bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–04–24
25 papers selected by
Ayesh Seneviratne, University of Toronto
  1. Measures of Clonal Hematopoiesis: Are We Missing Something?
  2. The role of nicotinamide mononucleotide (NMN) in anti-aging, longevity, and its potential for treating chronic conditions.
  3. Challenges of proving a causal role of somatic mutations in the aging process.
  4. Frailty among Older Adults and Its Distribution in England.
  5. Mitochondrial and metabolic alterations in cancer cells.
  6. Abnormal lipid synthesis as a therapeutic target for cancer stem cells.
  7. Role of the hematopoietic stem cells in immunological memory.
  8. Prospective Study of Ageing Trajectories in the European DO-HEALTH Study.
  9. Pooling of cohort studies and RCTs affects GRADE certainty of evidence in nutrition research.
  10. Appendicular Lean Mass and Frailty among Geriatric Outpatients.
  11. Bone Marrow Niches of Hematopoietic Stem and Progenitor Cells.
  12. Barth Syndrome Cardiomyopathy: An Update.
  13. The Influence of Heterochronic Non-Myeloablative Bone Marrow Transplantation on the Immune System, Frailty, General Health, and Longevity of Aged Murine Recipients.
  14. Calorie Restriction-Regulated Molecular Pathways and Its Impact on Various Age Groups: An Overview.
  15. Accuracy, feasibility and predictive ability of different frailty instruments in an acute geriatric setting.
  16. Tet1 Suppresses p21 to Ensure Proper Cell Cycle Progression in Embryonic Stem Cells.
  17. Calorie and Time Restriction in Weight Loss.
  18. The Aging Athlete.
  19. Four lessons from the pandemic to reboot the NIH.
  20. Editorial: Epigenetic Clock: A Novel Tool for Nutrition Studies of Healthy Ageing.
  21. Two Different Aging Paths in Human Blood Revealed by Integrated Analysis of Gene Expression, Mutation and Alternative Splicing.
  22. Early age-related atrophy of cutaneous lymph nodes precipitates an early functional decline in skin immunity in mice with aging.
  23. Metabolites Associated with Memory and Gait: A Systematic Review.
  24. Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases.
  25. ATP-citrate lyase (ACLY) inhibitors as therapeutic agents: a patenting perspective.
  1. Front Med (Lausanne). 2022 ;9 836141
    Measures of Clonal Hematopoiesis: Are We Missing Something?
    Leonid V Bystrykh, Mirjam E Belderbos.
      Clonal Hematopoiesis (CH) is a common, age-related phenomenon of growing scientific interest, due to its association with hematologic malignancy, cardiovascular disease and decreased overall survival. CH is commonly attributed to the preferential outgrowth of a mutant hematopoietic stem cell (HSC) with enhanced fitness, resulting in clonal imbalance. In-depth understanding of the relation between HSC clonal dynamics, CH and hematologic malignancy requires integration of fundamental lineage tracing studies with clinical data. However, this is hampered by lack of a uniform definition of CH and by inconsistency in the analytical methods used for its quantification. Here, we propose a conceptual and analytical framework for the definition and measurement of CH. First, we transformed the conceptual definition of CH into the CH index, which provides a quantitative measure of clone numbers and sizes. Next, we generated a set of synthetic data, based on the beta-distribution, to simulate clonal populations with different degrees of imbalance. Using these clonal distributions and the CH index as a reference, we tested several established indices of clonal diversity and (in-)equality for their ability to detect and quantify CH. We found that the CH index was distinct from any of the other tested indices. Nonetheless, the diversity indices (Shannon, Simpson) more closely resembled the CH index than the inequality indices (Gini, Pielou). Notably, whereas the inequality indices mainly responded to changes in clone sizes, the CH index and the tested diversity indices also responded to changes in the number of clones in a sample. Accordingly, these simulations indicate that CH can result not only by skewing clonal abundancies, but also by variation in their overall numbers. Altogether, our model-based approach illustrates how a formalized definition and quantification of CH can provide insights into its pathogenesis. In the future, use of the CH index or Shannon index to quantify clonal diversity in fundamental as well as clinical clone-tracing studies will promote cross-disciplinary discussion and progress in the field.
    Keywords:  ageing; clonal diversity; clone; hematopoiesis; lineage tracing; stem cell
    DOI:  https://doi.org/10.3389/fmed.2022.836141
  2. Mol Biol Rep. 2022 Apr 20.
    The role of nicotinamide mononucleotide (NMN) in anti-aging, longevity, and its potential for treating chronic conditions.
    Mounica Soma, Satya Kumar Lalam.
      Biosynthesis and regulation of nicotinamide adenine dinucleotide (NAD+) has recently gained a lot of attention. A systemic decline in NAD+ across many tissues is associated with all the hallmarks of aging. NAD+ can affect a variety of cellular processes, including metabolic pathways, DNA repair, and immune cell activity, both directly and indirectly. These cellular processes play a vital role in maintaining homeostasis, but as people get older, their tissue and cellular NAD+ levels decrease, and this drop in NAD+ levels has been connected to a number of age-related disorders. By restoring NAD+ levels, several of these age-related disorders can be delayed or even reversed. Some of the new studies conducted in mice and humans have targeted the NAD+ metabolism with NAD+ intermediates. Of these, nicotinamide mononucleotide (NMN) has been shown to offer great therapeutic potential with promising results in age-related chronic conditions such as diabetes, cardiovascular issues, cognitive impairment, and many others. Further, human interventions are required to study the long-term effects of supplementing NMN with varying doses. The paper focuses on reviewing the importance of NAD+ on human aging and survival, biosynthesis of NAD+ from its precursors, key clinical trial findings, and the role of NMN on various health conditions.
    Keywords:  Age-related disorders; Anti-aging; NAD+; NMN; Nicotinamide adenine dinucleotide; Nicotinamide mononucleotide; Therapeutic potential
    DOI:  https://doi.org/10.1007/s11033-022-07459-1
  3. Aging Cell. 2022 Apr 18. e13613
    Challenges of proving a causal role of somatic mutations in the aging process.
    Irene Franco, Gwladys Revêchon, Maria Eriksson.
      Aging is accompanied by the progressive accumulation of permanent changes to the genomic sequence, termed somatic mutations. Small mutations, including single-base substitutions and insertions/deletions, are key determinants of the malignant transformations leading to cancer, but their role as initiators of other age-related phenotypes is controversial. Here, we present recent advances in the study of somatic mutagenesis in aging tissues and posit that the current uncertainty about its causal effects in the aging process is due to technological and methodological weaknesses. We highlight classical and novel experimental systems, including premature aging syndromes, that could be used to model the increase of somatic mutation burden and understand its functional role. It is important that studies are designed to take into account the biological context and peculiarities of each tissue and that the downstream impact of somatic mutation accumulation is measured by methods able to resolve subtle cellular changes.
    Keywords:  DNA damage; DNA repair; accelerated aging; ageing; aging; mutagenesis; premature aging; progeria; somatic mutations
    DOI:  https://doi.org/10.1111/acel.13613
  4. J Frailty Aging. 2022 ;11(2): 163-168
    Frailty among Older Adults and Its Distribution in England.
    D R Sinclair, A Maharani, T Chandola, P Bower, B Hanratty, J Nazroo, T W O'Neill, G Tampubolon, C Todd, R Wittenberg, F E Matthews, N Pendleton.
       BACKGROUND: Information on the spatial distribution of the frail population is crucial to inform service planning in health and social care.
    OBJECTIVES: To estimate small-area frailty prevalence among older adults using survey data. To assess whether prevalence differs between urban, rural, coastal and inland areas of England.
    DESIGN: Using data from the English Longitudinal Study of Ageing (ELSA), ordinal logistic regression was used to predict the probability of frailty, according to age, sex and area deprivation. Probabilities were applied to demographic and economic information in 2020 population projections to estimate the district-level prevalence of frailty.
    RESULTS: The prevalence of frailty in adults aged 50+ (2020) in England was estimated to be 8.1 [95% CI 7.3-8.8]%. We found substantial geographic variation, with the prevalence of frailty varying by a factor of 4.0 [3.5-4.4] between the most and least frail areas. A higher prevalence of frailty was found for urban than rural areas, and coastal than inland areas. There are widespread geographic inequalities in healthy ageing in England, with older people in urban and coastal areas disproportionately frail relative to those in rural and inland areas.
    CONCLUSIONS: Interventions aimed at reducing inequalities in healthy ageing should be targeted at urban and coastal areas, where the greatest benefit may be achieved.
    Keywords:  Frailty; ageing; frailty index; health inequalities; rural
    DOI:  https://doi.org/10.14283/jfa.2021.55
  5. Eur J Cell Biol. 2022 Apr 13. pii: S0171-9335(22)00028-0. [Epub ahead of print]101(3): 151225
    Mitochondrial and metabolic alterations in cancer cells.
    Jacopo Di Gregorio, Sabrina Petricca, Roberto Iorio, Elena Toniato, Vincenzo Flati.
      Metabolic alterations have been observed in many cancer types. The deregulated metabolism has thus become an emerging hallmark of the disease, where the metabolism is frequently rewired to aerobic glycolysis. This has led to the concept of "metabolic reprogramming", which has therefore been extensively studied. Over the years, it has been characterized the enhancement of aerobic glycolysis, where key mutations in some of the enzymes of the TCA cycle, and the increased glucose uptake, are used by cancer cells to achieve a "metabolic phenotype" useful to gain a proliferation advantage. Many studies have highlighted in detail the signaling pathways and the molecular mechanisms responsible for the glycolytic switch. However, glycolysis is not the only metabolic process that cancer cells rely on. Oxidative Phosphorylation (OXPHOS), gluconeogenesis or the beta-oxidation of fatty acids (FAO) may be involved in the development and progression of several tumors. In some cases, these metabolisms are even more crucial than aerobic glycolysis for the tumor survival. This review will focus on the contribution of these alterations of metabolism to the development and survival of cancers. We will also analyze the molecular mechanisms by which the balance between these metabolic processes may be regulated, as well as some of the therapeutical approaches that can derive from their study.
    Keywords:  Amino acids; Cancer; Fatty acids; Metabolism; Mitochondria; OXPHOS
    DOI:  https://doi.org/10.1016/j.ejcb.2022.151225
  6. World J Stem Cells. 2022 Feb 26. 14(2): 146-162
    Abnormal lipid synthesis as a therapeutic target for cancer stem cells.
    Si-Yu Wang, Qin-Chao Hu, Tong Wu, Juan Xia, Xiao-An Tao, Bin Cheng.
      Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.
    Keywords:  Anti-cancer therapy; Cancer stem cells; Lipid anabolism; Lipid synthesis; Stem cell survival
    DOI:  https://doi.org/10.4252/wjsc.v14.i2.146
  7. Curr Stem Cell Rep. 2022 Mar;8(1): 35-43
    Role of the hematopoietic stem cells in immunological memory.
    Vinothini Govindarajah, Damien Reynaud.
       Purpose of review: Immunological memory is an important evolutionary adaptation of the immune system. Previously restricted to the adaptive immune system, the concept of memory has recently been broadened to the innate immune system. This review summarizes recent studies that highlight the contribution of the hematopoietic stem cells (HSCs) in supporting immunological memory.
    Recent findings: Short-lived innate immune cells can build a long-lasting memory of infection to improve their response to secondary challenges. Studies show that these unexpected properties of the innate immune system are sustained by epigenetic and metabolic changes in the HSC compartment.
    Summary: HSCs are durably altered in response to pathogens and serve as long-term support for innate immune memory. Many questions remain regarding the mechanisms contributing to the induction and the maintenance of this immune memory in HSCs. Answering these questions will open new perspectives to understand how environmental factors shape the HSC activity over time.
    Keywords:  Adaptive immune system; Hematopoietic stem cell; Immunological memory; Innate immune system; Trained immunity
    DOI:  https://doi.org/10.1007/s40778-021-00204-7
  8. Gerontology. 2022 Apr 20. 1-8
    Prospective Study of Ageing Trajectories in the European DO-HEALTH Study.
    DO-HEALTH research group
       INTRODUCTION: Ageing trajectories range from delayed ageing with extended health to accelerated ageing, with an increased risk of frailty. We evaluated the prevalence and prospective change between health states among community-dwelling European older adults.
    METHODS: This prospective study is a secondary analysis of DO-HEALTH, a randomized trial that included adults aged 70 years and older across 5 European countries. Healthy agers (HA) fulfilled the Nurses' Health Study healthy ageing criteria and accelerated agers were non-HA being at least pre-frail according to the Fried frailty criteria. We assessed the proportion of participants changing between health states over 4 assessments and evaluated the odds of changing to a more favourable category. To increase reliability and avoid regression to the mean, we averaged the first 2 years and compared them to the average of the last 2 years.
    RESULTS: Of 2,157 participants, 12.4% were excluded for meeting both healthy ageing and pre-frailty criteria simultaneously. Among the remaining 1,889 participants (mean age 75.1 years, 60.9% female), 23.1% were initially HA, 44.4% were non-HA but not pre-frail, and 32.6% were pre-frail or frail. Subsequently, 65.3% remained in the same health state, 12.0% improved to a healthier state, and 22.8% progressed to a less advantageous state. After adjusting for sex, study centre, treatment, and body mass index, each year of age was associated with 6% lower odds of improving health states. Women had 35% higher odds than men of following a disadvantageous trajectory.
    CONCLUSION: We observed dynamic trajectories of ageing where transitioning to a healthier state became less likely with advancing age and among women.
    Keywords:  Ageing trajectories; Healthy ageing; Successful ageing
    DOI:  https://doi.org/10.1159/000523923
  9. J Clin Epidemiol. 2022 Apr 15. pii: S0895-4356(22)00096-8. [Epub ahead of print]
    Pooling of cohort studies and RCTs affects GRADE certainty of evidence in nutrition research.
    Lukas Schwingshackl, Blin Nagavci, Julia Stadelmaier, Sarah S Werner, Carlos A Cuello Garcia, Holger J Schünemann, Joerg J Meerpohl.
       OBJECTIVE: There is little empirical evidence of the impact of pooling randomized controlled trials (RCTs) and cohort studies (CSs) on the certainty-of-evidence. To evaluate the hypothetical-scenario of pooling bodies-of-evidence from RCTs with matched bodies-of-evidence from CSs on the certainty-of-evidence.
    STUDY DESIGN AND SETTING: We extracted GRADE ratings of bodies-of-evidence from RCTs in Cochrane reviews, and rated the certainty-of-evidence from matched bodies-of-evidence from CSs. We then evaluated the impact of pooling both bodies-of-evidence on the overall certainty-of-evidence, and on individual GRADE domains.
    RESULTS: 42 pooled bodies-of-evidence were rated, ranging from very-low (bodies-of-evidenceRCTs:9.5%; bodies-of-evidenceCSs:40.5%; pooled-bodies-of-evidence:0%) to low (bodies-of-evidenceRCTs:38.1%; bodies-of-evidenceCSs:45.2%; pooled-bodies-of-evidence:19.1%), moderate (bodies-of-evidenceRCTs:33.4%; bodies-of-evidenceCSs:14.3%; pooled-bodies-of-evidence:57.1%), and high (bodies-of-evidenceRCTs:19%; bodies-of-evidenceCSs:0%; pooled-bodies-of-evidence:23.8%). Certainty-of-evidence was downgraded mostly for imprecision and risk of bias for bodies-of-evidence from RCTs, and for risk of bias and inconsistency for bodies-of-evidence from CSs. Pooling both bodies-of-evidence mitigates rating down for imprecision compared to bodies-of-evidence from RCTs and inconsistency compared to bodies-of-evidence from CSs.
    CONCLUSION: Our hypothetical study suggests that pooling both bodies-of-evidence would reduce the amount of very-low and low certainty-of-evidence ratings, but how to integrate RCTs and CSs and whether or not to pool these bodies-of-evidence requires proper guidance before systematic review authors or guideline developers should consider this approach.
    Keywords:  GRADE; RCTs; certainty of evidence; cohort studies; nutrition; pooling
    DOI:  https://doi.org/10.1016/j.jclinepi.2022.04.013
  10. J Frailty Aging. 2022 ;11(2): 177-181
    Appendicular Lean Mass and Frailty among Geriatric Outpatients.
    Tam N Nguyen, Tu N Nguyen, Anh T Nguyen, Hoa L Nguyen, Robert J Goldberg, Huong T T Nguyen, Thu T H Nguyen, Thanh X Nguyen, Huyen T T Vu.
      The objective of this observational study was to examine the association between appendicular lean mass and frailty in adults aged 60 years and older. This study was conducted in the Outpatient Department of the National Geriatric Hospital in Hanoi, Vietnam. Appendicular lean mass (kg) was assessed by using Dual energy X-ray absorptiometry scans. Frailty was defined according to Fried's frailty criteria. A total of 560 outpatients were included in the study, with a mean age of 70 years. The prevalence of frailty was 12.0%. Frail patients had significantly lower appendicular lean mass compared with non-frail outpatients (9.6 ± 2.0 kg vs. 11.7 ± 3.1 kg, p<0.001). On multivariable logistic regression models, higher appendicular lean mass was associated with significantly reduced odds for frailty (adjusted OR = 0.74, 95%CI 0.59 - 0.93). These findings suggest that the assessment of appendicular lean mass should be considered in older patients attending outpatient geriatric clinics.
    Keywords:  Frailty; lean mass; outpatients; sarcopenia
    DOI:  https://doi.org/10.14283/jfa.2022.9
  11. Int J Mol Sci. 2022 Apr 18. pii: 4462. [Epub ahead of print]23(8):
    Bone Marrow Niches of Hematopoietic Stem and Progenitor Cells.
    Oleg Kandarakov, Alexander Belyavsky, Ekaterina Semenova.
      The mammalian hematopoietic system is remarkably efficient in meeting an organism's vital needs, yet is highly sensitive and exquisitely regulated. Much of the organismal control over hematopoiesis comes from the regulation of hematopoietic stem cells (HSCs) by specific microenvironments called niches in bone marrow (BM), where HSCs reside. The experimental studies of the last two decades using the most sophisticated and advanced techniques have provided important data on the identity of the niche cells controlling HSCs functions and some mechanisms underlying niche-HSC interactions. In this review we discuss various aspects of organization and functioning of the HSC cell niche in bone marrow. In particular, we review the anatomy of BM niches, various cell types composing the niche, niches for more differentiated cells, metabolism of HSCs in relation to the niche, niche aging, leukemic transformation of the niche, and the current state of HSC niche modeling in vitro.
    Keywords:  3D modeling; aging; bone marrow; hematopoiesis; hematopoietic stem cells; hypoxia; leukemogenesis; mesenchymal stromal cells; metabolism; niches
    DOI:  https://doi.org/10.3390/ijms23084462
  12. Genes (Basel). 2022 Apr 08. pii: 656. [Epub ahead of print]13(4):
    Barth Syndrome Cardiomyopathy: An Update.
    Jing Pang, Yutong Bao, Kalia Mitchell-Silbaugh, Jennifer Veevers, Xi Fang.
      Barth syndrome (BTHS) is an X-linked mitochondrial lipid disorder caused by mutations in the TAFAZZIN (TAZ) gene, which encodes a mitochondrial acyltransferase/transacylase required for cardiolipin (CL) biosynthesis. Cardiomyopathy is a major clinical feature of BTHS. During the past four decades, we have witnessed many landmark discoveries that have led to a greater understanding of clinical features of BTHS cardiomyopathy and their molecular basis, as well as the therapeutic targets for this disease. Recently published Taz knockout mouse models provide useful experimental models for studying BTHS cardiomyopathy and testing potential therapeutic approaches. This review aims to summarize key findings of the clinical features, molecular mechanisms, and potential therapeutic approaches for BTHS cardiomyopathy, with particular emphasis on the most recent studies.
    Keywords:  Barth syndrome; TAFAZZIN; cardiolipin; cardiomyopathy
    DOI:  https://doi.org/10.3390/genes13040656
  13. Biomolecules. 2022 Apr 18. pii: 595. [Epub ahead of print]12(4):
    The Influence of Heterochronic Non-Myeloablative Bone Marrow Transplantation on the Immune System, Frailty, General Health, and Longevity of Aged Murine Recipients.
    Katerina Jazbec, Mojca Jež, Urban Švajger, Boštjan Smrekar, Simona Miceska, Uroš Rajčevič, Mojca Justin, Janja Završnik, Tadej Malovrh, Tanja Švara, Mitja Gombač, Živa Ramšak, Primož Rožman.
      The stem cell theory of aging postulates that stem cells become inefficient at maintaining the original functions of the tissues. We, therefore, hypothesized that transplanting young bone marrow (BM) to old recipients would lead to rejuvenating effects on immunity, followed by improved general health, decreased frailty, and possibly life span extension. We developed a murine model of non-myeloablative heterochronic BM transplantation in which old female BALB/c mice at 14, 16, and 18(19) months of age received altogether 125.1 ± 15.6 million nucleated BM cells from young male donors aged 7-13 weeks. At 21 months, donor chimerism was determined, and the immune system's innate and adaptive arms were analyzed. Mice were then observed for general health and frailty until spontaneous death, when their lifespan, post-mortem examinations, and histopathological changes were recorded. The results showed that the old mice developed on average 18.7 ± 9.6% donor chimerism in the BM and showed certain improvements in their innate and adaptive arms of the immune system, such as favorable counts of neutrophils in the spleen and BM, central memory Th cells, effector/effector memory Th and Tc cells in the spleen, and B1a and B1b cells in the peritoneal cavity. Borderline enhanced lymphocyte proliferation capacity was also seen. The frailty parameters, pathomorphological results, and life spans did not differ significantly in the transplanted vs. control group of mice. In conclusion, although several favorable effects are obtained in our heterochronic non-myeloablative transplantation model, additional optimization is needed for better rejuvenation effects.
    Keywords:  BMT; aging; bone marrow transplantation; cell isolation; frailty index; hematopoietic stem cells; immune system; longevity; mice
    DOI:  https://doi.org/10.3390/biom12040595
  14. DNA Cell Biol. 2022 Apr 22.
    Calorie Restriction-Regulated Molecular Pathways and Its Impact on Various Age Groups: An Overview.
    Anuradha Rachakatla, Rajender Rao Kalashikam.
      Calorie restriction (CR) if planned properly with regular exercise at different ages can result in healthy weight loss. CR can also have different beneficial effects on improving lifespan and decreasing the age-associated diseases by regulating physiological, biochemical, and molecular markers. The different pathways regulated by CR include:(1) AMP-activated protein kinase (AMPK), which involves PGC-1α, SIRT1, and SIRT3. AMPK also effects myocyte enhancer factor 2 (MEF2), peroxisome proliferator-activated receptor delta, and peroxisome proliferator-activated receptor alpha, which are involved in mitochondrial biogenesis and lipid oxidation; (2) Forkhead box transcription factor's signaling is related to the DNA repair, lipid metabolism, protection of protein structure, autophagy, and resistance to oxidative stress; (3) Mammalian target of rapamycin (mTOR) signaling, which involves key factors, such as S6 protein kinase-1 (S6K1), mTOR complex-1 (mTORC1), and 4E-binding protein (4E-BP). Under CR conditions, AMPK activation and mTOR inhibition helps in the activation of Ulk1 complex along with the acetyltransferase Mec-17, which is necessary for autophagy; (4) Insulin-like growth factor-1 (IGF-1) pathway downregulation protects against cancer and slows the aging process; (5) Nuclear factor kappa B pathway downregulation decreases the inflammation; and (6) c-Jun N-terminal kinase and p38 kinase regulation as a response to the stress. The acute and chronic CR both shows antidepression and anxiolytic action by effecting ghrelin/GHS-R1a signaling. CR also regulates GSK3β kinase and protects against age-related brain atrophy. CR at young age may show many deleterious effects by effecting different mechanisms. Parental CR before or during conception will also affect the health and development of the offspring by causing many epigenetic modifications that show transgenerational transmission. Maternal CR is associated with intrauterine growth retardation effecting the offspring in their adulthood by developing different metabolic syndromes. The epigenetic changes with response to paternal food supply also linked to offspring health. CR at middle and old age provides a significant preventive impact against the development of age-associated diseases.
    Keywords:  AMPK; ROS; calorie restriction; mTOR
    DOI:  https://doi.org/10.1089/dna.2021.0922
  15. Eur Geriatr Med. 2022 Apr 23.
    Accuracy, feasibility and predictive ability of different frailty instruments in an acute geriatric setting.
    Rafael Bielza, Cristina Balaguer, Francisco Zambrana, Estefanía Arias, Israel J Thuissard, Ana Lung, Carlos Oñoro, Patricia Pérez, Cristina Andreu-Vázquez, Marta Neira, Noemi Anguita, Carmen Sáez, Eva María Fernández de la Puente.
       PURPOSE: To analyze the feasibility, accuracy and the ability of different frailty instruments to predict adverse outcomes.
    METHODS: A prospective cohort study was conducted in patients ≥ 70 years admitted to the acute care setting (ACS). Feasibility and prevalence of frailty were assessed by FRAIL, Clinical Frailty Scale (CFS), hand grip strength (HGS) and the Spanish Frailty-VIG. Receiver operator characteristic (ROC) curves and area under the curve (AUC) were performed to identify frailty according to each instrument, setting VIG as the reference. For each instrument, multiple logistic regressions were used to examine the effect of frailty on primary outcome (i.e., three-month mortality) and secondary outcomes (i.e., in-hospital mortality, length of stay, institutionalization, functional decline and 30-day readmission).
    RESULTS: A total of 185 patients were included, with a median age of 89 years. The feasibility of the instruments was 100%, except for HGS (67%). The prevalence of frailty varied from 65.2% (FRAIL) to 86.7% (VIG). AUCs against VIG ranged from 0.69 (95% confidence interval [CI] 0.57-0.81: FRAIL) to 0.77 (95% CI 63.5-90.2: CFS). Frail patients defined by FRAIL were 2.7times more likely to have a prolonged length of stay than non-frail patients (95% CI 1.385-5.416). Three-month mortality occurred more among frail patients, either defined by FRAIL (OR 2.5; 95% CI 1.072-5.881) or CFS (OR 3.7; 95% CI 1.255-10.812), than in non-frail patients.
    CONCLUSION: The four instruments had high feasibility providing variable prevalence of frailty. FRAIL and CFS predicted well for three-month mortality, and FRAIL also for length of stay. However, none of the instruments predicted for the other secondary outcomes of the study.
    Keywords:  Accuracy; Acute care setting; Feasibility; Frailty
    DOI:  https://doi.org/10.1007/s41999-022-00645-1
  16. Cells. 2022 Apr 17. pii: 1366. [Epub ahead of print]11(8):
    Tet1 Suppresses p21 to Ensure Proper Cell Cycle Progression in Embryonic Stem Cells.
    Stephanie Chrysanthou, Julio C Flores, Meelad M Dawlaty.
      Ten eleven translocation 1 (Tet1) is a DNA dioxygenase that promotes DNA demethylation by oxidizing 5-methylcytosine. It can also partner with chromatin-activating and repressive complexes to regulate gene expressions independent of its enzymatic activity. Tet1 is highly expressed in embryonic stem cells (ESCs) and regulates pluripotency and differentiation. However, its roles in ESC cell cycle progression and proliferation have not been investigated. Using a series of Tet1 catalytic mutant (Tet1m/m), knockout (Tet1-/-) and wild type (Tet1+/+) mouse ESCs (mESCs), we identified a non-catalytic role of Tet1 in the proper cell cycle progression and proliferation of mESCs. Tet1-/-, but not Tet1m/m, mESCs exhibited a significant reduction in proliferation and delayed progression through G1. We found that the cyclin-dependent kinase inhibitor p21/Cdkn1a was uniquely upregulated in Tet1-/- mESCs and its knockdown corrected the slow proliferation and delayed G1 progression. Mechanistically, we found that p21 was a direct target of Tet1. Tet1 occupancy at the p21 promoter overlapped with the repressive histone mark H3K27me3 as well as with the H3K27 trimethyl transferase PRC2 component Ezh2. A loss of Tet1, but not loss of its catalytic activity, significantly reduced the enrichment of Ezh2 and H3K27 trimethylation at the p21 promoter without affecting the DNA methylation levels. We also found that the proliferation defects of Tet1-/- mESCs were independent of their differentiation defects. Together, these findings established a non-catalytic role for Tet1 in suppressing p21 in mESCs to ensure a rapid G1-to-S progression, which is a key hallmark of ESC proliferation. It also established Tet1 as an epigenetic regulator of ESC proliferation in addition to its previously defined roles in ESC pluripotency and differentiation.
    Keywords:  ESC; Tet1; cell cycle; p21; proliferation
    DOI:  https://doi.org/10.3390/cells11081366
  17. N Engl J Med. 2022 04 21. 386(16): 1572-1573
    Calorie and Time Restriction in Weight Loss.
    Blandine Laferrère, Satchidananda Panda.
      
    DOI:  https://doi.org/10.1056/NEJMe2202821
  18. PM R. 2022 Apr 19.
    The Aging Athlete.
    Michael Catapano, Marwa Ahmed, Rebecca G Breslow, Joanne Borg-Stein.
      Aging athletes, those in the 6th decade of life and above, are a growing population of mature, active individuals who value sports and exercise participation throughout their lifespan. Although recommendations for younger and masters athletes have been extrapolated to this population, there remains a paucity of specific guidelines, treatment algorithms, and considerations for aging athletes. The benefits of living an active lifestyle must be weighed against the risks for unique cardiovascular, metabolic, and musculoskeletal injuries requiring diagnostic and therapeutic interventions. In this article, we review the unique cardiovascular and muscular physiology of aging athletes and how it influences the risk of specific medical conditions. We also discuss general prevention and treatment strategies. Finally, we identify areas of future research priorities and emerging treatments. This article is protected by copyright. All rights reserved.
    Keywords:  Aging athlete; masters athlete; musculoskeletal; rehabilitation
    DOI:  https://doi.org/10.1002/pmrj.12814
  19. Nature. 2022 Apr 20.
    Four lessons from the pandemic to reboot the NIH.
    Max Kozlov.
      
    Keywords:  Funding; Government; Medical research
    DOI:  https://doi.org/10.1038/d41586-022-01101-7
  20. J Nutr Health Aging. 2022 ;26(4): 316-317
    Editorial: Epigenetic Clock: A Novel Tool for Nutrition Studies of Healthy Ageing.
    L He.
      
    DOI:  https://doi.org/10.1007/s12603-022-1773-0
  21. Gene. 2022 Apr 19. pii: S0378-1119(22)00320-1. [Epub ahead of print] 146501
    Two Different Aging Paths in Human Blood Revealed by Integrated Analysis of Gene Expression, Mutation and Alternative Splicing.
    Xin Tong, Wen-Xing Li, Jihao Liang, Yang Zheng, Shao-Xing Dai.
      Aging is a complex life process that human organs and tissues steadily and continuously decline. Aging has huge heterogeneity, which shows different aging rates among different individuals and in different tissues of the same individual. Many studies of aging are often contradictory and show little common signature. The integrated analysis of these transcriptome datasets will provide an unbiased global view of the aging process. Here, we integrated 8 transcriptome datasets including 757 samples from healthy human blood to study aging from three aspects of gene expression, mutations, and alternative splicing. Surprisingly, we found that transcriptome changes in blood are relatively independent of the chronological age. Further pseudotime analysis revealed two different aging paths (AgingPath1 and AgingPath2) in human blood. The differentially expressed genes (DEGs) along the two paths showed a limited overlap and are enriched in different biological processes. The mutations of DEGs in AgingPath1 are significantly increased in the aging process, while the opposite trend was observed in AgingPath2. Expression quantitative trait loci (eQTL) and splicing quantitative trait loci (sQTL) analysis identified 304 important mutations that can affect both gene expression and alternative splicing during aging. Finally, by comparison between aging and Alzheimer's disease, we identified 37 common DEGs in AgingPath1, AgingPath2 and Alzheimer's disease. These genes may contribute to the shift from aging state to Alzheimer's disease. In summary, this study revealed the two aging paths and the related genes and mutations, which provides a new insight into aging and aging-related disease.
    Keywords:  Aging; Alternative splicing; Alzheimer’s disease; Gene expression; Mutation
    DOI:  https://doi.org/10.1016/j.gene.2022.146501
  22. Proc Natl Acad Sci U S A. 2022 Apr 26. 119(17): e2121028119
    Early age-related atrophy of cutaneous lymph nodes precipitates an early functional decline in skin immunity in mice with aging.
    Sandip Ashok Sonar, Jennifer L Uhrlaub, Christopher P Coplen, Gregory D Sempowski, Jarrod A Dudakov, Marcel R M van den Brink, Bonnie J LaFleur, Mladen Jergović, Janko Nikolich-Žugich.
      SignificanceOlder adults are more vulnerable to infection and less capable of vigorously responding to vaccination. The contribution of peripheral T cell maintenance defects to these processes is incompletely understood. Here, we provide evidence that lymph nodes (LNs), which are critical for naive T (TN) cell maintenance and initiation of new immune responses, age asynchronously. Skin-draining LNs undergo early (6 to 9 mo) and deeper LN and spleen late-life (18 mo) atrophy, characterized by reduced ability to maintain TN cells, structural and numerical loss of LN stromal cell microenvironments, and reduced immunity to cutaneous vaccination. These results highlight the critical role of age-related LN atrophy in functional immunity and immune homeostasis.
    Keywords:  T cells; aging; homeostasis; secondary lymphoid organs
    DOI:  https://doi.org/10.1073/pnas.2121028119
  23. Metabolites. 2022 Apr 15. pii: 356. [Epub ahead of print]12(4):
    Metabolites Associated with Memory and Gait: A Systematic Review.
    Qu Tian, Brendan A Mitchell, Abigail E Corkum, Ruin Moaddel, Luigi Ferrucci.
      We recently found that dual decline in memory and gait speed was consistently associated with an increased risk of dementia compared to decline in memory or gait only or no decline across six aging cohorts. The mechanisms underlying this relationship are unknown. We hypothesize that individuals who experience dual decline may have specific pathophysiological pathways to dementia which can be indicated by specific metabolomic signatures. Here, we summarize blood-based metabolites that are associated with memory and gait from existing literature and discuss their relevant pathways. A total of 39 eligible studies were included in this systematic review. Metabolites that were associated with memory and gait belonged to five shared classes: sphingolipids, fatty acids, phosphatidylcholines, amino acids, and biogenic amines. The sphingolipid metabolism pathway was found to be enriched in both memory and gait impairments. Existing data may suggest that metabolites from sphingolipids and the sphingolipid metabolism pathway are important for both memory and gait impairments. Future studies using empirical data across multiple cohorts are warranted to identify metabolomic signatures of dual decline in memory and gait and to further understand its relationship with future dementia risk.
    Keywords:  dementia; gait; memory; metabolomics
    DOI:  https://doi.org/10.3390/metabo12040356
  24. Stem Cell Rev Rep. 2022 Apr 23.
    Telomeres and Mitochondrial Metabolism: Implications for Cellular Senescence and Age-related Diseases.
    Xingyu Gao, Xiao Yu, Chang Zhang, Yiming Wang, Yanan Sun, Hui Sun, Haiying Zhang, Yingai Shi, Xu He.
      Cellular senescence is an irreversible cell arrest process, which is determined by a variety of complicated mechanisms, including telomere attrition, mitochondrial dysfunction, metabolic disorders, loss of protein homeostasis, epigenetic changes, etc. Cellular senescence is causally related to the occurrence and development of age-related disease. The elderly is liable to suffer from disorders such as neurodegenerative diseases, cancer, and diabetes. Therefore, it is increasingly imperative to explore specific countermeasures for the treatment of age-related diseases. Numerous studies on humans and mice emphasize the significance of metabolic imbalance caused by short telomeres and mitochondrial damages in the onset of age-related diseases. Although the experimental data are relatively independent, more and more evidences have shown that there is mutual crosstalk between telomeres and mitochondrial metabolism in the process of cellular senescence. This review systematically discusses the relationship between telomere length, mitochondrial metabolic disorder, as well as their underlying mechanisms for cellular senescence and age-related diseases. Future studies on telomere and mitochondrial metabolism may shed light on potential therapeutic strategies for age-related diseases. Graphical Abstract The characteristics of cellular senescence mainly include mitochondrial dysfunction and telomere attrition. Mitochondrial dysfunction will cause mitochondrial metabolic disorders, including decreased ATP production, increased ROS production, as well as enhanced cellular apoptosis. While oxidative stress reaction to produce ROS, leads to DNA damage, and eventually influences telomere length. Under the stimulation of oxidative stress, telomerase catalytic subunit TERT mainly plays an inhibitory role on oxidative stress, reduces the production of ROS and protects telomere function. Concurrently, mitochondrial dysfunction and telomere attrition eventually induce a range of age-related diseases, such as T2DM, osteoporosis, AD, etc. :increase; :reduce;⟝:inhibition.
    Keywords:  Aging; Cellular senescence; Mitochondrial metabolism; Telomeres
    DOI:  https://doi.org/10.1007/s12015-022-10370-8
  25. Expert Opin Ther Pat. 2022 Apr 18.
    ATP-citrate lyase (ACLY) inhibitors as therapeutic agents: a patenting perspective.
    Carlotta Granchi.
       INTRODUCTION: ATP citrate lyase (ACLY) is a key enzyme in cellular metabolism, being the main source of acetyl-Coenzyme A, an important precursor for fatty acid, cholesterol and isoprenoid biosynthesis, and it is also involved in protein acetylation. Its expression changes are related to hyperlipidemia and cardiovascular diseases. Other studies have shown that ACLY is closely related to the occurrence of cancer: the increase in lipid synthesis provides the necessary building blocks for cell growth and division. Therefore, finding effective ACLY inhibitors has very important application prospects for lipid-related pathologies and cancer.
    AREAS COVERED: : This review covers patents concerning ACLY inhibitors and alternative strategies to modulate ACLY activity, with their potential therapeutic applications.
    EXPERT OPINION: In recent years ACLY as a drug target has become a hot spot in the research of innovative drugs for disorders of glucose and lipid metabolism. Many types of small-molecule ACLY inhibitors have been discovered, but few ACLY inhibitors proved to be highly effective in vitro and in vivo, since their main limitations were low cell penetration and low affinity to ACLY. The search for new effective ACLY inhibitors is of great significance and has broad application prospects for the treatment of hyperlipidemia and cancer.
    Keywords:  ATP citrate lyase; cancer; inhibitors; lipid metabolism
    DOI:  https://doi.org/10.1080/13543776.2022.2067478
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