bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–07–18
34 papers selected by
Ayesh Seneviratne, University of Toronto
  1. Determination of Biological Age: Geriatric Assessment vs Biological Biomarkers.
  2. Growing and aging of hematopoietic stem cells.
  3. Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration.
  4. TNF-α-induced alterations in stromal progenitors enhance leukemic stem cell growth via CXCR2 signaling.
  5. [Thrombopoietin regulates mitochondria homeostasis for hematopoietic stem cell maintenance].
  6. Leukemogenesis via aberrant self-renewal by the MLL/AEP-mediated transcriptional activation system.
  7. Epigenetic regulation of drug metabolism in aging.
  8. Linking Tumor Microenvironment to Plasticity of Cancer Stem Cells: Mechanisms and Application in Cancer Therapy.
  9. The regulation of healthspan and lifespan by dietary amino acids.
  10. Local Anesthetic Lidocaine and Cancer: Insight Into Tumor Progression and Recurrence.
  11. Efficacy of mobile health cardiovascular risk-reduction strategies in cancer survivors.
  12. Can immune responses predict which vaccines work best?
  13. The Brain: Is it a Next Frontier to Better Understand the Regulation and Control of Hematopoiesis for Future Modulation and Treatment?
  14. Editorial: the new age of clinical research in clonal hematopoiesis and myeloid malignancies.
  15. Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease.
  16. Dietary thiols accelerate aging of C. elegans.
  17. Associations between inflammation, cardiovascular biomarkers and incident frailty: the British Regional Heart Study.
  18. Trajectories of frailty in aging: Prospective cohort study.
  19. Mulberry leaf powder regulates antioxidative capacity and lipid metabolism in finishing pigs.
  20. The impact of mitochondria on cancer treatment resistance.
  21. Prevalence and Incidence of Frailty Among Community-dwelling Older Adults in Slovenia.
  22. Herbal Plants: The Role of AhR in Mediating Immunomodulation.
  23. The role and therapeutic implication of CPTs in fatty acid oxidation and cancers progression.
  24. Age-related alterations and senescence of mesenchymal stromal cells: Implications for regenerative treatments of bones and joints.
  25. [Aging foot syndrome: patients screening and routing.]
  26. Short Telomeres and a T-Cell Shortfall in COVID-19: The Aging Effect.
  27. Tocilizumab Induces Rapid, Sustained Improvement of Inflammatory Markers in COVID-19, With Clinical Improvement in Most Patients.
  28. 100 years of insulin: celebrating the past, present and future of diabetes therapy.
  29. The therapeutic properties of ketogenic diets, slow-wave sleep, and circadian synchrony.
  30. 'Inflammation clock' can reveal body's biological age.
  31. Resveratrol Ameliorates High-Fat-Diet-Induced Abnormalities in Hepatic Glucose Metabolism in Mice via the AMP-Activated Protein Kinase Pathway.
  32. Telomere dysfunction instigates inflammation in inflammatory bowel disease.
  33. A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.
  34. Relationship between frailty and mortality after gastrectomy in older patients with gastric cancer.
  1. Curr Oncol Rep. 2021 Jul 16. 23(9): 104
    Determination of Biological Age: Geriatric Assessment vs Biological Biomarkers.
    Lucas W M Diebel, Kenneth Rockwood.
       PURPOSE OF REVIEW: Biological age is the concept of using biophysiological measures to more accurately determine an individual's age-related risk of adverse outcomes. Grading of the degree of frailty and measuring biomarkers are distinct methods of measuring biological age. This review compares these strategies for estimating biological age for clinical purposes.
    RECENT FINDINGS: The degree of frailty predicts susceptibility to adverse outcomes independently of chronological age. The utility of this approach has been demonstrated across a range of clinical contexts. Biomarkers from various levels of the biological aging process are improving in accuracy, with the potential to identify aberrant aging trajectories before the onset of clinically manifest frailty. Grading of frailty is a demonstrably, clinically, and research-relevant proxy estimate of biological age. Emerging biomarkers can supplement this approach by identifying accelerated aging before it is clinically apparent. Some biomarkers may even offer a means by which interventions to reduce the rate of aging can be developed.
    Keywords:  Aging; Biomarkers; Comprehensive geriatric assessment; Epigenetics; Frailty; Frailty index; Oncogeriatrics
    DOI:  https://doi.org/10.1007/s11912-021-01097-9
  2. World J Stem Cells. 2021 Jun 26. 13(6): 594-604
    Growing and aging of hematopoietic stem cells.
    Ion Udroiu, Antonella Sgura.
      In the hematopoietic system, a small number of stem cells produce a progeny of several distinct lineages. During ontogeny, they arise in the aorta-gonad-mesonephros region of the embryo and the placenta, afterwards colonise the liver and finally the bone marrow. After this fetal phase of rapid expansion, the number of hematopoietic stem cells continues to grow, in order to sustain the increasing blood volume of the developing newborn, and eventually reaches a steady-state. The kinetics of this growth are mirrored by the rates of telomere shortening in leukocytes. During adulthood, hematopoietic stem cells undergo a very small number of cell divisions. Nonetheless, they are subjected to aging, eventually reducing their potential to produce differentiated progeny. The causal relationships between telomere shortening, DNA damage, epigenetic changes, and aging have still to be elucidated.
    Keywords:  Bone marrow; Fetus; Growth and development; Hematopoietic stem cells; Leukemia; Liver
    DOI:  https://doi.org/10.4252/wjsc.v13.i6.594
  3. Nat Cell Biol. 2021 Jul;23(7): 704-717
    Chemotherapy-induced transposable elements activate MDA5 to enhance haematopoietic regeneration.
    Thomas Clapes, Aikaterini Polyzou, Pia Prater, Sagar, Antonio Morales-Hernández, Mariana Galvao Ferrarini, Natalie Kehrer, Stylianos Lefkopoulos, Veronica Bergo, Barbara Hummel, Nadine Obier, Daniel Maticzka, Anne Bridgeman, Josip S Herman, Ibrahim Ilik, Lhéanna Klaeylé, Jan Rehwinkel, Shannon McKinney-Freeman, Rolf Backofen, Asifa Akhtar, Nina Cabezas-Wallscheid, Ritwick Sawarkar, Rita Rebollo, Dominic Grün, Eirini Trompouki.
      Haematopoietic stem cells (HSCs) are normally quiescent, but have evolved mechanisms to respond to stress. Here, we evaluate haematopoietic regeneration induced by chemotherapy. We detect robust chromatin reorganization followed by increased transcription of transposable elements (TEs) during early recovery. TE transcripts bind to and activate the innate immune receptor melanoma differentiation-associated protein 5 (MDA5) that generates an inflammatory response that is necessary for HSCs to exit quiescence. HSCs that lack MDA5 exhibit an impaired inflammatory response after chemotherapy and retain their quiescence, with consequent better long-term repopulation capacity. We show that the overexpression of ERV and LINE superfamily TE copies in wild-type HSCs, but not in Mda5-/- HSCs, results in their cycling. By contrast, after knockdown of LINE1 family copies, HSCs retain their quiescence. Our results show that TE transcripts act as ligands that activate MDA5 during haematopoietic regeneration, thereby enabling HSCs to mount an inflammatory response necessary for their exit from quiescence.
    DOI:  https://doi.org/10.1038/s41556-021-00707-9
  4. Cell Rep. 2021 Jul 13. pii: S2211-1247(21)00784-1. [Epub ahead of print]36(2): 109386
    TNF-α-induced alterations in stromal progenitors enhance leukemic stem cell growth via CXCR2 signaling.
    Puneet Agarwal, Hui Li, Kwangmin Choi, Kathleen Hueneman, Jianbo He, Robert S Welner, Daniel T Starczynowski, Ravi Bhatia.
      Chronic myeloid leukemia (CML) is propagated by leukemia stem cells (LSCs) that are not eradicated by tyrosine kinase inhibitor (TKI) treatment and persist as a source of disease recurrence. Bone marrow (BM) mesenchymal niches play an essential role in hematopoietic stem cell (HSC) and LSC maintenance. Using a murine CML model, we examine leukemia-induced alterations in mesenchymal cell populations. We show that 6C3+ stromal progenitors expand in CML BM and exhibit increased LSC but reduced HSC supportive capacity. Tumor necrosis factor alpha (TNF-α) signaling mediates expansion and higher expression of CXCL1 in CML BM 6C3+ cells and higher expression of the CXCL1 receptor CXCR2 in LSCs. CXCL1 enhances LSC proliferation and self-renewal, whereas CXCR2 inhibition reduces LSC growth and enhances LSC targeting in combination with tyrosine kinase inhibitors (TKIs). We find that TNF-α-mediated alterations in CML BM stromal niches enhance support of LSC maintenance and growth via CXCL1-CXCR2 signaling and that CXCR2 inhibition effectively depletes CML LSCs.
    Keywords:  6C3; CML; CXCL1; CXCR2; TNF-α; bone marrow microenvironment; inflammation; leukemic stem cells
    DOI:  https://doi.org/10.1016/j.celrep.2021.109386
  5. Rinsho Ketsueki. 2021 ;62(5): 521-527
    [Thrombopoietin regulates mitochondria homeostasis for hematopoietic stem cell maintenance].
    Ayako Nakamura-Ishizu.
      Cell cycle quiescence is a fundamental property of hematopoietic stem cells (HSCs). Quiescent HSCs form a healthy pool of cells that serve as a reserve for massive HSC expansion under various conditions of stress. We previously reported that thrombopoietin (THPO) maintains quiescent HSCs and stimulates mitochondrial metabolism, megakaryocyte-lineage differentiation, and proliferation of HSCs. The underlying mechanism by which THPO balances its contradictory effect of promoting proliferation or quiescence on HSCs remains unknown. This review explores the role of THPO signaling in HSC differentiation and quiescence regulation. We present our data, which suggests that a THPO-independent HSC subpopulation sustaining a low mitochondrial metabolic profile reverts to quiescence and regains stem cell potential with external stimuli. There is a possibility that THPO-independent HSCs form a non-quiescent reserve HSC pool from which quiescent HSCs originate in the adult bone marrow.
    Keywords:  Hematopoietic stem cell; Mitochondria; Quiescence; Thrombopoietin
    DOI:  https://doi.org/10.11406/rinketsu.62.521
  6. Cancer Sci. 2021 Jul 12.
    Leukemogenesis via aberrant self-renewal by the MLL/AEP-mediated transcriptional activation system.
    Akihiko Yokoyama.
      Homeostasis of the hematopoietic system is achieved in a hierarchy, with hematopoietic stem cells at the pinnacle. Because only hematopoietic stem cells (HSCs) can self-renew, the size of the hematopoietic system is strictly controlled. In hematopoietic reconstitution experiments, one HSC can reconstitute the entire hematopoietic system, whereas 50 multipotent progenitors cannot. This indicates that only HSCs self-renew, whereas non-HSC hematopoietic progenitors are programmed to differentiate or senesce. Oncogenic mutations of the mixed lineage leukemia gene (MLL) overcome this "programmed differentiation" by conferring the self-renewing ability on non-HSC hematopoietic progenitors. In leukemia, mutated MLL proteins constitutively activate a broad range of previously transcribed CpG-rich promoters by an MLL-mediated transcriptional activation system. This system promotes self-renewal by replicating an expression profile similar to that of the mother cell in its daughter cells. In this transcriptional activation system, MLL binds to unmethylated CpG-rich promoters and recruits RNA polymerase II. MLL recruits p300/CBP through its transcriptional activation domain, which acetylates histone H3 at lysines 9, 18, and 27. The AF4 family/ENL family/P-TEFb complex (AEP) binds to acetylated H3K9/18/27 to activate transcription. Gene rearrangements of MLL with AEP- or CBP /p300-complex components generate constitutively active transcriptional machinery of this transcriptional activation system, which causes aberrant self-renewal of leukemia stem cells. Inhibitors of the components of this system effectively decrease their leukemogenic potential.
    Keywords:  Leukemia; molecular therapy; self-renewal; transcriptional machinery
    DOI:  https://doi.org/10.1111/cas.15054
  7. Aging (Albany NY). 2021 Jul 11. undefined(undefined):
    Epigenetic regulation of drug metabolism in aging.
    Joseph L McClay.
      
    Keywords:  DNA methylation; cytochrome P450; histones; liver; xenobiotic metabolism
    DOI:  https://doi.org/10.18632/aging.203312
  8. Front Oncol. 2021 ;11 678333
    Linking Tumor Microenvironment to Plasticity of Cancer Stem Cells: Mechanisms and Application in Cancer Therapy.
    Xiaobo Zheng, Chune Yu, Mingqing Xu.
      Cancer stem cells (CSCs) are a minority subset of cancer cells that can drive tumor initiation, promote tumor progression, and induce drug resistance. CSCs are difficult to eliminate by conventional therapies and eventually mediate tumor relapse and metastasis. Moreover, recent studies have shown that CSCs display plasticity that renders them to alter their phenotype and function. Consequently, the varied phenotypes result in varied tumorigenesis, dissemination, and drug-resistance potential, thereby adding to the complexity of tumor heterogeneity and further challenging clinical management of cancers. In recent years, tumor microenvironment (TME) has become a hotspot in cancer research owing to its successful application in clinical tumor immunotherapy. Notably, emerging evidence shows that the TME is involved in regulating CSC plasticity. TME can activate stemness pathways and promote immune escape through cytokines and exosomes secreted by immune cells or stromal cells, thereby inducing non-CSCs to acquire CSC properties and increasing CSC plasticity. However, the relationship between TME and plasticity of CSCs remains poorly understood. In this review, we discuss the emerging investigations on TME and CSC plasticity to illustrate the underlying mechanisms and potential implications in suppressing cancer progression and drug resistance. We consider that this review can help develop novel therapeutic strategies by taking into account the interlink between TME and CSC plasticity.
    Keywords:  cancer progression; cancer stem cell; plasticity; resistance; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2021.678333
  9. Transl Med Aging. 2021 ;5 17-30
    The regulation of healthspan and lifespan by dietary amino acids.
    Reji Babygirija, Dudley W Lamming.
      As a key macronutrient and source of essential macromolecules, dietary protein plays a significant role in health. For many years, protein-rich diets have been recommended as healthy due to the satiety-inducing and muscle-building effects of protein, as well as the ability of protein calories to displace allegedly unhealthy calories from fats and carbohydrates. However, clinical studies find that consumption of dietary protein is associated with an increased risk of multiple diseases, especially diabetes, while studies in rodents have demonstrated that protein restriction can promote metabolic health and even lifespan. Emerging evidence suggests that the effects of dietary protein on health and longevity are not mediated simply by protein quantity but are instead mediated by protein quality - the specific amino acid composition of the diet. Here, we discuss how dietary protein and specific amino acids including methionine, the branched chain amino acids (leucine, isoleucine, and valine), tryptophan and glycine regulate metabolic health, healthspan, and aging, with attention to the specific molecular mechanisms that may participate in these effects. Finally, we discuss the potential applicability of these findings to promoting healthy aging in humans.
    Keywords:  aging; amino acids; branched-chain amino acids; methionine; protein restriction
    DOI:  https://doi.org/10.1016/j.tma.2021.05.001
  10. Front Oncol. 2021 ;11 669746
    Local Anesthetic Lidocaine and Cancer: Insight Into Tumor Progression and Recurrence.
    Caihui Zhang, Cuiyu Xie, Yao Lu.
      Cancer is a leading contributor to deaths worldwide. Surgery is the primary treatment for resectable cancers. Nonetheless, it also results in inflammatory response, angiogenesis, and stimulated metastasis. Local anesthetic lidocaine can directly and indirectly effect different cancers. The direct mechanisms are inhibiting proliferation and inducing apoptosis via regulating PI3K/AKT/mTOR and caspase-dependent Bax/Bcl2 signaling pathways or repressing cytoskeleton formation. Repression invasion, migration, and angiogenesis through influencing the activation of TNFα-dependent, Src-induced AKT/NO/ICAM and VEGF/PI3K/AKT signaling pathways. Moreover, the indirect influences are immune regulation, anti-inflammation, and postoperative pain relief. This review summarizes the latest evidence that revealed potential clinical benefits of lidocaine in cancer treatment to explore the probable molecular mechanisms and the appropriate dose.
    Keywords:  cancer; lidocaine; metastasis; molecular mechanisms; recurrence; surgery; tumor
    DOI:  https://doi.org/10.3389/fonc.2021.669746
  11. Eur J Prev Cardiol. 2021 Jul 10. 28(7): e4-e6
    Efficacy of mobile health cardiovascular risk-reduction strategies in cancer survivors.
    Alexandra C Murphy, Anoop N Koshy, Johanna Mousley, Georgina Meehan, Phelia Kunniardy, David Clark, Leighton Kearney, Belinda Yeo, Omar Farouque, Matias B Yudi.
      
    DOI:  https://doi.org/10.1177/2047487320907548
  12. Science. 2021 07 09. 373(6551): 142-143
    Can immune responses predict which vaccines work best?
    Jon Cohen.
      
    DOI:  https://doi.org/10.1126/science.373.6551.142
  13. Stem Cell Rev Rep. 2021 Jul 13.
    The Brain: Is it a Next Frontier to Better Understand the Regulation and Control of Hematopoiesis for Future Modulation and Treatment?
    Hal E Broxmeyer, Karmen K Yoder, Yu-Chien Wu, Gary D Hutchins, Scott H Cooper, Sherif S Farag.
      We wish to suggest the possibility there is a link between the brain and hematopoiesis in the bone marrow and that in the future it may be possible to use such information for better understanding of the regulation of hematopoiesis, and for efficacious treatment of hematopoietic disorders.
    Keywords:  Brain; Brain Imaging; Hematopoiesis; Hematopoietic Stem and Progenitor Cells; Microenvironment; NeuroTransmitter; Neurons
    DOI:  https://doi.org/10.1007/s12015-021-10203-0
  14. Curr Opin Hematol. 2021 Jul 13.
    Editorial: the new age of clinical research in clonal hematopoiesis and myeloid malignancies.
    Borhane Guezguez.
      
    DOI:  https://doi.org/10.1097/MOH.0000000000000677
  15. N Engl J Med. 2021 07 15. 385(3): 228-238
    Ruxolitinib for Glucocorticoid-Refractory Chronic Graft-versus-Host Disease.
    REACH3 Investigators
       BACKGROUND: Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD.
    METHODS: This phase 3 open-label, randomized trial evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator's choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. The primary end point was overall response (complete or partial response) at week 24; key secondary end points were failure-free survival and improved score on the modified Lee Symptom Scale at week 24.
    RESULTS: A total of 329 patients underwent randomization; 165 patients were assigned to receive ruxolitinib and 164 patients to receive control therapy. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P = 0.001). The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was similar in the two groups.
    CONCLUSIONS: Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response. The incidence of thrombocytopenia and anemia was greater with ruxolitinib. (Funded by Novartis and Incyte; REACH3 ClinicalTrials.gov number, NCT03112603.).
    DOI:  https://doi.org/10.1056/NEJMoa2033122
  16. Nat Commun. 2021 07 15. 12(1): 4336
    Dietary thiols accelerate aging of C. elegans.
    Ivan Gusarov, Ilya Shamovsky, Bibhusita Pani, Laurent Gautier, Svetlana Eremina, Olga Katkova-Zhukotskaya, Alexander Mironov, Alexander А Makarov, Evgeny Nudler.
      Glutathione (GSH) is the most abundant cellular antioxidant. As reactive oxygen species (ROS) are widely believed to promote aging and age-related diseases, and antioxidants can neutralize ROS, it follows that GSH and its precursor, N-acetyl cysteine (NAC), are among the most popular dietary supplements. However, the long- term effects of GSH or NAC on healthy animals have not been thoroughly investigated. We employed C. elegans to demonstrate that chronic administration of GSH or NAC to young or aged animals perturbs global gene expression, inhibits skn-1-mediated transcription, and accelerates aging. In contrast, limiting the consumption of dietary thiols, including those naturally derived from the microbiota, extended lifespan. Pharmacological GSH restriction activates the unfolded protein response and increases proteotoxic stress resistance in worms and human cells. It is thus advantageous for healthy individuals to avoid excessive dietary antioxidants and, instead, rely on intrinsic GSH biosynthesis, which is fine-tuned to match the cellular redox status and to promote homeostatic ROS signaling.
    DOI:  https://doi.org/10.1038/s41467-021-24634-3
  17. Age Ageing. 2021 Jul 10. pii: afab143. [Epub ahead of print]
    Associations between inflammation, cardiovascular biomarkers and incident frailty: the British Regional Heart Study.
    Douglas G J McKechnie, A Olia Papacosta, Lucy T Lennon, Sheena E Ramsay, Peter H Whincup, S Goya Wannamethee.
       INTRODUCTION: cardiovascular disease (CVD) and chronic inflammation are implicated in the development of frailty. Longitudinal analyses of inflammatory markers, biomarkers of cardiac dysfunction and incidence of frailty are limited.
    METHODS: in the British Regional Heart Study, 1,225 robust or pre-frail men aged 71-92 years underwent a baseline examination, with questionnaire-based frailty assessment after 3 years. Frailty definitions were based on the Fried phenotype. Associations between incident frailty and biomarkers of cardiac dysfunction (high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro B-type natriuretic peptide (NT-proBNP)) and inflammation (C-reactive protein (CRP) and interleukin-6 (IL-6)) were examined, by tertile, with the lowest as reference.
    RESULTS: follow-up data were available for 981 men. Ninety one became frail. Adjusted for age, pre-frailty, prevalent and incident CVD, comorbidity, polypharmacy and socioeconomic status, IL-6 (third tertile OR 2.36, 95% CI 1.07-5.17) and hs-cTnT (third tertile OR 2.24, 95% CI 1.03-4.90) were associated with increased odds of frailty. CRP (third tertile OR 1.83, 95% CI 0.97-4.08) and NT-proBNP (second tertile OR 0.48, 95% CI 0.23-1.01) showed no significant association with incident frailty. The top tertiles of CRP, IL-6, hscTnT and NT-proBNP were strongly associated with mortality prior to follow-up.
    CONCLUSION: IL-6 is associated with incident frailty, supporting the prevailing argument that inflammation is involved in the pathogenesis of frailty. Cardiomyocyte injury may be associated with frailty risk. Associations between elevated CRP and frailty cannot be fully discounted; NT-proBNP may have a non-linear relationship with incident frailty. CRP, IL-6, hs-cTnT and NT-proBNP are vulnerable to survivorship bias.
    Keywords:  aging; biomarkers; frailty; inflammation; older people; pro-brain natriuretic peptide (1–76); troponin T
    DOI:  https://doi.org/10.1093/ageing/afab143
  18. PLoS One. 2021 ;16(7): e0253976
    Trajectories of frailty in aging: Prospective cohort study.
    Joe Verghese, Emmeline Ayers, Sanish Sathyan, Richard B Lipton, Sofiya Milman, Nir Barzilai, Cuiling Wang.
       BACKGROUND: Emerging evidence suggests that there is significant variability in the progression of frailty in aging. We aimed to identify latent subpopulations of frailty trajectories, and examine their clinical and biological correlates.
    METHODS: We characterized frailty using a 41-item cumulative deficit score at baseline and annual visits up to 12 years in 681 older adults (55% women, mean age 74·6 years). Clinical risk profile and walking while talking performance as a clinical marker of trajectories were examined. Mortality risk associated with trajectories was evaluated using Cox regression adjusted for established survival predictors, and reported as hazard ratios (HR). Proteome-wide analysis was done.
    FINDINGS: Latent class modeling identified 4 distinct frailty trajectories: relatively stable (34·4%) as well as mild (36·1%), moderate (24·1%) and severely frail (5·4%). Four distinct classes of frailty trajectories were also shown in an independent sample of 515 older adults (60% women, 68% White, 26% Black). The stable group took a median of 31 months to accumulate one additional deficit compared to 20 months in the severely frail group. The worst trajectories were associated with modifiable risk factors such as low education, living alone, obesity, and physical inactivity as well as slower walking while talking speed. In the pooled sample, mild (HR 2·33, 95% CI 1·30-4·18), moderate (HR 2·49, 95% CI 1·33-4·66), and severely frail trajectories (HR 5·28, 95% CI 2·68-10·41) had higher mortality compared to the stable group. Proteomic analysis showed 11 proteins in lipid metabolism and growth factor pathways associated with frailty trajectories.
    CONCLUSION: Frailty shows both stable and accelerated patterns in aging, which can be distinguished clinically and biologically.
    DOI:  https://doi.org/10.1371/journal.pone.0253976
  19. Anim Nutr. 2021 Jun;7(2): 421-429
    Mulberry leaf powder regulates antioxidative capacity and lipid metabolism in finishing pigs.
    Yingying Liu, Yinghui Li, Yi Xiao, Yinglin Peng, Jianhua He, Chen Chen, Dingfu Xiao, Yulong Yin, Fengna Li.
      This study evaluated the potential of mulberry leaf powder as an unconventional feed material for finishing pigs by assessing the growth performance, antioxidative properties, fatty acid profile, and lipid metabolism in 180 Xiangcun black pigs. Pigs with an initial body weight (BW) of 71.64 ± 1.46 kg were randomly assigned to 5 treatment groups, including the control diet and 4 experimental diets. The corn, soybean meal, and wheat bran in the control diet were partly replaced by 3%, 6%, 9%, or 12% mulberry leaf powder in experimental diets. There were 6 replicates (pens) of 6 pigs per replicate in each treatment. Blood and muscle samples were collected after the 50-day feed experiment. Compared with the control group, the 3%, 6%, and 9% mulberry diets had no adverse effect (P > 0.05) on the growth performance of pigs. The serum glutathione peroxidase activity and glutathione concentration increased linearly (P < 0.05) with the increase in dietary mulberry inclusion. There was no significant difference in the relative expression levels of antioxidant-related genes in muscle tissue between the control and mulberry groups. Inclusion of dietary mulberry powder increased (P < 0.05) the content of polyunsaturated fatty acids, especially in the longissimus dorsi (LD) muscle, up-regulated (P < 0.05) the relative mRNA expression level of uncoupling protein-3 in muscle tissue, but down-regulated (P < 0.05) the relative mRNA expression levels of hormone-sensitive lipase, acetyl CoA carboxylase α, lipoprotein lipase, and peroxisome proliferator-activated receptor γ in LD in a linear pattern. The nuclear respiratory factor 2 expression level in the LD muscle of pigs fed the 9% mulberry diet was higher (P < 0.01) than that in the other mulberry groups and control group. The inclusion of less than 12% dietary mulberry did not detrimentally affect the growth performance of Xiangcun black pigs, but enhanced the serum antioxidant property, increased the polyunsaturated fatty acid content, and inhibited lipid oxidation by regulating gene expression levels of lipid metabolism and mitochondrial uncoupling protein in muscle tissue. Mulberry leaves can be utilized as a forage crop in the diet of finishing pigs.
    Keywords:  Antioxidative capacity; Fatty acid; Lipid metabolism; Mulberry; Xiangcun black pig
    DOI:  https://doi.org/10.1016/j.aninu.2020.08.005
  20. Cell Oncol (Dordr). 2021 Jul 09.
    The impact of mitochondria on cancer treatment resistance.
    Michelle van der Merwe, Gustav van Niekerk, Carla Fourie, Manisha du Plessis, Anna-Mart Engelbrecht.
       BACKGROUND: The ability of cancer cells to develop treatment resistance is one of the primary factors that prevent successful treatment. Although initially thought to be dysfunctional in cancer, mitochondria are significant players that mediate treatment resistance. Literature indicates that cancer cells reutilize their mitochondria to facilitate cancer progression and treatment resistance. However, the mechanisms by which the mitochondria promote treatment resistance have not yet been fully elucidated.
    CONCLUSIONS AND PERSPECTIVES: Here, we describe various means by which mitochondria can promote treatment resistance. For example, mutations in tricarboxylic acid (TCA) cycle enzymes, i.e., fumarate hydratase and isocitrate dehydrogenase, result in the accumulation of the oncometabolites fumarate and 2-hydroxyglutarate, respectively. These oncometabolites may promote treatment resistance by upregulating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, inhibiting the anti-tumor immune response, or promoting angiogenesis. Furthermore, stromal cells can donate intact mitochondria to cancer cells after therapy to restore mitochondrial functionality and facilitate treatment resistance. Targeting mitochondria is, therefore, a feasible strategy that may dampen treatment resistance. Analysis of tumoral DNA may also be used to guide treatment choices. It will indicate whether enzymatic mutations are present in the TCA cycle and, if so, whether the mutations or their downstream signaling pathways can be targeted. This may improve treatment outcomes by inhibiting treatment resistance or promoting the effectiveness of anti-angiogenic agents or immunotherapy.
    Keywords:  2-Hydroxyglutarate; Fumarate; Mitochondria; Mitochondrial transfer; Treatment resistance
    DOI:  https://doi.org/10.1007/s13402-021-00623-y
  21. Zdr Varst. 2021 Sep;60(3): 190-198
    Prevalence and Incidence of Frailty Among Community-dwelling Older Adults in Slovenia.
    Janja Jazbar, Špela Pišek, Igor Locatelli, Mitja Kos.
       Introduction: Frailty is recognized as one of the most important global health challenges as the population is aging. The aim of this study was to evaluate prevalence and incidence of frailty, and associated factors, among the population of older adults in Slovenia compared to other European countries.
    Methods: The prevalence and 4-year incidence of frailty among older adults (≥65 years) were evaluated using data from the Survey of Health, Ageing and Retirement in Europe (SHARE). Frailty was defined by the SHARE operationalization of Frailty phenotype. Multiple logistic regression model was used to explore factors associated with frailty.
    Results: Age-standardized prevalence (95% CI) of frailty and pre-frailty in Slovenia were 14.9% (13.3-16.5) and 42.5% (39.8-45.2), respectively. Factors (OR, 95% CI) associated with increased frailty in Slovenia included age (7584 years: 5.03 (3.08-8.22); ≥85 years 21.7 (10.6-44.7) vs. 65-74 years), self-rated health (fair: 4.58 (2.75-7.61), poor: 54.6 (28.1-105.9) vs. excellent/very good/good), number of chronic diseases (1.20 (1.03-1.40)), and polypharmacy (yes: 3.25 (1.93-5.48) vs. no). Female gender and lower education were significantly associated with pre-frailty, but not frailty, in the adjusted model. Independently of these characteristics, age-standardized prevalence of frailty varied among geographical regions. Age-standardized 4-year incidence of frailty and pre-frailty in Slovenia were 6.6% (3.0-10.1) and 40.2% (32.7-47.6), respectively.
    Conclusion: Among the Slovenian population of older adults aged 65 years and older, the age-standardized prevalence of frailty is 15% and 4-year incidence of frailty is 7%. Regional differences in Slovenia show the lowest prevalence in central Slovenian regions and the highest in northeastern Slovenian regions.
    Keywords:  SHARE survey; frailty; incidence; older adults; prevalence
    DOI:  https://doi.org/10.2478/sjph-2021-0027
  22. Front Immunol. 2021 ;12 697663
    Herbal Plants: The Role of AhR in Mediating Immunomodulation.
    Izzah Bungsu, Nurolaini Kifli, Siti Rohaiza Ahmad, Hazim Ghani, Anne Catherine Cunningham.
      The prevalence of chronic inflammatory diseases including inflammatory bowel disease (IBD), autoimmunity and cancer have increased in recent years. Herbal-based compounds such as flavonoids have been demonstrated to contribute to the modulation of these diseases although understanding their mechanism of action remains limited. Flavonoids are able to interact with cellular immune components in a distinct way and influence immune responses at a molecular level. In this mini review, we highlight recent progress in our understanding of the modulation of immune responses by the aryl hydrocarbon receptor (AhR), a ligand-dependent transcription factor whose activity can be regulated by diverse molecules including flavonoids. We focus on the role of AhR in integrating signals from flavonoids to modulate inflammatory responses using in vitro and experimental animal models. We also summarize the limitations of these studies. Medicinal herbs have been widely used to treat inflammatory disorders and may offer a valuable therapeutic strategy to treat aberrant inflammatory responses by modulation of the AhR pathway.
    Keywords:  AhR; flavonoids; herbal plants; immune response; immunomodulatory
    DOI:  https://doi.org/10.3389/fimmu.2021.697663
  23. Am J Cancer Res. 2021 ;11(6): 2477-2494
    The role and therapeutic implication of CPTs in fatty acid oxidation and cancers progression.
    Junmin Wang, Hongjiao Xiang, Yifei Lu, Tao Wu, Guang Ji.
      Cancer cells must maintain metabolic homeostasis under a wide range of conditions and meet their own energy needs in order to survive and reproduce. In addition to glycolysis, cancer cells can also perform various metabolic strategies, such as fatty acid oxidation (FAO). It has been found that the proliferation, survival, drug resistance and metastasis of cancer cells depend on FAO. The carnitine palmitoyltransferase (CPT), including CPT1 and CPT2, located on the mitochondrial membrane, are important mediators of FAO. In recent years, many researchers have found that CPT has a close relationship with the metabolic development of tumor cells, not only provides energy for cancer cells development and metastasis by promoting FAO but also affects the occurrence and invasion through other signal pathways or cytokines or microRNA. This review summarized the role of CPTs in several kinds of tumors and the developed targeted inhibitors of CPTs, as well as the potential gene therapy and immunotherapy of CPTs, hoping to better explore the mechanism and role of CPTs in the future and providing useful ideas for clinical treatment.
    Keywords:  CPT1; CPT2; FAO; cancers; inhibitors
  24. Mech Ageing Dev. 2021 Jul 06. pii: S0047-6374(21)00111-1. [Epub ahead of print] 111539
    Age-related alterations and senescence of mesenchymal stromal cells: Implications for regenerative treatments of bones and joints.
    Janja Zupan, Klemen Strazar, Roland Kocijan, Thomas Nau, Johannes Grillari, Darja Marolt Presen.
      The most common clinical manifestations of age-related musculoskeletal degeneration are osteoarthritis and osteoporosis, and these represent an enormous burden on modern society. Mesenchymal stromal cells (MSCs) have pivotal roles in musculoskeletal tissue development. In adult organisms, MSCs retain their ability to regenerate tissues following bone fractures, articular cartilage injuries, and other traumatic injuries of connective tissue. However, their remarkable regenerative ability appears to be impaired through aging, and in particular in age-related diseases of bones and joints. Here, we review age-related alterations of MSCs in musculoskeletal tissues, and address the underlying mechanisms of aging and senescence of MSCs. Furthermore, we focus on the properties of MSCs in osteoarthritis and osteoporosis, and how their changes contribute to onset and progression of these disorders. Finally, we consider current treatments that exploit the enormous potential of MSCs for tissue regeneration, as well as for innovative cell-free extracellular-vesicle-based and anti-aging treatment approaches.
    Keywords:  Aging; Mesenchymal stromal cells; Osteoarthritis; Osteoporosis; Senescence
    DOI:  https://doi.org/10.1016/j.mad.2021.111539
  25. Adv Gerontol. 2021 ;34(2): 293-299
    [Aging foot syndrome: patients screening and routing.]
    S G Gorelik, A N Ilnitski, K I Prashchayeu, O A Osipova, E S Butikova, E V Fesenko.
      The article proves that when providing medical and social care to patients of older age groups, it is advisable to pay attention not only to the patients' somatic and geriatric status, but also to perform screening of local geriatric syndromes that affect the patients' functional status, such as, in particular, aging foot syndrome. Implementation of rehabilitation treatment measures that we propose allows to maintain the patients' mobility level and consequently their general functional capability level and quality of life.
    Keywords:  aging foot syndrome; general geriatric syndromes; local geriatric syndromes; rehabilitation treatment; screening
  26. medRxiv. 2021 Jul 10. pii: 2021.05.19.21257474. [Epub ahead of print]
    Short Telomeres and a T-Cell Shortfall in COVID-19: The Aging Effect.
    James J Anderson, Ezra Susser, Konstantin G Arbeev, Anatoliy I Yashin, Daniel Levy, Simon Verhulst, Abraham Aviv.
      The slow pace of global vaccination and the rapid emergence of SARS-CoV-2 variants suggest recurrent waves of COVID-19 in coming years. Therefore, understanding why deaths from COVID-19 are highly concentrated among older adults is essential for global health. Severe COVID-19 T-cell lymphopenia is more common among older adults, and it entails poor prognosis. Much about the primary etiology of this form of lymphopenia remains unknown, but regardless of its causes, offsetting the decline in T-cell count during SARS-CoV-2 infection demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent. We have built a model that captures the effect of age-dependent TL shortening in hematopoietic cells and its effect on T-cell clonal expansion capacity. The model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity plummets by more than 90% over the next ten years. The collapse coincides with the steep increase in COVID-19 mortality with age. HCTL metrics may thus explain the vulnerability of older adults to COVID-19. That said, the wide inter-individual variation in HCTL across the general population means that some younger adults with inherently short HCTL might be at risk of severe COVID-19 lymphopenia and mortality from the disease.
    Significance Statement: Declining immunity with advancing age is a general explanation for the increased mortality from COVID-19 among older adults. This mortality far exceeds that from viral illnesses such as the seasonal influenza, and it thus requires specific explanations. One of these might be diminished ability with age to offset the development of severe T-cell lymphopenia (a low T-cell count in the blood) that often complicates COVID-19. We constructed a model showing that age-dependent shortening of telomeres might constrain the ability of T-cells of some older COVID-19 patients to undertake the massive proliferation required to clear the virus that causes the infection. The model predicts that individuals with short telomeres, principally seniors, might be at a higher risk of death from COVID-19.
    DOI:  https://doi.org/10.1101/2021.05.19.21257474
  27. Am J Ther. 2021 Jul 05.
    Tocilizumab Induces Rapid, Sustained Improvement of Inflammatory Markers in COVID-19, With Clinical Improvement in Most Patients.
    Scott J Morin, Chinmay Jani, Arashdeep Rupal, Harpreet Singh, Daniel Bourque, Robert C Colgrove.
      
    DOI:  https://doi.org/10.1097/MJT.0000000000001412
  28. Nat Med. 2021 Jul;27(7): 1154-1164
    100 years of insulin: celebrating the past, present and future of diabetes therapy.
    Emily K Sims, Alice L J Carr, Richard A Oram, Linda A DiMeglio, Carmella Evans-Molina.
      The year 2021 marks the centennial of Banting and Best's landmark description of the discovery of insulin. This discovery and insulin's rapid clinical deployment effectively transformed type 1 diabetes from a fatal diagnosis into a medically manageable chronic condition. In this Review, we describe key accomplishments leading to and building on this momentous occasion in medical history, including advancements in our understanding of the role of insulin in diabetes pathophysiology, the molecular characterization of insulin and the clinical use of insulin. Achievements are also viewed through the lens of patients impacted by insulin therapy and the evolution of insulin pharmacokinetics and delivery over the past 100 years. Finally, we reflect on the future of insulin therapy and diabetes treatment, as well as challenges to be addressed moving forward, so that the full potential of this transformative discovery may be realized.
    DOI:  https://doi.org/10.1038/s41591-021-01418-2
  29. Curr Opin Endocrinol Diabetes Obes. 2021 Jul 15.
    The therapeutic properties of ketogenic diets, slow-wave sleep, and circadian synchrony.
    L Amber O'Hearn.
       PURPOSE OF REVIEW: To summarize emerging connections between sleep, ketogenic diets, and health.
    RECENT FINDINGS: Mechanisms involved in the therapeutic benefits of ketogenic diets continue to be elucidated. Concurrently, the importance of sleep quality and circadian rhythms in their effects on metabolic and cognitive health is increasingly appreciated. Advances in the understanding of the actions of adenosine, nicotinamide adenine dinucleotide, and slow-wave sleep underscore connections between these areas of research.
    SUMMARY: Many molecular pathways activated during ketogenic diets are known to modulate sleep-wake cycles, circadian rhythms, and sleep stages. Ketogenic diets often have beneficial effects on sleep at the same time as having beneficial effects on particular medical conditions. Enhancement of slow-wave sleep and rejuvenation of circadian programming may be synergistic with or causally involved in the benefits of ketogenic diets.
    DOI:  https://doi.org/10.1097/MED.0000000000000660
  30. Nature. 2021 Jul 13.
    'Inflammation clock' can reveal body's biological age.
    Max Kozlov.
      
    Keywords:  Ageing; Health care; Immunology; Machine learning
    DOI:  https://doi.org/10.1038/d41586-021-01915-x
  31. Evid Based Complement Alternat Med. 2021 ;2021 6616906
    Resveratrol Ameliorates High-Fat-Diet-Induced Abnormalities in Hepatic Glucose Metabolism in Mice via the AMP-Activated Protein Kinase Pathway.
    Caiping Lu, Hanying Xing, Linquan Yang, Kaiting Chen, Linyi Shu, Xiaojian Zhao, Guangyao Song.
      Diabetes mellitus is highly prevalent worldwide. High-fat-diet (HFD) consumption can lead to liver fat accumulation, impair hepatic glycometabolism, and cause insulin resistance and the development of diabetes. Resveratrol has been shown to improve the blood glucose concentration of diabetic mice, but its effect on the abnormal hepatic glycometabolism induced by HFD-feeding and the mechanism involved are unknown. In this study, we determined the effects of resveratrol on the insulin resistance of high-fat-diet-fed mice and a hepatocyte model by measuring serum biochemical indexes, key indicators of glycometabolism, glucose uptake, and glycogen synthesis in hepatocytes. We found that resveratrol treatment significantly ameliorated the HFD-induced abnormalities in glucose metabolism in mice, increased glucose absorption and glycogen synthesis, downregulated protein phosphatase 2A (PP2A) and activated Ca2+/CaM-dependent protein kinase kinase β (CaMKKβ), and increased the phosphorylation of AMP-activated protein kinase (AMPK). In insulin-resistant HepG2 cells, the administration of a PP2A activator or CaMKKβ inhibitor attenuated the effects of resveratrol, but the administration of an AMPK inhibitor abolished the effects of resveratrol. Resveratrol significantly ameliorates abnormalities in glycometabolism induced by HFD-feeding and increases glucose uptake and glycogen synthesis in hepatocytes. These effects are mediated through the activation of AMPK by PP2A and CaMKKβ.
    DOI:  https://doi.org/10.1155/2021/6616906
  32. Proc Natl Acad Sci U S A. 2021 Jul 20. pii: e2024853118. [Epub ahead of print]118(29):
    Telomere dysfunction instigates inflammation in inflammatory bowel disease.
    Deepavali Chakravarti, Rumi Lee, Asha S Multani, Andrea Santoni, Zachery Keith, Wen-Hao Hsu, Kyle Chang, Laura Reyes, Asif Rashid, Chang-Jiun Wu, Jun Li, Jiexin Zhang, Hong Seok Shim, Krishna Chandra, Pingna Deng, Denise J Spring, Ole Haagen Nielsen, Lene Buhl Riis, Kavya Kelagere Mayigegowda, Sarah E Blutt, Jianhua Zhang, Mamoun Younes, Andrew DuPont, Selvi Thirumurthi, Eduardo Vilar, Mary K Estes, Simona Colla, Noah F Shroyer, Ronald A DePinho.
      Inflammatory bowel disease (IBD) is a chronic inflammatory condition driven by diverse genetic and nongenetic programs that converge to disrupt immune homeostasis in the intestine. We have reported that, in murine intestinal epithelium with telomere dysfunction, DNA damage-induced activation of ataxia-telangiectasia mutated (ATM) results in ATM-mediated phosphorylation and activation of the YAP1 transcriptional coactivator, which in turn up-regulates pro-IL-18, a pivotal immune regulator in IBD pathogenesis. Moreover, individuals with germline defects in telomere maintenance genes experience increased occurrence of intestinal inflammation and show activation of the ATM/YAP1/pro-IL-18 pathway in the intestinal epithelium. Here, we sought to determine the relevance of the ATM/YAP1/pro-IL-18 pathway as a potential driver of IBD, particularly older-onset IBD. Analysis of intestinal biopsy specimens and organoids from older-onset IBD patients documented the presence of telomere dysfunction and activation of the ATM/YAP1/precursor of interleukin 18 (pro-IL-18) pathway in the intestinal epithelium. Employing intestinal organoids from healthy individuals, we demonstrated that experimental induction of telomere dysfunction activates this inflammatory pathway. In organoid models from ulcerative colitis and Crohn's disease patients, pharmacological interventions of telomerase reactivation, suppression of DNA damage signaling, or YAP1 inhibition reduced pro-IL-18 production. Together, these findings support a model wherein telomere dysfunction in the intestinal epithelium can initiate the inflammatory process in IBD, pointing to therapeutic interventions for this disease.
    Keywords:  DNA damage; Yap1; inflammatory bowel disease; pro-IL-18; telomere dysfunction
    DOI:  https://doi.org/10.1073/pnas.2024853118
  33. Blood Adv. 2021 Jul 13. 5(13): 2740-2750
    A phase 2 trial of the histone deacetylase inhibitor panobinostat for graft-versus-host disease prevention.
    Lia Perez, Hugo Fernandez, Mohamed Kharfan-Dabaja, Farhad Khimani, Brian Betts, Asmita Mishra, Ernesto Ayala, Frederick L Locke, Leonel Ochoa-Bayona, Michael Nieder, Joseph Pidala, Alex Achille, John Powers, Eva Sahakian, Ram Thapa, Xuefeng Wang, Claudio Anasetti.
      Immunomodulatory properties of histone deacetylase inhibitors represent a reasonable approach for acute graft-versus-host disease (aGVHD) prevention. We report a phase 2 trial evaluating panobinostat (PANO) administered over 26 weeks, starting on day -5 (5 mg orally 3 times a week) with tacrolimus initiated on day -3 plus sirolimus on day -1, with a median patient age of 58 years (range, 19-72 years) (n = 38). Donor source consisted of HLA 8/8-matched donors, related (n = 13) or unrelated (n = 25), using granulocyte colony-stimulating factor-stimulated peripheral blood stem cells. Myeloablative (n = 18) or reduced-intensity (n = 20) conditioning regimens were used for patients with acute myeloid leukemia (n = 17), myelodysplastic syndrome (n = 13), or other malignancies (n = 8). The cumulative incidence of aGVHD II-IV by day 100 was 18.4% (90% confidence interval [CI], 9.4% to 29.9%). Cumulative incidence of chronic GVHD at 1 year was 31.6% (90% CI, 19.5% to 44.3%). Adverse events related to PANO were thrombocytopenia (n = 5), leukopenia (n = 6), gastrointestinal toxicity (n = 3), rash (n = 4), renal failure/peripheral edema (n = 1), and periorbital edema (n = 1). At 1 year, overall survival was 89.5% (90% CI, 81.6% to 98.0%), relapse-free survival was 78.9% (90% CI, 68.8% to 90.6%), nonrelapse mortality was 2.6% (90% CI, 0.3% to 9.9%), and GVHD relapse-free survival was 60.5% (90% CI, 48.8% to 75.1%). PANO hits histone 3 as early as day 15 in CD8, CD4 and T regs. In conclusion, PANO combination met the primary study end point for aGVHD prevention and warrants further testing. This trial was registered at www.clinicaltrials.gov as #NCT02588339.
    DOI:  https://doi.org/10.1182/bloodadvances.2021004225
  34. J Geriatr Oncol. 2021 Jul 13. pii: S1879-4068(21)00158-2. [Epub ahead of print]
    Relationship between frailty and mortality after gastrectomy in older patients with gastric cancer.
    Ju-Ri Jeong, Ji-Won Choi, Seong-Yeob Ryu, Yu-Ri Choe.
       OBJECTIVES: Frail older adults with gastric cancer are at an increased risk of poor postoperative outcomes. We assessed whether geriatric frailty assessed using the Study of Osteoporotic Fractures (SOF) index could predict post-gastrectomy mortality.
    MATERIALS AND METHODS: We retrospectively assessed older adults (age ≥ 65 years) who underwent gastrectomy for gastric cancer between April 2012 and September 2015. Frailty status was assessed using the SOF index (range, 0-3) and categorized as robust (0), pre-frail (1), and frail (2-3). The Kaplan-Meier method and log-rank tests were used to compare survival between frailty groups. Univariate and multivariate analyses were used to identify mortality-associated risk factors.
    RESULTS: Among 231 patients (the median age 72.04 years and 140 (60.6%) men), 138 (59.7%) were robust, 58 (25.1%) were pre-frail, and 35 (15.2%) were frail. The mortality rate was 14.5% among robust patients, 20.7% among pre-frail patients, and 20.0% among frail patients (log-rank test, P = 0.032). Frail patients had more than a 3-fold increased risk of mortality compared with robust patients (adjusted HR = 3.331; 95% CI, 1.161-9.559). Multivariate analysis revealed that the SOF index and TNM stage were associated with increased mortality.
    CONCLUSIONS: SOF index predicted post-gastrectomy mortality among older patients independently of age, sex, TNM stage, type of approach, gastrectomy type, and extent of lymph node dissection. SOF index may be used with ease to assess frailty status among older patients with gastric cancer in busy clinics and subgroups that may benefit from targeted frailty interventions before cancer treatments.
    Keywords:  Frailty; Gastric cancer; Mortality; SOF index
    DOI:  https://doi.org/10.1016/j.jgo.2021.06.010
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