bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–04–10
eleven papers selected by
Ayesh Seneviratne, University of Toronto
  1. The Function of Metformin in Aging-Related Musculoskeletal Disorders.
  2. Novel Insights into the Roles and Mechanisms of GLP-1 Receptor Agonists against Aging-Related Diseases.
  3. Lipids as Regulators of Cellular Senescence.
  4. Early Dinner Time and Caloric Restriction Lapse Contribute to the Longevity of Nonagenarians and Centenarians of the Italian Abruzzo Region: A Cross-Sectional Study.
  5. TET2-Driven Clonal Hematopoiesis and Response to Canakinumab: An Exploratory Analysis of the CANTOS Randomized Clinical Trial.
  6. Leveling the playing field in long-term care.
  7. Fluvoxamine for Acute COVID-19 Infection: Weak Hypothesis, Predictable Failure.
  8. Aging Impairs the Cellular Interplay between Myeloid Cells and Mesenchymal Cells during Skin Healing in Mice.
  9. Dehydroepiandrosterone, Cancer, and Aging.
  10. Anti-aging mechanism of calorie restriction in humans.
  11. Frailty as a predictor of clinical problems and events that require elderly patients with heart failure to use health resources.
  1. Front Pharmacol. 2022 ;13 865524
    The Function of Metformin in Aging-Related Musculoskeletal Disorders.
    Yanhong Song, Ziyi Wu, Ping Zhao.
      Metformin is a widely accepted first-line hypoglycemic agent in current clinical practice, and it has been applied to the clinic for more than 60 years. Recently, researchers have identified that metformin not only has an efficient capacity to lower glucose but also exerts anti-aging effects by regulating intracellular signaling molecules. With the accelerating aging process and mankind's desire for a long and healthy life, studies on aging have witnessed an unprecedented boom. Osteoporosis, sarcopenia, degenerative osteoarthropathy, and frailty are age-related diseases of the musculoskeletal system. The decline in motor function is a problem that many elderly people have to face, and in serious cases, they may even fail to self-care, and their quality of life will be seriously reduced. Therefore, exploring potential treatments to effectively prevent or delay the progression of aging-related diseases is essential to promote healthy aging. In this review, we first briefly describe the origin of metformin and the aging of the movement system, and next review the evidence associated with its ability to extend lifespan. Furthermore, we discuss the mechanisms related to the modulation of aging in the musculoskeletal system by metformin, mainly its contribution to bone homeostasis, muscle aging, and joint degeneration. Finally, we analyze the protective benefits of metformin in aging-related diseases of the musculoskeletal system.
    Keywords:  aging; bone homeostasis; drug effects; metformin; musculoskeletal diseases
    DOI:  https://doi.org/10.3389/fphar.2022.865524
  2. Aging Dis. 2022 Apr;13(2): 468-490
    Novel Insights into the Roles and Mechanisms of GLP-1 Receptor Agonists against Aging-Related Diseases.
    Wei Peng, Rui Zhou, Ze-Fang Sun, Jia-Wei Long, Yong-Qiang Gong.
      Aging and aging-related diseases have emerged as increasingly severe health and social problems. Therefore, it is imperative to discover novel and effective therapeutics to delay the aging process and to manage aging-related diseases. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), one of the classes of antihyperglycemic drugs, have been recommended to manage type 2 diabetes mellitus (T2DM). Moreover, GLP-1 RAs have been shown to protect against oxidative stress, cellular senescence and chronic inflammation, which are widely accepted as the major risk factors of aging. However, their significance in aging or aging-related diseases has not been elucidated. Herein, we explain the underlying mechanisms and protective roles of GLP-1 RAs in aging from a molecular, cellular and phenotypic perspective. We provide novel insights into the broad prospect of GLP-1 RAs in preventing and treating aging-related diseases. Additionally, we highlight the gaps for further studies in clinical applications of GLP-1 RAs in aging-related diseases. This review forms a basis for further studies on the relationship between aging-related diseases and GLP-1 RAs.
    Keywords:  GLP-1 receptor agonists; aging; aging-related diseases; glucagon-like peptide-1
    DOI:  https://doi.org/10.14336/AD.2021.0928
  3. Front Physiol. 2022 ;13 796850
    Lipids as Regulators of Cellular Senescence.
    Shruthi Hamsanathan, Aditi U Gurkar.
      Lipids are key macromolecules that perform a multitude of biological functions ranging from maintaining structural integrity of membranes, energy storage, to signaling molecules. Unsurprisingly, variations in lipid composition and its levels can influence the functional and physiological state of the cell and its milieu. Cellular senescence is a permanent state of cell cycle arrest and is a hallmark of the aging process, as well as several age-related pathologies. Senescent cells are often characterized by alterations in morphology, metabolism, chromatin remodeling and exhibit a complex pro-inflammatory secretome (SASP). Recent studies have shown that the regulation of specific lipid species play a critical role in senescence. Indeed, some lipid species even contribute to the low-grade inflammation associated with SASP. Many protein regulators of senescence have been well characterized and are associated with lipid metabolism. However, the link between critical regulators of cellular senescence and senescence-associated lipid changes is yet to be elucidated. Here we systematically review the current knowledge on lipid metabolism and dynamics of cellular lipid content during senescence. We focus on the roles of major players of senescence in regulating lipid metabolism. Finally, we explore the future prospects of lipid research in senescence and its potential to be targeted as senotherapeutics.
    Keywords:  aging; bioactive lipids; cellular senescence; lipids; senolytics
    DOI:  https://doi.org/10.3389/fphys.2022.796850
  4. Front Nutr. 2022 ;9 863106
    Early Dinner Time and Caloric Restriction Lapse Contribute to the Longevity of Nonagenarians and Centenarians of the Italian Abruzzo Region: A Cross-Sectional Study.
    Donato Angelino, Francesca Pietrangeli, Mauro Serafini.
      Recent findings showed the role of late-night eating in metabolic disorders, highlighting the importance of meal timing for health. No evidence is available on the role of meal timing for longevity. The aim of this study was to survey, in a cross-sectional study, meal timing and dietary habits of 68 nonagenarians and centenarians of the Abruzzo region, Italy. Results showed an early dinner (7:13 p.m.) and a calorie restriction lapse of 17.5 h between dinner and the following lunch. The frequency of consumption was high for cereals, vegetables, fruits, and legumes; low for meat, processed meat, and eggs; and negligible for sweets. Subjects were physically active throughout life. Our results support the importance of a daily caloric restriction lapse, hampering nocturnal postprandial stress and optimizing metabolic response, associated with high consumption of plant-based foods and physical activity for the longevity of centenarians from Abruzzo.
    Keywords:  Abruzzo; caloric restriction lapse; centenarians; chrono-nutrition; dietary habits; lifestyle; longevity
    DOI:  https://doi.org/10.3389/fnut.2022.863106
  5. JAMA Cardiol. 2022 Apr 06.
    TET2-Driven Clonal Hematopoiesis and Response to Canakinumab: An Exploratory Analysis of the CANTOS Randomized Clinical Trial.
    Eric C Svensson, Aviv Madar, Catarina D Campbell, Yunsheng He, Marc Sultan, Margaret L Healey, Huilei Xu, Katie D'Aco, Anita Fernandez, Clarisse Wache-Mainier, Peter Libby, Paul M Ridker, Michael T Beste, Craig T Basson.
       Importance: Clonal hematopoiesis of indeterminate potential (CHIP) is associated with increased risk of atherosclerotic cardiovascular disease, and mouse experiments suggest that CHIP related to Tet2 loss of function in myeloid cells accelerates atherosclerosis via augmented interleukin (IL) 1β signaling.
    Objective: To assess whether individuals with CHIP have greater cardiovascular event reduction in response to IL-1β neutralization in the Canankinumab Anti-inflammatory Thrombosis Outcomes Trial (CANTOS).
    Design, Setting, and Participants: This randomized clinical trial took place from April 2011 to June 2017 at more than 1000 clinical sites in 39 countries. Targeted deep sequencing of genes previously associated with CHIP in a subset of trial participants using genomic DNA prepared from baseline peripheral blood samples were analyzed. All participants had prior myocardial infarction and elevated high-sensitivity C-reactive protein level above 0.20 mg/dL. Analysis took place between June 2017 and December 2021.
    Interventions: Canakinumab, an anti-IL-1β antibody, given at doses of 50, 150, and 300 mg once every 3 months.
    Main Outcomes and Measures: Major adverse cardiovascular events (MACE).
    Results: A total of 338 patients (8.6%) were identified in this subset with evidence for clonal hematopoiesis. As expected, the incidence of CHIP increased with age; the mean (SD) age of patients with CHIP was 66.3 (9.2) years and 61.5 (9.6) years in patients without CHIP. Unlike other populations that were not preselected for elevated C-reactive protein, in the CANTOS population variants in TET2 were more common than DNMT3A (119 variants in 103 patients vs 86 variants in 85 patients). Placebo-treated patients with CHIP showed a nonsignificant increase in the rate of MACE compared with patients without CHIP using a Cox proportional hazard model (hazard ratio, 1.32 [95% CI, 0.86-2.04]; P = .21). Exploratory analyses of placebo-treated patients with a somatic variant in either TET2 or DNMT3A (n = 58) showed an equivocal risk for MACE (hazard ratio, 1.65 [95% CI, 0.97-2.80]; P = .06). Patients with CHIP due to somatic variants in TET2 also had reduced risk for MACE while taking canakinumab (hazard ratio, 0.38 [95% CI, 0.15-0.96]) with equivocal difference compared with others (P for interaction = .14).
    Conclusions and Relevance: These results are consistent with observations of increased risk for cardiovascular events in patients with CHIP and raise the possibility that those with TET2 variants may respond better to canakinumab than those without CHIP. Future studies are required to further substantiate this hypothesis.
    Trial Registration: ClinicalTrials.gov Identifier: NCT01327846.
    DOI:  https://doi.org/10.1001/jamacardio.2022.0386
  6. CMAJ. 2022 Apr 04. 194(13): E501
    Leveling the playing field in long-term care.
    Joel Wohlgemut.
      
    DOI:  https://doi.org/10.1503/cmaj.81199
  7. Am J Ther. 2022 Mar 29.
    Fluvoxamine for Acute COVID-19 Infection: Weak Hypothesis, Predictable Failure.
    Peter Manu.
      
    DOI:  https://doi.org/10.1097/MJT.0000000000001502
  8. Aging Dis. 2022 Apr;13(2): 540-551
    Aging Impairs the Cellular Interplay between Myeloid Cells and Mesenchymal Cells during Skin Healing in Mice.
    Saeid Amini-Nik, Abdikarim Abdullahi, Roohi Vinaik, Ren Jie Robert Yao, Nancy Yu, Andrea Datu, Cassandra Belo, Marc G Jeschke.
      Impaired wound healing is a major issue in the elderly population and is associated with substantial health and economic burden, which is exponentially increasing with the growing aging population. While the underlying pathobiology of disturbed skin healing by aging is linked to several genetic and epigenetic factors, little is known about the cell-cell interaction during the wound healing process in aged individuals, particularly the mesenchymal stem cell (MSCs)-macrophages axis. In this study, by using a thermal injury animal model in which we compared the wound healing process of adult and young mice, we found that the insufficient pool of MSCs in adult animals are deficient in migrating to the wound bed and instead are restricted to the wound edge. We identified a deficiency of a CD90-positive MSC subpopulation in the wounds of adult animals, which is positively correlated with the number of F4/80+ macrophages. In vitro, we found that CD90+ cells preferentially adhere to the myeloid cells forming doublet cells. Thus, our findings highlight that in adult mice subjected to a thermal injury, impaired wound healing is likely mediated by a disturbed cellular interplay between myeloid cells and mesenchymal cells.
    Keywords:  burns; elderly; macrophages; mesenchymal stem cells; thermal injury; wound healing
    DOI:  https://doi.org/10.14336/AD.2021.1008
  9. Aging Dis. 2022 Apr;13(2): 423-432
    Dehydroepiandrosterone, Cancer, and Aging.
    Arthur G Schwartz.
      The biological significance of dehydroepiandrosterone (DHEA) which, in the form of its sulfated ester is the most abundant steroid hormone in human plasma, is an enigma. Over the past years, numerous investigators have reported preclinical findings that DHEA has preventive and therapeutic efficacy in treating major age-associated diseases, including cancer, atherosclerosis, diabetes, obesity, as well as ameliorating the deleterious effects of excess cortisol exposure. Epidemiological studies have also found that low DHEA(S) levels predict an increased all-cause mortality. However, clinical trials, in which oral doses of DHEA at 50 mg-100 mg have been administered to elderly individuals for up to two years, have produced no clear evidence of benefit in parameters such as body composition, peak volume of oxygen consumption, muscle strength, or insulin sensitivity. I discuss why clinical trials, which use doses of DHEA in the 100 mg range, which are the human equivalent of about 1/20th the doses used in animal studies, are an inadequate test of DHEA's therapeutic potential. I also discuss three mechanisms of DHEA action that very likely contribute to its biological effects in animal studies. Lastly, I describe the development of a DHEA analog which lacks DHEA's androgenic and estrogenic action and that demonstrates enhanced potency and is currently in clinical trials. The use of such analogs may provide a better understanding of DHEA's potential therapeutic utility.
    Keywords:  Cortisol; DHEA; G6PD; NADPH; NOX
    DOI:  https://doi.org/10.14336/AD.2021.0913
  10. Kidney Int. 2022 Apr 01. pii: S0085-2538(22)00261-7. [Epub ahead of print]
    Anti-aging mechanism of calorie restriction in humans.
    Sho Hasegawa, Masaomi Nangaku.
      
    Keywords:  chronic kidney disease; inflammation
    DOI:  https://doi.org/10.1016/j.kint.2022.03.016
  11. Arch Gerontol Geriatr. 2022 Mar 31. pii: S0167-4943(22)00079-6. [Epub ahead of print]101 104698
    Frailty as a predictor of clinical problems and events that require elderly patients with heart failure to use health resources.
    F J Flores-Álvarez, A Sillero-Herrera, J Cuesta-Gaviño, M L Fernández-Sánchez, J Vega-Sánchez, J L López-Fe, F M Gamboa-Antiñolo, D Utrilla-Ayala, A Aguirre-Palacio, E De Villar-Conde, S Vergara-López.
       BACKGROUND: The clinical management of elderly patients with heart failure (HF) is not firmly established. Decision-making should be individualized depending on the biological deterioration of each patient, from aggressive management to a palliative approach. Frailty can serve as the basis for this comprehensive individualized management. Our objective was to evaluate the importance of the main clinical problems, as well as the events that required the use of health resources, based the degree of frailty, in elderly patients with HF.
    METHODS AND RESULTS: Retrospective observational cohort study. Frailty was defined according to the deficit accumulation construct. A total of 546 patients hospitalized for acute HF were included. The median age (Q1-Q3) was 82 (78-86) years. A total of 454 patients (83%) showed some degree of frailty: 221 (48.7%) mild, 207 (45.6%) moderate and 26 (5.7%) advanced. There was a significant tendency towards polypharmacy from no to severe frailty. Hospital events were recorded for 4 (1-6) patients with mild frailty, 4 (2-6) patients with moderate frailty and 2 ((1-4) patients with advanced frailty (p = 0.045). A total of 204 patients (37.4%) died during follow-up. The median time to death was 11.4 (4-16.8), 6.7 (3.3-11.6), 6.5 (3.4-12.2) and 4.1 (0.8-7.7) months for patients with no, mild, moderate, or advanced frailty, respectively (p = 0.006).
    CONCLUSIONS: Frailty due to deficit accumulation is a good predictor of clinical problems and events that require the use of health resources; therefore, it can serve as a basis for the management of HF in the elderly.
    Keywords:  deficit accumulation construct; elderly; frailty; healthcare resources; heart failure
    DOI:  https://doi.org/10.1016/j.archger.2022.104698
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