bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2021–09–19
twenty-six papers selected by
Ayesh Seneviratne, University of Toronto



  1. Sci Rep. 2021 Sep 13. 11(1): 18135
      Metabolites in human biofluids reflect individual physiological states influenced by various factors. Using liquid chromatography-mass spectrometry (LC-MS), we conducted non-targeted, non-invasive metabolomics using saliva of 27 healthy volunteers in Okinawa, comprising 13 young (30 ± 3 year) and 14 elderly (76 ± 4 year) subjects. Few studies have comprehensively identified age-dependent changes in salivary metabolites. Among 99 salivary metabolites, 21 were statistically age-related. All of the latter decline in abundance with advancing age, except ATP, which increased 1.96-fold in the elderly, possibly due to reduced ATP consumption. Fourteen age-linked and highly correlated compounds function in a metabolic network involving the pentose-phosphate pathway, glycolysis/gluconeogenesis, amino acids, and purines/pyrimidines nucleobases. The remaining seven less strongly correlated metabolites, include ATP, anti-oxidation-related glutathione disulfide, muscle-related acetyl-carnosine, N-methyl-histidine, creatinine, RNA-related dimethyl-xanthine and N-methyl-adenosine. In addition, glutamate and N-methyl-histidine are related to taste, so their decline suggests that the elderly lose some ability to taste. Reduced redox metabolism and muscle activity are suggested by changes in glutathione and acetyl-carnosine. These age-linked salivary metabolites together illuminate a metabolic network that reflects a decline of oral functions during human aging.
    DOI:  https://doi.org/10.1038/s41598-021-97623-7
  2. Blood. 2021 Sep 15. pii: blood.2021011570. [Epub ahead of print]
      Ageing is associated with impaired hematopoietic and immune function. This is caused in part by decreased hematopoietic stem cell (HSC) population fitness and an increased myeloid differentiation bias. The reasons for this aging-associated HSC impairment are incompletely understood. We here demonstrate that aged specific pathogen free (SPF) wild-type mice in contrast to young SPF mice produce more IL-1a/b in steady-state bone marrow (BM), with most of IL-1a/b being derived from myeloid BM cells. Further, blood of steady-state aged SPF wild-type mice contains higher levels of microbe associated molecular patterns (MAMPs), specifically TLR4 and TLR8 ligands. Also, BM myeloid cells from aged mice produce more IL-1b in vitro, and aged mice show higher and more durable IL-1a/b responses upon LPS stimulation in vivo. To test if HSC ageing is driven via IL-1a/b, we evaluated HSCs from IL-1 receptor 1 (IL-1R1) knock-out mice. Indeed, aged HSCs from IL-1R1 knock-out mice show significantly mitigated ageing-associated inflammatory signatures. Moreover, HSCs from aged IL-1R1KO and also from germ-free mice maintain unbiased lympho-myeloid hematopoietic differentiation upon transplantation, thus resembling this functionality of young HSCs. Importantly, in vivo antibiotic suppression of microbiota or pharmacologic blockade of IL-1 signaling in aged wild-type mice was similarly sufficient to reverse myeloid biased output of their HSC populations. Collectively, our data defines the microbiome-IL-1/IL-1R1 axis as a key, self-sustaining, but also therapeutically partially reversible driver of HSC inflamm-ageing.
    DOI:  https://doi.org/10.1182/blood.2021011570
  3. Mech Ageing Dev. 2021 Sep 10. pii: S0047-6374(21)00139-1. [Epub ahead of print] 111567
      NAD+ is a fundamental molecule in human life and health as it participates in energy metabolism, cell signalling, mitochondrial homeostasis, and in dictating cell survival or death. Emerging evidence from preclinical and human studies indicates an age-dependent reduction of cellular NAD+, possibly due to reduced synthesis and increased consumption. In preclinical models, NAD+ repletion extends healthspan and / or lifespan and mitigates several conditions, such as premature ageing diseases and neurodegenerative diseases. These findings suggest that NAD+ replenishment through NAD+ precursors has great potential as a therapeutic target for ageing and age-predisposed diseases, such as Alzheimer's disease. Here, we provide an updated review on the biological activity, safety, and possible side effects of NAD+ precursors in preclinical and clinical studies. Major NAD+ precursors focused on by this review are nicotinamide riboside (NR), nicotinamide mononucleotide (NMN), and the new discovered dihydronicotinamide riboside (NRH). In summary, NAD+ precursors have an exciting therapeutic potential for ageing, metabolic and neurodegenerative diseases.
    Keywords:  Alzheimer’s disease; NAD(+); ageing; healthspan
    DOI:  https://doi.org/10.1016/j.mad.2021.111567
  4. High Blood Press Cardiovasc Prev. 2021 Sep 13.
       INTRODUCTION: Lifestyle changes present a fundamental role in cardiovascular prevention. Nutraceuticals also supplementing diet could help in controlling the cardiometabolic risk.
    AIM: (1) to evaluate acute effects of a combination of nutraceuticals (cNUT) on vascular function, BP, metabolism in dyslipidaemic patients before and after smoking; (2) to evaluate 12 weeks effects of the cNUT on lipid profile, insulin resistance and vascular function in patients with hypercholesterolemia not on statins.
    METHODS: After 14 d run-in period, 33 patients assumed a cNUT [patented formula containing: berberine (531.25 mg), red yeast rice powder (220 mg, 3.3 mg monacolin K) and leaf extract of Morus alba (200 mg) (LopiGLIK®, Akademy Pharma)]. To evaluate acute effects, cNUT or cNUT + smoking (in smoking subjects) on the morning of the first day of the study and then 26 patients prolonged 12 weeks effects.
    RESULTS: In non smokers, cNUT improved FMD (p = 0.041 for treatment). In smokers, FMD decreased after smoking, this was counteracted by intake of cNUT. In smokers, DBP increased after smoking a cigarette (p = 0.042 for treatment), counteracted by the cNUT intake. In non smokers, thermogenesis was increased after cNUT administration (p < 0.0001 for treatment). After 12 weeks of cNUT, FMD significantly increased (p < 0.05) and SBP (p = 0.04), total cholesterol and LDL cholesterol (p = 0.03) decreased.
    CONCLUSIONS: Our study suggests benefits of cNUT on cardiovascular prevention in hypercolesterolemic patients, non statin treated, that goes beyond the cholesterol and insulin resistance reduction protecting the subject from negative effects induced by smoking too.
    Keywords:  Cardiovascular risk; Flavonoids; Hypercholesterolemia; Nutraceuticals; Smoking
    DOI:  https://doi.org/10.1007/s40292-021-00468-4
  5. Cell Metab. 2021 Sep 08. pii: S1550-4131(21)00376-4. [Epub ahead of print]
      Aging leads to profound changes in glucose homeostasis, weight, and adiposity, which are considered good predictors of health and survival in humans. Direct evidence that these age-associated metabolic alterations are recapitulated in animal models is lacking, impeding progress to develop and test interventions that delay the onset of metabolic dysfunction and promote healthy aging and longevity. We compared longitudinal trajectories, rates of change, and mortality risks of fasting blood glucose, body weight, and fat mass in mice, nonhuman primates, and humans throughout their lifespans and found similar trajectories of body weight and fat in the three species. In contrast, fasting blood glucose decreased late in life in mice but increased over the lifespan of nonhuman primates and humans. Higher glucose was associated with lower mortality in mice but higher mortality in nonhuman primates and humans, providing a cautionary tale for translating age-associated metabolic changes from mice to humans.
    Keywords:  fasting blood glucose; humans; metabolism; mice; mortality; nonhuman primates; predictors
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.013
  6. Aging (Albany NY). 2021 Sep 11. undefined(undefined):
      
    Keywords:  cancer stem cells; epigenetic; head and neck cancer; signaling pathways; tumorigenesis
    DOI:  https://doi.org/10.18632/aging.203535
  7. Cell Metab. 2021 Sep 08. pii: S1550-4131(21)00417-4. [Epub ahead of print]
      Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging.
    Keywords:  RPS23; aging; archaea; mTOR; protein synthesis; proteostasis; ribosome; translation; translation accuracy; translation fidelity
    DOI:  https://doi.org/10.1016/j.cmet.2021.08.017
  8. Clin Rev Allergy Immunol. 2021 Sep 18.
      The inflammaging concept was introduced in 2000 by Prof. Franceschi. This was an evolutionary or rather a revolutionary conceptualization of the immune changes in response to a lifelong stress. This conceptualization permitted to consider the lifelong proinflammatory process as an adaptation which could eventually lead to either beneficial or detrimental consequences. This dichotomy is influenced by both the genetics and the environment. Depending on which way prevails in an individual, the outcome may be healthy longevity or pathological aging burdened with aging-related diseases. The concept of inflammaging has also revealed the complex, systemic nature of aging. Thus, this conceptualization opens the way to consider age-related processes in their complexity, meaning that not only the process but also all counter-processes should be considered. It has also opened the way to add new concepts to the original one, leading to better understanding of the nature of inflammaging and of aging itself. Finally, it showed the way towards potential multimodal interventions involving a holistic approach to optimize the aging process towards a healthy longevity.
    Keywords:  Cytokines; Free radicals; Immunobiography; Immunosenescence; Inflammaging; Macrophages; Microbiome; Mitochondria; SASP; Signaling; Trained immunity
    DOI:  https://doi.org/10.1007/s12016-021-08899-6
  9. Blood Cancer J. 2021 Sep 14. 11(9): 152
      Even though genetic perturbations and mutations are important for the development of myeloid malignancies, the effects of an inflammatory microenvironment are a critical modulator of carcinogenesis. Activation of the innate immune system through various ligands and signaling pathways is an important driver of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The DAMPs, or alarmins, which activate the inflammasome pathway via the TLR4/NLR signaling cascade causes the lytic cell death of hematopoietic stem and progenitor cells (HSPCs), ineffective hematopoiesis, and β-catenin-induced proliferation of cancer cells, leading to the development of MDS/AML phenotype. It is also associated with other myeloid malignancies and involved in the pathogenesis of associated cytopenias. Ongoing research suggests the interplay of inflammasome mediators with immune modulators and transcription factors to have a significant role in the development of myeloid diseases, and possibly therapy resistance. This review discusses the role and importance of inflammasomes and immune pathways in myeloid malignancies, particularly MDS/AML, to better understand the disease pathophysiology and decipher the scope of therapeutic interventions.
    DOI:  https://doi.org/10.1038/s41408-021-00547-8
  10. Lifestyle Genom. 2021 Sep 08. 1-9
       BACKGROUND: For thousands of years, disabilities due to nutrient deficiencies have plagued humanity. Rickets, scurvy, anemia, stunted growth, blindness, and mental handicaps due to nutrient deficiencies affected up to 1/10 of the world's population prior to 1900. The discovery of essential amino acids, vitamins, and minerals, in the early 1900s, led to a fundamental change in our understanding of food and a revolution in human health. Widespread vitamin and mineral supplementation, the development of recommended dietary allowances, and the implementation of food labeling and testing along with significant improvements in food production and food quality have meant that nutrient-related disorders have almost vanished in the developed world. The success of nutritional science in preventing disease at a population-wide level is one of the great scientific triumphs of the 20th century. The challenge for nutritional science in the 21st century is to understand how to use nutrients and other food constituents to enhance human health or prevent disease at a more personal level. This is the primary goal of precision nutrition.
    SUMMARY: Precision nutrition is an emerging branch of nutrition science that aims to use modern omics technologies (genomics, proteomics, and metabolomics) to assess an individual's response to specific foods or dietary patterns and thereby determine the most effective diet or lifestyle interventions to prevent or treat specific diseases in that individual. Metabolomics is vital to nearly every aspect of precision nutrition. It can be used to comprehensively characterize the thousands of chemicals in foods, to identify food byproducts in human biofluids or tissues, to characterize nutrient deficiencies or excesses, to monitor biochemical responses to dietary interventions, to track long-term or short-term dietary habits, and to guide the development of nutritional therapies. In this review, we will describe how metabolomics has been used to advance the field of precision nutrition by providing some notable examples or use cases. First, we will describe how metabolomics helped launch the field of precision nutrition through the diagnosis and dietary therapy of individuals with inborn errors of metabolism. Next, we will describe how metabolomics is being used to comprehensively characterize the full chemical complexity of many key foods, and how this is revealing much more about nutrients than ever imagined. Third, we will describe how metabolomics is being used to identify food consumption biomarkers and how this opens the door to a more objective and quantitative assessments of an individual's diet and their response to certain foods. Finally, we will describe how metabolomics is being coupled with other omics technologies to develop custom diets and lifestyle interventions that are leading to positive health benefits. Key Message: Metabolomics is vital to the advancement of nutritional science and in making the dream of precision nutrition a reality.
    Keywords:  Biomarkers of health; Lifestyle interventions; Metabolomics; Precision nutrition
    DOI:  https://doi.org/10.1159/000518489
  11. J Cachexia Sarcopenia Muscle. 2021 Sep 15.
       BACKGROUND: Age-related chronic low-grade inflammation (inflammaging) is one of the proposed mechanisms behind sarcopenia. However, findings regarding inflammatory markers in sarcopenic older adults are conflicting. This study aimed to determine the association between inflammatory markers, prevalent as well as incident sarcopenia, sarcopenia-defining parameters, quality of life (QoL), and physical activity in middle-aged and older men.
    METHODS: Men aged 40-79 years (mean 59.66 ± 11.00y) were recruited from population registers in eight European centres for participation in the European Male Aging study (EMAS). Subjects were assessed at baseline (2003-2005) and again after a median follow-up of 4.29 years. In 2577 participants, associations between baseline inflammatory markers [high-sensitive C-reactive protein (hs-CRP), white blood cell count (WBC), albumin] and baseline physical activity (PASE) and QoL (SF-36) were analysed. In the Leuven and Manchester cohort (n = 447), data were available on muscle mass (whole-body dual X-ray absorptiometry) and strength. In this subgroup, cross-sectional associations between baseline inflammatory markers and sarcopenia-defining parameters (handgrip strength, chair stand test, appendicular lean mass, and gait speed) and prevalent sarcopenia were examined. In a further subgroup (n = 277), associations with knee extensor strength were explored. Longitudinally, predictive value of baseline inflammation on functional decline, physical activity, QoL, and incident sarcopenia was examined. Subgroup analyses were performed in subgroups with chronic inflammation and stratified by age. Linear and logistic regressions were used, adjusted for age, body mass index, centre, and smoking.
    RESULTS: At baseline, hs-CRP and WBC were negatively associated with PASE score (hs-CRP: β = -7.920, P < 0.001; and WBC: β = -4.552, P < 0.001) and the physical component score of SF-36 (hs-CRP: β = -1.025, P < 0.001; and WBC: β = -0.364, P < 0.001). Baseline WBC levels were negatively associated with gait speed (β = -0.013; P = 0.025), quadriceps isometric 90° (β = -5.983; P = 0.035) and isokinetic 60°/s peak torque/body weight (β = -5.532; P = 0.027). The prevalence of sarcopenia at baseline was 18.1% (n = 81). Of those without sarcopenia at baseline, 64 (18.6%) satisfied criteria for sarcopenia at follow-up. There were no significant associations between baseline inflammatory markers and either prevalent or incident sarcopenia, or change in level of sarcopenia-defining parameters between baseline and follow-up.
    CONCLUSIONS: In middle-aged and older men, hs-CRP and WBC were negatively associated with QoL and PASE scores, while WBC was negatively associated with gait speed and knee strength. Associations with hs-CRP remained significant in all ages, whereas WBC levels were only associated with PASE, gait speed and knee strength in older adults (60-79 years). Baseline inflammatory markers (hs-CRP, WBC and albumin) did not predict functional decline, decline in physical activity, decreased QoL or incident sarcopenia.
    Keywords:  Ageing; Inflammaging; Inflammation; Muscle strength; Older adult; Sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.12785
  12. Aging Clin Exp Res. 2021 Sep 15.
      Aging is a universal complex and multifactorial physiological process that leads to the increasing incidence of various diseases including cancer. Indeed, 40% of individuals aged 65 years and over will have newly diagnosed cancers. Although most treated patients are elderly people, a low inclusion of the geriatric population is observed in most clinical trials. Furthermore, lethal side effects of antineoplastic therapy are markedly exacerbated with aging. Most cancer therapies were validated on young mice models, complicating results transposition to elderly patients. Thus, understanding the role of aging in tumor progression and response to cancer therapies with accurate preclinical models must be investigated. Therefore, this review aimed to summarize the state of the literature about preclinical models used to investigate the impact of aging microenvironment on tumorigenic potential, and on antineoplastic therapy response. Despite the advances in technology, and the increasing incidence of cancer in the elderly population, this present review focuses on the few studies using preclinical tumor model of aging. Since the biology of aging is challenging, aging animal models are an inevitable prelude. New emerging tools such as human organoid offer a promising path in research dedicated to aging.
    Keywords:  Aging; Antineoplastic treatments; Cancer; Preclinical model
    DOI:  https://doi.org/10.1007/s40520-021-01981-1
  13. Sci Rep. 2021 Sep 15. 11(1): 18333
      The increase in inflammatory cytokines associated with a reduction in the bioavailability of zinc has been used as a marker for inflammation. Despite the high inflammatory state found in institutionalized older individuals, few studies have proposed verifying the factors associated with this condition in this population. To verify the factors associated with inflamm-aging in institutionalized older people. A total of 178 older people (≥ 60 years old) living in nursing homes in Natal/RN were included in the study. Cluster analysis was used to identify three groups according to their inflammatory state. Analysis anthropometric, biochemical, sociodemographic, and health-related variables was carried out. In sequence, an ordinal logistic regression was performed for a confidence level of 95% in those variables with p < 0.20 in the bivariate analysis. IL-6, TNF-α, zinc, low-density lipids (LDL), high-density lipids (HDL), and triglycerides were associated with inflamm-aging. The increase of 1 unit of measurement of LDL, HDL, and triglycerides increased the chance of inflammation-aging by 1.5%, 4.1%, and 0.9%, respectively, while the oldest old (≥ 80 years old) had an 84.9% chance of presenting inflamm-aging in relation to non-long-lived older people (< 80 years). The association between biochemical markers and inflamm-aging demonstrates a relationship between endothelial injury and the inflammatory state. In addition, the presence of a greater amount of fat in the blood may present a higher relative risk of death.
    DOI:  https://doi.org/10.1038/s41598-021-97225-3
  14. Mech Ageing Dev. 2021 Sep 09. pii: S0047-6374(21)00141-X. [Epub ahead of print] 111569
      Nicotinamide adenine dinucleotide (NAD+) is a vital coenzyme in redox reactions. NAD+ is also important in cellular signalling as it is consumed by PARPs, SARM1, sirtuins and CD38. Cellular NAD+ levels regulate several essential processes including DNA repair, immune cell function, senescence, and chromatin remodelling. Maintenance of these cellular processes is important for healthy ageing and lifespan. Interestingly, the levels of NAD+ decline during ageing in several organisms, including humans. Declining NAD+ levels have been linked to several age-related diseases including various metabolic diseases and cognitive decline. Decreasing tissue NAD+ concentrations have been ascribed to an imbalance between biosynthesis and consumption of the dinucleotide, resulting from, for instance, reduced levels of the rate limiting enzyme NAMPT along with an increased activation state of the NAD+-consuming enzymes PARPs and CD38. The progression of some age-related diseases can be halted or reversed by therapeutic augmentation of NAD+ levels. NAD+ metabolism has therefore emerged as a potential target to ameliorate age-related diseases. The present review explores how ageing affects NAD+ metabolism and current approaches to reverse the age-dependent decline of NAD+.
    Keywords:  NAD biosynthesis; NAD metabolism; PARP; Sirtuins; ageing
    DOI:  https://doi.org/10.1016/j.mad.2021.111569
  15. Food Sci Nutr. 2021 Sep;9(9): 5229-5243
      Docosahexaenoic acid (DHA) is the predominant omega-3 long-chain polyunsaturated fatty acid found in human brain and eyes. There are a number of studies in the literature showing the health benefits of DHA. It is critical throughout all life stages from the need for fetal development, the prevention of preterm birth, and the prevention of cardiovascular disease to the improvements in the cognitive function and the eye health of adults and elderly. These benefits might be related to the modulation of gut microbiota by DHA. In addition, there are some discrepancies in the literature regarding certain health benefits of DHA, and this review is intended to explore and understand these discrepancies. Besides the variations in the DHA contents of different supplement sources, bioavailability is crucial for the efficacy of DHA supplements, which depends on several factors. For example, DHA in phospholipid and triglyceride forms are more readily to be absorbed by the body than that in ethyl ester form. In addition, dietary lipids in meals and emulsification of DHA oil can increase the bioavailability of DHA. Estrogens stimulated the biosynthesis of DHA, whereas testosterone stimulus induced a decrease in DHA. The roles of DHA through human lifespan, the sources, and its recommended daily intake in different countries are also discussed to provide a better understanding of the importance of this review.
    Keywords:  bioavailability; cardiovascular disease; cognitive function; docosahexaenoic acid; polyunsaturated fatty acids; prebiotics
    DOI:  https://doi.org/10.1002/fsn3.2299
  16. Risk Manag Healthc Policy. 2021 ;14 3729-3738
       Purpose: Successful aging is an effective approach to coping with population aging; however, the definition and associated factors vary due to culture and demographic distribution differences. This study was designed to assess successful aging of the older adults in China and explore the associated factors.
    Methods: A community-based cross-sectional study was performed in Liaoning, China. After double-cognitive function screening, 3558 older adults (1656 males and 1902 females) ≥65 years of age served as our subjects. Successful aging was assessed based on the following: physical disability; cognitive function; activities of daily living; and self-rated psychological/mood status.
    Results: The rate of successful aging was 31.7% in males and 29.4% in females. After adjustment for age, multivariate logistic regression showed that successful aging was significantly associated with, in odds ratio sequence, visual ability, self-rated chronic disease, marital status, and filial piety in males, and with visual ability, self-rated chronic disease, watching television, and ethnicity in females.
    Conclusion: The level of successful aging in China is lower than in other countries. Demographic characteristics, health status, individual behavior, and social-psychological factors are all associated with successful aging. Overall, visual ability had the most crucial role in successful aging for the older adults, whether males or females.
    Keywords:  associated factors; epidemiology; older adults; successful aging; visual ability
    DOI:  https://doi.org/10.2147/RMHP.S324095
  17. Science. 2021 Sep 17. 373(6561): 1294-1295
      [Figure: see text].
    DOI:  https://doi.org/10.1126/science.acx9099
  18. Front Pharmacol. 2021 ;12 723040
      Plant polyphenols have promoting health features, including anti-mutagenic, anti-inflammatory, anti-thrombotic, anti-atherogenic, and anti-allergic effects. These polyphenols improve the immune system by affecting the white blood cell proliferation, as well as by the synthesis of cytokines and other factors, which contribute to immunological resistance. Olive trees are one of the most famous trees in the world. Whereas, olive olive oil and derivatives represent a large group of feeding resource for farm animals. In recent years, remarkable studies have been carried out to show the possible use of olive oil and derivatives for improvement of both animal performance and product quality. In vivo application of olive oil and its derived products has shown to maintain oxidative balance owing to its polyphenolic content. Consumption of extra virgin olive oil reduces the inflammation, limits the risk of liver damage, and prevents the progression of steatohepatitis through its potent antioxidant activities. Also, the monounsaturated fatty acids content of olive oil (particularly oleic acid), might have positive impacts on lipid peroxidation and hepatic protection. Therefore, this review article aims to highlight the nutritional applications and beneficial health aspects of olive oil and its effect on poultry production.
    Keywords:  Health; feed; nutrition; olive oil; poultry
    DOI:  https://doi.org/10.3389/fphar.2021.723040
  19. Nat Rev Mol Cell Biol. 2021 Sep 13.
      Dietary restriction with adequate nutrition is the gold standard for delaying ageing and extending healthspan and lifespan in diverse species, including rodents and non-human primates. In this Review, we discuss the effects of dietary restriction in these mammalian model organisms and discuss accumulating data that suggest that dietary restriction results in many of the same physiological, metabolic and molecular changes responsible for the prevention of multiple ageing-associated diseases in humans. We further discuss how different forms of fasting, protein restriction and specific reductions in the levels of essential amino acids such as methionine and the branched-chain amino acids selectively impact the activity of AKT, FOXO, mTOR, nicotinamide adenine dinucleotide (NAD+), AMP-activated protein kinase (AMPK) and fibroblast growth factor 21 (FGF21), which are key components of some of the most important nutrient-sensing geroprotective signalling pathways that promote healthy longevity.
    DOI:  https://doi.org/10.1038/s41580-021-00411-4
  20. Aging Cell. 2021 Sep 18. e13439
      Several biomarkers of healthy aging have been proposed in recent years, including the epigenetic clocks, based on DNA methylation (DNAm) measures, which are getting increasingly accurate in predicting the individual biological age. The recently developed "next-generation clock" DNAmGrimAge outperforms "first-generation clocks" in predicting longevity and the onset of many age-related pathological conditions and diseases. Additionally, the total number of stochastic epigenetic mutations (SEMs), also known as the epigenetic mutation load (EML), has been proposed as a complementary DNAm-based biomarker of healthy aging. A fundamental biological property of epigenetic, and in particular DNAm modifications, is the potential reversibility of the effect, raising questions about the possible slowdown of epigenetic aging by modifying one's lifestyle. Here, we investigated whether improved dietary habits and increased physical activity have favorable effects on aging biomarkers in healthy postmenopausal women. The study sample consists of 219 women from the "Diet, Physical Activity, and Mammography" (DAMA) study: a 24-month randomized factorial intervention trial with DNAm measured twice, at baseline and the end of the trial. Women who participated in the dietary intervention had a significant slowing of the DNAmGrimAge clock, whereas increasing physical activity led to a significant reduction of SEMs in crucial cancer-related pathways. Our study provides strong evidence of a causal association between lifestyle modification and slowing down of DNAm aging biomarkers. This randomized trial elucidates the causal relationship between lifestyle and healthy aging-related epigenetic mechanisms.
    Keywords:  DNA methylation; dietary habits; epigenetic clock; epigenetic mutation load; physical activity; postmenopausal women; primary prevention trial
    DOI:  https://doi.org/10.1111/acel.13439
  21. J Nutr Biochem. 2021 Sep 10. pii: S0955-2863(21)00281-3. [Epub ahead of print] 108861
      Adequate nutrition is vital for immune homeostasis. However, the incidence of obesity is increasing worldwide due to the adoption of the Western diet and a sedentary lifestyle. Obesity is associated with chronic inflammation which alters the function of adipose tissue, liver, pancreas, and the nervous system. Inflammation is related to cellular senescence, distinguished by irreversible cell cycle arrest. Senescent cells secrete the senescence-associated secretory phenotype (SASP) which contains pro-inflammatory factors. Targeting processes in senescence might have a salutary approach to obesity. The present review highlights the impact of an unhealthy diet on tissues affected by obesity, and the mechanisms that promote the consequent inflammation and senescence.
    Keywords:  aging; diet; inflammation; microbiota obesity; senescence
    DOI:  https://doi.org/10.1016/j.jnutbio.2021.108861
  22. Mech Ageing Dev. 2021 Sep 10. pii: S0047-6374(21)00142-1. [Epub ahead of print]199 111570
      measures of health quantify the aging process of individuals. They should be interpretable, associated with future adverse outcomes, and straightforward to assemble. We use the rank-ordering of risk within a population to construct a quantile frailty index (QFI) that avoids dichotomization, is convenient and interpretable, and is associated with adverse outcomes. We show that the QFI outperforms previous frailty index (FI) measures on cross-sectional laboratory data (NHANES, CSHA, and ELSA). We construct the QFI by ranking the risk of individuals with respect to a reference population. Sex-specific reference populations narrow male-female FI differences as a function of age, and improve predictive performance. With a fixed reference population of 80-85 year olds, our QFI appears similar to earlier FI measures. With an age-matched reference population for each individual, we obtain a QFI that contains very little age information and that has similar predictive performance as other age-controlled FI measures. Adding age as an auxiliary variable leads to significantly better performance. We conclude that age should be controlled for when evaluating the predictive performance of summary measures of health. This is straight-forward to do with the QFI.
    Keywords:  Aging; Dichotomization; Frailty index (FI); Quantile; Summary measures of health
    DOI:  https://doi.org/10.1016/j.mad.2021.111570
  23. Front Mol Neurosci. 2021 ;14 732120
      Ketone bodies are metabolites that replace glucose as the main fuel of the brain in situations of glucose scarcity, including prolonged fasting, extenuating exercise, or pathological conditions such as diabetes. Beyond their role as an alternative fuel for the brain, the impact of ketone bodies on neuronal physiology has been highlighted by the use of the so-called "ketogenic diets," which were proposed about a century ago to treat infantile seizures. These diets mimic fasting by reducing drastically the intake of carbohydrates and proteins and replacing them with fat, thus promoting ketogenesis. The fact that ketogenic diets have such a profound effect on epileptic seizures points to complex biological effects of ketone bodies in addition to their role as a source of ATP. In this review, we specifically focus on the ability of ketone bodies to regulate neuronal excitability and their effects on gene expression to respond to oxidative stress. Finally, we also discuss their capacity as signaling molecules in brain cells.
    Keywords:  acetoacetate; brain metabolism; epilepsy; ketogenic diet; ketone bodies; metabolic signaling; neuronal excitability; β-hydroxybutyrate
    DOI:  https://doi.org/10.3389/fnmol.2021.732120
  24. Front Immunol. 2021 ;12 740847
      Cellular therapies such as allogeneic hematopoietic stem cell transplantation (HSCT) and immune-effector cell therapy (IECT) continue to have a critical role in the treatment of patients with high risk malignancies and hematologic conditions. These therapies are also associated with inflammatory conditions such as graft-versus-host disease (GVHD) and cytokine release syndrome (CRS) which contribute significantly to the morbidity and mortality associated with these therapies. Recent advances in our understanding of the immunological mechanisms that underly GVHD and CRS highlight an important role for Janus kinases (JAK). JAK pathways are important for the signaling of several cytokines and are involved in the activation and proliferation of several immune cell subsets. In this review, we provide an overview of the preclinical and clinical evidence supporting the use of JAK inhibitors for acute and chronic GVHD and CRS.
    Keywords:  JAK - STAT signaling pathway; cell therapy (CT); cytokine release syndrome (CRS); graft-versus-host disease (GvHD); transplantation
    DOI:  https://doi.org/10.3389/fimmu.2021.740847