bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–01–30
thirty papers selected by
Ayesh Seneviratne, University of Toronto



  1. Ageing Res Rev. 2022 Jan 24. pii: S1568-1637(22)00015-0. [Epub ahead of print] 101573
      Indoleamine 2,3-dioxygenase 1 (IDO1) is activated in chronic inflammatory states, e.g., in the aging process and age-related diseases. IDO1 enzyme catabolizes L-tryptophan (L-Trp) into kynurenine (KYN) thus stimulating the KYN pathway. The depletion of L-Trp inhibits the proliferation of immune cells in inflamed tissues and it also reduces serotonin synthesis predisposing to psychiatric disorders. Interestingly, IDO1 protein contains two immunoreceptor tyrosine-based inhibitory motifs (ITIM) which trigger suppressive signaling through the binding of PI3K p110 and SHP-1 proteins. This immunosuppressive activity is not dependent on the catalytic activity of IDO1. KYN and its metabolite, kynurenic acid (KYNA), are potent activators of the aryl hydrocarbon receptor (AhR) which can enhance immunosuppression. IDO1-KYN-AhR signaling counteracts excessive pro-inflammatory responses in acute inflammation but in chronic inflammatory states it has many harmful effects. A chronic low-grade inflammation is associated with the aging process, a state called inflammaging. There is substantial evidence that the activation of the IDO1-KYN-AhR pathway robustly increases with the aging process. The activation of IDO1-KYN-AhR signaling does not only suppress the functions of effector immune cells, probably promoting immunosenescence, but it also impairs autophagy, induces cellular senescence, and remodels the extracellular matrix as well as enhancing the development of osteoporosis and vascular diseases. I will review the function of IDO1-KYN-AhR signaling and discuss its activation with aging as an enhancer of the aging process.
    Keywords:  Ageing; MDSC; NAD; RelB; Tolerance
    DOI:  https://doi.org/10.1016/j.arr.2022.101573
  2. J Nutr Health Aging. 2022 ;26(1): 30-36
       OBJECTIVES: To examine whether intrinsic capacity (IC) could predict frailty, whether declines in specific domains of IC could lead to frailty, and whether different combinations of domains could represent different risks of developing frailty.
    SETTING: Community.
    PARTICIPANTS: Chinese people aged 65 years and older.
    MEASUREMENTS: Using data from a prospective cohort study, we derived a summary score for IC and scores for the five domains (cognitive, locomotor, vitality, sensory, psychological) for each participant at baseline. Frailty was assessed according to the Fried's frailty phenotype at baseline, 2- and 4-year follow-ups. Participants were classified as frail if they had ≥3 of the following criteria: weight loss, self-rated exhaustion, weakness, slow walking speed, and low physical activity.
    RESULTS: Four thousand participants were interviewed at baseline. Overall mean age was 72.5 years; 50% were women. Between baseline and the 2-year follow-up, 5.7% of non-frail participants developed frailty; between 2- and 4-year follow-ups, 5.7% of non-frail participants developed frailty. The average annual incidence rate of frailty was 2.9%. Higher scores on IC at baseline were associated with a lower risk of incident frailty at both follow-ups (year 2, odds ratio (OR)=0.64, 95% confidence interval (CI)=0.59-0.71); year 4, OR=0.64, 95%CI=0.58-0.71) after adjustment for age, sex, educational level, and chronic diseases. Across the five domains, vitality was the strongest predictor of incident frailty at each follow-up (year 2, OR=0.33, 95%CI=0.24-0.45; year 4, OR=0.33, 95%CI=0.23-0.46). Compared to other combinations of any two domains, having 'high' scores on both vitality and locomotor domains was associated with the lowest risk of incident frailty (year 2, OR=0.11, 95%CI=0.06-0.22, area under the curve (AUC)=0.770; year 4, OR=0.18, 95%CI=0.10-0.32, AUC=0.782).
    CONCLUSION: This study provides evidence that IC was independently associated with incident frailty. It also finds that vitality was the domain most strongly associated with incident frailty. Finally, it suggests that optimizing multiple domains of IC, particularly vitality and locomotor, may prevent frailty.
    Keywords:  Frailty; ICOPE; healthy ageing; incidence; intrinsic capacity
    DOI:  https://doi.org/10.1007/s12603-021-1715-2
  3. Cell Stem Cell. 2022 Jan 13. pii: S1934-5909(21)00519-1. [Epub ahead of print]
      Host microbiota crosstalk is essential for the production and functional modulation of blood-cell lineages. Whether, and if so how, the microbiota influences hematopoietic stem cells (HSCs) is unclear. Here, we show that the microbiota regulates HSC self-renewal and differentiation under stress conditions by modulating local iron availability in the bone marrow (BM). In microbiota-depleted mice, HSC self-renewal was enhanced during regeneration, while the commitment toward differentiation was dramatically compromised. Mechanistically, microbiota depletion selectively impaired the recycling of red blood cells (RBCs) by BM macrophages, resulting in reduced local iron levels without affecting systemic iron homeostasis. Limiting iron availability in food (in vivo) or in culture (ex vivo), or by CD169+ macrophage depletion, enhanced HSC self-renewal and expansion. These results reveal an intricate interplay between the microbiota, macrophages, and iron, and their essential roles in regulating critical HSC fate decisions under stress.
    Keywords:  erythrophagocytosis; fate decision; hematopoietic regeneration; hematopoietic stem cell; iron; macrophage; microbiota; self-renewal
    DOI:  https://doi.org/10.1016/j.stem.2021.12.009
  4. Leuk Lymphoma. 2022 Jan 22. 1-10
      The world is aging and with it an associated increase in malignancies. Haematological malignancies especially Acute Myeloid Leukemia (AML) are no exception to this trend. With scientific advances, development of new AML treatments has improved patient mortality. One future research interest would be Leukeamic Stem Cells (LSC). This review aims to briefly highlight main LSC characteristics and their relationship with hematopoietic stem cells. Key LSC characteristics include dysregulated apoptosis, capacity for self-renewal, genomic instability, dysregulated energetics, immune privilege and an altered tumor microenvironment. Similar characteristics are also found in HSCs though in a regulated form. Classifying these characteristics will aid in the development of clinical biomarkers for LSC which is a potential clinical application of LSC biology. LSC biomarkers might prove to be critical in future AML management through improving accuracy of AML diagnosis, providing targeted treatment to minimize side effects, refinement of prognosis and relapse risk for earlier intervention.
    Keywords:  Acute myeloid leukemia; hematopoeitic stem cells; leukaemic stem cells
    DOI:  https://doi.org/10.1080/10428194.2022.2027401
  5. Front Oncol. 2021 ;11 800110
      Despite advances in the understanding of the genetic landscape of acute myeloid leukemia (AML) and the addition of targeted biological and epigenetic therapies to the available armamentarium, achieving long-term disease-free survival remains an unmet need. Building on growing knowledge of the interactions between leukemic cells and their bone marrow microenvironment, strategies to battle AML by immunotherapy are under investigation. In the current review we describe the advances in immunotherapy for AML, with a focus on chimeric antigen receptor (CAR) T cell therapy. CARs constitute powerful immunologic modalities, with proven clinical success in B-Cell malignancies. We discuss the challenges and possible solutions for CAR T cell therapy development in AML, and examine the path currently being paved by preclinical and clinical efforts, from autologous to allogeneic products.
    Keywords:  acute myeloid leukemia; allogeneic; cancer immunotherapy; chimeric antigen receptor T cells; immune effector cell therapy
    DOI:  https://doi.org/10.3389/fonc.2021.800110
  6. mSystems. 2022 Jan 25. e0122321
      The effort to use nutrients as interventions to treat human disease has been important to medicine. A current example in this vein pertains to NAD+ boosters, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which are in many clinical trials in a variety of disease conditions. Independent laboratories have shown that ingested NR (or NMN) has mitigating effects on metabolic syndrome in mice. V. V. Lozada-Fernández, O. deLeon, S. L. Kellogg, F. L. Saravia, et al. (mSystems 7:e00230-21, 2022, https://doi.org/10.1128/mSystems.00230-21) show that NR shifts gut microbiome contents and that the transplantation of an NR-conditioned microbiome by fecal transfer reproduces some effects of NR in mice on a high-fat diet. The involvement of the gut microbiome as a factor in NR effects is linked to changes to the gut microbiome and its activity to transform NR and downstream catabolites. This commentary draws attention to these findings and focuses on some puzzling aspects of NAD+ boosters, exploring the still murky interactions between NAD+ metabolism, energy homeostasis, and the gut microbiome.
    Keywords:  NAD+; NAD+ metabolism; energy metabolism; metabolic syndrome; microbiome; nicotinamide riboside
    DOI:  https://doi.org/10.1128/msystems.01223-21
  7. Age Ageing. 2022 01 06. pii: afab189. [Epub ahead of print]51(1):
      Populations in Asian developed economies are rapidly ageing, such that, currently, Hong Kong and Japan have the longest life expectancy at birth for both men and women. However, extended lifespan is not necessarily accompanied by prolongation of health span, such that there is increasing prevalence of frailty and dependency, which translates into increase in complex health and social needs as well as increase in absolute numbers of older adults that require such needs. Consideration of social determinants of healthy ageing would be important in the design of equitable health and social care systems. There is a trend towards development of integrated medical social care in the community in Asian countries. Long-term care insurance and also philanthropic support play a role in the financing of such care models.
    Keywords:  Asia; community care; frailty; healthy ageing; life expectancy; social determinants
    DOI:  https://doi.org/10.1093/ageing/afab189
  8. Curr Opin Crit Care. 2022 Jan 25.
       PURPOSE OF REVIEW: To highlight recent findings on the evaluation and impact of frailty in the management of patients with traumatic brain injury (TBI).
    RECENT FINDINGS: Frailty is not a direct natural consequence of aging. Rather, it commonly results from the intersection of age-related decline with chronic diseases and conditions. It is associated with adverse outcomes such as institutionalization, falls, and worsening health status. Growing evidence suggests that frailty should be a key consideration both in care planning and in adverse outcome prevention. The prevalence of elderly patients with TBI is increasing, and low-energy trauma (i.e., ground or low-level falls, which are typical in frail patients) is the major cause. Establishing the real incidence of frailty in TBI requires further studies. Failure to detect frailty potentially exposes patients to interventions that may not benefit them, and may even harm them. Moreover, considering patients as 'nonfrail' purely on the basis of their age is unacceptable. The future challenge is to shift to a new clinical paradigm characterized by more appropriate, goal-directed care of frail patients.
    SUMMARY: The current review highlights the crucial importance of frailty evaluation in TBI, also given the changing epidemiology of this condition. To ensure adequate assessment, prevention and management, both in and outside hospital, there is an urgent need for a valid screening tool and a specific frailty-based and comorbidity-based clinical approach.
    DOI:  https://doi.org/10.1097/MCC.0000000000000915
  9. J Nutr Health Aging. 2022;26(1):26(1): 67-76
      As humans age, their immune system undergoes modifications, including a low-grade inflammatory status called inflammaging. These changes are associated with a loss of physical and immune resilience, amplifying the risk of being malnourished and frail. Under the COVID-19 scenario, inflammaging increases the susceptibility to poor prognostics. We aimed to bring the current concepts of inflammaging and its relationship with frailty and COVID-19 prognostic; highlight the importance of evaluating the nutritional risk together with frailty aiming to monitor older adults in COVID-19 scenario; explore some compounds with potential to modulate inflammaging in perspective to manage the COVID-19 infection. Substances such as probiotics and senolytics can help reduce the high inflammatory status. Also, the periodic evaluation of nutrition risk and frailty will allow interventions, assuring the appropriate care.
    Keywords:  COVID-19; diet; inflammaging; nutritional risk; probiotics; senolytics
    DOI:  https://doi.org/10.1007/s12603-021-1720-5
  10. Cochrane Database Syst Rev. 2022 01 26. 1 CD015308
       BACKGROUND: Interleukin-1 (IL-1) blocking agents have been used for treating severe coronavirus disease 2019 (COVID-19), on the premise that their immunomodulatory effect might be beneficial in people with COVID-19.
    OBJECTIVES: To assess the effects of IL-1 blocking agents compared with standard care alone or with placebo on effectiveness and safety outcomes in people with COVID-19. We will update this assessment regularly.
    SEARCH METHODS: We searched the Cochrane COVID-19 Study Register and the COVID-19 L-OVE Platform (search date 5 November 2021). These sources are maintained through regular searches of MEDLINE, Embase, CENTRAL, trial registers and other sources. We also checked the World Health Organization International Clinical Trials Registry Platform, regulatory agency websites, Retraction Watch (search date 3 November 2021).
    SELECTION CRITERIA: We included randomised controlled trials (RCTs) evaluating IL-1 blocking agents compared with standard care alone or with placebo for people with COVID-19, regardless of disease severity.
    DATA COLLECTION AND ANALYSIS: We followed Cochrane methodology. The protocol was amended to reduce the number of outcomes considered. Two researchers independently screened and extracted data and assessed the risk of bias with the Cochrane Risk of Bias 2 tool. We rated the certainty of evidence using the GRADE approach for the critical outcomes of clinical improvement (Day 28; ≥ D60); WHO Clinical Progression Score of level 7 or above (i.e. the proportion of participants with mechanical ventilation +/- additional organ support OR death) (D28; ≥ D60); all-cause mortality (D28; ≥ D60); incidence of any adverse events; and incidence of serious adverse events.
    MAIN RESULTS: We identified four RCTs of anakinra (three published in peer-reviewed journals, one reported as a preprint) and two RCTs of canakinumab (published in peer-reviewed journals). All trials were multicentre (2 to 133 centres). Two trials stopped early (one due to futility and one as the trigger for inferiority was met). The median/mean age range varied from 58 to 68 years; the proportion of men varied from 58% to 77%. All participants were hospitalised; 67% to 100% were on oxygen at baseline but not intubated; between 0% and 33% were intubated at baseline. We identified a further 16 registered trials with no results available, of which 15 assessed anakinra (four completed, four terminated, five ongoing, three not recruiting) and one (completed) trial assessed canakinumab. Effectiveness of anakinra for people with COVID-19 Anakinra probably results in little or no increase in clinical improvement at D28 (risk ratio (RR) 1.08, 95% confidence interval (CI) 0.97 to 1.20; 3 RCTs, 837 participants; absolute effect: 59 more per 1000 (from 22 fewer to 147 more); moderate-certainty evidence. The evidence is uncertain about an effect of anakinra on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.67, 95% CI 0.36 to 1.22; 2 RCTs, 722 participants; absolute effect: 55 fewer per 1000 (from 107 fewer to 37 more); low-certainty evidence) and ≥ D60 (RR 0.54, 95% CI 0.30 to 0.96; 1 RCT, 606 participants; absolute effect: 47 fewer per 1000 (from 72 fewer to 4 fewer) low-certainty evidence); and 2) all-cause mortality at D28 (RR 0.69, 95% CI 0.34 to 1.39; 2 RCTs, 722 participants; absolute effect: 32 fewer per 1000 (from 68 fewer to 40 more); low-certainty evidence).  The evidence is very uncertain about an effect of anakinra on 1) the proportion of participants with clinical improvement at ≥ D60 (RR 0.93, 95% CI 0.78 to 1.12; 1 RCT, 115 participants; absolute effect: 59 fewer per 1000 (from 186 fewer to 102 more); very low-certainty evidence); and 2) all-cause mortality at ≥ D60 (RR 1.03, 95% CI 0.68 to 1.56; 4 RCTs, 1633 participants; absolute effect: 8 more per 1000 (from 84 fewer to 147 more); very low-certainty evidence). Safety of anakinra for people with COVID-19 Anakinra probably results in little or no increase in adverse events (RR 1.02, 95% CI 0.94 to 1.11; 2 RCTs, 722 participants; absolute effect: 14 more per 1000 (from 43 fewer to 78 more); moderate-certainty evidence).  The evidence is uncertain regarding an effect of anakinra on serious adverse events (RR 0.95, 95% CI 0.58 to 1.56; 2 RCTs, 722 participants; absolute effect: 12 fewer per 1000 (from 104 fewer to 138 more); low-certainty evidence). Effectiveness of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in clinical improvement at D28 (RR 1.05, 95% CI 0.96 to 1.14; 2 RCTs, 499 participants; absolute effect: 42 more per 1000 (from 33 fewer to 116 more); moderate-certainty evidence).  The evidence of an effect of canakinumab is uncertain on 1) the proportion of participants with a WHO Clinical Progression Score of level 7 or above at D28 (RR 0.72, 95% CI 0.44 to 1.20; 2 RCTs, 499 participants; absolute effect: 35 fewer per 1000 (from 69 fewer to 25 more); low-certainty evidence); and 2) all-cause mortality at D28 (RR:0.75; 95% CI 0.39 to 1.42); 2 RCTs, 499 participants; absolute effect: 20 fewer per 1000 (from 48 fewer to 33 more); low-certainty evidence).  The evidence is very uncertain about an effect of canakinumab on all-cause mortality at ≥ D60 (RR 0.55, 95% CI 0.16 to 1.91; 1 RCT, 45 participants; absolute effect: 112 fewer per 1000 (from 210 fewer to 227 more); very low-certainty evidence). Safety of canakinumab for people with COVID-19 Canakinumab probably results in little or no increase in adverse events (RR 1.02; 95% CI 0.86 to 1.21; 1 RCT, 454 participants; absolute effect: 11 more per 1000 (from 74 fewer to 111 more); moderate-certainty evidence). The evidence of an effect of canakinumab on serious adverse events is uncertain (RR 0.80, 95% CI 0.57 to 1.13; 2 RCTs, 499 participants; absolute effect: 44 fewer per 1000 (from 94 fewer to 28 more); low-certainty evidence).
    AUTHORS' CONCLUSIONS: Overall, we did not find evidence for an important beneficial effect of IL-1 blocking agents. The evidence is uncertain or very uncertain for several outcomes. Sixteen trials of anakinra and canakinumab with no results are currently registered, of which four are completed, and four terminated. The findings of this review are updated on the COVID-NMA platform (covid-nma.com).
    DOI:  https://doi.org/10.1002/14651858.CD015308
  11. Aging Pathobiol Ther. 2020 Mar 27. 2(1): 58-61
      GHK (glycyl-L-histidyl-L-lysine) is a naturally occurring peptide found in human serum with levels averaging 200 ng/ml at age 20 but declining to an average of 80 ng/ml by age 60. The molecule has a very high affinity for copper and forms the chelate GHK-Cu. The peptide as well as its Cu (II) chelate have anti-inflammatory and tissue remodeling properties. GHK-Cu has been shown to promote skin remodeling, wound healing and regeneration, and has prominent antioxidant and anti-inflammatory effects in in vitro and in vivo studies. In addition, preliminary observations suggest GHK can partially reverse cognitive impairment in aging mice by targeting anti-inflammatory and epigenetic pathways. The evidence as presented provides the rationale to further investigate this naturally occurring peptide in preclinical and clinical aging studies.
    Keywords:  GHK peptide; GHK-Cu chelate; age-related cognitive impairment; anti-aging; anti-inflammatory; antioxidant
    DOI:  https://doi.org/10.31491/apt.2020.03.014
  12. Cold Spring Harb Perspect Med. 2022 Jan 24. pii: a041162. [Epub ahead of print]
      Endothelial cells (ECs) line all vessels of all vertebrates and are fundamental to organismal metabolism. ECs rely on their metabolism both to transport nutrients in and out of underlying parenchyma, and to support their own cellular activities, including angiogenesis. ECs primarily consume glucose, and much is known of how ECs transport and consume glucose and other carbohydrates. In contrast, how lipids are transported, and the role of lipids in normal EC function, has garnered less attention. We review here recent developments on the role of lipids in endothelial metabolism, with a focus on lipid uptake and transport in quiescent endothelium, and the use of lipid pathways during angiogenesis.
    DOI:  https://doi.org/10.1101/cshperspect.a041162
  13. Harefuah. 2022 Jan;161(1): 21-25
       INTRODUCTION: Geriatric oncology is the clinical field of cancer treatment in older adults (above 65 years) and in the oldest-old (above 80 years). As age is the most significant risk factor for cancer, and with the aging of the population, there is a vast increase in the number of older cancer patients.
    BACKGROUND: The cases highlight the unique challenges in geriatric oncology: disease goals may differ; treatment toxicities are higher; the extensive use of prescription medication increases the chances of harmful drug-drug interactions; finally, older adults have unique psychosocial needs. Cancer treatment in older adults poses a risk of under-treatment as well as a risk for over-treatment.
    DISCUSSION: 'Onco-geriatrics' is a field in geriatrics in which a comprehensive geriatric assessment (CGA) is performed. The CGA focuses on specific therapeutic challenges of the older patient, on frailty and on toxicity-risk assessment. In geriatric oncology, a field in oncology aimed at providing care to older cancer adults, the most important first step is to define treatment intent - cure or palliation. Achievement of cure usually mandates a multi-disciplinary aggressive approach. Compromising any component of the treatment may hamper its success rate, yet administering the full therapeutic plan may be too toxic. Thus, each older patient being considered for definitive treatment must be discussed in a multi-disciplinary tumor board, and preferably assessed by a dedicated geriatrician prior to decision-making. In cases in which treatment intent is palliative - i.e. prolongation of survival and/or improvement in quality of life, we propose the following scheme - accurate definition of the palliative goal; adaptation of the therapeutic regime to the patient's geriatric condition; frequent clinical monitoring and flexibility in administration; continued treatment as long as palliative benefit is achieved, and early cessation in its absence. Such a scheme maintains the principal of 'primum non nocere' while facilitating the palliative benefit for older adults.
  14. Hypertens Res. 2022 Jan 26.
      In older adults, functional decline, such as frailty and the need for nursing care, has a significant impact on quality of daily life (QOL) and life expectancy, and this is also true for older patients with hypertension. It has been shown that hypertensive patients with frailty or those in need of nursing care might be disadvantaged by conventional hypertension treatment according to the guidelines, while it is also known that inappropriate antihypertensive treatment may cause functional impairment. Therefore, in the management of older hypertensive patients, it is important to understand a patient's condition using functional assessments, such as a comprehensive geriatric assessment (CGA) or frailty assessments, and it is strongly recommended to determine the antihypertensive target and select the antihypertensive treatment according to the degree of functional impairment or frailty.
    Keywords:  Comprehensive geriatric assessment; Frailty; Functional impairment; Hypertension; Older adults
    DOI:  https://doi.org/10.1038/s41440-021-00846-4
  15. Aging Clin Exp Res. 2022 Jan 27.
       BACKGROUND: An area of extraordinary longevity (i.e., Sardinian Blue Zone) characterized by a very high prevalence of long-lived successful agers has been validated in Sardinia, an Italian island located in the Mediterranean Sea.
    AIMS: This study was primarily aimed at examining whether dietary habits (intake of vegetables and fruit, animal-derived proteins, and carbohydrates-rich food), time spent on hobbies, subjective physical health, and socio-cultural context (Sardinian Blue Zone vs. another Sardinian rural area) predicted self-reported depressive symptoms in older adults recruited in the Sardinian Blue Zone and another Sardinian rural area not being characterized by a higher prevalence of long-lived individuals.
    METHODS: Three hundred and eighteen community-dwellers, age 65 years and older, 188 females and 130 males (Mage = 79.1 years, SD = 6.9 years) were recruited from the Sardinian Blue Zone and another Sardinian rural area. Each participant individually completed a battery of instruments to assess lifestyle, food habits, perceived physical health, and depressive symptoms through the CES-D inventory.
    RESULTS: Significant associations were found between depressive signs, perceived physical health, time spent gardening, proteins, and carbohydrates intake, respectively. Approximately 17% of the variance in the CES-D condition was predicted by socio-cultural context, perceived physical health, and gardening. Participants recruited in the Sardinian Blue Zone spent more time gardening and self-reported better physical health.
    CONCLUSIONS: current results suggest that a socio-cultural context where people age well (i.e., the Sardinian Blue Zone), and a healthy and physically active lifestyle are crucial for promoting well-being in late adulthood.
    Keywords:  Aging; Blue zone; Depression; Longevity; Nutrition; Physical health
    DOI:  https://doi.org/10.1007/s40520-021-02068-7
  16. Eur J Nutr. 2022 Jan 24.
       PURPOSE: For decades, it has been customary to relate human health to the nutritional composition of foods, and from there was born food composition databases, composition labelling scores and the recommendation to eat varied foods. However, individuals can fully address their nutritional needs and become chronically ill. The nutrient balance of a food is only a small part of its overall health potential. In this paper, we discussed the proof of concept that the increased risk of chronic diseases worldwide is primarily associated with the degradation and artificialization of food matrices, rather than only their nutrient contents, based on the assumption that "food matrices govern the metabolic fate of nutrients".
    METHODS: An empirico-inductive proof of concept research design has been used, based on scientific data linking the degree of food processing, food matrices and human health, notably on the glycaemic index, nutrient bioavailability, satiety potential, and synergistic effects.
    RESULTS: We postulate that if the nutrient content is insufficient to fully characterize the diet-global health relationship, one other dimensions is necessary, i.e., the food matrix through the degree of processing. Both matrix and nutrient composition dimensions have been included under the new concept of the 3V index for Real (Vrai), Vegetal (Végétal), and Varied (Varié) foods. The Real metric, reflecting the integrity of the initial food matrix, is the most important, followed by the Vegetal (nutrient origin) and the Varied ("composition" effect) metrics.
    CONCLUSION: Concerning their effects on health, food matrix comes first, and then nutrient composition, and calorie quality matters more than calorie quantity.
    Keywords:  Chronic diseases; Food matrix; Food synergy; Nutrient contents; The 3 V index; Ultra-processed foods
    DOI:  https://doi.org/10.1007/s00394-021-02786-8
  17. Arch Gerontol Geriatr. 2022 Mar-Apr;99:pii: S0167-4943(22)00005-X. [Epub ahead of print]99 104624
      
    Keywords:  Healthy aging; Healthy longevity; Multidomain intervention
    DOI:  https://doi.org/10.1016/j.archger.2022.104624
  18. Mech Ageing Dev. 2022 Jan 20. pii: S0047-6374(22)00015-X. [Epub ahead of print]202 111633
      Aging is a process involving physiological changes that lead to the decline of biological functions of various tissues and organs of the body. Therefore, it is crucial to find anti-aging drugs that can intervene with the changes induced because of aging and slow down the degeneration of the biological functions. Among many signaling pathways linked with aging and aging-related diseases, PI3K-AKT signaling pathway has attracted major attention in aging biology. In this research paper, we have demonstrated that AKT inhibitor GSK690693 can extend lifespan in Drosophila irrespective of start of the treatment from the beginning of life or the mid-life. Effect of GSK690693 for lifespan extension has been primarily related to the improvements in oxidative resistance, intestinal integrity and increased autophagy, but not in physical activity or starvation resistance. Furthermore, GSK690693 treatment reduced the activation of AKT and ERK, consequently activating FOXO, GSK-3β and apoptosis to modulate longevity of flies. Remarkably, GSK690693 did not induce hyperglycemia after treatment. The results indicate that GSK690693 may become an effective compound for anti-aging intervention.
    Keywords:  AKT; Anti-aging; Autophagy; Drosophila; GSK690693
    DOI:  https://doi.org/10.1016/j.mad.2022.111633
  19. Blood Cancer J. 2022 Jan 25. 12(1): 10
      Preclinically, enasidenib and azacitidine (ENA + AZA) synergistically enhance cell differentiation, and venetoclax (VEN), a small molecule Bcl2 inhibitor (i) is particularly effective in IDH2 mutated acute myeloid leukemia (IDH2mutAML). This open label phase II trial enrolled patients (pts) with documented IDH2mutAML. All patients received AZA 75 mg/m2/d x 7 d/cycle and ENA 100 mg QD continuously. Concomitant Bcl2i and FLT3i were allowed (NCT03683433).Twenty-six pts received ENA + AZA (median 68 years, range, 24-88); 7 newly diagnosed (ND) and 19 relapsed/refractory (R/R). In R/R AML patients, three had received prior ENA and none had received prior VEN. The composite complete remission rate (CRc) [complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)] was 100% in ND AML, and 58% in R/R AML. Median OS was not reached in ND AML with median follow-up of 13.1 months (mo); Pts treated in first relapse had improved OS than those with ≥2 relapse (median OS not reached vs 5.2 mo; HR 0.24, 95% CI 0.07-0.79, p = 0.04). Two patients received ENA + AZA with a concomitant FLT3i, one responding ND AML patient and one nonresponding R/R AML patient. Seven R/R AML pts received ENA + AZA + VEN triplet, and with median follow up of 11.2 mo, median OS was not reached and 6-mo OS was 70%. The most frequent treatment-emergent adverse events include febrile neutropenia (23%). Adverse events of special interest included all-grade IDH differentiation syndrome (8%) and indirect hyperbilirubinemia (35%). ENA + AZA was a well-tolerated, and effective therapy for elderly pts with IDH2mut ND AML as well as pts with R/R AML. The addition of VEN to ENA + AZA appears to improve outcomes in R/R IDH2mutAML.Clinical trial registration information: https://clinicaltrials.gov/.NCT03683433.
    DOI:  https://doi.org/10.1038/s41408-021-00604-2
  20. Crit Care Med. 2022 Jan 26.
    CO-FRAIL Study Group and EPICCoV Study Group, for COVID HCFMUSP Study Group
       OBJECTIVES: As the pandemic advances, the interest in the long-lasting consequences of COVID-19 increases. However, a few studies have explored patient-centered outcomes in critical care survivors. We aimed to investigate frailty and disability transitions in COVID-19 patients admitted to ICUs.
    DESIGN: Prospective cohort study.
    SETTING: University hospital in Sao Paulo.
    PATIENTS: Survivors of COVID-19 ICU admissions.
    INTERVENTIONS: None.
    MEASUREMENTS AND MAIN RESULTS: We assessed frailty using the Clinical Frailty Scale (CFS). We also evaluated 15 basic, instrumental, and mobility activities. Baseline frailty and disability were defined by clinical conditions 2-4 weeks before COVID-19, and post-COVID-19 was characterized 90 days (day 90) after hospital discharge. We used alluvial flow diagrams to visualize transitions in frailty status, Venn diagrams to describe the overlap between frailty and disabilities in activities of daily living, and linear mixed models to explore the occurrence of new disabilities following critical care in COVID-19. We included 428 participants with a mean age of 64 years, 57% males, and a median Simplified Acute Physiology Score-3 score of 59. Overall, 14% were frail at baseline. We found that 124/394 participants (31%) were frail at day 90, 70% of whom were previously non-frail. The number of disabilities also increased (mean difference, 2.46; 95% CI, 2.06-2.86), mainly in participants who were non-frail before COVID-19. Higher pre-COVID-19 CFS scores were independently associated with new-onset disabilities. At day 90, 135 patients (34%) were either frail or disabled.
    CONCLUSIONS: Frailty and disability were more frequent 90 days after hospital discharge compared with baseline in COVID-19 patients admitted to the ICU. Our results show that most COVID-19 critical care survivors transition to poorer health status, highlighting the importance of long-term medical follow-up for this population.
    DOI:  https://doi.org/10.1097/CCM.0000000000005488
  21. Clin Transl Gastroenterol. 2022 Jan 12.
      The number of Americans 65 years or older in 2060 will be more than double what it was in 2014. Approximately 40% of patients seen in gastroenterology (GI) and hepatology practices in the United States are 60 years or older. Adapting care delivery models, curating data on shifting risk-benefit decisions with geriatric syndromes, understanding appropriate assessments, and focusing on tailored implementation strategies are challenges that are actively confronting us as we provide care for a burgeoning population of older adults. Limited availability of geriatric specialists results in an onus of specialists caring for older adults, such as gastroenterologists, to innovate and develop tailored, comprehensive, and evidence-based care for adults in later life stages. In this article, we present the 5M framework from geriatrics to achieve age-friendly healthcare. The 5Ms are medications, mind, mobility, multicomplexity, and what matters most. We apply the 5M framework to 2 chronic conditions commonly encountered in clinical GI practice: inflammatory bowel diseases and cirrhosis. We highlight knowledge gaps and outline future directions to expand evidence-based care and advance the creation of age-friendly GI care.
    DOI:  https://doi.org/10.14309/ctg.0000000000000445
  22. Nat Commun. 2022 01 25. 13(1): 446
      Following acute infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) a significant proportion of individuals develop prolonged symptoms, a serious condition termed post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) or long COVID. Predictors of PACS are needed. In a prospective multicentric cohort study of 215 individuals, we study COVID-19 patients during primary infection and up to one year later, compared to healthy subjects. We discover an immunoglobulin (Ig) signature, based on total IgM and IgG3 levels, which - combined with age, history of asthma bronchiale, and five symptoms during primary infection - is able to predict the risk of PACS independently of timepoint of blood sampling. We validate the score in an independent cohort of 395 individuals with COVID-19. Our results highlight the benefit of measuring Igs for the early identification of patients at high risk for PACS, which facilitates the study of targeted treatment and pathomechanisms of PACS.
    DOI:  https://doi.org/10.1038/s41467-021-27797-1
  23. Proc Natl Acad Sci U S A. 2022 Jan 25. pii: e2107742119. [Epub ahead of print]119(4):
      Proinflammatory cytokine production by innate immune cells plays a crucial role in inflammatory diseases, but the molecular mechanisms controlling the inflammatory responses are poorly understood. Here, we show that TANK-binding kinase 1 (TBK1) serves as a vital regulator of proinflammatory macrophage function and protects against tissue inflammation. Myeloid cell-conditional Tbk1 knockout (MKO) mice spontaneously developed adipose hypertrophy and metabolic disorders at old ages, associated with increased adipose tissue M1 macrophage infiltration and proinflammatory cytokine expression. When fed with a high-fat diet, the Tbk1-MKO mice also displayed exacerbated hepatic inflammation and insulin resistance, developing symptoms of nonalcoholic steatohepatitis. Furthermore, myeloid cell-specific TBK1 ablation exacerbates inflammation in experimental colitis. Mechanistically, TBK1 functions in macrophages to suppress the NF-κB and MAP kinase signaling pathways and thus attenuate induction of proinflammatory cytokines, particularly IL-1β. Ablation of IL-1 receptor 1 (IL-1R1) eliminates the inflammatory symptoms of Tbk1-MKO mice. These results establish TBK1 as a pivotal anti-inflammatory mediator that restricts inflammation in different disease models.
    Keywords:  TBK1; fatty liver disease; inflammation; macrophages; metabolic disorders
    DOI:  https://doi.org/10.1073/pnas.2107742119
  24. Evid Based Complement Alternat Med. 2022 ;2022 1368576
      This study was conducted to assess the effects and safety of Chinese herbal medicine (CHM) on blood lipids among adults with overweight or obesity. Fourteen bibliographic databases were comprehensively searched, from their respective inceptions up to April 2021, for randomised placebo-controlled weight-loss trials using CHM formulation on total cholesterol, triglycerides, LDL cholesterol, and HDL cholesterol over ≥4 weeks. Data collection, risk of bias assessment, and statistical analyses were guided by the Cochrane Handbook (v6.1). Continuous outcomes were expressed as the mean difference with 95% confidence intervals, and categorical outcomes were expressed as a risk ratio with 95% confidence intervals. All analyses were two-tailed with a statistical significance of p < 0.05. Fifteen eligible studies with 1,533 participants were included in this meta-analysis. Findings from meta-analyses indicated that CHM interventions, compared to placebo, reduced triglyceride (MD -0.21 mmol/L, 95% CI -0.41 to -0.02, I 2 = 81%) and increased HDL cholesterol (MD 0.16 mmol/L, 95% CI 0.04 to 0.27, I 2 = 94%) over a median of 12 weeks. The reduction in total cholesterol and LDL cholesterol were not statistically significant. Furthermore, the tendency of reduced triglycerides was identified among overweight participants with high baseline triglycerides. Attrition rates and frequency of adverse events were indifferent between the two groups. CHM may provide lipid-modulating benefits on triglycerides and HDL cholesterol among participants with overweight/obesity, with the tendency for significant triglyceride reduction observed among overweight participants with high baseline triglycerides. However, rigorously conducted randomised controlled trials with larger sample sizes are required to validate these findings.
    DOI:  https://doi.org/10.1155/2022/1368576