bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–09–05
24 papers selected by
Ayesh Seneviratne, University of Toronto



  1. Curr Atheroscler Rep. 2021 Sep 01. 23(11): 66
       PURPOSE OF REVIEW: Clonal hematopoiesis of indeterminate potential (CHIP) is a novel cardiovascular risk factor that develops as aging hematopoietic stem cells (HSCs) acquire somatic mutations which confer a clonal survival advantage in their progeny. These cells confer increased leukemogenic risk but confer a greater absolute risk of cardiovascular disease-which appears to be mediated through altered inflammatory pathways. Here we review the evidence the risk of cardiovascular disease conferred by CHIP. We also review the evidence regarding risk factors associated with CHIP.
    RECENT FINDINGS: The most recent evidence suggests that CHIP is associated with increased cardiovascular risk beyond atherosclerosis, which has been established in multiple studies, but also in heart failure and aortic valve stenosis. Additionally, the list of conditions associated with CHIP continues to grow including germline genetics, smoking, cancer therapies, radiation exposure, premature menopause, and unhealthy diet. CHIP is a cardiovascular risk factor of increasingly recognized importance, and new data continues to emerge about the risks it confers, which will need more prospective validation. Although risk factors for CHIP are being identified, relatively little is known about the mechanisms by which CHIP develops, which requires further study.
    Keywords:  Atherosclerosis; Clonal hematopoiesis; Genomics; Preventive cardiology
    DOI:  https://doi.org/10.1007/s11883-021-00966-9
  2. Exp Hematol. 2021 Aug 28. pii: S0301-472X(21)00289-7. [Epub ahead of print]
      Hematopoietic stem cells (HSCs) are immature blood cells that exhibit multi-lineage differentiation capacity. Homeostasis is critical for HSC potential and life-long hematopoiesis, and HSC homeostasis is tightly governed by both intrinsic molecular networks and microenvironmental signals. The evolutionarily conserved serine/threonine protein kinase B (PKB, also referred to as Akt) -mammalian target of rapamycin (mTOR) pathway is universal to nearly all multicellular organisms and plays an integral role in most cellular processes. Emerging evidence has revealed a central role of the Akt-mTOR network in HSC homeostasis, as it responses to multiple intracellular and extracellular signals and regulates various downstream targets, eventually affecting several cellular processes, including the cell cycle, mitochondrial metabolism, and protein synthesis. The dysregulated Akt-mTOR signaling greatly affects HSC self-renewal, maintenance, differentiation, survival, and autophagy, and aging, as well as transformation of HSCs to leukemia stem cells (LSCs). Here, we review recent works and provide an advanced understanding of how the Akt-mTOR network regulates HSC homeostasis, thus offering insights for future clinical applications.
    Keywords:  Akt-mTOR; Hematopoietic stem cells; Homeostasis; Leukemia stem cells
    DOI:  https://doi.org/10.1016/j.exphem.2021.08.009
  3. J Hematol Oncol. 2021 08 28. 14(1): 133
       BACKGROUND: Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors' clinical experience treating patients in the trial.
    METHODS: QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug.
    RESULTS: A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1-80) oral azacitidine treatment cycles or 6 (1-73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3-4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications.
    CONCLUSION: Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy. Trial registration This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012.
    Keywords:  CC-486; Maintenance; Oral azacitidine; Safety
    DOI:  https://doi.org/10.1186/s13045-021-01142-x
  4. Inflamm Res. 2021 Sep 02.
       BACKGROUND: The insulin/IGF-1 signaling pathway has a major role in the regulation of longevity both in Caenorhabditis elegans and mammalian species, i.e., reduced activity of this pathway extends lifespan, whereas increased activity accelerates the aging process. The insulin/IGF-1 pathway controls protein and energy metabolism as well as the proliferation and differentiation of insulin/IGF-1-responsive cells. Insulin/IGF-1 signaling also regulates the functions of the innate and adaptive immune systems. The purpose of this review was to elucidate whether insulin/IGF-1 signaling is linked to immunosuppressive STAT3 signaling which is known to promote the aging process.
    METHODS: Original and review articles encompassing the connections between insulin/IGF-1 and STAT3 signaling were examined from major databases including Pubmed, Scopus, and Google Scholar.
    RESULTS: The activation of insulin/IGF-1 receptors stimulates STAT3 signaling through the JAK and AKT-driven signaling pathways. STAT3 signaling is a major activator of immunosuppressive cells which are able to counteract the chronic low-grade inflammation associated with the aging process. However, the activation of STAT3 signaling stimulates a negative feedback response through the induction of SOCS factors which not only inhibit the activity of insulin/IGF-1 receptors but also that of many cytokine receptors. The inhibition of insulin/IGF-1 signaling evokes insulin resistance, a condition known to be increased with aging. STAT3 signaling also triggers the senescence of both non-immune and immune cells, especially through the activation of p53 signaling.
    CONCLUSIONS: Given that cellular senescence, inflammaging, and counteracting immune suppression increase with aging, this might explain why excessive insulin/IGF-1 signaling promotes the aging process.
    Keywords:  Ageing; Alzheimer’s; FoxO; Immunosenescence; Tolerance; mTOR
    DOI:  https://doi.org/10.1007/s00011-021-01498-3
  5. Elife. 2021 09 01. pii: e63453. [Epub ahead of print]10
      Mitochondrial activity determines aging rate and the onset of chronic diseases. The mitochondrial permeability transition pore (mPTP) is a pathological pore in the inner mitochondrial membrane thought to be composed of the F-ATP synthase (complex V). OSCP, a subunit of F-ATP synthase, helps protect against mPTP formation. How the destabilization of OSCP may contribute to aging, however, is unclear. We have found that loss OSCP in the nematode Caenorhabditis elegans initiates the mPTP and shortens lifespan specifically during adulthood, in part via initiation of the mitochondrial unfolded protein response (UPRmt). Pharmacological or genetic inhibition of the mPTP inhibits the UPRmt and restores normal lifespan. Loss of the putative pore-forming component of F-ATP synthase extends adult lifespan, suggesting that the mPTP normally promotes aging. Our findings reveal how an mPTP/UPRmt nexus may contribute to aging and age-related diseases and how inhibition of the UPRmt may be protective under certain conditions.
    Keywords:  C. elegans; F-ATP synthase; aging; c-subunit; cell biology; mitochondrial permeability transition pore; mitochondrial unfolded protein response; oscp/atp-3
    DOI:  https://doi.org/10.7554/eLife.63453
  6. Geroscience. 2021 Aug 31.
      The overarching mission of the Einstein-Nathan Shock Center (E-NSC) is to make scientific discoveries in geroscience, leveraging on the expertise in our center in 6 out of the 7 pillars of aging, and to translate their effects towards drug discovery. The relevance of this basic biology of aging discoveries to humans will be confirmed through the unique gero-human resource at E-NSC. This is achieved through services provided by E-NSC, connectivity among its members, attracting worldwide investigators, and providing them with the opportunities to become future leaders. The two central components of the E-NSC are (a) cutting-edge research programs and (b) unique E-NSC research support cores. E-NSC scientists lead NIH-supported cutting-edge research programs that integrate key hallmarks of aging including proteostasis/autophagy, metabolism/inflammaging, genetic/epigenetics, stem cells/regeneration, and translational aging/longevity. Since the inception of the E-NSC, the well-integrated, collaborative, and innovative nature of the multiple supporting state-of-the-art E-NSC research cores form the bedrock of research success at the E-NSC. The three state-of-the-art E-NSC research cores, (i) Proteostasis of Aging Core (PAC), (ii) the Health Span Core (HSC), and (iii) the Human Multi-Omics Core (HMOC), have allowed impressive expansion of translational biological research programs. Expansion was facilitated through the wealth of data coming from genomics/proteomics and metabolomic analysis on human longevity studies, due to access to a variety of biological samples from elderly subjects in clinical trials with aging-targeting drugs, and new drug design services via the PAC to target the hallmarks of aging.
    Keywords:  Autophagy; Genomics; Health span; Metabolism; Parabiosis; Proteomics; Proteostasis
    DOI:  https://doi.org/10.1007/s11357-021-00428-9
  7. Blood. 2021 Sep 01. pii: blood.2021012775. [Epub ahead of print]
      The BCL2 inhibitor venetoclax has established therapeutic roles in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia. As BCL2 is an important determinant of survival of both myeloid progenitor and B cells, we investigated whether clinical and molecular abnormalities arise in the myeloid compartment during long-term continuous venetoclax treatment for CLL in 89 patients (87 with relapsed/refractory CLL). Over a median follow-up of 75 (range 21-98) months, persistent cytopenias (³ 1 of neutropenia, thrombocytopenia, anemia) lasting ³4 months and unrelated to CLL occurred in 25 patients (28%). Of these patients, 20 (80%) displayed clonal hematopoiesis, including 10 with therapy-related myeloid neoplasms (tMNs). tMNs occurred exclusively in patients previously exposed to fludarabine-alkylator combination therapy with a cumulative 5-year incidence of 10.4% after venetoclax initiation, consistent with rates reported for patients exposed to fludarabine-alkylator combination therapy without venetoclax. To determine whether the altered myelopoiesis reflected acquisition of mutations, we analyzed samples from patients with no or minimal bone marrow CLL burden (n = 41). Mutations in the apoptosis effector BAX were identified in 32% (13/41). In cellular assays, C-terminal BAX mutants abrogated outer mitochondrial membrane localization of BAX and engendered resistance to venetoclax killing. BAX-mutated clonal hematopoiesis occurred independently of prior fludarabine-alkylator combination therapy exposure and was not associated with tMNs. Single cell sequencing revealed clonal co-occurrence of mutations in BAX with DNMT3A or ASXL1. We also observed simultaneous BCL2 mutations within CLL cells and BAX mutations in the myeloid compartment of the same patients, indicating lineage-specific adaptation to venetoclax therapy.
    DOI:  https://doi.org/10.1182/blood.2021012775
  8. J Am Heart Assoc. 2021 Sep 02. e022187
      
    Keywords:  Editorials; elderly individuals; frailty; heart failure; social frailty
    DOI:  https://doi.org/10.1161/JAHA.121.022187
  9. Age Ageing. 2021 Aug 28. pii: afab177. [Epub ahead of print]
       BACKGROUND: oral frailty (OFr) may be called a syndrome lacking a consensus on its definition.
    OBJECTIVE: the aim was to prove the relationship between OFr to the phenotype of frailty, general health and nutrition in long-term care.
    DESIGN: the FINnish ORAL Health Study in Long-Term Care study is a cross-sectional clinical research comprising findings on oral and general health and nutrition.
    SETTING: participants were divided into groups according to the number of OFr signs: Group 1 (0-1 sign), Group 2 (2-4 signs) and Group 3 (5-6 signs).
    SUBJECTS: the study includes data on 349 older residents of long-term care facilities in Helsinki, Finland.
    METHODS: frailty status was defined according to Fried's frailty phenotype. OFr was evaluated with six signs: dry mouth, diet of pureed or soft food, residue of food on oral surfaces, unclear speech, inability to keep mouth open during the clinical oral examination and pain expression during the examination.
    RESULTS: a significant linear relationship across the OFr groups with Fried's frailty phenotype was found (P for linearity = 0.008, adjusted by gender and age). A linear trend existed between OFr groups and general health; prevalence of dementia and malnutrition increased from Group 1 to Group 3. The need for help with eating and oral hygiene procedures increased from Group 1 to Group 3. Moreover, OFr had a linear relationship with chewing and swallowing difficulties.
    CONCLUSIONS: OFr is related to Fried's frailty phenotype, general health, nutrition and need for help with daily activities.
    Keywords:  frailty; long-term facilities; older adults; older people; oral frailty
    DOI:  https://doi.org/10.1093/ageing/afab177
  10. Cold Spring Harb Perspect Biol. 2021 Sep 01. pii: a040576. [Epub ahead of print]13(9):
      
    DOI:  https://doi.org/10.1101/cshperspect.a040576
  11. Rev Panam Salud Publica. 2021 ;45 e116
      
    Keywords:  Aging; Americas; Caribbean region; Latin America; healthy aging
    DOI:  https://doi.org/10.26633/RPSP.2021.116
  12. JAMA Intern Med. 2021 Aug 30.
       Importance: Using the same level of estimated glomerular filtration rate (eGFR) to define chronic kidney disease (CKD) regardless of patient age may classify many elderly people with a normal physiological age-related eGFR decline as having a disease.
    Objective: To compare the outcomes associated with CKD as defined by a fixed vs an age-adapted eGFR threshold.
    Design, Setting, and Participants: This population-based cohort study was conducted in Alberta, Canada and used linked administrative and laboratory data from adults with incident CKD from April 1, 2009, to March 31, 2017, defined by a sustained reduction in eGFR for longer than 3 months below a fixed or an age-adapted eGFR threshold. Non-CKD controls were defined as being 65 years or older with a sustained eGFR of 60 to 89 mL/min/1.73 m2 for longer than 3 months and normal/mild albuminuria. The follow-up ended on March 31, 2019. The data were analyzed from February to April 2020.
    Exposures: A fixed eGFR threshold of 60 vs thresholds of 75, 60, and 45 mL/min/1.73 m2 for age younger than 40, 40 to 64, and 65 years or older, respectively.
    Main Outcomes and Measures: Competing risks of kidney failure (kidney replacement initiation or sustained eGFR <15 mL/min/1.73 m2 for >3 months) and death without kidney failure.
    Results: The fixed and age-adapted CKD cohorts included 127 132 (69 546 women [54.7%], 57 586 men [45.3%]) and 81 209 adults (44 582 women [54.9%], 36 627 men [45.1%]), respectively (537 vs 343 new cases per 100 000 person-years). The fixed-threshold cohort had lower risks of kidney failure (1.7% vs 3.0% at 5 years) and death (21.9% vs 25.4%) than the age-adapted cohort. A total of 53 906 adults were included in both cohorts. Of the individuals included in the fixed-threshold cohort only (n = 72 703), 54 342 (75%) were 65 years or older and had baseline eGFR of 45 to 59 mL/min/1.73 m2 with normal/mild albuminuria. The 5-year risks of kidney failure and death among these elderly people were similar to those of non-CKD controls, with a risk of kidney failure of 0.12% or less in both groups across all age categories and a risk of death at 69, 122, 279, and 935 times higher than the risk of kidney failure for 65 to 69, 70 to 74, 75 to 79, and 80 years or older, respectively.
    Conclusions and Relevance: This cohort study of adults with CKD suggests that the current criteria for CKD that use the same eGFR threshold for all ages may result in overestimation of the CKD burden in an aging population, overdiagnosis, and unnecessary interventions in many elderly people who have age-related loss of eGFR.
    DOI:  https://doi.org/10.1001/jamainternmed.2021.4813
  13. Ther Adv Hematol. 2021 ;12 20406207211040335
      In recent years, one of the most successful advances in treating acute myeloid leukaemia (AML) has been the combination of the B-cell lymphoma 2 (BCL-2) inhibitor venetoclax with hypomethylating agents (decitabine or azacytidine). This combination treatment has an accelerated approval by the Food and Drug Administration for newly diagnosed AML adults who are 75 years of age or older or who have comorbidities and are not eligible to receive intensive induction chemotherapy. AML is the most common form of acute leukaemia in adults, with a median age at diagnosis of 68 years. Consequently, most of the patients included in the studies are elderly. Traditionally, young patients achieve higher remission rates compared with the elderly AML population. Although venetoclax combination therapy could become a treatment option for treating young patients with relapsed/refractory AML, this regimen has not been systematically tested in this setting. In this study, we summarize the currently available evidence on the treatment of venetoclax in combination with hypomethylating agents for the treatment of young relapsed/refractory AML patients, in addition to our experience in clinical practice with two case reports. Venetoclax, combined with hypomethylating agents, seems to be an effective option for young relapsed/refractory AML patients. However, due to the poor quality of the evidence, additional well-designed studies with greater numbers of patients are needed to confirm the effectiveness and safety of venetoclax combination regimens for this population.
    Keywords:  acute myeloid leukaemia; hypomethylating agent; refractory; relapsed; venetoclax; young patients
    DOI:  https://doi.org/10.1177/20406207211040335
  14. J Clin Invest. 2021 Aug 31. pii: 148329. [Epub ahead of print]
      The heterogeneity of human hematopoietic stem (HSCs) and progenitor cells (HPCs) under stress conditions such as ex vivo expansion is poorly understood. Here we report that the frequencies of SCID repopulating cells (SRCs) were greatly decreased in cord blood(CB)CD34+ HSCs and HPCs upon ex vivo culture. Transcriptome analysis and metabolic profiling demonstrated that mitochondrial oxidative stress of human CB HSCs and HPCs notably increased along with loss of stemness. Limiting dilution analysis (LDA) revealed that functional human HSCs were enriched in cell populations with low levels of mitochondrial reactive oxygen species (mitoROS) during ex vivo culture. Using single cell RNA sequencing (scRNA-seq) analysis of mitoROS low cell population, we demonstrated that functional HSCs were substantially enriched in the Adhesion G protein-coupled receptor G1 positive (ADGRG1+) population of CD34+CD133+ CB cells upon ex vivo expansion stress. GSEA analysis revealed that HSC signature genes including MSI2 and MLLT3 are enriched in CD34+CD133+ ADGRG1+ CB HSCs. Our study reveals that ADGRG1 enriches for functional human HSCs under oxidative stress during ex vivo culture, which can be a reliable target for drug screening of agonists of HSC expansion.
    Keywords:  Cell stress; Hematopoietic stem cells; Human stem cells; Stem cells
    DOI:  https://doi.org/10.1172/JCI148329
  15. J Food Biochem. 2021 Sep 01. e13902
      The immune function of the human body is highly influenced by the dietary intake of certain nutrients and bioactive compounds present in foods. The preventive effects of these bioactive ingredients against various diseases have been well investigated. Functional foods are consumed across various diverse cultures, in some form or the other, which provide benefits greater than the basic nutritional needs. Novel functional foods are being developed using novel bioactive ingredients such as probiotics, polyunsaturated fatty acids, and various phytoconstituents, which have a range of immunomodulatory properties. Apart from immunomodulation, these ingredients also affect immunity by their antioxidant, antibacterial, and antiviral properties. The global pandemic of Severe Acute Respiratory Syndrome Coronavirus-2 has forced the scientific community to race against time to find a proper and effective drug or a vaccine. In this review, various non-pharmacological interventions using nutraceuticals and functional foods have been discussed. PRACTICAL APPLICATIONS: Despite a plethora of research being undertaken to understand the immunity boosting properties of the various bioactive present in food, the findings are not translating to nutraceutical products in the market. Immunity has proved to be one of the most important factors for the health and well-being of an individual, especially when the world has been under the grip of the novel coronavirus Severe Acute Respiratory Syndrome Coronavirus-2. The anti-inflammatory properties of various nutraceuticals can come out as potential inhibitors of the various inflammatory processes such as cytokine storms, usually being observed in COVID 19. This review gives an insight into how various nutraceuticals can help in the prevention of various diseases through different mechanisms. The lack of awareness and proper clinical trials pose a challenge to the nutraceutical industry. This review will help and encourage researchers to further design and develop various functional foods, which might help in building immunity.
    Keywords:  PUFAs; SARS-CoV-2; antiviral; beta-glucans; immunomodulation; phytochemicals
    DOI:  https://doi.org/10.1111/jfbc.13902
  16. Leukemia. 2021 Aug 30.
      Acute myeloid leukemia (AML) is considered a poor prognosis malignancy where patients exhibit altered glucose metabolism and stem cell signatures that contribute to AML growth and maintenance. Here, we report that the epigenetic factor, Ten-Eleven Translocation 3 (TET3) dioxygenase is overexpressed in AML patients and functionally validated human leukemic stem cells (LSCs), is required for leukemic growth by virtue of its regulation of glucose metabolism in AML cells. In human AML cells, TET3 maintains 5-hydroxymethylcytosine (5hmC) epigenetic marks and expression of early myeloid progenitor program, critical glucose metabolism and STAT5A signaling pathway genes, which also positively correlate with TET3 expression in AML patients. Consequently, TET3 depletion impedes hexokinase activity and L-Lactate production in AML cells. Conversely, overexpression of TET3 in healthy human hematopoietic stem progenitors (HSPCs) upregulates the expression of glucose metabolism, STAT5A signaling and AML associated genes, and impairs normal HSPC lineage differentiation in vitro. Finally, TET3 depletion renders AML cells highly sensitive to blockage of the TET3 downstream pathways glycolysis and STAT5 signaling via the combination of 2-Deoxy-D-glucose and STAT5 inhibitor which preferentially targets AML cells but spares healthy CD34+ HSPCs.
    DOI:  https://doi.org/10.1038/s41375-021-01390-3
  17. Rev Panam Salud Publica. 2021 ;45 e113
      
    Keywords:  Aged; Caribbean region; Latin America; healthy aging
    DOI:  https://doi.org/10.26633/RPSP.2021.113
  18. Cell Metab. 2021 Aug 26. pii: S1550-4131(21)00367-3. [Epub ahead of print]
      Aging impairs the integrated immunometabolic responses, which have evolved to maintain core body temperature in homeotherms to survive cold stress, infections, and dietary restriction. Adipose tissue inflammation regulates the thermogenic stress response, but how adipose tissue-resident cells instigate thermogenic failure in the aged are unknown. Here, we define alterations in the adipose-resident immune system and identify that type 2 innate lymphoid cells (ILC2s) are lost in aging. Restoration of ILC2 numbers in aged mice to levels seen in adults through IL-33 supplementation failed to rescue old mice from metabolic impairment and increased cold-induced lethality. Transcriptomic analyses revealed intrinsic defects in aged ILC2, and adoptive transfer of adult ILC2s are sufficient to protect old mice against cold. Thus, the functional defects in adipose ILC2s during aging drive thermogenic failure.
    Keywords:  IL-33; ILC2; adipose; aging; inflammation; metabolism; thermogenesis
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.004
  19. J Gerontol A Biol Sci Med Sci. 2021 Sep 03. pii: glab259. [Epub ahead of print]
      According to the free radical theory of aging, accumulation of reactive oxygen species (ROS) within mitochondria throughout lifespan leads to impairment of the main biological macromolecules as DNA, lipids and proteins, which might be at the basis of premature aging. One way to test experimentally such a hypothesis consists in intervention studies using antioxidant nutrients aimed at limiting or inhibiting ROS production that should be able to reduce the aging rate and disease pathogenesis. Grape seed flour (GSF) contains high level of phytochemicals among which bioactive polyphenols exhibit numerous biological properties and beneficial health effects as antioxidant, anti-inflammatory, anti-carcinogenic, multi-organ (heart, liver, kidney, and brain among others) protective. The present study aimed at testing the ability of high dosing GSF (4 g/kg bw) used as a nutritional supplement to slow down aging and prolong lifespan of Wistar rats when administered from early life (one month-old animals) till their natural death. Data clearly show that high dose GSF extends organism longevity and healthspan by improving multi-organ damages, systemic fuelling metabolism declines, and alleviated oxidative stress and inflammation in aging rats. Our data support the extending longevity effect of grape polyphenols especially when used as high dosing nutritional supplement or as natural medicine whose appropriate galenic form as solid lipid nanoformulation, is currently under investigation.
    Keywords:  Grape seed flour; Inflammation; Longevity; Oxidative stress
    DOI:  https://doi.org/10.1093/gerona/glab259
  20. Cancer Discov. 2021 Aug 30. pii: candisc.0032.2021. [Epub ahead of print]
      Ineffective hematopoiesis is a fundamental process leading to the pathogenesis of myelodysplastic syndromes (MDS). However, the pathobiological mediators of ineffective hematopoiesis in MDS remain unclear. Here, we demonstrated that overwhelming mitochondrial fragmentation in mutant hematopoietic stem cells and progenitors (HSC/Ps) triggers ineffective hematopoiesis in MDS. Mouse modeling of CBL exon-deletion with RUNX1 mutants, previously unreported co-mutations in MDS patients, recapitulated not only clinically relevant MDS phenotypes but also a distinct MDS-related gene signature. Mechanistically, dynamin-related protein 1 (DRP1)-dependent excessive mitochondrial fragmentation in HSC/Ps led to excessive ROS production, induced inflammatory signaling activation, and promoted subsequent dysplasia formation and impairment of granulopoiesis. Mitochondrial fragmentation was generally observed in patients with MDS. Pharmacological inhibition of DRP1 attenuated mitochondrial fragmentation and rescued ineffective hematopoiesis phenotypes in MDS mice. These findings provide mechanistic insights into ineffective hematopoiesis and indicate that dysregulated mitochondrial dynamics could be a therapeutic target for bone marrow failure in MDS.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0032
  21. Cell Rep. 2021 Aug 31. pii: S2211-1247(21)01077-9. [Epub ahead of print]36(9): 109634
      Fibroblasts residing in the connective tissues constitute the stem cell niche, particularly in organs such as skin. Although the effect of fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unresolved. We report a mechanism of redox-dependent activation of transcription factor JunB, which, through concomitant upregulation of p16INK4A and repression of insulin growth factor-1 (IGF-1), initiates the installment of fibroblast senescence. Fibroblast senescence profoundly disrupts the metabolic and structural niche, and its essential interactions with different stem cells thus enforces depletion of stem cells pools and skin tissue decline. In fact, silencing of JunB in a fibroblast-niche-specific manner-by reinstatement of IGF-1 and p16 levels-restores skin stem cell pools and overall skin tissue integrity. Here, we report a role of JunB in the control of connective tissue niche and identified targets to combat skin aging and associated pathologies.
    Keywords:  IGF-1; JunB; aging; fibroblasts; p16(INK4A); redox imbalance; skin; stem cell niche
    DOI:  https://doi.org/10.1016/j.celrep.2021.109634