bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–09–26
forty papers selected by
Ayesh Seneviratne, University of Toronto



  1. NPJ Regen Med. 2021 Sep 23. 6(1): 57
      Life expectancy has increased by three decades since the mid-twentieth century. Parallel healthspan expansion has however not followed, largely impeded by the pandemic of chronic diseases afflicting a growing older population. The lag in quality of life is a recognized challenge that calls for prioritization of disease-free longevity. Contemporary communal, clinical and research trends aspiring to extend the health horizon are here outlined in the context of an evolving epidemiology. A shared action integrating public and societal endeavors with emerging interventions that target age-related multimorbidity and frailty is needed. A multidimensional buildout of a curative perspective, boosted by modern anti-senescent and regenerative technology with augmented decision making, would require dedicated resources and cost-effective validation to responsibly bridge the healthspan-lifespan gap for a future of equitable global wellbeing.
    DOI:  https://doi.org/10.1038/s41536-021-00169-5
  2. Blood. 2021 Jun 03. pii: blood.2020010483. [Epub ahead of print]
      While clonal hematopoiesis (CH) can precede the development of acute myeloid leukemia (AML), it can also persist after achieving remission. Long-term clonal dynamics and clinical implications of persistent CH are not well understood. Here, we studied the prevalence, dynamics and clinical implications of post-remission CH in 164 AML patients who attained complete remission after induction chemotherapies. Post-remission CH was identified in 79 (49%) patients. Post-remission CH persisted long-term in 91% of the trackable patients despite treatment with various types of consolidation and maintenance therapies. Post-remission CH was eradicated in 20 out of 21 (95%) patients who underwent allogeneic stem cell transplant. While patients with post-remission CH as a group had comparable hematopoiesis with those without it, patients with persistent TET2 mutations showed significant neutropenia long-term. Post-remission CH had little impact on relapse risk, non-relapse mortality, and incidence of atherosclerotic cardiovascular disease, although the clinical impact of post-CR CH was heterogeneous among different mutations. These data suggest that while residual clonal hematopoietic stem cells (HSCs) are generally resistant to consolidation and maintenance therapies, they retain the ability to maintain normal hematopoiesis and have little impact on clinical outcomes, although larger study is needed to dissect the gene-specific heterogeneity.
    DOI:  https://doi.org/10.1182/blood.2020010483
  3. Blood Adv. 2021 Sep 24. pii: bloodadvances.2021005236. [Epub ahead of print]
      We have recently identified the G protein-coupled neuropeptide receptor Calcitonin receptor-like (CALCRL) as an independent prognostic biomarker and a therapeutic target in more than 1500 adult patients with acute myeloid leukemia (AML). Here, we confirmed CALCRL expression as a prognostic factor in a cohort of 284 pediatric patients with AML. High CALCRL expression was independently associated with event free survival (EFS) (hazard ratio [HR], 1.87; 95% confidence interval [CI], 1.36-2.57; P=0.0001), overall survival (OS) (HR, 1.55; 95% [CI], 1.06-2.27; P=0.025) and cumulative incidence of relapse (CIR) (HR, 2.10; 95% CI, 1.49-1.96; P<0.0001) when adjusting for age, white blood cell count and genetic risk. Despite its association with leukemia stem cell (LSC) signatures, CALCRL expression remained associated with all endpoints when compared to the LSC17 score. The strong association of CALCRL expression with the risk of relapse also in the pediatric population supports its role as novel age-independent master regulator of relapse-initiating drug-tolerant AML cells in humans.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005236
  4. Cell Syst. 2021 Sep 16. pii: S2405-4712(21)00338-0. [Epub ahead of print]
      NAD+ is an essential coenzyme for all living cells. NAD+ concentrations decline with age, but whether this reflects impaired production or accelerated consumption remains unclear. We employed isotope tracing and mass spectrometry to probe age-related changes in NAD+ metabolism across tissues. In aged mice, we observed modest tissue NAD+ depletion (median decrease ∼30%). Circulating NAD+ precursors were not significantly changed, and isotope tracing showed the unimpaired synthesis of nicotinamide from tryptophan. In most tissues of aged mice, turnover of the smaller tissue NAD+ pool was modestly faster such that absolute NAD+ biosynthetic flux was maintained, consistent with more active NAD+-consuming enzymes. Calorie restriction partially mitigated age-associated NAD+ decline by decreasing consumption. Acute inflammatory stress induced by LPS decreased NAD+ by impairing synthesis in both young and aged mice. Thus, the decline in NAD+ with normal aging is relatively subtle and occurs despite maintained NAD+ production, likely due to increased consumption.
    Keywords:  CD38; NAD; NADH; PARP; PARP1; SIRT1; aging; flux; mononucleotide; niacin; nicotinamide; redox; riboside; sirtuins
    DOI:  https://doi.org/10.1016/j.cels.2021.09.001
  5. Blood Adv. 2021 Sep 23. pii: bloodadvances.2021005089. [Epub ahead of print]
      Development of normal blood cells is often suppressed in juvenile myelomonocytic leukemia (JMML), a myeloproliferative neoplasm (MPN) of childhood, causing complications and impacting therapeutic outcomes. However, the mechanism underlying this phenomenon remains uncharacterized. To address this question, we induced the most common mutation identified in JMML (Ptpn11E76K) specifically in the myeloid lineage with hematopoietic stem cells (HSCs) spared. These mice uniformly developed a JMML-like MPN. Importantly, HSCs in the same bone marrow (BM) microenvironment were aberrantly activated and differentiated at the expense of self-renewal. As a result, HSCs lost quiescence and became exhausted. A similar result was observed in wild-type (WT) donor HSCs when co-transplanted with Ptpn11E76K/+ BM cells into WT mice. Co-culture testing demonstrated that JMML/MPN cells robustly accelerated differentiation in mouse and human normal hematopoietic stem/progenitor cells. Cytokine profiling revealed that Ptpn11E76K/+ MPN cells produced excessive IL-1β, but not IL-6, TNF-α, IFN-γ, IL-1α, or other inflammatory cytokines. Depletion of the IL-1β receptor effectively restored HSC quiescence, normalized their pool size, and rescued them from exhaustion in Ptpn11E76K/+/IL-1R-/- double mutant mice. These findings suggest IL-1β signaling as a potential therapeutic target for preserving normal hematopoietic development in JMML.
    DOI:  https://doi.org/10.1182/bloodadvances.2021005089
  6. Cell Metab. 2021 Sep 18. pii: S1550-4131(21)00418-6. [Epub ahead of print]
      Dietary restriction (DR) has long been viewed as the most robust nongenetic means to extend lifespan and healthspan. Many aging-associated mechanisms are nutrient responsive, but despite the ubiquitous functions of these pathways, the benefits of DR often vary among individuals and even among tissues within an individual, challenging the aging research field. Furthermore, it is often assumed that lifespan interventions like DR will also extend healthspan, which is thus often ignored in aging studies. In this review, we provide an overview of DR as an intervention and discuss the mechanisms by which it affects lifespan and various healthspan measures. We also review studies that demonstrate exceptions to the standing paradigm of DR being beneficial, thus raising new questions that future studies must address. We detail critical factors for the proposed field of precision nutrigeroscience, which would utilize individualized treatments and predict outcomes using biomarkers based on genotype, sex, tissue, and age.
    Keywords:  aging; biomarkers; caloric restriction; dietary restriction; healthspan; lifespan; precision medicine; precision nutrigeroscience; senescence
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.018
  7. Clin Nutr. 2021 Aug 10. pii: S0261-5614(21)00367-8. [Epub ahead of print]40(10): 5269-5277
       OBJECTIVE: To examine associations between intake of simple sugars and cancer incidence, cancer mortality, and total mortality in a prospective cohort study based on the PREDIMED trial conducted from 2003 to 2010.
    METHODS: Participants were older individuals at high cardiovascular risk. Exposures were total sugar, glucose and fructose from solid or liquid sources, and fructose from fruit and 100% fruit juice. Cancer incidence was the primary outcome; cancer mortality and all-cause mortality were secondary outcomes. Multivariable-adjusted, time-dependent Cox proportional hazard models were used.
    RESULTS: Of 7447 individuals enrolled, 7056 (94.7%) were included (57.6% women, aged 67.0 ± 6.2 years). 534 incident cancers with 152 cancer deaths and 409 all-cause deaths were recorded after a median follow-up of 6 years. Intake of simple sugars in solid form was unrelated to outcomes. Higher cancer incidence was found per 5 g/day increase in intake of liquid sugars, with multivariable-adjusted HR of 1.08 (95% CI, 1.03-1.13) for total liquid sugar, 1.19 (95% CI, 1.07-1.31) for liquid glucose, 1.14 (95% CI, 1.05-1.23) for liquid fructose, and 1.39 (95% CI, 1.10-1.74) for fructose from fruit juice. Cancer and all-cause mortality increased to a similar extent with intake of all sugars in liquid form. In categorical models, cancer risk was dose-related for all liquid sugars.
    CONCLUSIONS: Simple sugar intake in drinks and fruit juice was associated with an increased risk of overall cancer incidence and mortality and all-cause mortality. This suggests that sugary beverages are a modifiable risk factor for cancer and all-cause mortality.
    Keywords:  Dietary sugar; Fructose; Fruit juice; Glucose; Liquid form; Observational study
    DOI:  https://doi.org/10.1016/j.clnu.2021.07.031
  8. J Nutr Health Aging. 2021 ;25(8): 949-950
      
    Keywords:  Robotics; aging; robotic caregivers
    DOI:  https://doi.org/10.1007/s12603-021-1658-7
  9. Aging Med (Milton). 2019 Dec;2(4): 216-222
      Immunosenescence, also known as immune aging, refers to the degeneration, compensation, and reconstruction of the immune system with aging. Immune aging is an important factor in the increased susceptibility of the elderly to infectious diseases, malignant tumors, and a variety of chronic diseases and has long been a hotspot in geriatrics and immunology research. In this paper, the characteristics and progression of immune aging are briefly reviewed for clinicians' reference.
    Keywords:  immune aging; immune cells; immune organs; immunosenescence
    DOI:  https://doi.org/10.1002/agm2.12089
  10. J Frailty Aging. 2021 ;10(4): 313-319
      The find solutions for optimizing healthy aging and increase health span is one of the main challenges for our society. A novel healthcare model based on integration and a shift on research and care towards the maintenance of optimal functional levels are now seen as priorities by the WHO. To address this issue, an integrative global strategy mixing longitudinal and experimental cohorts with an innovative transverse understanding of physiological functioning is missing. While the current approach to the biology of aging is mainly focused on parenchymal cells, we propose that age-related loss of function is largely determined by three elements which constitute the general ground supporting the different specific parenchyma: i.e. the stroma, the immune system and metabolism. Such strategy that is implemented in INSPIRE projects can strongly help to find a composite biomarker capable of predicting changes in capacity across the life course with thresholds signalling frailty and care dependence.
    Keywords:  Biomarkers; dependence; frailty; healthy aging
    DOI:  https://doi.org/10.14283/jfa.2021.15
  11. Transplant Cell Ther. 2021 Sep 16. pii: S2666-6367(21)01225-2. [Epub ahead of print]
       BACKGROUND: In the COVID-19 pandemic era, the numbers of haploidentical hematopoietic cell transplantation (HCT) with peripheral blood (PB) versus bone marrow (BM) grafts increased significantly, which may be associated with adverse outcomes.
    METHODS: We compared outcomes of BM vs PB grafts in patients ≥18 years with hematological malignancy who underwent T-cell replete haploidentical HCT and graft-versus-host disease (GVHD) prophylaxis with post-transplantation cyclophosphamide, tacrolimus and mycophenolate mofetil.
    FINDINGS: Of 264 patients, 180 (68%) received BM and 84 (32%) received PB graft. Median age was 50 years in both groups. Majority (n=199, 75%) received reduced-intensity conditioning. More patients had acute leukemia or myelodysplastic syndrome in BM (n=152, 85%) than PB (n=46, 55%), p<0.01. The median time to neutrophil and platelet engraftment, and incidence of grade II-IV and III-IV acute GVHD (aGVHD) was comparable in both groups. Among grade II-IV aGVHD, steroid-refractory aGVHD (SR-aGVHD) was 9% (95% CI 5-18) in BM vs 32% (95% CI 19-54) in PB; hazard ratio (HR) 3.7, 95% CI 1.5-9.3, p=0.006. Chronic GVHD (cGVHD) was 8% (95% CI 4-13) vs 22% (95% CI 14-36); HR 3.0, 95% CI 1.4-6.6, p=0.005 and systemic therapy-requiring cGVHD was 2.5% (95% CI 1-7) vs 14% (95% CI 7-27), respectively; HR 5.6, 95% CI 1.7-18, p=0.004 at 1 year. PB group had a significantly higher risk of bacterial and viral infections with no appreciable advantage in the duration of hospitalization, immune reconstitution, relapse, non-relapse mortality, or survival.
    INTERPRETATION: Our data suggest the use of BM over PB graft for haploidentical HCT.
    DOI:  https://doi.org/10.1016/j.jtct.2021.09.003
  12. Aging (Albany NY). 2021 Sep 20. 13(undefined):
      Aging is debatably one of the biggest mysteries for humanity, a process consisting of myriads of genetic, molecular, environmental, and stochastic deleterious events, leading to a progressive loss of organism functionality. Aging research currently lacks a common conceptual framework, and one challenge in establishing it is the fact that aging is a highly complex process. To help develop a framework of standard aging rules, we suggest the use of deductive reasoning based on particle physics' principles. Specifically, the principles that we suggest applying to study aging are discreteness of processes, transformation as a result of interaction, and understanding of threshold. Using this framework, biological aging may be described as a sequence of highly discrete molecular transformations caused by a combination of various specific internal and external factors. Internal organismal function and interaction of an organism with the environment result in chronic accumulation of molecular damage and other deleterious consequences of metabolism and the consequent loss of system's functionality. The loss of functionality occurs as a series of thresholds the organism reaches before it turns into an utterly non-functional state. We discuss how having a common ground may benefit aging research, introduce the logic of new principles and analyze specific examples of how this framework could be used to study aging and design longevity interventions.
    Keywords:  aging; damage; framework; particle physics; theory
    DOI:  https://doi.org/10.18632/aging.203555
  13. J Natl Compr Canc Netw. 2021 Sep 20. pii: jnccnlw1909. [Epub ahead of print]19(9): 1111-1113
      
    DOI:  https://doi.org/10.6004/jnccn.2021.7086
  14. Am J Clin Nutr. 2021 Sep 24. pii: nqab317. [Epub ahead of print]
       BACKGROUND: Frailty occurs in 10-15% of community-living older adults and inflammation is a key determinant of frailty. Though diet is a modulator of inflammation, there are few prospective studies elucidating the role of diet-associated inflammation on frailty.
    OBJECTIVE: To determine whether a pro-inflammatory diet was associated with increased odds of frailty in adults from the Framingham Heart Study (FHS).
    DESIGN AND METHODS: This study is nested in a prospective cohort that included individuals without frailty. Diet was assessed in 1998-2001 using a valid food frequency questionnaire (FFQ) and frailty was measured in 2011-2014. FFQ-derived energy-adjusted dietary inflammatory index (E-DII®) scores were computed, with higher E-DII scores indicating a more pro-inflammatory diet. Frailty was defined as fulfilling ≥3 of 5 Fried Phenotype criteria. Information on potential mediators, serum interleukin-6 and C-reactive protein was obtained in 1998-2001. Logistic regression estimated odds ratios (OR) and 95% confidence intervals (95% CI) for E-DII (as continuous and in quartiles) and frailty onset adjusting for relevant confounders.
    RESULTS: Of 1,701 individuals without frailty at baseline (mean age = 58 years, SD = 8, range: 33-81; 55% female), 224 developed frailty (13% incidence) over ∼12 years. Mean E-DII score was -1.95 (SD = 2.20; range: -6.71 to +5.40). After adjusting for relevant confounders, a one-unit higher E-DII score was associated with 16% increased odds of developing frailty (95% CI = 1.07, 1.25). In categorical analyses, participants in the highest (pro-inflammatory) vs. lowest quartile of E-DII had >2-fold increased odds of frailty (ORquartile4vs.1 = 2.22, 95% CI = 1.37, 3.60, Ptrend<0.01). Interleukin-6 and C-reactive protein were not major contributors in the pathway.
    CONCLUSIONS: In this cohort of middle-aged and older adults, a pro-inflammatory diet was associated with increased odds of frailty over ∼12 years of follow-up. Trials designed to increase consumption of anti-inflammatory foods for frailty prevention are warranted.Clinical registry number and website: Not applicable.
    Keywords:  aging; community-based; diet; epidemiology; food frequency questionnaire; frailty; inflammation; prospective cohort study
    DOI:  https://doi.org/10.1093/ajcn/nqab317
  15. Science. 2021 09 24. 373(6562): 1439-1440
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.abl8679
  16. Front Nutr. 2021 ;8 717343
      The human diet and dietary patterns are closely linked to the health status. High-calorie Western-style diets have increasingly come under scrutiny as their caloric load and composition contribute to the development of non-communicable diseases, such as diabetes, cancer, obesity, and cardiovascular disorders. On the other hand, calorie-reduced and health-promoting diets have shown promising results in maintaining health and reducing disease burden throughout aging. More recently, pharmacological Caloric Restriction Mimetics (CRMs) have gained interest of the public and scientific community as promising candidates that mimic some of the myriad of effects induced by caloric restriction. Importantly, many of the CRM candidates activate autophagy, prolong life- and healthspan in model organisms and ameliorate diverse disease symptoms without the need to cut calories. Among others, glycolytic inhibitors (e.g., D-allulose, D-glucosamine), hydroxycitric acid, NAD+ precursors, polyamines (e.g., spermidine), polyphenols (e.g., resveratrol, dimethoxychalcones, curcumin, EGCG, quercetin) and salicylic acid qualify as CRM candidates, which are naturally available via foods and beverages. However, it is yet unclear how these bioactive substances contribute to the benefits of healthy diets. In this review, we thus discuss dietary sources, availability and intake levels of dietary CRMs. Finally, since translational research on CRMs has entered the clinical stage, we provide a summary of their effects in clinical trials.
    Keywords:  caloric restriction mimetics; clinical trials; healthy diet; nutrition; polyamines; polyphenols; spermidine
    DOI:  https://doi.org/10.3389/fnut.2021.717343
  17. Cell Death Differ. 2021 Sep 23.
      Developing methods to improve the regenerative capacity of somatic stem cells (SSCs) is a major challenge in regenerative medicine. Here, we propose the forced expression of LIN28A as a method to modulate cellular metabolism, which in turn enhances self-renewal, differentiation capacities, and engraftment after transplantation of various human SSCs. Mechanistically, in undifferentiated/proliferating SSCs, LIN28A induced metabolic reprogramming from oxidative phosphorylation (OxPhos) to glycolysis by activating PDK1-mediated glycolysis-TCA/OxPhos uncoupling. Mitochondria were also reprogrammed into healthy/fused mitochondria with improved functional capacity. The reprogramming allows SSCs to undergo cell proliferation more extensively with low levels of oxidative and mitochondrial stress. When the PDK1-mediated uncoupling was untethered upon differentiation, LIN28A-SSCs differentiated more efficiently with an increase of OxPhos by utilizing the reprogrammed mitochondria. This study provides mechanistic and practical approaches of utilizing LIN28A and metabolic reprogramming in order to improve SSCs utility in regenerative medicine.
    DOI:  https://doi.org/10.1038/s41418-021-00873-1
  18. BMJ Open. 2021 Sep 23. 11(9): e046713
      The median age for total hip arthroplasty (THA) is over 70 years with the corollary that many individuals have multiple multimorbidities. Despite the predicted improvement in quality of life, THA might be denied even to those with low levels of multimorbidity.
    OBJECTIVE: To evaluate how pre-existing levels of multimorbidity influence the likelihood and timing of THA.
    SETTING: Longitudinal record linkage study of a UK sample linking their primary care to their secondary care records.
    PARTICIPANTS: A total of 28 025 patients were included, based on the recording of the diagnosis of hip osteoarthritis in a national primary care register, Clinical Practice Research Datalink. Data were extracted from the database on background health and morbidity status using five different constructs: Charlson Comorbidity Index, Electronic Frailty Index and counts of chronic diseases (from list of 17), prescribed medications and number of primary care visits prior to recording of osteoarthritis.
    OUTCOME MEASURES: The record of having received a THA as recorded in the primary care record and the linked secondary care database: Hospital Episode Statistics.
    RESULTS: 40% had THA: median follow 10 months (range 1-17 years). Increased multimorbidity was associated with a decreased likelihood of undergoing THA, irrespective of the method of assessing multimorbidity although the impact varied by approach.
    CONCLUSION: Markers of pre-existing ill health influence the decision for THA in the elderly with end-stage hip osteoarthritis, although these effects are modest for indices of multimorbidity other than eFI. There is evidence of this influence being present even in people with moderate decrements in their health, despite the balance of benefits to risk in these individuals being positive.
    Keywords:  geriatric medicine; health policy; hip; surgery
    DOI:  https://doi.org/10.1136/bmjopen-2020-046713
  19. Mitochondrion. 2021 Sep 15. pii: S1567-7249(21)00121-5. [Epub ahead of print]
      Mitochondria are dynamic, interactive organelles that connect cellular signaling and whole-cell homeostasis. This "mitochatting" allows the cell to receive information about the mitochondria's condition before accommodating energy demands. Mitofusin 2 (Mfn2), an outer mitochondrial membrane fusion protein specializes in mediating mitochondrial homeostasis. Early studies defined the biological significance of Mfn2, latter studies highlighted its role in substrate metabolism. However, determining Mfn2 potential to contribute to energy homeostasis needs study. This review summarizes current literature on mitochondrial metabolic processes, dynamics, and evidence of interactions among Mfn2 and regulatory processes that may link Mfn2's role in maintaining mitochondrial function and substrate metabolism.
    Keywords:  fatty acid oxidation; fission; fusion; glycolysis; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.1016/j.mito.2021.09.003
  20. Clin Immunol. 2021 Sep 21. pii: S1521-6616(21)00194-7. [Epub ahead of print] 108857
      Aging can alter immunity affecting host defense. COVID-19 has the most devastating clinical outcomes in older adults, raising the implication of immune aging in determining its severity and mortality. We investigated biological predictors for clinical outcomes in a dataset of 13,642 ambulatory and hospitalized adult COVID-19 patients, including younger (age < 65, n = 566) and older (age ≥ 65, n = 717) subjects, with in-depth analyses of inflammatory molecules, cytokines and comorbidities. Disease severity and mortality in younger and older adults were associated with discrete immune mechanisms, including predominant T cell activation in younger adults, as measured by increased soluble IL-2 receptor alpha, and increased IL-10 in older adults although both groups also had shared inflammatory processes, including acute phase reactants, contributing to clinical outcomes. These observations suggest that progression to severe disease and death in COVID-19 may proceed by different immunologic mechanisms in younger versus older subjects and introduce the possibility of age-based immune directed therapies.
    Keywords:  Aging; COVID-19; Clinical outcome; Human; Immune
    DOI:  https://doi.org/10.1016/j.clim.2021.108857
  21. Aging Med (Milton). 2021 Sep;4(3): 221-233
      Sarcopenia is a comprehensive degenerative disease with the progressive loss of skeletal muscle mass with age, accompanied by the loss of muscle strength and muscle dysfunction. As a new type of senile syndrome, sarcopenia seriously threatens the health of the elderly. The first-line treatment for sarcopenia is exercise and nutritional supplements. However, pharmacotherapy will provide more reliable and sustainable interventions in geriatric medicine. Clinical trials of new drugs targeting multiple molecules are ongoing. This article focuses on the latest progress in pharmacotherapeutic approaches of sarcopenia in recent years by comprehensively reviewing the clinical outcomes of the existing and emerging pharmacotherapies as well as the molecular mechanisms underlying their therapeutic benefits and side effects.
    Keywords:  aging; muscle wasting; pathogenesis; pharmacotherapy; sarcopenia; signaling
    DOI:  https://doi.org/10.1002/agm2.12168
  22. Bio Protoc. 2021 Aug 20. 11(16): e4130
      In vertebrates, hematopoietic stem cells (HSCs) regulate the supply of blood cells throughout the lifetime and help to maintain homeostasis. Due to their long lifespan, genetic integrity is paramount for these cells, and accordingly, a number of stem cell-specific mechanisms are employed. However, HSCs tend to show more DNA damage with increasing age due to an imbalance between proliferation rates and DNA damage responses. The comet assay is the most common and reliable method to study DNA strand breaks at the single-cell level. This procedure is based on the electrophoresis of agarose-embedded lysed cells. Following the electrophoretic mobilization of DNA, it is stained with fluorescent DNA-binding dye. Broken DNA strands migrate based on fragment size and form a tail-like structure called "the comet," whereas intact nuclear DNA remains a part of the head of the comet. Since the alkaline comet assay fails to differentiate between single and double-strand breaks (DSBs), we used a neutral comet assay to quantitate the DSBs in HSCs upon aging and other physiological stresses. The protocol presented here provides procedural details on this highly sensitive, rapid, and cost-effective assay, which can be used for rare populations of cells such as HSCs. Graphical abstract: The neutral comet assay is an extremely useful tool that allows the detection and quantitation of double-strand DNA breaks at the single-cell level. The graphical abstract represents a flowchart for the neutral comet assay procedure.
    Keywords:  DNA damage; Double-strand breaks; Hematopoietic stem cells; Neutral comet assay
    DOI:  https://doi.org/10.21769/BioProtoc.4130
  23. Front Nutr. 2021 ;8 731356
      Frailty is an age-related clinical syndrome that may increase the risk of falls, disability, hospitalization, and death in older adults. Delaying the progression of frailty helps improve the quality of life in older adults. Caloric restriction (CR) may extend lifespan and reduce the risk of age-related diseases. However, few studies have explored the relationship between CR and frailty. In this review, we focused on the impact of CR on frailty and aimed to identify potential associated mechanisms. Although CR may help prevent frailty, further studies are required to determine the underlying mechanisms and specific CR regimens suitable for use in humans.
    Keywords:  caloric restriction; frailty; lifespan; older adults; sarcopenia
    DOI:  https://doi.org/10.3389/fnut.2021.731356
  24. Health (London). 2021 Sep 22. 13634593211038460
      'Frailty' is increasingly used as a clinical term to refer and respond to a particular bodily presentation, with numerous scores and measures to support its clinical determination. While these tools are typically quantitative in nature and based primarily on physical capacity, qualitative research has revealed that frailty is also associated with a range of social, economic and environmental factors. Here, we progress the understanding of frailty in older people via a new materialist synthesis of recent qualitative studies of frailty and ageing. We replace a conception of frailty as a bodily attribute with a relational understanding of a 'frailty assemblage'. Within this more-than-human assemblage, materialities establish the on-going 'becoming' of the frail body. What clinicians refer to as 'frailty' is one becoming among many, produced during the daily activities and interactions of older people. Acknowledging the complexity of these more-than-human becomings is essential to make sense of frailty, and how to support and enhance the lives of frail older people.
    Keywords:  Deleuze and Guattari; ageing; becoming; frailty; new materialism
    DOI:  https://doi.org/10.1177/13634593211038460
  25. Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00730-9. [Epub ahead of print]81(18): 3659-3664
      To celebrate our Focus Issue, we asked a selection of researchers working on different aspects of metabolism what they are excited about and what is still to come. They discuss emerging concepts, unanswered questions, things to consider, and technologies that are enabling new discoveries, as well as developing and integrating approaches to drive the field forward.
    DOI:  https://doi.org/10.1016/j.molcel.2021.08.040
  26. Trends Cogn Sci. 2021 Sep 16. pii: S1364-6613(21)00226-6. [Epub ahead of print]
      Individuals with a greater sense of purpose maintain better cognitive function and have lower dementia risk. We review evidence linking purpose in life to healthier cognitive aging across adulthood and diverse demographic groups. Experimental work is now needed to test causal mechanisms to evaluate the utility of purpose as an intervention target.
    Keywords:  cognitive aging; dementia; healthy cognition; sense of purpose
    DOI:  https://doi.org/10.1016/j.tics.2021.08.009
  27. Aging Cell. 2021 Sep 24. e13475
      Satellite cell-dependent skeletal muscle regeneration declines during aging. Disruptions within the satellite cells and their niche, together with alterations in the myofibrillar environment, contribute to age-related dysfunction and defective muscle regeneration. In this study, we demonstrated an age-related decline in satellite cell viability and myogenic potential and an increase in ROS and cellular senescence. We detected a transient upregulation of miR-24 in regenerating muscle from adult mice and downregulation of miR-24 during muscle regeneration in old mice. FACS-sorted satellite cells were characterized by decreased levels of miR-24 and a concomitant increase in expression of its target: Prdx6. Using GFP reporter constructs, we demonstrated that miR-24 directly binds to its predicted site within Prdx6 mRNA. Subtle changes in Prdx6 levels following changes in miR-24 expression indicate miR-24 plays a role in fine-tuning Prdx6 expression. Changes in miR-24 and Prdx6 levels were associated with altered mitochondrial ROS generation, increase in the DNA damage marker: phosphorylated-H2Ax and changes in viability, senescence, and myogenic potential of myogenic progenitors from mice and humans. The effects of miR-24 were more pronounced in myogenic progenitors from old mice, suggesting a context-dependent role of miR-24 in these cells, with miR-24 downregulation likely a part of a compensatory response to declining satellite cell function during aging. We propose that downregulation of miR-24 and subsequent upregulation of Prdx6 in muscle of old mice following injury are an adaptive response to aging, to maintain satellite cell viability and myogenic potential through regulation of mitochondrial ROS and DNA damage pathways.
    Keywords:  Prdx6; aging; miR-24; muscle regeneration; oxidative stress; satellite cells; senescence
    DOI:  https://doi.org/10.1111/acel.13475
  28. Exp Gerontol. 2021 Sep 16. pii: S0531-5565(21)00339-9. [Epub ahead of print] 111557
      High blood pressure (BP) affects 75% of people aged over 70. Ageing alters BP homeostasis, resulting in postural hypotension and increased BP variability. Co-morbidity and frailty add complexity to understanding BP changes in later life. Longitudinal BP declines are likely driven by accumulating co-morbidity and are accelerated in both frailty and dementia. This narrative review summarises what is known about the association between BP and frailty, the clinical management of BP in frailty and the association between BP, cognitive decline and dementia.
    Keywords:  Ageing; Blood pressure; Dementia; Frailty; Hypertension
    DOI:  https://doi.org/10.1016/j.exger.2021.111557
  29. Rev Med Virol. 2021 09;31(5): 1-13
      Viruses have evolved to manipulate host lipid metabolism to benefit their replication cycle. Enveloped viruses, including coronaviruses, use host lipids in various stages of the viral life cycle, particularly in the formation of replication compartments and envelopes. Host lipids are utilised by the virus in receptor binding, viral fusion and entry, as well as viral replication. Association of dyslipidaemia with the pathological development of Covid-19 raises the possibility that exploitation of host lipid metabolism might have therapeutic benefit against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In this review, promising host lipid targets are discussed along with potential inhibitors. In addition, specific host lipids are involved in the inflammatory responses due to viral infection, so lipid supplementation represents another potential strategy to counteract the severity of viral infection. Furthermore, switching the lipid metabolism through a ketogenic diet is another potential way of limiting the effects of viral infection. Taken together, restricting the access of host lipids to the virus, either by using lipid inhibitors or supplementation with exogenous lipids, might significantly limit SARS-CoV-2 infection and/or severity.
    Keywords:  Covid-19; SARS-CoV-2; inflammation; lipids inhibitors; lipids supplementation
    DOI:  https://doi.org/10.1002/rmv.2214
  30. Rev Prat. 2021 May;71(5): 514-518
      Mesures préventives du vieillissement de la colonne vertébrale. More than 20% of the general population have a normal ageing spine without any pathologies. Because ageing touch more or less quickly, more or less deeply all of the constitutive tissues of the spine bones, joints as muscle and ligaments, prevention measures will be started relatively early around the 50ths and turned toward physical as well as neurosensory exercises in conjunction with cognitive development. If pain, walking difficulties or deformity appears it is necessary to obtain the opinion of a geriatric specialized team including neurologist, nutritional specialist, physical therapist people as well as trained spine surgeon for elderly people in case of the seldom but sometimes mandatory surgical indications.
    Keywords:  Aging; Primary Prevention; Spine
  31. Curr Med Chem. 2021 Sep 21.
      Vascular aging is a crucial risk factor for atherosclerotic ischemic stroke. Vascular aging is characterized by oxidative stress, endothelial dysfunction, inflammation, intimal and media thickening, as well as the gradual development of arterial stiffness, among other pathophysiological features. Regarding oxidative stress, increased concentration of reactive oxygen and nitrogen species is linked to atherosclerotic ischemic stroke in vascular aging. Additionally, oxidative stress is associated with an inflammatory response. Inflammation is related to aging through the "inflammaging" theory, which is characterized by decreased ability to cope with a variety of stressors, in combination with an increased pro-inflammatory state. Vascular aging is correlated with changes in cerebral arteries that are considered predictors of the risk for atherosclerotic ischemic stroke. The aim of the present review is to present the role of oxidative stress and inflammation in vascular aging, as well as their involvement in atherosclerotic ischemic stroke.
    Keywords:  Atherosclerotic ischemic stroke; Inflammation; Oxidative stress; Vascular aging
    DOI:  https://doi.org/10.2174/0929867328666210921161711
  32. Front Cell Dev Biol. 2021 ;9 672545
      In multicellular organisms, tissue generation, maintenance, and homeostasis depend on stem cells. Cellular metabolic status is an essential component of different differentiated states, from stem to fully differentiated cells. Threonine (Thr) metabolism has emerged as a critical factor required to maintain pluripotent/multipotent stem cells in both plants and animals. Thus, both kingdoms conserved or converged upon this fundamental feature of stem cell function. Here, we examine similarities and differences in Thr metabolism-dependent mechanisms supporting stem cell maintenance in these two kingdoms. We then consider common features of Thr metabolism in stem cell maintenance and predict and speculate that some knowledge about Thr metabolism and its role in stem cell function in one kingdom may apply to the other. Finally, we outline future research directions to explore these hypotheses.
    Keywords:  embryonic stem cells; epigenetic modifications; one-carbon metabolism; root apical meristem; stem cells; threonine catabolism; threonine metabolism; threonine synthesis
    DOI:  https://doi.org/10.3389/fcell.2021.672545
  33. Front Med (Lausanne). 2021 ;8 720402
      End-stage renal disease (ESRD) patients exhibit clinical features of premature ageing, including frailty, cardiovascular disease, and muscle wasting. Accelerated ageing also concerns the immune system. Patients with ESRD have both immune senescence and chronic inflammation that are resumed in the so-called inflammaging syndrome. Immune senescence is particularly characterised by premature loss of thymic function that is associated with hyporesponsiveness to vaccines, susceptibility to infections, and death. ESRD-related chronic inflammation has multiple causes and participates to accelerated cardiovascular disease. Although, both characterisation of immune senescence and its consequences are relatively well-known, mechanisms are more uncertain. However, prevention of immune senescence/inflammation or/and rejuvenation of the immune system are major goal to ameliorate clinical outcomes of ESRD patients.
    Keywords:  end-stage renal disease; immune senescence; inflammaging; kidney transplantation; thymus
    DOI:  https://doi.org/10.3389/fmed.2021.720402
  34. Lancet Neurol. 2021 Oct;pii: S1474-4422(21)00248-9. [Epub ahead of print]20(10): 854-867
      The enormous societal and financial burden of Alzheimer's disease and related dementias requires the identification of risk factors and pathways to reduce dementia risk. Blood pressure (BP) management and control is one promising area, in which data have been inconclusive. Accumulating evidence over the past 5 years shows the effectiveness of BP management interventions among older individuals at risk, most notably from the SPRINT-MIND trial. These findings have been coupled with longitudinal observational data. However, to date, the results do not concur on the optimal timing and target of BP lowering, and further study in diverse populations is needed. Given the long preclinical phase of dementia and data supporting the importance of BP control earlier in the lifecourse, long-term interventional and observational studies in ethnically and racially diverse populations, with novel imaging and blood-based biomarkers of neurodegeneration and vascular cognitive impairment to understand the pathophysiology, are needed to advance the field.
    DOI:  https://doi.org/10.1016/S1474-4422(21)00248-9
  35. Aging (Albany NY). 2021 Sep 19. 13(undefined):
      Dulaglutide, a glucagon-like peptide-1 receptor (GLP-1R) agonist, is widely used to treat diabetes. However, its effects on muscle wasting due to aging are poorly understood. In the current study, we investigated the therapeutic potential and underlying mechanism of dulaglutide in muscle wasting in aged mice. Dulaglutide improved muscle mass and strength in aged mice. Histological analysis revealed that the cross-sectional area of the tibialis anterior (TA) in the dulaglutide-treated group was thicker than that in the vehicle group. Moreover, dulaglutide increased the shift toward middle and large-sized fibers in both young and aged mice compared to the vehicle. Dulaglutide increased myofiber type I and type IIa in young (18.5% and 8.2%) and aged (1.8% and 19.7%) mice, respectively, compared to the vehicle group. Peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, decreased but increased by dulaglutide in aged mice. The expression of atrophic factors such as myostatin, atrogin-1, and muscle RING-finger protein-1 was decreased in aged mice, whereas that of the myogenic factor, MyoD, was increased in both young and aged mice following dulaglutide treatment. In aged mice, optic atrophy-1 (OPA-1) protein was decreased, whereas Toll-like receptor-9 (TLR-9) and its targeting inflammatory cytokines (interleukin-6 [IL-6] and tumor necrosis factor-α [TNF-α]) were elevated in the TA and quadriceps (QD) muscles. In contrast, dulaglutide administration reversed this expression pattern, thereby significantly attenuating the expression of inflammatory cytokines in aged mice. These data suggest that dulaglutide may exert beneficial effects in the treatment of muscle wasting due to aging.
    Keywords:  dulaglutide; glucagon-like peptide-1; inflammation; optic atrophy-1; sarcopenia
    DOI:  https://doi.org/10.18632/aging.203546
  36. NPJ Regen Med. 2021 Sep 24. 6(1): 58
      Mitochondria are cellular organelles critical for numerous cellular processes and harboring their own circular mitochondrial DNA (mtDNA). Most mtDNA associated disorders (either deletions, mutations, or depletion) lead to multisystemic disease, often severe at a young age, with no disease-modifying therapies. Mitochondria have a capacity to enter eukaryotic cells and to be transported between cells. We describe a method of ex vivo augmentation of hematopoietic stem and progenitor cells (HSPCs) with normal exogenous mitochondria, termed mitochondrial augmentation therapy (MAT). Here, we show that MAT is feasible and dose dependent, and improves mitochondrial content and oxygen consumption of healthy and diseased HSPCs. Ex vivo mitochondrial augmentation of HSPCs from a patient with a mtDNA disorder leads to superior human engraftment in a non-conditioned NSGS mouse model. Using a syngeneic mouse model of accumulating mitochondrial dysfunction (Polg), we show durable engraftment in non-conditioned animals, with in vivo transfer of mitochondria to recipient hematopoietic cells. Taken together, this study supports MAT as a potential disease-modifying therapy for mtDNA disorders.
    DOI:  https://doi.org/10.1038/s41536-021-00167-7
  37. NPJ Breast Cancer. 2021 Sep 24. 7(1): 129
      Adipocytes influence breast cancer behaviour via fatty acid release into the tumour microenvironment. Co-culturing human adipocytes and breast cancer cells increased CD36 expression, with fatty acid import into breast cancer cells. Genetic ablation of CD36 attenuates adipocyte-induced epithelial-mesenchymal transition (EMT) and stemness. We show a feedforward loop between CD36 and STAT3; where CD36 activates STAT3 signalling and STAT3 binds to the CD36 promoter, regulating its expression. CD36 expression results in metabolic reprogramming, with a shift towards fatty acid oxidation. CD36 inhibition induces de novo lipogenesis in breast cancer cells. Increased CD36 expression occurs with increased FABP4 expression. We showed that CD36 directly interacts with FABP4 to regulate fatty acid import, transport, and metabolism. CD36 and FABP4 inhibition induces apoptosis in tumour cells. These results indicate that CD36 mediates fatty acid import from adipocytes into cancer cells and activates signalling pathways that drive tumour progression. Targeting CD36 may have a potential for therapy, which will target the tumour microenvironment.
    DOI:  https://doi.org/10.1038/s41523-021-00324-7