bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021‒01‒10
fifty-eight papers selected by
Ayesh Seneviratne
University of Toronto

  1. Aging Med (Milton). 2020 Dec;3(4): 266-275
    Wang C, Chen B, Feng Q, Nie C, Li T.
      As percentages of elderly people rise in many societies, age-related diseases have become more prevalent than ever. Research interests have been shifting to delaying age-related diseases by delaying or reversing aging itself. We use metformin as an entry point to talk about the important molecular and genetic longevity-regulating mechanisms that have been extensively studied with it. Then we review a number of observational studies, animal studies, and clinical trials to reflect the clinical potentials of the mechanisms in lifespan extension, cardiovascular diseases, tumors, and neurodegeneration. Finally, we highlight remaining concerns that are related to metformin and future anti-aging research.
    Keywords:  aging; clinical pharmacology; longevity; metformin
  2. Int J Mol Med. 2020 Nov 25.
    Sun X, Wang Z, Cong X, Lv Y, Li Z, Rong L, Yang T, Yu D.
      The mitochondria have been proven to be involved in processes of aging; however, the mechansims through which mitoepigenetics affect the cytological behaviors of cardiomyocytes during the aging process are not yet fully understood. In the present study, two senescence models were constructed, replicative senescence (RS) and stress‑induced premature senescence (SIPS), using human heart mesenchymal stem cells (HMSCs). First, the differences in age‑related gene expression levels and telomere length were compared between the HMSCs in the RS and SIPS models by PCR. Subsequently, protein expression and the mitochondrial DNA (mtDNA) methylation status of cytochrome c oxidase subunit II (COX2) was measured by western blot analysis and bisulfite genomic sequencing (BSP). Finally, the value of the DNA methyltransferase (Dnmt) inhibitor, 5‑aza‑2'‑deoxycytidine (AdC), in delaying the senescence of HMSCs was evaluated. It was found that the p16, p27 and p53 mRNA expression levels increased in the senescent cells, whereas p21 mRNA expression did not. It was also found that telomere shortening only occurred in the RS model, but not in the SIPS model. Along with the senescence of HMSCs, COX2 gene methylation increased and its protein expression level significantly decreased. It was demonstrated that AdC inhibited COX2 methylation and downregulated COX2 expression. The addition of exogenous COX2 or the administration of AdC promoted cell proliferation and delayed cell aging. On the whole, the present study demonstrates that COX2 methylation and downregulation are biomarkers of HMSC senescence. Thus, COX2 may have potential for use as a therapeutic target of cardiovascular diseases and this warrants further investigation.
  3. J Cell Mol Med. 2021 Jan 04.
    Moncan M, Mnich K, Blomme A, Almanza A, Samali A, Gorman AM.
      The endoplasmic reticulum (ER) is the site of protein folding and secretion, Ca2+ storage and lipid synthesis in eukaryotic cells. Disruption to protein folding or Ca2+ homeostasis in the ER leads to the accumulation of unfolded proteins, a condition known as ER stress. This leads to activation of the unfolded protein response (UPR) pathway in order to restore protein homeostasis. Three ER membrane proteins, namely inositol-requiring enzyme 1 (IRE1), protein kinase RNA-like ER kinase (PERK) and activating transcription factor 6 (ATF6), sense the accumulation of unfolded/misfolded proteins and are activated, initiating an integrated transcriptional programme. Recent literature demonstrates that activation of these sensors can alter lipid enzymes, thus implicating the UPR in the regulation of lipid metabolism. Given the presence of ER stress and UPR activation in several diseases including cancer and neurodegenerative diseases, as well as the growing recognition of altered lipid metabolism in disease, it is timely to consider the role of the UPR in the regulation of lipid metabolism. This review provides an overview of the current knowledge on the impact of the three arms of the UPR on the synthesis, function and regulation of fatty acids, triglycerides, phospholipids and cholesterol.
    Keywords:  PRKR-like endoplasmic reticulum kinase; activating transcription factor 6; cholesterol; endoplasmic reticulum; fatty acid; inositol-requiring enzyme 1; lipid metabolism; phospholipid; triglyceride; unfolded protein response
  4. Leukemia. 2021 Jan 07.
    Benmebarek MR, Cadilha BL, Herrmann M, Lesch S, Schmitt S, Stoiber S, Darwich A, Augsberger C, Brauchle B, Rohrbacher L, Oner A, Seifert M, Schwerdtfeger M, Gottschlich A, Rataj F, Fenn NC, Klein C, Subklewe M, Endres S, Hopfner KP, Kobold S.
      Targeted T cell therapy is highly effective in disease settings where tumor antigens are uniformly expressed on malignant cells and where off-tumor on-target-associated toxicity is manageable. Although acute myeloid leukemia (AML) has in principle been shown to be a T cell-sensitive disease by the graft-versus-leukemia activity of allogeneic stem cell transplantation, T cell therapy has so far failed in this setting. This is largely due to the lack of target structures both sufficiently selective and uniformly expressed on AML, causing unacceptable myeloid cell toxicity. To address this, we developed a modular and controllable MHC-unrestricted adoptive T cell therapy platform tailored to AML. This platform combines synthetic agonistic receptor (SAR) -transduced T cells with AML-targeting tandem single chain variable fragment (scFv) constructs. Construct exchange allows SAR T cells to be redirected toward alternative targets, a process enabled by the short half-life and controllability of these antibody fragments. Combining SAR-transduced T cells with the scFv constructs resulted in selective killing of CD33+ and CD123+ AML cell lines, as well as of patient-derived AML blasts. Durable responses and persistence of SAR-transduced T cells could also be demonstrated in AML xenograft models. Together these results warrant further translation of this novel platform for AML treatment.
  5. Neurochem Res. 2021 Jan 02.
    Vetrovoy O, Stratilov V, Nimiritsky P, Makarevich P, Tyulkova E.
      Prenatal hypoxia is among leading causes of progressive brain pathologies in postnatal life. This study aimed to analyze the characteristics of the hippocampal glutamatergic system and behavior of rats in early (2 weeks), adult (3 months) and advanced (18 months) postnatal ontogenesis after exposure to prenatal severe hypoxia (PSH, 180 Torr, 5% O2, 3 h) during the critical period in the formation of the hippocampus (days 14-16 of gestation). We have shown an age-dependent progressive decrease in the hippocampal glutamate levels, a decrease of the neuronal cell number in the CA1 hippocampal region, as well as impairment of spatial long-term memory in the Morris water navigation task. The gradual decrease of glutamate was accompanied by decreased expression of the genes that mediate glutamate metabolism and recycling in the hippocampus. That deficiency apparently correlated with an increase of the metabotropic glutamate receptor type 1 (mGluR1) and synaptophysin expression. Generation of the lipid peroxidation products in the hippocampus of adult rats subjected to prenatal severe hypoxia (PSH rats) was not increased compared to the control animals when tested in a model of glutamate excitotoxicity induced by severe hypoxia. This demonstrates that excessive glutamate sensitivity in PSH rats does not compensate for glutamate deficiency. Our results show a significant contribution of the glutamate system dysfunction to age-associated decrease of this mediator, cognitive decline, and early neuronal loss in PSH rats.
    Keywords:  Cognitive decline; Glutamate system; Hippocampus; Neuronal loss; Premature aging; Prenatal severe hypoxia
  6. Diabetol Metab Syndr. 2021 Jan 06. 13(1): 3
    Yari Z, Naser-Nakhaee Z, Karimi-Shahrbabak E, Cheraghpour M, Hedayati M, Mohaghegh SM, Ommi S, Hekmatdoost A.
      BACKGROUND: Regarding the increasing prevalence of cardiometabolic abnormalities, and its association with non-communicable chronic diseases, providing preventive and therapeutic strategies is a priority. A randomized placebo-controlled study was conducted to assess the effects of combination therapy of milled brown flaxseed and hesperidin during lifestyle intervention on controlling cardiovascular risk in prediabetes.METHODS: A total of forty-eight subjects were randomly assigned to receive lifestyle intervention plus combination therapy of brown flaxseed (30 g milled) and hesperidin (two 500 mg capsules) or lifestyle modification alone for 12 weeks. Changes from baseline in anthropometric measures, lipid profile and atherogenic indices, glucose homeostasis parameters, and inflammatory biomarkers was assessed as a primary end point.
    RESULTS: Anthropometric data comparison between the two groups showed a significant reduction in weight (p = 0.048). Waist circumference reduction was about twice that of the control group (- 6.75 cm vs - 3.57 cm), but this difference was not statistically significant. Comparison of blood pressure changes throughout the study indicated a greater reduction in blood pressure in the intervention group rather than control group (- 5.66 vs. - 1.56 mmHg, P = 0.049). Improvements of lipid profile and atherogenic indices, glucose homeostasis parameters, and inflammatory biomarkers in flaxseed-hesperidin group was significantly more than the control group after 12 weeks of intervention (p < 0.05).
    CONCLUSION: Our results indicate that co-administration of flaxseed and hesperidin as an adjunct to lifestyle modification program is more effective than lifestyle modification alone in the metabolic abnormalities remission of prediabetic patients.
    TRIAL REGISTRATION:  The trial was registered with, number NCT03737422. Registered 11 November 2018. Retrospectively registered, .
    Keywords:  cardiometabolic; flaxseed; hesperidin; lifestyle modification; prediabetes
  7. Precis Clin Med. 2020 Dec;3(4): 245-259
    Liu T, Gatto NM, Chen Z, Qiu H, Lee G, Duerksen-Hughes P, Fraser G, Wang C.
      A long-term vegetarian diet plays a role in the longevity and maintenance of the healthspan, but the underlying mechanisms for these observations are largely unknown. Particularly, it is not known whether a long-term vegetarian dietary pattern may affect the circulating miRNA expression in such a way as to modulate the healthspan. The Adventist Health Study-2 (AHS-2) cohort includes a large number of older adults who primarily follow vegetarian dietary patterns and reside in Loma Linda, California, one of five "Blue Zones" in the world in which a higher proportion of the population enjoys a longer than average lifespan. We performed miRNA-seq in 96 subjects selected from the AHS-2 cohort with different dietary patterns. We identified several differentially expressed miRNAs between vegetarians and non-vegetarians, which are involved in immune response and cytokine signaling, cell growth and proliferation as well as age-related diseases such as cardiovascular diseases and neurodegenerative diseases. Overall, our study showed that a vegetarian diet modulates aging-associated circulating miRNAs in a sex-dependent manner of differential expression for certain miRNAs, which may be related in a beneficial manner to the healthspan. Further investigation is needed to validate these miRNAs as potential biomarkers for diet-modulated longevity in humans.
    Keywords:  Blue Zone; aging; circulating miRNA; miRNA sequencing; vegetarian diet
  8. Cell Rep. 2021 Jan 05. pii: S2211-1247(20)31568-0. [Epub ahead of print]34(1): 108579
    Murakami K, Kurotaki D, Kawase W, Soma S, Fukuchi Y, Kunimoto H, Yoshimi R, Koide S, Oshima M, Hishiki T, Hayakawa N, Matsuura T, Oda M, Yanagisawa K, Kobayashi H, Haraguchi M, Atobe Y, Funakoshi K, Iwama A, Takubo K, Okamoto S, Tamura T, Nakajima H.
      O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT) is a unique enzyme introducing O-GlcNAc moiety on target proteins, and it critically regulates various cellular processes in diverse cell types. However, its roles in hematopoietic stem and progenitor cells (HSPCs) remain elusive. Here, using Ogt conditional knockout mice, we show that OGT is essential for HSPCs. Ogt is highly expressed in HSPCs, and its disruption induces rapid loss of HSPCs with increased reactive oxygen species and apoptosis. In particular, Ogt-deficient hematopoietic stem cells (HSCs) lose quiescence, cannot be maintained in vivo, and become vulnerable to regenerative and competitive stress. Interestingly, Ogt-deficient HSCs accumulate defective mitochondria due to impaired mitophagy with decreased key mitophagy regulator, Pink1, through dysregulation of H3K4me3. Furthermore, overexpression of PINK1 restores mitophagy and the number of Ogt-deficient HSCs. Collectively, our results reveal that OGT critically regulates maintenance and stress response of HSCs by ensuring mitochondrial quality through PINK1-dependent mitophagy.
    Keywords:  O-GlcNAcylation; O-linked N-acetylglucosamine transferase; OGT; PINK1; hematopoietic progenitor cell; hematopoietic stem cell; mitochondria; mitophagy
  9. NPJ Aging Mech Dis. 2021 Jan 04. 7(1): 1
    Aon MA, Cortassa S, Juhaszova M, González-Reyes JA, Calvo-Rubio M, Villalba JM, Lachance AD, Ziman BD, Mitchell SJ, Murt KN, Axsom JEC, Alfaras I, Britton SL, Koch LG, de Cabo R, Lakatta EG, Sollott SJ.
      The intrinsic aerobic capacity of an organism is thought to play a role in aging and longevity. Maximal respiratory rate capacity, a metabolic performance measure, is one of the best predictors of cardiovascular- and all-cause mortality. Rats selectively bred for high-(HCR) vs. low-(LCR) intrinsic running-endurance capacity have up to 31% longer lifespan. We found that positive changes in indices of mitochondrial health in cardiomyocytes (respiratory reserve, maximal respiratory capacity, resistance to mitochondrial permeability transition, autophagy/mitophagy, and higher lipids-over-glucose utilization) are uniformly associated with the extended longevity in HCR vs. LCR female rats. Cross-sectional heart metabolomics revealed pathways from lipid metabolism in the heart, which were significantly enriched by a select group of strain-dependent metabolites, consistent with enhanced lipids utilization by HCR cardiomyocytes. Heart-liver-serum metabolomics further revealed shunting of lipidic substrates between the liver and heart via serum during aging. Thus, mitochondrial health in cardiomyocytes is associated with extended longevity in rats with higher intrinsic exercise capacity and, probably, these findings can be translated to other populations as predictors of outcomes of health and survival.
  10. J Clin Invest. 2021 Jan 04. pii: 140177. [Epub ahead of print]131(1):
    Capitano ML, Mohamad SF, Cooper S, Guo B, Huang X, Gunawan AM, Sampson C, Ropa J, Srour EF, Orschell CM, Broxmeyer HE.
      Bone marrow (BM) hematopoietic stem cells (HSCs) become dysfunctional during aging (i.e., they are increased in number but have an overall reduction in long-term repopulation potential and increased myeloid differentiation) compared with young HSCs, suggesting limited use of old donor BM cells for hematopoietic cell transplantation (HCT). BM cells reside in an in vivo hypoxic environment yet are evaluated after collection and processing in ambient air. We detected an increase in the number of both young and aged mouse BM HSCs collected and processed in 3% O2 compared with the number of young BM HSCs collected and processed in ambient air (~21% O2). Aged BM collected and processed under hypoxic conditions demonstrated enhanced engraftment capability during competitive transplantation analysis and contained more functional HSCs as determined by limiting dilution analysis. Importantly, the myeloid-to-lymphoid differentiation ratio of aged BM collected in 3% O2 was similar to that detected in young BM collected in ambient air or hypoxic conditions, consistent with the increased number of common lymphoid progenitors following collection under hypoxia. Enhanced functional activity and differentiation of old BM collected and processed in hypoxia correlated with reduced "stress" associated with ambient air BM collection and suggests that aged BM may be better and more efficiently used for HCT if collected and processed under hypoxia so that it is never exposed to ambient air O2.
    Keywords:  Aging; Bone marrow transplantation; Hematology; Hematopoietic stem cells; hypoxia
  11. Clin Nutr. 2020 Dec 21. pii: S0261-5614(20)30697-X. [Epub ahead of print]
    Tappy L.
      BACKGROUND &AIMS: Dietary sugars are absorbed in the hepatic portal circulation as glucose, fructose, or galactose. The gut and liver are required to process fructose and galactose into glucose, lactate, and fatty acids. A high sugar intake may favor the development of cardio-metabolic diseases by inducing Insulin resistance and increased concentrations of triglyceride-rich lipoproteins.METHODS: A narrative review of the literature regarding the metabolic effects of fructose-containing sugars.
    RESULTS: Sugars' metabolic effects differ from those of starch mainly due to the fructose component of sucrose. Fructose is metabolized in a set of fructolytic cells, which comprise small bowel enterocytes, hepatocytes, and kidney proximal tubule cells. Compared to glucose, fructose is readily metabolized in an insulin-independent way, even in subjects with diabetes mellitus, and produces minor increases in glycemia. It can be efficiently used for energy production, including during exercise. Unlike commonly thought, fructose when ingested in small amounts is mainly metabolized to glucose and organic acids in the gut, and this organ may thus shield the liver from potentially deleterious effects.
    CONCLUSIONS: The metabolic functions of splanchnic organs must be performed with homeostatic constraints to avoid exaggerated blood glucose and lipid concentrations, and thus to prevent cellular damages leading to non-communicable diseases. Excess fructose intake can impair insulin-induced suppression of glucose production, stimulate de novo lipogenesis, and increase intrahepatic and blood triglyceride concentrations. With chronically high fructose intake, enterocyte can switch to lipid synthesis and accumulation of triglyceride, possibly causing an enterocyte dysfunction.
    Keywords:  Enterocyte; Fructose; Gluconeogenesis; Hepatocyte; Intrahepatic fat concentration; de novo lipogenesis
  12. J Pharmacol Exp Ther. 2021 Jan 07. pii: JPET-AR-2020-000187. [Epub ahead of print]
    Poll BG, Xu J, Jun S, Sanchez J, Zaidman N, He X, Lester L, Berkowitz D, Paolocci N, Gao WD, Pluznick J.
      Short-chain fatty acids (SCFAs) are metabolites produced almost exclusively by the gut microbiota and are an essential mechanism by which gut microbes influence host physiology. Given that SCFAs induce vasodilation, we hypothesized that they might have additional cardiovascular effects. In this study, novel mechanisms of SCFA action were uncovered by examining the acute effects of SCFAs on cardiovascular physiology in vivo and ex vivo Acute delivery of SCFAs in conscious radiotelemetry implanted mice results in a simultaneous decrease in both mean arterial pressure and heart rate. Inhibition of sympathetic tone by the selective β-1 adrenergic receptor antagonist atenolol blocks the acute drop in HR seen with acetate administration, yet the decrease in mean arterial pressure persists. Treatment with tyramine, an indirect sympathomimetic, also blocks the acetate-induced acute drop in HR. Langendorff preparations show that acetate lowers HR only after long term exposure and at a smaller magnitude than seen in vivo. Pressure-volume loops after acetate injection show a decrease in load-independent measures of cardiac contractility. Isolated trabecular muscle preparations also show a reduction in force generation upon SCFA treatment, though only at supraphysiological concentrations. These experiments demonstrate a direct cardiac component of the SCFA cardiovascular response. These data show that acetate affects blood pressure and cardiac function through parallel mechanisms and establish a role for SCFAs in modulating sympathetic tone and cardiac contractility. These results further advance our understanding of the role of SCFAs in blood pressure regulation. Significance Statement Acetate, a short-chain fatty acid, acutely lowers HR as well as MAP in vivo in radiotelemetry implanted mice. Acetate is acting in a sympatholytic manner on HR and exerts negative inotropic effects in vivo This work has implications for potential short-chain fatty acid therapeutics as well as gut dysbiosis-related disease states.
    Keywords:  acetate; blood pressure; heart/cardiac
  13. Ageing Res Rev. 2020 Dec 31. pii: S1568-1637(20)30385-8. [Epub ahead of print]66 101250
    Zhou H, Ren J, Toan S, Mui D.
      Myocardial infarction (MI) is the irreversible death of cardiomyocyte secondary to prolonged lack of oxygen or fresh blood supply. Historically considered as merely cardiomyocyte powerhouse that manufactures ATP and other metabolites, mitochondrion is recently being identified as a signal regulator that is implicated in the crosstalk and signal integration of cardiomyocyte contraction, metabolism, inflammation, and death. Mitochondria quality surveillance is an integrated network system modifying mitochondrial structure and function through the coordination of various processes including mitochondrial fission, fusion, biogenesis, bioenergetics, proteostasis, and degradation via mitophagy. Mitochondrial fission favors the elimination of depolarized mitochondria through mitophagy, whereas mitochondrial fusion preserves the mitochondrial network upon stress through integration of two or more small mitochondria into an interconnected phenotype. Mitochondrial biogenesis represents a regenerative program to replace old and damaged mitochondria with new and healthy ones. Mitochondrial bioenergetics is regulated by a metabolic switch between glucose and fatty acid usage, depending on oxygen availability. To maintain the diversity and function of mitochondrial proteins, a specialized protein quality control machinery regulates protein dynamics and function through the activity of chaperones and proteases, and induction of the mitochondrial unfolded protein response. In this review, we provide an overview of the molecular mechanisms governing mitochondrial quality surveillance and highlight the most recent preclinical and clinical therapeutic approaches to restore mitochondrial fitness during both MI and post-MI heart failure.
    Keywords:  Fission; Fusion; Mitochondrial quality surveillance; Mitophagy; Myocardial infarction; Proteostasis
  14. Front Oncol. 2020 ;10 537930
    Mukha A, Dubrovska A.
      Most human tumors possess a high heterogeneity resulting from both clonal evolution and cell differentiation program. The process of cell differentiation is initiated from a population of cancer stem cells (CSCs), which are enriched in tumor-regenerating and tumor-propagating activities and responsible for tumor maintenance and regrowth after treatment. Intrinsic resistance to conventional therapies, as well as a high degree of phenotypic plasticity, makes CSCs hard-to-target tumor cell population. Reprogramming of CSC metabolic pathways plays an essential role in tumor progression and metastatic spread. Many of these pathways confer cell adaptation to the microenvironmental stresses, including a shortage of nutrients and anti-cancer therapies. A better understanding of CSC metabolic dependences as well as metabolic communication between CSCs and the tumor microenvironment are of utmost importance for efficient cancer treatment. In this mini-review, we discuss the general characteristics of CSC metabolism and potential metabolic targeting of CSC populations as a potent strategy to enhance the efficacy of conventional treatment approaches.
    Keywords:  OXPHOS; cancer stem cells; fatty acid metabolism; glutamine metabolism; glycolysis; metabolic targeting; therapy resistance; tumor microenvironment
  15. Aging (Albany NY). 2020 Dec 19. 12
    Lo CJ, Ko YS, Chang SW, Tang HY, Huang CY, Huang YC, Ho HY, Lin CM, Cheng ML.
      To identify the association between metabolites and muscle mass in 305 elderly Taiwanese subjects, we conducted a multivariate analysis of 153 plasma samples. Based on appendicular skeletal muscle mass index (ASMI) quartiles, female and male participants were divided into four groups. Quartile 4 (Men: 5.67±0.35, Women: 4.70±0.32 Kg/m2) and quartile 1 (Men: 7.60±0.29, Women: 6.56±0.53 Kg/m2) represented low muscle mass and control groups, respectively. After multivariable adjustment, except for physical function, we found that blood urea nitrogen, creatinine, and age were associated with ASMI in men. However, only triglyceride level was related to ASMI in women. The multiple logistic regression models were used to analyze in each baseline characteristic and metabolite concentration. After the adjustment, we identify amino acid-related metabolites and show that glutamate levels in women and alpha-aminoadipate, Dopa, and citrulline/ornithine levels in men are gender-specific metabolic signatures of muscle mass loss.
    Keywords:  amino acid-related metabolites; elderly; metabolomics; muscle mass loss; sarcopenia
  16. Physiol Rep. 2021 Jan;9(1): e14673
    Mann G, Adegoke OAJ.
      Branched-chain amino acids (BCAAs) are regulators of protein metabolism. However, elevated levels of BCAAs and their metabolites are linked to insulin resistance. We previously demonstrated that the leucine metabolite, α-ketoisocaproate (KIC), inhibited insulin-stimulated glucose transport in myotubes. Like KIC, inflammatory factors are implicated in the development of insulin resistance. Here, we analyzed the effect of KIC and inflammatory factors (homocysteine [50 μM], TNF-α [10 ng/ml], and interleukin 6 (IL-6) [10 ng/ml]) on myotubes. Although KIC suppressed insulin-stimulated glucose transport, addition of the inflammatory factors did not worsen this effect. Depletion of branched-chain aminotransferase 2, the enzyme that catalyzes the conversion of leucine into KIC, abrogated the effect of KIC and the inflammatory factors. The effect of insulin on AKTS473 and S6K1T389 phosphorylation was not modified by treatments. There were no treatment effects on glycogen synthase phosphorylation. Depletion of E1α subunit of branched-chain α-keto acid dehydrogenase, the enzyme that catalyzes the oxidative decarboxylation of KIC, suppressed insulin-stimulated glucose transport, especially in cells incubated in KIC. Thus, defects in BCAA catabolism are contributory to insulin resistance of glucose transport in myotubes, especially in the presence of KIC. Interventions that increase BCAA catabolism may promote muscle glucose utilization and improve insulin resistance and its sequelae.
    Keywords:  BCAAs; BCAT2; BCKD; insulin resistance; insulin sensitivity; skeletal muscle
  17. Aging (Albany NY). 2021 Jan 06. 12
    Yoon KJ, Ahn A, Park SH, Kwak SH, Kwak SE, Lee W, Yang YR, Kim M, Shin HM, Kim HR, Moon HY.
      Although several evidence has suggested the impact of exercise on the prevention of aging phenotypes, few studies have been conducted on the mechanism by which exercise alters the immune-cell profile, thereby improving metabolism in senile obesity. In this study, we confirmed that 4-week treadmill exercise sufficiently improved metabolic function, including increased lean mass and decreased fat mass, in 88-week-old mice. The expression level of the senescence marker p16 in the white adipose tissue (WAT) was decreased after 4-weeks of exercise. Exercise induced changes in the profiles of immune-cell subsets, including natural killer (NK) cells, central memory CD8+ T cells, eosinophils, and neutrophils, in the stromal vascular fraction of WAT. In addition, it has been shown through transcriptome analysis of WAT that exercise can activate pathways involved in the interaction between WAT and immune cells, in particular NK cells, in aged mice. These results suggest that exercise has a profound effect on changes in immune-cell distribution and senescent-cell scavenging in WAT of aged mice, eventually affecting overall energy metabolism toward a more youthful state.
    Keywords:  NK cell; aging; exercise; immunosenescence; metabolism
  18. Cell Rep. 2021 Jan 05. pii: S2211-1247(20)31586-2. [Epub ahead of print]34(1): 108597
    Chen P, Hsu WH, Han J, Xia Y, DePinho RA.
      Cancer stem cells (CSCs) are self-renewing cells that facilitate tumor initiation, promote metastasis, and enhance cancer therapy resistance. Transcriptomic analyses across many cancer types have revealed a prominent association between stemness and immune signatures, potentially implying a biological interaction between such hallmark features of cancer. Emerging experimental evidence has substantiated the influence of CSCs on immune cells, including tumor-associated macrophages, myeloid-derived suppressor cells, and T cells, in the tumor microenvironment and, reciprocally, the importance of such immune cells in sustaining CSC stemness and its survival niche. This review covers the cellular and molecular mechanisms underlying the symbiotic interactions between CSCs and immune cells and how such heterotypic signaling maintains a tumor-promoting ecosystem and informs therapeutic strategies intercepting this co-dependency.
    Keywords:  T cells; cancer stem cell; immunity; immunotherapy; myeloid-derived suppressor cells; stemness; symbiotic interaction; tumor-associated macrophages
  19. Ann Geriatr Med Res. 2020 Dec;24(4): 232-242
    Yalcin G, Lee CK.
      Caloric restriction (CR) has been shown to extend the lifespan of many species. Research to identify compounds that imitate the results of CR has shown extensions of both lifespan and healthspan via different mechanisms. For example, mechanistic target of rapamycin (mTOR) inhibitors such as rapamycin, phenols, and flavonoids show antioxidant characteristics, while spermidine induces autophagy. Herein, we summarize research progress and proposed mechanisms for the most well-known compounds showing lifespan-extending potential for anti-aging characteristics.
    Keywords:   Anti-aging; Lifespan extension; Caloric restriction mimetics
  20. Cancer Metab. 2021 Jan 07. 9(1): 2
    Nagarajan SR, Butler LM, Hoy AJ.
      Tumor cellular metabolism exhibits distinguishing features that collectively enhance biomass synthesis while maintaining redox balance and cellular homeostasis. These attributes reflect the complex interactions between cell-intrinsic factors such as genomic-transcriptomic regulation and cell-extrinsic influences, including growth factor and nutrient availability. Alongside glucose and amino acid metabolism, fatty acid metabolism supports tumorigenesis and disease progression through a range of processes including membrane biosynthesis, energy storage and production, and generation of signaling intermediates. Here, we highlight the complexity of cellular fatty acid metabolism in cancer, the various inputs and outputs of the intracellular free fatty acid pool, and the numerous ways that these pathways influence disease behavior.
    Keywords:  Cellular membrane; De novo synthesis; Fatty acid; Lipid; Lipid droplets; Mitochondria; Oxidation; Peroxisome
  21. N Engl J Med. 2021 01 07. pii: 10.1056/NEJMc2032806#sa2. [Epub ahead of print]384(1): 93-94
    Anderson MS, Chaimowitz NS, Forbes LR.
  22. N Engl J Med. 2021 01 07. 384(1): 11-19
    Farag SS, Abu Zaid M, Schwartz JE, Thakrar TC, Blakley AJ, Abonour R, Robertson MJ, Broxmeyer HE, Zhang S.
      BACKGROUND: Dipeptidyl peptidase 4 (DPP-4; also known as CD26), a transmembrane receptor expressed on T cells, has a costimulatory function in activating T cells. In a mouse model, down-regulation of CD26 prevented graft-versus-host disease (GVHD) but preserved graft-versus-tumor effects. Whether inhibition of DPP-4 with sitagliptin may prevent acute GVHD after allogeneic stem-cell transplantation is not known.METHODS: We conducted a two-stage, phase 2 clinical trial to test whether sitagliptin plus tacrolimus and sirolimus would reduce the incidence of grade II to IV acute GVHD from 30% to no more than 15% by day 100. Patients received myeloablative conditioning followed by mobilized peripheral-blood stem-cell transplants. Sitagliptin was given orally at a dose of 600 mg every 12 hours starting the day before transplantation until day 14 after transplantation.
    RESULTS: A total of 36 patients who could be evaluated, with a median age of 46 years (range, 20 to 59), received transplants from matched related or unrelated donors. Acute GVHD occurred in 2 of 36 patients by day 100; the incidence of grade II to IV GVHD was 5% (95% confidence interval [CI], 1 to 16), and the incidence of grade III or IV GVHD was 3% (95% CI, 0 to 12). Nonrelapse mortality was zero at 1 year. The 1-year cumulative incidences of relapse and chronic GVHD were 26% (95% CI, 13 to 41) and 37% (95% CI, 22 to 53), respectively. GVHD-free, relapse-free survival was 46% (95% CI, 29 to 62) at 1 year. Toxic effects were similar to those seen in patients undergoing allogeneic stem-cell transplantation.
    CONCLUSIONS: In this nonrandomized trial, sitagliptin in combination with tacrolimus and sirolimus resulted in a low incidence of grade II to IV acute GVHD by day 100 after myeloablative allogeneic hematopoietic stem-cell transplantation. (Funded by the National Heart, Lung, and Blood Institute; number, NCT02683525.).
  23. Cancer Res. 2021 Jan 07. pii: canres.1504.2020. [Epub ahead of print]
    Ding H, Vincelette ND, McGehee CD, Kohorst MA, Koh BD, Venkatachalam A, Meng XW, Schneider PA, Flatten KS, Peterson KL, Correia C, Lee SH, Patnaik M, Webster JA, Ghiaur G, Smith BD, Karp JE, Pratz KW, Li H, Karnitz LM, Kaufmann SH.
      Although inhibitors of the kinases CHK1, ATR, and WEE1 are undergoing clinical testing, it remains unclear how these three classes of agents kill susceptible cells and whether they utilize the same cytotoxic mechanism. Here we observed that CHK1 inhibition induces apoptosis in a subset of acute leukemia cell lines in vitro, including TP53-null acute myeloid leukemia (AML) and BCR/ABL-positive acute lymphoid leukemia (ALL), and inhibits leukemic colony formation in clinical AML samples ex vivo. In further studies, downregulation or inhibition of CHK1 triggered signaling in sensitive human acute leukemia cell lines that involved CDK2 activation followed by AP1-dependent TNF transactivation, TNFa production, and engagement of a TNFR1- and BID-dependent apoptotic pathway. AML lines that were intrinsically resistant to CHK1 inhibition exhibited high CHK1 expression and were sensitized by CHK1 downregulation. Signaling through this same CDK2-AP1-TNF cytotoxic pathway was also initiated by ATR or WEE1 inhibitors in vitro and during CHK1 inhibitor treatment of AML xenografts in vivo. Collectively, these observations not only identify new contributors to the antileukemic cell action of CHK1, ATR, and WEE1 inhibitors, but they also delineate a previously undescribed pathway leading from aberrant CDK2 activation to death ligand-induced killing that can potentially be exploited for acute leukemia treatment.
  24. Front Aging Neurosci. 2020 ;12 609517
    Cuenoud B, Ipek Ö, Shevlyakova M, Beaumont M, Cunnane SC, Gruetter R, Xin L.
      The brain requires a large amount of energy, mostly derived from the metabolism of glucose, which decreases substantially with age and neurological diseases. While mounting evidence in model organisms illustrates the central role of brain nicotinamide adenine dinucleotide (NAD) for maintaining energy homeostasis, similar data are sparse in humans. This study explores the correlations between brain NAD, energy production and membrane phospholipid metabolism by 31-phosphorous magnetic resonance spectroscopy (31P-MRS) across 50 healthy participants including a young (mean age 27.1-year-old) and middle-aged (mean age 56.4-year-old) group. The analysis revealed that brain NAD level and NAD+/NADH redox ratio were positively associated with ATP level and the rate of energy production, respectively. Moreover, a metabolic network linking NAD with membrane phospholipid metabolism, energy production, and aging was identified. An inverted trend between age and NAD level was detected. These results pave the way for the use of 31P-MRS as a powerful non-invasive tool to support the development of new therapeutic interventions targeting NAD associated phospho-metabolic pathways in brain aging and neurological diseases.
    Keywords:  31P-MRS; ATP metabolism; ATP synthase; NAD; brain energy; creatine kinase; membrane phospholipid metabolism; redox ratio
  25. Aging Cell. 2021 Jan 04. e13301
    Li Q, Cheng JC, Jiang Q, Lee WY.
      The decline in bone mass and bone strength and musculoskeletal problems associated with aging constitute a major challenge for affected individuals and the healthcare system globally. Sirtuins 1-7 (SIRT1-SIRT7) are a family of nicotinamide adenine dinucleotide-dependent deacetylases with remarkable abilities to promote longevity and counteract age-related diseases. Sirtuin knockout and transgenic models have provided novel insights into the function and signaling of these proteins in bone homeostasis. Studies have revealed that sirtuins play a critical role in normal skeletal development and homeostasis through their direct action on bone cells and that their dysregulation might contribute to different bone diseases. Preclinical studies have demonstrated that mice treated with sirtuin agonists show protection against age-related, postmenopausal, and immobilization-induced osteoporosis. These findings suggest that sirtuins could be potential targets for the modulation of the imbalance in bone remodeling and treatment of osteoporosis and other bone disorders. The aim of this review was to provide a comprehensive updated review of the current knowledge on sirtuin biology, focusing specifically on their roles in bone homeostasis and osteoporosis, and potential pharmacological interventions targeting sirtuins for the treatment of osteoporosis.
    Keywords:  aging; bone remodeling; osteoporosis; sirtuins
  26. Cancer Res. 2021 Jan 07. pii: canres.2571.2020. [Epub ahead of print]
    Tamiro F, Weng AP, Giambra V.
      The concept that different leukemias are developmentally distinct and, like in normal hematopoiesis, generated by restricted populations of cells named leukemia-initiating cells (LIC), is becoming more established. These cancer stem-like cells have been assumed to have unique properties, including the capability of self-renewing and giving rise to "differentiated" or non-LIC that make up the whole tumor. Cell populations enriched with LIC-activity have been characterized in different hematopoietic malignancies, including human acute lymphoblastic leukemia (ALL). Related studies have also demonstrated that LIC are functionally distinct from bulk cells and modulated by distinct molecular signaling pathways and epigenetic mechanisms. Here we review several biological and clinical aspects related to LIC in ALL, including: 1) immunophenotypic characterization of LIC-enriched subsets in human and mouse models of ALL; 2) emerging therapeutics against regulatory signaling pathways involved in LIC progression and maintenance in T- and B-cell leukemias; 3) novel epigenetic and age-related mechanisms of LIC propagation, and 4) ongoing efforts in immunotherapy to eradicate LIC-enriched cell subsets in relapsed and refractory ALL cases. Current conventional treatments do not efficiently eliminate LIC. Therefore, innovative therapeutics that exclusively target LIC hold great promise for developing an effective cure for ALL.
  27. Curr Opin Hematol. 2020 Dec 24. Publish Ahead of Print
    Wilk CM, Manz MG, Boettcher S.
      PURPOSE OF REVIEW: Clonal hematopoiesis (CH) is characterized by the acquisition of somatic mutations and subsequent expansion of mutated hematopoietic stem and progenitor cell (HSPC) clones without clinical evidence for a hematologic neoplasm. The prevalence of CH continuously increases with age reaching double-digit percentages in individuals >60 years. CH is associated with an increased risk for hematologic neoplasms and cardiovascular disease. We will review recent efforts to investigate how CH influences patient outcomes in hematopoietic stem cell transplantation - both autologous (ASCT) and allogeneic (allo-HSCT).RECENT FINDINGS: Donor-engrafted CH is common in allo-HSCT recipients. Apart from a higher incidence of chronic GvHD and the rare but devastating complication of donor-derived leukemia, CH does not appear to negatively impact outcomes in allo-HSCT recipients. In lymphoma patients undergoing ASCT, however, CH is associated with an excess mortality driven by therapy-related myeloid neoplasms and cardiovascular events. Interestingly, inferior overall survival in patients with CH undergoing ASCT for multiple myeloma (MM) is due to an increased rate of MM progression.
    SUMMARY: CH is highly prevalent in both allo-HSCT and ASCT patients suggesting a clinically relevant but context-dependent impact on adverse outcomes. Given the current lack of therapeutic interventions, systematic screening for CH in the transplant setting is currently not indicated outside of clinical studies.
  28. J Clin Invest. 2021 Jan 04. pii: 143296. [Epub ahead of print]131(1):
    von Locquenghien M, Rozalén C, Celià-Terrassa T.
      Interferons (IFNs) are pleiotropic cytokines critical for regulation of epithelial cell functions and for immune system regulation. In cancer, IFNs contribute to tumor-intrinsic and -extrinsic mechanisms that determine the quality of antitumor immunity and response to immunotherapy. In this Review, we focus on the different types of tumor IFN sensitivity that determine dynamic tumor-immune interactions and their coevolution during cancer progression and metastasis. We extend the discussion to new evidence supporting immunotherapy-mediated immunoediting and the dual opposing roles of IFNs that lead to immune checkpoint blockade response or resistance. Understanding the intricate dynamic responses to IFN will lead to novel immunotherapeutic strategies to circumvent protumorigenic effects of IFN while exploiting IFN-mediated antitumor immunity.
  29. J Clin Invest. 2021 Jan 04. pii: 144655. [Epub ahead of print]131(1):
    Cedernaes J, Bass J.
      The neuronal mechanisms that establish 24-hour rhythms in feeding and metabolism remain incompletely understood. In this issue of the JCI, Adlanmerini and colleagues explored the relationship between temporal and homeostatic control of energy balance by focusing on mice that lacked the genes encoding the clock repressor elements REV-ERBα and -β, specifically in the tuberal hypothalamus. Notably, the clock transcription cycle mediated intraneuronal response to the adipostatic hormone leptin. These results show that REV-ERBα and -β in the hypothalamus are necessary for maintaining leptin responsiveness and metabolic homeostasis and lay the foundation to explore how transcriptional changes may link energy-sensing cell types with day/night rhythms. Such information may lead to therapeutics that alleviate the adverse effects of chronic shift work.
  30. JCI Insight. 2021 Jan 07. pii: 139946. [Epub ahead of print]
    Lyu K, Zhang D, Song JD, Li X, Perry RJ, Samuel VT, Shulman GI.
      Insulin-mediated suppression of white adipose tissue (WAT) lipolysis is an important anabolic function that is dysregulated in states of overnutrition. However, the mechanism of short-term high-fat diet (HFD)-induced WAT insulin resistance is poorly understood. Based on our recent studies we hypothesize that a short-term HFD causes WAT insulin resistance through increases in plasma membrane (PM) sn-1,2-diacylglycerols (DAG), which promotes protein kinase C-ε (PKCε) activation to impair insulin signaling by phosphorylating insulin receptor (Insr) Thr1160. To test this hypothesis, we assessed WAT insulin action in 7-day HFD-fed versus regular chow diet-fed rats during a hyperinsulinemic-euglycemic clamp. HFD feeding caused WAT insulin resistance, reflected by reductions in both insulin-mediated WAT glucose uptake and suppression of WAT lipolysis. These changes were specifically associated with increased PM sn-1,2-diacylglycerol (DAG) content, increased PKCε activation and impaired insulin-stimulated InsrY1162 phosphorylation. In order to examine the role of InsrT1160 phosphorylation in mediating lipid-induced WAT insulin resistance, we examined these same parameters in short-term HFD-fed InsrT1150A knockin mice (mouse homolog for human Thr1160). Similar to the rat study HFD feeding induced WAT insulin resistance in WT control mice but failed to induce WAT insulin resistance in InsrT1150A mice. Taken together these data demonstrate that the PM sn-1,2-DAG - PKCε - InsrT1160 phosphorylation pathway plays an important role in mediating lipid-induced WAT insulin resistance and represents a potential therapeutic target to improve insulin sensitivity in WAT.
    Keywords:  Adipose tissue; Endocrinology; Glucose metabolism; Insulin signaling; Metabolism
  31. Int J Mol Sci. 2020 Dec 31. pii: E387. [Epub ahead of print]22(1):
    Wang Z, Snyder M, Kenison JE, Yang K, Lara B, Lydell E, Bennani K, Novikov O, Federico A, Monti S, Sherr DH.
      For decades, the aryl hydrocarbon receptor (AHR) was studied for its role in environmental chemical toxicity i.e., as a quirk of nature and a mediator of unintended consequences of human pollution. During that period, it was not certain that the AHR had a "normal" physiological function. However, the ongoing accumulation of data from an ever-expanding variety of studies on cancer, cancer immunity, autoimmunity, organ development, and other areas bears witness to a staggering array of AHR-controlled normal and pathological activities. The objective of this review is to discuss how the AHR has gone from a likely contributor to genotoxic environmental carcinogen-induced cancer to a master regulator of malignant cell progression and cancer aggression. Particular focus is placed on the association between AHR activity and poor cancer outcomes, feedback loops that control chronic AHR activity in cancer, and the role of chronically active AHR in driving cancer cell invasion, migration, cancer stem cell characteristics, and survival.
    Keywords:  AHR; aryl hydrocarbon receptor; cancer; kynurenine pathway
  32. Front Cell Dev Biol. 2020 ;8 589752
    Mo Y, Lu Z, Wang L, Ji C, Zou C, Liu X.
      The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that promotes cell responses to small molecules derived from the diet, microorganisms, metabolism and pollutants. The AhR signal regulates many basic cellular processes, including cell cycle progression, adhesion, migration, apoptosis and cell proliferation. Many studies have shown that AhR is associated with chronic kidney disease (CKD) and its complications. This article reviews the current knowledge about the role of AhR in CKD, showing that AhR mediates CKD complications, including cardiovascular disease, anemia, bone disorders, cognitive dysfunction and malnutrition, and that it influences drug metabolism in individuals with CKD. AhR enhances the intestinal barrier function to reduce the harmful effects of uremic toxins. Therefore, understanding the complex roles of AhR during CKD is important to be able to target this transcription factor safely and effectively for CKD prevention and treatment.
    Keywords:  CKD complications; aryl hydrocarbon receptor; chronic kidney disease; intestine homeostasis; tryptophan metabolism; uremic toxin
  33. Cell Death Dis. 2021 Jan 07. 12(1): 52
    Alza NP, Conde MA, Scodelaro-Bilbao PG, Salvador GA.
      α-synuclein (α-syn) accumulation and aggregation is a common pathological factor found in synucleinopathies, a group of neurodegenerative disorders that includes Parkinson´s disease (PD). It has been proposed that lipid dyshomeostasis is responsible for the occurrence of PD-related processes, however, the precise role of lipids in the onset and progression of neurodegenerative disorders remains unclear. Our aim was to investigate the effect of α-syn overexpression on neutral lipid metabolism and how this impacts on neuronal fate. We found lipid droplet (LD) accumulation in cells overexpressing α-syn to be associated with a rise in triacylglycerol (TAG) and cholesteryl ester (CE) levels. α-syn overexpression promoted diacylglycerol acyltransferase 2 upregulation and acyl-CoA synthetase activation, triggering TAG buildup, that was accompanied by an increase in diacylglycerol acylation. Moreover, the CE increment was associated with higher activity of acyl-CoA:cholesterol acyltransferase. Interestingly, α-syn overexpression increased cholesterol lysosomal accumulation. We observed that sterol regulatory element-binding protein (SREBP)-1 and SREBP-2 were differentially regulated by α-syn overexpression. The latter gave rise to a reduction in SREBP-1 nuclear translocation and consequently in fatty acid synthase expression, whereas it produced an increase in SREBP-2 nuclear localization. Surprisingly, and despite increased cholesterol levels, SREBP-2 downstream genes related to cholesterolgenesis were not upregulated as expected. Notably, phospholipid (PL) levels were diminished in cells overexpressing α-syn. This decrease was related to the activation of phospholipase A2 (PLA2) with a concomitant imbalance of the PL deacylation-acylation cycle. Fatty acids released from PLs by iPLA2 and cPLA2 action were esterified into TAGs, thus promoting a biological response to α-syn overexpression with uncompromised cell viability. When the described steady-state was disturbed under conditions favoring higher levels of α-syn, the response was an enhanced LD accumulation, this imbalance ultimately leading to neuronal death.
  34. Aging Clin Exp Res. 2021 Jan 03.
    Capurso A, Capurso C.
    Keywords:  Beetroot; Blood pressure; Leafy vegetables; Nitrate
  35. Curr HIV/AIDS Rep. 2021 Jan 05.
    Cabrera DM, Diaz MM, Grimshaw A, Salvatierra J, Garcia PJ, Hsieh E.
      PURPOSE OF REVIEW: With the establishment of antiretroviral treatment (ART) programs in low- and middle-income countries, people with HIV (PWH) in Latin America and the Caribbean (LAC) are living longer, subsequently developing chronic non-communicable diseases (NCDs). Few studies focus on the impact of aging among older LAC PWH. This systematic review aims to fill this information gap and understand the burden of aging with HIV in LAC. We identified peer-reviewed literature published in English, Spanish, or Portuguese from several databases to assess currently available evidence on the burden of aging with HIV in LAC and selected six common NCDs found in older PWH (cardiovascular disease [CVD], bone and musculoskeletal [MSK] disorders, cancer, renal disease, neurocognitive impairment [NCI], and depression).RECENT FINDINGS: Of the 5942 publications reviewed, only 53 articles were found with populations 40 years and older or age-related findings (27 CVD, 13 NCI or depression, 6 MSK disorders, 4 renal disease, 3 cancer). Most (79%) publications were from Brazil with few longitudinal studies on aging with HIV. Prevalence of illnesses such as CVD, NCI, depression, or osteoporosis varied widely depending on the screening instrument utilized and geographic population surveyed. Age was a significant predictor of comorbidity in nearly all studies. Our results demonstrate the need for longitudinal studies and validated screening instruments appropriate for use among PWH in LAC. Understanding the mechanisms behind aging in HIV and the roles of sociocultural factors and genetic diversity specific to LAC is needed to appropriately manage chronic comorbidities as PWH age.
    Keywords:  Aging; HIV; Latin America; Morbidity; The Caribbean
  36. Aging Cell. 2021 Jan 03. e13285
    Squarzoni S, Schena E, Sabatelli P, Mattioli E, Capanni C, Cenni V, D'Apice MR, Andrenacci D, Sarli G, Pellegrino V, Festa A, Baruffaldi F, Storci G, Bonafè M, Barboni C, Sanapo M, Zaghini A, Lattanzi G.
      Hutchinson-Gilford progeria syndrome (HGPS) causes premature aging in children, with adipose tissue, skin and bone deterioration, and cardiovascular impairment. In HGPS cells and mouse models, high levels of interleukin-6, an inflammatory cytokine linked to aging processes, have been detected. Here, we show that inhibition of interleukin-6 activity by tocilizumab, a neutralizing antibody raised against interleukin-6 receptors, counteracts progeroid features in both HGPS fibroblasts and LmnaG609G / G609G progeroid mice. Tocilizumab treatment limits the accumulation of progerin, the toxic protein produced in HGPS cells, rescues nuclear envelope and chromatin abnormalities, and attenuates the hyperactivated DNA damage response. In vivo administration of tocilizumab reduces aortic lesions and adipose tissue dystrophy, delays the onset of lipodystrophy and kyphosis, avoids motor impairment, and preserves a good quality of life in progeroid mice. This work identifies tocilizumab as a valuable tool in HGPS therapy and, speculatively, in the treatment of a variety of aging-related disorders.
    Keywords:  accelerated aging; ageing; anti-aging; cellular senescence; cytokines; inflammation; laminopathies; nuclear lamina
  37. Geroscience. 2021 Jan 07.
    Brandhorst S.
      The increasingly older population in most developed countries will likely experience aging-related chronic diseases such as diabetes, metabolic syndrome, heart and lung diseases, osteoporosis, arthritis, dementia, and/or cancer. Genetic and environmental factors, but also lifestyle choices including physical activity and dietary habits, play essential roles in disease onset and progression. Sixty-five percent of Americans diagnosed with cancer now survive more than 5 years, making the need for informed lifestyle choices particularly important to successfully complete their treatment, increase the recovery from the cytotoxic therapy options, and improve cancer-free survival. This review will discuss the findings on the use of prolonged fasting, as well as fasting-mimicking diets to augment cancer treatment. Preclinical studies in rodents strongly support the implementation of these dietary interventions and a small number of clinical trials begin to provide encouraging results for cancer patients and cancer survivors.
    Keywords:  Cancer; Chemotherapy; Fasting; Fasting-mimicking diet
  38. J Nutr Biochem. 2020 Dec 31. pii: S0955-2863(20)30609-4. [Epub ahead of print] 108577
    Ye S, Matthan NR, Lamon-Fava S, Aguilar GS, Turner JR, Walker ME, Chai Z, Lakshman S, Jr JFU, Lichtenstein AH.
      Diet quality and statin therapy are established modulators of coronary artery disease (CAD) progression, but their effect on the gastrointestinal tract (GIT) and subsequent sequelae that could affect CAD progression are relatively unexplored. To address this gap, Ossabaw pigs (N = 32) were randomly assigned to receive isocaloric amounts of a Western-type diet (WD; high in saturated fat, refined carbohydrate, and cholesterol, and low in fiber) or a heart healthy-type diet (HHD; high in unsaturated fat, whole grains, fruits and vegetables, supplemented with fish oil, and low in cholesterol), with or without atorvastatin, for six months. At the end of the study, RNA sequencing with 100 base pair single end reads on NextSeq 500 platform was conducted in isolated pig jejunal mucosa. A 2-factor edgeR analysis revealed that the dietary patterns resulted in three differentially expressed genes related to lipid metabolism (SCD, FADS1, and SQLE). The expression of these genes was associated with cardiometabolic risk factors and atherosclerotic lesion severity. Subsequent gene enrichment analysis indicated the WD, compared to the HHD, resulted in higher interferon signaling and inflammation, with some of these genes being significantly associated with serum TNF-α and/or hsCRP concentrations, but not atherosclerotic lesion severity. No significant effect of atorvastatin therapy on gene expression, nor its interaction with dietary patterns, were identified. In conclusion, Western and heart healthy-type dietary patterns differentially affect the expression of genes associated with lipid metabolism, interferon signaling and inflammation in the jejunum of Ossabaw pigs.
    Keywords:  Atherosclerosis; Cardiometabolic risk factors; Dietary patterns; Jejunum; Lipid; OSSABAW pig
  39. ACS Omega. 2020 Dec 29. 5(51): 33186-33195
    Kim S, Kim J, Kim N, Lee D, Lee H, Lee DY, Kim KH.
      Sucrose induces flavonoid accumulation in plants as a defense mechanism against various stresses. However, the relationship between the biosynthesis of flavonoids as secondary metabolites and sucrose levels remains unknown. To understand the change in flavonoid biosynthesis by sucrose, we conducted secondary metabolite profiling in Melissa officinalis treated with different levels of sucrose using ultraperformance liquid chromatography/quadrupole time-of-flight mass spectrometry. The partial least squares-discriminant and hierarchical clustering analyses showed significant differences in secondary metabolite profiles in M. officinalis at 50, 150, and 300 mM sucrose levels. The levels of 3 flavonoids such as quercetin 3-O-β-d-glucosyl-(1→2)-β-d-glucoside, 6-methoxyaromadendrin 3-O-acetate, and 3-hydroxycoumarin and 19 flavonoids including 6-methoxyaromadendrin 3-O-acetate, aureusidin, iridin, flavonol 3-O-(6-O-malonyl-β-d-glucoside) quercetin 3-O-glucoside, and rutin increased at 150 and 300 mM sucrose, respectively, compared to 50 mM sucrose, indicating that the flavonoids were accumulated in M. officinalis by a higher concentration of sucrose. This is the first investigation of the change in individual flavonoids as secondary metabolites in M. officinalis by varying sucrose levels, and the results demonstrate that the sucrose causes the accumulation of certain flavonoids as a defense mechanism against osmotic stress.
  40. Chembiochem. 2021 Jan 07.
    Ukale D, Lönnberg T.
      Synthetic efforts towards nucleosides, nucleotides, oligonucleotides and nucleic acids covalently mercurated at one or more of their base moieties are summarized, followed by a discussion of the proposed, realized and abandoned applications of this unique class of compounds. Special emphasis is given to fields where active research is ongoing, notably the use of Hg(II)-mediated base pairing to improve the hybridization properties of oligonucleotide probes. Finally, this minireview attempts to anticipate potential future applications of organomercury nucleic acids.
    Keywords:  base pairing; coordination; mercury; nucleic acids; organometallic
  41. Elife. 2021 Jan 08. pii: e58064. [Epub ahead of print]10
    Yang D, Haemmig S, Zhou H, Pérez-Cremades D, Sun X, Chen L, Li J, Haneo-Mejia J, Yang T, Hollan I, Feinberg MW.
      Endothelial cell (EC) activation is an early hallmark in the pathogenesis of chronic vascular diseases. MicroRNA-181b (MiR-181b) is an important anti-inflammatory mediator in the vascular endothelium affecting endotoxemia, atherosclerosis, and insulin resistance. Herein, we identify that the drug methotrexate (MTX) and its downstream metabolite adenosine exert anti-inflammatory effects in the vascular endothelium by targeting and activating MiR-181b expression. Both systemic and endothelial-specific MiR-181a2b2-deficient mice develop vascular inflammation, white adipose tissue (WAT) inflammation, and insulin resistance in a diet-induced obesity model. Moreover, MTX attenuated diet-induced WAT inflammation, insulin resistance, and EC activation in a MiR-181a2b2-dependent manner. Mechanistically, MTX attenuated cytokine-induced EC activation through a unique adenosine-adenosine receptor A3-SMAD3/4-MiR-181b signaling cascade. These findings establish an essential role of endothelial MiR-181b in controlling vascular inflammation and that restoring MiR-181b in ECs by high dose MTX or adenosine signaling may provide a potential therapeutic opportunity for anti-inflammatory therapy.
    Keywords:  human; immunology; inflammation; medicine; mouse
  42. Chin J Integr Med. 2021 Jan 09.
    Ke SY, Yu SJ, Liu DH, Shi GY, Wang M, Zhou B, Wu L, Song ZM, Zhu JM, Wu CD, Qian XX.
      OBJECTIVE: To investigate whether ginsenoside Rb1 (Rb1) can protect human umbilical vein endothelial cells (HUVECs) against high glucose-induced apoptosis and examine the underlying mechanism.METHODS: HUVECs were divided into 5 groups: control group (5.5 mmol/L glucose), high glucose (HG, 40 mmol/L) treatment group, Rb1 (50 µ mol/L) treatment group, Rb1 plus HG treatment group, and Rb1 and 3-(1H-1,2,3-triazol-4-yl) pyridine (3-TYP, 16 µ mol/L) plus HG treatment group. Cell viability was evaluated by cell counting kit-8 assay. Mitochondrial and intracellular reactive oxygen species were detected by MitoSox Red mitochondrial superoxide indicator and dichloro-dihydro-fluorescein diacetate assay, respectively. Annexin V/propidium iodide staining and fluorescent dye staining were used to measure the apoptosis and the mitochondrial membrane potential of HUVECs, respectively. The protein expressions of apoptosis-related proteins [Bcl-2, Bax, cleaved caspase-3 and cytochrome c (Cyt-c)], mitochondrial biogenesis-related proteins [proliferator-activated receptor gamma coactivator 1-alpha, nuclear respiratory factor-1 and mitochondrial transcription factor A)], acetylation levels of forkhead box O3a and SOD2, and sirtuin-3 (SIRT3) signalling pathway were measured by immunoblotting and immunoprecipitation.
    RESULTS: Rb1 ameliorated survival in cells in which apoptosis was induced by high glucose (P<0.05 or P<0.01). Upon the addition of Rb1, mitochondrial and intracellular reactive oxygen species generation and malondialdehyde levels were decreased (P<0.01), while the activities of antioxidant enzymes were increased (P<0.05 or P<0.01). Rb1 preserved the mitochondrial membrane potential and reduced the release of Cyt-c from the mitochondria into the cytosol (P<0.01). In addition, Rb1 upregulated mitochondrial biogenesis-associated proteins (P<0.01). Notably, the cytoprotective effects of Rb1 were correlated with SIRT3 signalling pathway activation (P<0.01). The effect of Rb1 against high glucose-induced mitochondria-related apoptosis was restrained by 3-TYP (P<0.05 or P<0.01).
    CONCLUSION: Rb1 could protect HUVECs from high glucose-induced apoptosis by promoting mitochondrial function and suppressing oxidative stress through the SIRT3 signalling pathway.
    Keywords:  SIRT3 signalling pathway; apoptosis; ginsenoside Rb1; high glucose; human umbilical vein endothelial cells; mitochondria
  43. Mol Cell Biochem. 2021 Jan 07.
    Zegallai HM, Hatch GM.
      Barth syndrome is a rare X-linked genetic disease classically characterized by cardiomyopathy, skeletal myopathy, growth retardation, neutropenia, and 3-methylglutaconic aciduria. It is caused by mutations in the tafazzin gene localized to chromosome Xq28.12. Mutations in tafazzin may result in alterations in the level and molecular composition of the mitochondrial phospholipid cardiolipin and result in large elevations in the lysophospholipid monolysocardiolipin. The increased monolysocardiolipin:cardiolipin ratio in blood is diagnostic for the disease, and it leads to disruption in mitochondrial bioenergetics. In this review, we discuss cardiolipin structure, synthesis, and function and provide an overview of the clinical and cellular pathophysiology of Barth Syndrome. We highlight known pharmacological management for treatment of the major pathological features associated with the disease. In addition, we discuss non-pharmacological management. Finally, we highlight the most recent promising therapeutic options for this rare mitochondrial disease including lipid replacement therapy, peroxisome proliferator-activated receptor agonists, tafazzin gene replacement therapy, induced pluripotent stem cells, mitochondria-targeted antioxidants and peptides, and the polyphenolic compound resveratrol.
    Keywords:  Barth syndrome; Cardiolipin; Cholesterol; Genetic disease; Heart; Mitochondria; Neutropenia; Pharmacological management; Resveratrol; Skeletal muscle; Tafazzin
  44. Oncogene. 2021 Jan 08.
    Formaggio N, Rubin MA, Theurillat JP.
      Targeting the androgen receptor (AR) signaling axis has been, over decades, the mainstay of prostate cancer therapy. More potent inhibitors of androgen synthesis and antiandrogens have emerged and have been successfully implemented in clinical practice. That said, the stronger inhibition of the AR signaling axis has led in recent years to an increase of prostate cancers that de-differentiate into AR-negative disease. Unfortunately, this process is intimately linked with a poor prognosis. Here, we review the molecular mechanisms that enable cancer cells to switch from an AR-positive to an AR-negative disease and efforts to prevent/revert this process and thereby maintain/restore AR-dependence.
  45. Diabetes Metab Syndr. 2020 Nov-Dec;14(6):pii: S1871-4021(20)30464-1. [Epub ahead of print]14(6): 2131-2138
    Pirouzeh R, Heidarzadeh-Esfahani N, Morvaridzadeh M, Izadi A, Yosaee S, Potter E, Heshmati J, Pizarro AB, Omidi A, Heshmati S.
      BACKGROUND AND AIMS: Oxidative stress (OS) is one of the main risk factors for several chronic diseases. The Dietary Approaches to Stop Hypertension (DASH) contain many antioxidants and may contribute to managing OS.OBJECTIVE: To perform a systematic review and meta-analysis to examine the impacts of the DASH diet on OS parameters.
    METHODS: A comprehensive electronic search in MEDLINE, Scopus, EMBASE, and the Cochrane Central Register of Controlled Trials was performed through September 2020 to find related studies evaluating the impact of the DASH diet on OS parameters. Standardized mean differences were pooled using random-effects meta-analysis.
    RESULTS: Eight studies with a total of 317 subjects met our inclusion criteria. Four studies included in meta-analysis model with 200 participants (100 in treatment and 100 in control group). The DASH diet was associated with a statistically significant decrease in malondialdehyde (MDA) (SMD: -0.53; 95% CI: -0.89, -0.16; I2 = 42.1%), and a significant increase in glutathione (GSH) (SMD: 0.83; 95% CI: 0.36, 1.03; I2 = 42.1%). Meta-analysis found no statistically significant effect of DASH diet on nitric oxide (NO) (SMD: -1.40; 95% CI: -0.12, 1.93; I2 = 92.6%) or total antioxidant capacity (TAC) levels (SMD: 0.95; 95% CI: -0.10, 1.99; I2 = 87.6%).
    CONCLUSION: Our results demonstrated that a DASH diet could significantly increase GSH and decrease MDA levels. Furthermore, there is a trend to improve TAC, NO, and f2-isoprostanes by the adherence to the DASH diet. However, long-term, large sample size and well-designed randomized clinical trials are still needed to draw concrete conclusions about DASH diet's effects on OS parameters.
    Keywords:  DASH diet; Glutathione (GSH); Malondialdehyde (MDA); Oxidative stress
  46. Acad Med. 2020 Dec 29. Publish Ahead of Print
    Daniel M, Morrison G, Hauer KE, Pock A, Seibert C, Amiel J, Poag M, Ismail N, Dalrymple JL, Esposito K, Pettepher C, Santen SA.
      Calls for curricular reform in medical schools and enhanced integration of basic and clinical science have resulted in a shift towards preclerkship curricula that enhance the clinical relevance of foundational science instruction and provide students with earlier immersion in the clinical environment. These reforms have resulted in shortened preclerkship curricula, yet the promise of integrated basic science education into clerkships has not been sufficiently realized because of barriers such as the nature of clinical practice, time constraints, and limited faculty knowledge. As personalized medicine requires that physicians have a more nuanced understanding of basic science, this is cause for alarm. To address this problem, several schools have developed instructional and assessment strategies to better integrate basic science into the clinical curriculum. In this article, faculty and deans from 11 U.S. medical schools discuss the strategies they implemented and the lessons they learned to provide guidance to other schools seeking to enhance basic science education during clerkships. The strategies include program-level interventions (e.g., longitudinal sessions dedicated to basic science during clerkships; weeks of lessons dedicated to basic science interspersed in clerkships), clerkship-level interventions (e.g., case-based learning with online modules; multidisciplinary clerkship dedicated to applied science), bedside-level interventions (e.g., basic science teaching scripts; self-directed learning), and changes to formative and summative assessments (e.g., spaced repetition/leveraging test-enhanced learning; developing customized examinations). The authors discovered that: interventions were more successful when buy-in from faculty and students was considered; central oversight by curricular committees collaborating with faculty was key; and some integration efforts may require schools to provide significant resources. All schools administered the United States Medical Licensing Examination Step 1 exam to students after clerkship, with positive outcomes. The authors have demonstrated that it is feasible to incorporate basic science into clinical clerkships, but certain challenges remain.
  47. Obes Res Clin Pract. 2020 Dec 23. pii: S1871-403X(20)30623-2. [Epub ahead of print]
    McNeill JN, Lau ES, Paniagua SM, Liu EE, Wang JK, Bassett IV, Selvaggi CA, Lubitz SA, Foulkes AS, Ho JE.
      Obesity has emerged as a significant risk factor for severe COVID-19 worldwide. Given both COVID-19 infection and obesity have been associated with increased systemic inflammation, we evaluated inflammatory markers in obese and non-obese individuals hospitalized for COVID-19 at Massachusetts General Hospital. We hypothesized that obese patients would have a more exuberant inflammatory response as evidenced by higher initial and peak inflammatory markers along with worse clinical outcomes. Of the 781 patients, 349 were obese (45%). Obese individuals had higher initial and peak levels of CRP and ESR as well as higher peak d-dimer (P < 0.01 for all) in comparison to non-obese individuals, while. IL-6 and ferritin were similar. In addition, obese individuals had a higher odds of requiring vasopressor use (OR 1.54, 95% CI 1.00-2.38, P = 0.05), developing hypoxemic respiratory failure (OR 1.58, 95% CI 1.04-2.40, P = 0.03) and death (OR 2.20, 95% CI 1.31-3.70, P = 0.003) within 28 days of presentation to care. Finally, higher baseline levels of CRP and D-dimer were associated with worse clinical outcomes even after adjustment for BMI. Our findings suggest greater disease severity in obese individuals is characterized by more exuberant inflammation.
    Keywords:  COVID-19; CRP; D-dimer; ESR; Inflammation; Obesity
  48. Aging Clin Exp Res. 2021 Jan 03.
    de Boissieu P, Guerin S, Suissa V, Ecarnot F, Letty A, Sanchez S.
      BACKGROUND: There is a compelling need to prepare our societies and healthcare systems to deal with the oncoming wave of population ageing. The majority of older persons maintain a desire to be valued and useful members of society and of their social networks.AIMS: We sought to investigate the perception of usefulness among persons aged 65 years and over in four European countries.
    METHODS: We performed a cross-sectional survey with a representative sample of individuals aged 65 years or older from the population of retired persons (including recently retired persons and oldest-old individuals) from 4 European countries selected using quota sampling. In February 2016, an internet questionnaire was sent to all selected individuals. The characteristics used for the quota sampling method were sex, age, socio-professional category, region, city size, number of persons in household, autonomy, marital status, place of residence, income and educational status. The questionnaire contained 57 questions. Sociodemographic characteristics were recorded. Responses were analysed with principal components analysis (PCA).
    RESULTS: A total of 4025 persons participated; 51% were males, and 70% were aged 65-75 years. PCA identified six classes of individuals, of which two classes (Classes 2 and 3) were characterized by more socially isolated individuals with little or no sense of usefulness, low self-esteem and a poor sense of well-being. These two classes accounted for almost 20% of the population. Younger and more autonomous classes reported a more salient sense of usefulness.
    CONCLUSIONS: The loss of the sense of usefulness is associated with dissatisfaction with life and a loss of pleasure, and persons with profiles corresponding to Classes 2 and 3 should, therefore, be targeted for interventions aimed at restoring social links.
    Keywords:  Ageing; Ageing-well; Europe; Useful
  49. Health Sociol Rev. 2020 Jul;29(2): 140-148
    Scambler G.
      In this brief paper, I argue that the coronavirus pandemic is functioning like an ethnomethodological 'breaching experiment'. In short, it is putting a gigantic spanner in the works of neoliberal governance, in the process exposing the widening cracks and fissures of what I have called the 'fractured society'. I begin by recalling Garfinkel's notion of the breaching experiment and by listing the principal attributes of the fractured society. I then explore the response to the coronavirus in the UK, from the government's initial commitment to 'herd immunity' to its present policy of 'muddling through'. The bulk of the remainder of this contribution addresses precisely how this global health crisis shines a harsh and unforgiving searchlight on the strategies and policies pursued by governments in the UK since 2010, and most especially after the passing of the Health and Social Care Act of 2012. In the closing paragraphs, I examine possible scenarios for a post-fractured society, making particular use of Fraser's concepts on 'reactionary' versus 'progressive populism', and conclude with a comment on sociology and engagement.
    Keywords:  Breaching experiment; COVID-19; NHS; fractured society; future scenarios
  50. Antioxidants (Basel). 2021 Jan 06. pii: E62. [Epub ahead of print]10(1):
    An MY, Lee SR, Hwang HJ, Yoon JG, Lee HJ, Cho JA.
      The excessive release of reactive oxygen species (ROS) can result in the development of chronic inflammation. The mechanisms involved in inflammation are various, with endoplasmic reticulum (ER) stress known to be among them. We have previously shown that black ginseng (BG) reduced lipid accumulation in and enhanced the antioxidant function of the liver in vitro and in vivo mostly due to ginsenoside Rb1, Rg3 and Rk1 components. Therefore, this study investigated the antioxidant effect of BG on the intestines and its possible mechanistic pathway through ER stress. The results showed that BG extract decreased ROS and nitric oxide (NO) production and reduced inducible nitric oxide synthase (iNOS) expression levels in vitro, and these results were confirmed by zebrafish embryos in vivo. However, this phenotype was abolished in the absence of inositol-requiring enzyme 1 (IRE1α) but not in the absence of protein kinase RNA (PKR)-like ER-resistant kinase (PERK) or X-box-binding protein 1 (XBP1) in the mouse embryo fibroblast (MEF) knockout (KO) cells, suggesting that BG elicits an antioxidant effect in an IRE1α-dependent manner. Antioxidant and anti-inflammatory effects were assessed in the liver and intestines of the mouse model affected by nonalcoholic fatty liver disease (NAFLD), which was induced by a high-fat/high-fructose diet. In the liver, BG treatment rescued NAFLD-induced glutathione (GSH), catalase (CAT), tumor necrosis factor-α (TNF-α) and interleukin (IL)-6 expression. In the intestines, BG also rescued NAFLD-induced shortened villi, inflammatory immune cell infiltration, upregulated IL-6, cytosine-cytosine-adenosine-adenosine-thymidine (CCAAT)/enhancer-binding homologous protein (CHOP) and binding immunoglobulin protein (BiP) expression. In conclusion, our results show that BG reduces ROS and NO production followed by inflammation in an IRE1α-dependent and XBP1-independent manner. The results suggest that BG provides antioxidant and anti-inflammatory effects through an ER stress mechanism.
    Keywords:  ER stress; Korean black ginseng; anti-inflammatory; antioxidant
  51. J Pediatr (Rio J). 2021 Jan 02. pii: S0021-7557(20)30255-2. [Epub ahead of print]
    Grumach AS, Goudouris ES.
      OBJECTIVES: Inborn Errors of Immunity are characterized by infectious conditions and manifestations of immune dysregulation. The diversity of clinical phenotypes can make it difficult to direct the laboratory investigation. This article aims to update the investigation of immunological competence in the context of primary defects of the immune system.SOURCE OF DATA: Searches were carried out on Pubmed to review articles published in the last five years, in English, French or Spanish, using the terms "diagnosis" OR "investigation" AND "immunodeficiency" or "primary immunodeficiency" or "inborn errors of immunity" NOT "HIV". Recent textbook editions have also been consulted.
    SUMMARY OF FINDINGS: The immune system competence investigation should be started based on clinical phenotypes. Relevant data are: characterization of infectious conditions (location, recurrence, types of infectious agents, response to treatment), age during symptom onset and associated manifestations (growth impairment, allergy, autoimmunity, malignancies, fever and signs of inflammation without the identification of infection or autoimmunity) and family history. These data contribute to the selection of tests to be performed.
    CONCLUSIONS: The diagnostic investigation of Inborn Errors of Immunity should be guided by the clinical characterization of patients, aiming to optimize the use of complementary tests. Many diagnoses are attained only through genetic tests, which are not always available. However, the absence of a diagnosis of certainty should never delay the implementation of therapeutic measures that preserve patient life and health.
    Keywords:  Diagnosis; Immunodeficiencies; Immunological evaluation; Inborn Errors of Immunity; Investigation; Laboratory tests
  52. Int Nurs Rev. 2021 Jan 06.
    Lee J, Cho HS, Shin SR.
      In this indefinite pandemic situation, roles of nurses have been most illuminated by the public, but the nurses may soon start experiencing burnout. This paper highlights roles of nurses in COVID care in Korea and nursing strategies for the post-COVID era. As we are the frontline advocators of the public, when we develop strategies for their health and quality of life, we receive public support that can help resolve our issues. We will improve our poor working environments through mutual cooperation, as we are one. IMPLICATIONS FOR NURSING: Nurses need to possess a variety of abilities, such as the digital literacy required by the non-contact era after COVID-19, and to expand the boundaries of the nursing profession in convergence of health services with technology.
    Keywords:  nursing; nursing strategy; post-COVID; response
  53. Sci Signal. 2021 Jan 05. pii: eabc4436. [Epub ahead of print]14(664):
    Crooks DR, Maio N, Lang M, Ricketts CJ, Vocke CD, Gurram S, Turan S, Kim YY, Cawthon GM, Sohelian F, De Val N, Pfeiffer RM, Jailwala P, Tandon M, Tran B, Fan TW, Lane AN, Ried T, Wangsa D, Malayeri AA, Merino MJ, Yang Y, Meier JL, Ball MW, Rouault TA, Srinivasan R, Linehan WM.
      Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)-encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.
  54. Nat Med. 2021 Jan 04.
    Becher T, Palanisamy S, Kramer DJ, Eljalby M, Marx SJ, Wibmer AG, Butler SD, Jiang CS, Vaughan R, Schöder H, Mark A, Cohen P.
      White fat stores excess energy, whereas brown and beige fat are thermogenic and dissipate energy as heat. Thermogenic adipose tissues markedly improve glucose and lipid homeostasis in mouse models, although the extent to which brown adipose tissue (BAT) influences metabolic and cardiovascular disease in humans is unclear1,2. Here we retrospectively categorized 134,529 18F-fluorodeoxyglucose positron emission tomography-computed tomography scans from 52,487 patients, by presence or absence of BAT, and used propensity score matching to assemble a study cohort. Scans in the study population were initially conducted for indications related to cancer diagnosis, treatment or surveillance, without previous stimulation. We report that individuals with BAT had lower prevalences of cardiometabolic diseases, and the presence of BAT was independently correlated with lower odds of type 2 diabetes, dyslipidemia, coronary artery disease, cerebrovascular disease, congestive heart failure and hypertension. These findings were supported by improved blood glucose, triglyceride and high-density lipoprotein values. The beneficial effects of BAT were more pronounced in individuals with overweight or obesity, indicating that BAT might play a role in mitigating the deleterious effects of obesity. Taken together, our findings highlight a potential role for BAT in promoting cardiometabolic health.