bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2023–12–10
ten papers selected by
Ayesh Seneviratne, Western University
  1. Isoleucine dietary restriction boosts healthspan and longevity in mice.
  2. Vitamin B12 boosts cellular reprogramming.
  3. Mechanical resistance to tumor initiation deteriorates with tissue aging.
  4. Aging and the Emerging Role of Cellular Senescence in Osteoarthritis.
  5. Aging and Inflammation.
  6. A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation.
  7. DNA methylation rates scale with maximum lifespan across mammals.
  8. Clonal hematopoiesis of indeterminate potential: implications for the cardiologists.
  9. Diet Quality and Incident Frailty in Adults 65 Years or Older: The Israeli Longitudinal Study on Aging.
  10. New Statin Use, Mortality and First Cardiovascular Events in Older US Veterans by Frailty Status.
  1. Nat Aging. 2023 Dec 06.
    Isoleucine dietary restriction boosts healthspan and longevity in mice.
    Yahyah Aman.
      
    DOI:  https://doi.org/10.1038/s43587-023-00547-2
  2. Nat Aging. 2023 Dec 05.
    Vitamin B12 boosts cellular reprogramming.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-023-00546-3
  3. Nat Aging. 2023 Dec 05.
    Mechanical resistance to tumor initiation deteriorates with tissue aging.
    Hannah Walters.
      
    DOI:  https://doi.org/10.1038/s43587-023-00545-4
  4. Osteoarthritis Cartilage. 2023 Dec 02. pii: S1063-4584(23)00997-4. [Epub ahead of print]
    Aging and the Emerging Role of Cellular Senescence in Osteoarthritis.
    Brian O Diekman, Richard F Loeser.
       OBJECTIVE: The correlation between age and incidence of osteoarthritis (OA) is well known but the causal mechanisms involved are not completely understood. This narrative review summarizes selected key findings from the past 30 years that have elucidated key aspects of the relationship between aging and OA.
    METHODS: The peer-reviewed English language literature was searched on PubMed using key words including senescence, aging, cartilage, and osteoarthritis, for original studies and reviews published from 1993-2023 with a major focus on more recent studies. Manuscripts most relevant to aging and OA that examined one or more of the hallmarks of aging were selected for further review.
    RESULTS: All proposed hallmarks of aging have been observed in articular cartilage and some have also been described in other joint tissues. Hallmarks include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, disabled macroautophagy, chronic inflammation, and dysbiosis. There is evidence that these age-related changes contribute to the development of OA in part by promoting cellular senescence. Senescence may therefore serve as a downstream mediator that connects numerous aging hallmarks to OA, likely through the senescence-associated secretory phenotype (SASP) that is characterized by increased production of proinflammatory cytokines and matrix metalloproteinases.
    CONCLUSIONS: Progress over the past 30 years has provided the foundation for emerging therapies, such as senolytics and senomorphics, that hold promise for OA disease modification. Mechanistic studies utilizing physiologically-aged animals and cadaveric human joint tissues will be important for continued progress.
    Keywords:  Aging; Chondrocyte; cartilage; senescence
    DOI:  https://doi.org/10.1016/j.joca.2023.11.018
  5. Cold Spring Harb Perspect Med. 2023 Dec 05. pii: a041197. [Epub ahead of print]
    Aging and Inflammation.
    Amit Singh, Shepherd H Schurman, Arsun Bektas, Mary Kaileh, Roshni Roy, David M Wilson, Ranjan Sen, Luigi Ferrucci.
      Aging can be conceptualized as the progressive disequilibrium between stochastic damage accumulation and resilience mechanisms that continuously repair that damage, which eventually cause the development of chronic disease, frailty, and death. The immune system is at the forefront of these resilience mechanisms. Indeed, aging is associated with persistent activation of the immune system, witnessed by a high circulating level of inflammatory markers and activation of immune cells in the circulation and in tissue, a condition called "inflammaging." Like aging, inflammaging is associated with increased risk of many age-related pathologies and disabilities, as well as frailty and death. Herein we discuss recent advances in the understanding of the mechanisms leading to inflammaging and the intrinsic dysregulation of the immune function that occurs with aging. We focus on the underlying mechanisms of chronic inflammation, in particular the role of NF-κB and recent studies targeting proinflammatory mediators. We further explore the dysregulation of the immune response with age and immunosenescence as an important mechanistic immune response to acute stressors. We examine the role of the gastrointestinal microbiome, age-related dysbiosis, and the integrated stress response in modulating the inflammatory "response" to damage accumulation and stress. We conclude by focusing on the seminal question of whether reducing inflammation is useful and the results of related clinical trials. In summary, we propose that inflammation may be viewed both as a clinical biomarker of the failure of resilience mechanisms and as a causal factor in the rising burden of disease and disabilities with aging. The fact that inflammation can be reduced through nonpharmacological interventions such as diet and exercise suggests that a life course approach based on education may be a successful strategy to increase the health span with few adverse consequences.
    DOI:  https://doi.org/10.1101/cshperspect.a041197
  6. bioRxiv. 2023 Nov 21. pii: 2023.11.20.567963. [Epub ahead of print]
    A mitochondria-regulated p53-CCF circuit integrates genome integrity with inflammation.
    Karl N Miller, Brightany Li, Hannah R Pierce-Hoffman, Xue Lei, Aaron P Havas, Shreeya Patel, Carolina Cano Macip, Stella G Victorelli, Seung-Hwa Woo, Anthony B Lagnado, Tianhui Liu, Nirmalya Dasgupta, Jun Lyu, Yoav Altman, Rebecca A Porritt, Guillermina Garcia, Carolin Mogler, Zhixun Dou, Chongyi Chen, João F Passos, Peter D Adams.
      Genomic instability and inflammation are distinct hallmarks of aging, but the connection between them is poorly understood. Understanding their interrelationship will help unravel new mechanisms and therapeutic targets of aging and age-associated diseases. Here we report a novel mechanism directly linking genomic instability and inflammation in senescent cells, through a mitochondria-regulated molecular circuit that connects the p53 tumor suppressor and cytoplasmic chromatin fragments (CCF), a driver of inflammation through the cGAS-STING pathway. Activation or inactivation of p53 by genetic and pharmacologic approaches showed that p53 suppresses CCF accumulation and the downstream inflammatory senescence-associated secretory phenotype (SASP), independent of its effects on cell cycle arrest. p53 activation suppressed CCF formation by promoting DNA repair, reflected in maintenance of genomic integrity, particularly in subtelomeric regions, as shown by single cell genome resequencing. Activation of p53 by pharmacological inhibition of MDM2 in old mice decreased features of SASP in liver, indicating a senomorphic role in vivo . Remarkably, mitochondria in senescent cells suppressed p53 activity by promoting CCF formation and thereby restricting ATM-dependent nuclear DNA damage signaling. These data provide evidence for a mitochondria-regulated p53-CCF circuit in senescent cells that controls DNA repair, genome integrity and inflammatory SASP, and is a potential target for senomorphic healthy aging interventions.
    DOI:  https://doi.org/10.1101/2023.11.20.567963
  7. Nat Aging. 2023 Dec 04.
    DNA methylation rates scale with maximum lifespan across mammals.
    Samuel J C Crofts, Eric Latorre-Crespo, Tamir Chandra.
      DNA methylation rates have previously been found to broadly correlate with maximum lifespan in mammals, yet no precise relationship has been observed. We developed a statistically robust framework to compare methylation rates at conserved age-related sites across mammals. We found that methylation rates negatively scale with maximum lifespan in both blood and skin. The emergence of explicit scaling suggests that methylation rates are, or are linked to, an evolutionary constraint on maximum lifespan acting across diverse mammalian lineages.
    DOI:  https://doi.org/10.1038/s43587-023-00535-6
  8. J Cardiovasc Med (Hagerstown). 2023 Nov 27.
    Clonal hematopoiesis of indeterminate potential: implications for the cardiologists.
    Edoardo Sciatti, Emilia D'Elia, Mauro Gori, Aurelia Grosu, Giulio Balestrieri, Michele Senni, Tiziano Barbui, Antonello Gavazzi.
      Myeloproliferative neoplasms, including polycythemia vera, essential thrombocythemia, and myelofibrosis, are characterized by somatic gene mutations in bone marrow stem cells, which trigger an inflammatory response influencing the development of associated cardiovascular complications. In recent years, the same mutations were found in individuals with cardiovascular diseases even in the absence of hematological alterations. These genetic events allow the identification of a new entity called 'clonal hematopoiesis of indeterminate potential' (CHIP), as it was uncertain whether it could evolve toward hematological malignancies. CHIP is age-related and, remarkably, myocardial infarction, stroke, and heart failure were frequently reported in these individuals and attributed to systemic chronic inflammation driven by the genetic mutation. We reviewed the connection between clonal hematopoiesis, inflammation, and cardiovascular diseases, with a practical approach to improve clinical practice and highlight the current unmet needs in this area of knowledge.
    DOI:  https://doi.org/10.2459/JCM.0000000000001520
  9. Mayo Clin Proc. 2023 Dec;pii: S0025-6196(23)00408-1. [Epub ahead of print]98(12): 1774-1784
    Diet Quality and Incident Frailty in Adults 65 Years or Older: The Israeli Longitudinal Study on Aging.
    Abigail Goshen, Uri Goldbourt, Yael Benyamini, Tal Shimony, Lital Keinan-Boker, Yariv Gerber.
       OBJECTIVE: To prospectively examine the association between diet quality and frailty incidence in the oldest-old age group.
    METHODS: We studied an older adult (65+ years) cohort participating in the Israeli National Health and Nutrition Survey of Older Adults in 2005-2006 (T1 [N=1799]). Survivors of T1 were contacted, and between 2017 and 2019, an extensive interview and a functional assessment were conducted (T2) of 604 past participants. A 24-hour dietary recall, assessed at T1, was used to calculate the Healthy Eating Index (HEI-2015) score. A frailty index based on an accumulation of deficits, including clinical, functional, and cognitive measures, was computed. Frail participants at T1 were excluded from the analysis. Logistic regression models were constructed to assess the association of HEI-2015 score with frailty incidence. Inverse probability weighting was used to minimize selection bias due to attrition.
    RESULTS: Of the 479 T2 participants analyzed (mean [SD] age, 84 [5] years; 50% women), 225 (46%) were classified as frail. Frail participants were older, were less educated, and had a lower household income and a higher comorbidity burden at baseline than non-frail participants. After adjustment for sociodemographic and lifestyle factors, a higher HEI-2015 score was associated with decreased odds of incident frailty (odds ratio, 0.57 [95% CI, 0.35 to 0.91] for the upper tertile and 0.66 [95% CI, 0.42 to 1.06] for the middle tertile compared with the lower tertile; Ptrend=.02).
    CONCLUSION: In this cohort study of oldest-old participants, improved diet quality was inversely associated with frailty incidence in a dose-dependent manner.
    DOI:  https://doi.org/10.1016/j.mayocp.2023.08.015
  10. J Am Geriatr Soc. 2023 Dec 06.
    New Statin Use, Mortality and First Cardiovascular Events in Older US Veterans by Frailty Status.
    Ariela R Orkaby, Bing Lu, Yuk-Lam Ho, Timothy Treu, Ashley Galloway, Peter W F Wilson, Kelly Cho, J Michael Gaziano, Karen P Alexander, David R Gagnon, Luc Djousse, Daniel E Forman, Jane A Driver.
       BACKGROUND: Statins are part of long-term medical regimens for many older adults. Whether frailty modifies the protective relationship between statins, mortality, and major adverse cardiovascular events (MACE) is unknown.
    METHODS: This was a retrospective study of US Veterans ≥65, without CVD or prior statin use seen in 2002-2012, followed through 2017. A 31-item frailty index was used. The co-primary endpoint was all-cause mortality or MACE (MI, stroke/TIA, revascularization, or cardiovascular death). Cox proportional hazards models were developed to evaluate the association of statin use with outcomes; propensity score overlap weighting accounted for confounding by indication.
    RESULTS: We identified 710,313 Veterans (mean age (SD) 75.3(6.5), 98% male, 89% white); 86,327 (12.1%) were frail. Over mean follow up of 8(5) years, there were 48.6 and 72.6 deaths per 1000 person-years (PY) among non-frail statin-users vs nonusers (weighted Incidence Rate Difference (wIRD)/1000 person years (PY), -24.0[95% CI, -24.5 to -23.6]), and 90.4 and 130.4 deaths per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -40.0[95% CI, -41.8 to -38.2]). There were 51.7 and 60.8 MACE per 1000PY among non-frail statin-users vs nonusers (wIRD/1000PY, -9.1[95% CI, -9.7 to -8.5]), and 88.2 and 102.0 MACE per 1000PY among frail statin-users vs nonusers (wIRD/1000PY, -13.8[95% CI, -16.2 to -11.4]). There were no significant interactions by frailty for statin users vs non-users by either mortality or MACE outcomes, p-interaction 0.770 and 0.319, respectively. Statin use was associated with lower risk of all-cause mortality (HR, 0.61 (0.60-0.61)) and MACE (HR 0.86 (0.85-0.87)).
    CONCLUSIONS: New statin use is associated with a lower risk of mortality and MACE, independent of frailty. These findings should be confirmed in a randomized clinical trial. This article is protected by copyright. All rights reserved.
    Keywords:  Statins; cardiovascular disease; frailty; prevention
    DOI:  https://doi.org/10.1111/jgs.18700
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