial biogenesis, and enhances oxidative metabolism in vascular cells of humans and rodents with vascular pathologies. As such, NAD+ has emerged as a potential target for combatting age-related cardiovascular and cerebrovascular disorders. This review discusses NAD+-regulated mechanisms critical for vascular health and summarizes new advances in NAD+ research directly related to vascular aging and disease, including hypertension, atherosclerosis, coronary artery disease, and aortic aneurysms. Finally, we enumerate challenges and opportunities for NAD+ repletion therapy while anticipating the future of this exciting research field, which will have a major impact on vascular medicine.
    Keywords:  Aging; Autophagy; Hypertension; Inflammation; Mitochondria; Nicotinamide adenine dinucleotide; Vascular disease
    DOI:  https://doi.org/10.12997/jla.2022.11.2.111
  3. Lab Anim (NY). 2022 Jun;51(6): 156
    Metrics for rat blood aging.
    Alexandra Le Bras.
      
    DOI:  https://doi.org/10.1038/s41684-022-00991-4
  4. Exp Gerontol. 2022 May 25. pii: S0531-5565(22)00148-6. [Epub ahead of print] 111840
    Nutritional quality of calorie restricted diets in the CALERIE™ 1 trial.
    Susan B Racette, Valene Garr Barry, Connie W Bales, Megan A McCrory, Kathleen A Obert, Cheryl H Gilhooly, Susan B Roberts, Corby K Martin, Catherine Champagne, Sai Krupa Das.
       OBJECTIVES: The aim was to determine the nutritional adequacy of calorie restricted (CR) diets during CR interventions up to 12 months.
    METHODS: The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE™) phase 1 trial consisted of 3 single-site studies to test the feasibility and effectiveness of CR in adults without obesity. After baseline assessments, participants who were randomized to a CR intervention received education and training from registered dietitians on how to follow a healthful CR diet. Food diaries were completed at baseline and during the CR interventions (~6, 9, and 12 months) when participants were self-selecting CR diets. Diaries were analyzed for energy, macronutrients, fiber, 11 vitamins, and 9 minerals. Nutritional adequacy was defined by sex- and age-specific Estimated Average Requirement (EAR) or Adequate Intake (AI) criteria for each nutrient. Diet quality was evaluated using the PANDiet diet quality index.
    RESULTS: Eighty-eight CR participants (67% women, age 40 ± 9 y, BMI 27.7 ± 1.5 kg/m2) were included in the analysis. Dietary intake of fiber and most vitamins and minerals increased during CR. More than 90% of participants achieved 100% of EAR or AI during CR for 2 of 4 macronutrients (carbohydrate and protein), 6 of 11 vitamins (A, B1, B2, B3, B6, B12), and 6 of 9 minerals assessed (copper, iron, phosphorus, selenium, sodium, zinc). Nutrients for which <90% of participants achieved adequacy included fiber, omega-3 fatty acids, vitamins B5, B9, C, E, and K, and the minerals calcium, magnesium, and potassium. The PANDiet diet quality index improved from 72.9 ± 6.0% at baseline to 75.7 ± 5.2% during CR (p < 0.0001).
    CONCLUSION: Long-term, calorie-restricted diets were nutritionally equal or superior to baseline ad libitum diets among adults without obesity. Our results support modest calorie restriction as a safe strategy to promote healthy aging without compromising nutritional adequacy or diet quality.
    Keywords:  Calorie restriction; Diet quality; Nutritional adequacy; PANDiet
    DOI:  https://doi.org/10.1016/j.exger.2022.111840
  5. Nature. 2022 Jun 01.
    Blood's life history traced through genomic scars.
    Aswin Sekar, Benjamin L Ebert.
      
    Keywords:  Ageing; Genetics; Stem cells
    DOI:  https://doi.org/10.1038/d41586-022-01304-y
  6. Nature. 2022 Jun 01.
    The longitudinal dynamics and natural history of clonal haematopoiesis.
    Margarete A Fabre, José Guilherme de Almeida, Edoardo Fiorillo, Emily Mitchell, Aristi Damaskou, Justyna Rak, Valeria Orrù, Michele Marongiu, Michael Spencer Chapman, M S Vijayabaskar, Joanna Baxter, Claire Hardy, Federico Abascal, Nicholas Williams, Jyoti Nangalia, Iñigo Martincorena, Peter J Campbell, Eoin F McKinney, Francesco Cucca, Moritz Gerstung, George S Vassiliou.
      Clonal expansions driven by somatic mutations become pervasive across human tissues with age, including in the haematopoietic system, where the phenomenon is termed clonal haematopoiesis1-4. The understanding of how and when clonal haematopoiesis develops, the factors that govern its behaviour, how it interacts with ageing and how these variables relate to malignant progression remains limited5,6. Here we track 697 clonal haematopoiesis clones from 385 individuals 55 years of age or older over a median of 13 years. We find that 92.4% of clones expanded at a stable exponential rate over the study period, with different mutations driving substantially different growth rates, ranging from 5% (DNMT3A and TP53) to more than 50% per year (SRSF2P95H). Growth rates of clones with the same mutation differed by approximately ±5% per year, proportionately affecting slow drivers more substantially. By combining our time-series data with phylogenetic analysis of 1,731 whole-genome sequences of haematopoietic colonies from 7 individuals from an older age group, we reveal distinct patterns of lifelong clonal behaviour. DNMT3A-mutant clones preferentially expanded early in life and displayed slower growth in old age, in the context of an increasingly competitive oligoclonal landscape. By contrast, splicing gene mutations drove expansion only later in life, whereas TET2-mutant clones emerged across all ages. Finally, we show that mutations driving faster clonal growth carry a higher risk of malignant progression. Our findings characterize the lifelong natural history of clonal haematopoiesis and give fundamental insights into the interactions between somatic mutation, ageing and clonal selection.
    DOI:  https://doi.org/10.1038/s41586-022-04785-z
  7. JAMA Netw Open. 2022 Jun 01. 5(6): e2214916
    Association of Diet Quality With Longevity and Successful Aging in Israeli Adults 65 Years or Older.
    Abigail Goshen, Uri Goldbourt, Yael Benyamini, Tal Shimony, Lital Keinan-Boker, Yariv Gerber.
       Importance: To our knowledge, the role of overall diet quality in successful aging has not been conclusively demonstrated.
    Objective: To prospectively examine the association between diet quality and longevity and successful aging in a population-based cohort of older adults.
    Design, Setting, and Participants: Participants in "Mabat Zahav" (the Israeli National Health and Nutrition Survey of Older Adults), an older adult cohort (aged ≥65 years) consisting of a random sample of 1770 individuals, were recruited from July 2005 to December 2006 (time 1 [T1]). Survivors of T1 were again contacted and asked to participate in a second interview. From May 2017 to June 2019 (time 2 [T2]), an extensive face-to-face interview and a functional assessment were conducted in each participant's home in a subsample of 604 participants from T1, representing 72.7% of 820 surviving individuals who were able to complete interviews and assessments.
    Exposures: A 24-hour dietary recall, assessed at T1, was used to calculate scores from the 2015 version of the Healthy Eating Index (HEI-2015) (scores range from 0 [worst diet] to 100 [best diet]).
    Main Outcomes and Measures: Time to death, with follow-up lasting through June 2019, and successful aging. The latter, based on T2 assessment, was defined as (objectively measured) preserved physical and cognitive function and (subjective) mental well-being and favorable self-rated health. Inverse probability weighting was used in the analysis to minimize attrition bias.
    Results: At T1, the study included 1770 participants (mean [SD] age, 74.6 [6.2] years; 943 women [53%]). On average, participants with higher HEI-2015 scores had healthier lifestyles and higher socioeconomic status at T1. During a median follow-up duration of 12.6 years (IQR, 7.6-13.2 years), 893 deaths occurred. Among the 596 T2 participants analyzed (mean [SD] age, 84.1 [4.4] years; 334 [56%] women), 242 (40%) met successful aging criteria. After adjustment for sociodemographic and lifestyle risk factors, a higher HEI-2015 score was inversely associated with mortality (hazard ratios, 0.85; 95% CI, 0.72-0.99 in the upper tertile and 0.83; 95% CI, 0.71-0.98 in the middle tertile vs the lower tertile; P = .04 for trend) and was positively associated with successful aging (odds ratios, 1.73; 95% CI, 1.10-2.72 in the upper tertile and 1.30; 95% CI, 0.83-2.03 in the middle tertile vs the lower tertile; P = .03 for trend).
    Conclusions and Relevance: In this cohort study of older adults in Israel, improved diet quality was associated with increased longevity and successful aging in a dose-dependent manner. These data contribute to the body of literature that suggests diet quality is associated with aging in the older age group.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2022.14916
  8. Nature. 2022 Jun 01.
    Clonal dynamics of haematopoiesis across the human lifespan.
    Emily Mitchell, Michael Spencer Chapman, Nicholas Williams, Kevin J Dawson, Nicole Mende, Emily F Calderbank, Hyunchul Jung, Thomas Mitchell, Tim H H Coorens, David H Spencer, Heather Machado, Henry Lee-Six, Megan Davies, Daniel Hayler, Margarete A Fabre, Krishnaa Mahbubani, Federico Abascal, Alex Cagan, George S Vassiliou, Joanna Baxter, Inigo Martincorena, Michael R Stratton, David G Kent, Krishna Chatterjee, Kourosh Saeb Parsy, Anthony R Green, Jyoti Nangalia, Elisa Laurenti, Peter J Campbell.
      Age-related change in human haematopoiesis causes reduced regenerative capacity1, cytopenias2, immune dysfunction3 and increased risk of blood cancer4-6, but the reason for such abrupt functional decline after 70 years of age remains unclear. Here we sequenced 3,579 genomes from single cell-derived colonies of haematopoietic cells across 10 human subjects from 0 to 81 years of age. Haematopoietic stem cells or multipotent progenitors (HSC/MPPs) accumulated a mean of 17 mutations per year after birth and lost 30 base pairs per year of telomere length. Haematopoiesis in adults less than 65 years of age was massively polyclonal, with high clonal diversity and a stable population of 20,000-200,000 HSC/MPPs contributing evenly to blood production. By contrast, haematopoiesis in individuals aged over 75 showed profoundly decreased clonal diversity. In each of the older subjects, 30-60% of haematopoiesis was accounted for by 12-18 independent clones, each contributing 1-34% of blood production. Most clones had begun their expansion before the subject was 40 years old, but only 22% had known driver mutations. Genome-wide selection analysis estimated that between 1 in 34 and 1 in 12 non-synonymous mutations were drivers, accruing at constant rates throughout life, affecting more genes than identified in blood cancers. Loss of the Y chromosome conferred selective benefits in males. Simulations of haematopoiesis, with constant stem cell population size and constant acquisition of driver mutations conferring moderate fitness benefits, entirely explained the abrupt change in clonal structure in the elderly. Rapidly decreasing clonal diversity is a universal feature of haematopoiesis in aged humans, underpinned by pervasive positive selection acting on many more genes than currently identified.
    DOI:  https://doi.org/10.1038/s41586-022-04786-y
  9. Front Bioeng Biotechnol. 2022 ;10 870324
    Inflammatory Microenvironment Accelerates Bone Marrow Mesenchymal Stem Cell Aging.
    Xin Peng, Xin Zhou, Ying Yin, Beibei Luo, Yang Liu, Cheng Yang.
      MSC senescence is considered a contributing factor in aging-related diseases. We investigated the influence of the inflammatory microenvironment on bone marrow mesenchymal stem cells (BMSCs) under aging conditions and the underlying mechanism to provide new ideas for stem cell therapy for age-related osteoporosis. The BMSCs were cultured until passage 3 (P3) (young group) and passage 10 (P10) (aging group) in vitro. The supernatant was collected as the conditioned medium (CM). The young BMSCs were cultured in the CM of P3 or P10 cells. The effects of CM from different groups on the aging and stemness of the young BMSCs were examined. A Quantibody® mouse inflammation array on serum extracts from young (aged 8 weeks) and old (aged 78 weeks) mice was performed, and differentially expressed factors were screened out. We discovered that the CM from senescent MSCs changed the physiology of young BMSCs. Systemic inflammatory microenvironments changed with age in the mice. In particular, the pro-inflammatory cytokine IL-6 increased, and the anti-inflammatory cytokine IL-10 decreased. The underlying mechanism was investigated by GO and KEGG analyses, and there was a change in the JAK-STAT signaling pathway, which is closely related to IL-6 and IL-10. Collectively, our results demonstrated that the age-related inflammatory microenvironment has a significant effect on the biological functions of BMSCs. Targeted reversal of this inflammatory environment may provide a new strategy for stem cell therapy to treat aging-related skeletal diseases.
    Keywords:  aging; aging-related skeletal diseases; bone marrow mesenchymal stem cell; inflammatory microenvironment; stem cell therapy
    DOI:  https://doi.org/10.3389/fbioe.2022.870324
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