bims-minfam Biomed News
on Inflammation and metabolism in ageing and cancer
Issue of 2022–04–17
25 papers selected by
Ayesh Seneviratne, University of Toronto
  1. Inflammation and hematopoietic stem cells aging.
  2. Cell Origin-Dependent Cooperativity of Mutant Dnmt3a and Npm1 in Clonal Hematopoiesis and Myeloid Malignancy.
  3. Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging.
  4. Regulation of Aging and Longevity by Ion Channels and Transporters.
  5. The lifespan secret: why giraffes live longer than ferrets.
  6. Mitochondrial-to-nuclear communication in aging: an epigenetic perspective.
  7. Characterization of cellular senescence in doxorubicin-induced aging mice.
  8. Itaconate prolongs the healthy lifespan by activating UPRmt in Caenorhabditis elegans.
  9. Iron Metabolism in Aging and Age-Related Diseases.
  10. Covid-19 Boosters - Where from Here?
  11. Signs of ageing.
  12. Vaccine Booster Dose Appears to Reduce Omicron Hospitalizations.
  13. Nandrolone Supplementation Promotes AMPK Activation and Divergent 18[FDG] PET Brain Connectivity in Adult and Aged Mice.
  14. Pharmaceutical and nutraceutical activation of FOXO3 for healthy longevity.
  15. Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.
  16. [Frailty syndrome as an independent predictor of adverse prognosis in patients with chronic heart failure].
  17. Hematopoietic Stem Cell Factors: Their Functional Role in Self-Renewal and Clinical Aspects.
  18. Nonresolving inflammation redux.
  19. Senotherapeutics in Cancer and HIV.
  20. Aging and HFpEF: Are we running out of time?
  21. Metabolomics reveals the impact of the saturation of dietary lipids on the aging and longevity of C. elegans.
  22. Short-term senolytic treatment: a paradigm to promote fracture repair during aging.
  23. Dysmetabolism and Neurodegeneration: Trick or Treat?
  24. Structured Long-Chain Omega-3 Fatty Acids for Improvement of Cognitive Function during Aging.
  25. Nutraceutical Role of Polyphenols and Triterpenes Present in the Extracts of Fruits and Leaves of Olea europaea as Antioxidants, Anti-Infectives and Anticancer Agents on Healthy Growth.
  1. Blood Sci. 2021 Jan;3(1): 1-5
    Inflammation and hematopoietic stem cells aging.
    Hanqing He, Jianwei Wang.
      Hematopoietic stem cells (HSCs) replenish all lineages of blood cells throughout the lifespan. During aging, the repopulation capacity of HSCs declined, and aged HSCs display a tendency for myeloid differentiation. Several intrinsic and extrinsic factors have been identified to promote HSCs aging. In this review, we focus on the contribution of aging-associated inflammation in provoking HSCs aging and discuss the future research direction of inflammation and HSC aging.
    Keywords:  Hematopoietic stem cells aging; Inflammation
    DOI:  https://doi.org/10.1097/BS9.0000000000000063
  2. Blood Adv. 2022 Apr 12. pii: bloodadvances.2022006968. [Epub ahead of print]
    Cell Origin-Dependent Cooperativity of Mutant Dnmt3a and Npm1 in Clonal Hematopoiesis and Myeloid Malignancy.
    Jennifer M SanMiguel, Elizabeth Eudy, Matthew A Loberg, Linde A Miles, Tim Stearns, Jayna J Mistry, Michael J Rauh, Ross L Levine, Jennifer Trowbridge.
      In adult acute myeloid leukemia (AML), acquisition of driver somatic mutations may be preceded by a benign state termed clonal hematopoiesis (CH). To develop therapeutic strategies to prevent leukemia development from CH, it is important to understand the mechanisms by which CH-driving and AML-driving mutations cooperate. Here, we use mice with inducible mutant alleles common in human CH (DNMT3AR882; mouse Dnmt3aR878H) and AML (NPM1c; mouse Npm1cA). We find that Dnmt3aR878H/+ hematopoietic stem cells (HSCs), but not multipotent progenitor cell (MPP) subsets, have reduced expression of cytokine and pro-inflammatory transcriptional signatures and a functional competitive advantage over their wild-type counterparts. Dnmt3aR878H/+ HSCs are the most potent cell type transformed by Npm1cA, generating myeloid malignancies in which few additional cooperating somatic mutation events were detected. At a molecular level, Npm1cA in cooperation with Dnmt3aR878H acutely increased accessibility of a distinct set of promoters in HSCs compared to MPP cells. These promoters were enriched for cell cycling, PI3K/AKT/mTOR signaling, stem cell signatures, and targets of transcription factors including NFAT and the chromatin binding factor HMGB1, which have been implicated in human AML. These results demonstrate cooperativity between pre-existing Dnmt3aR878H and Npm1cA at the chromatin level, where specific loci altered in accessibility by Npm1cA are dependent on cell context as well as Dnmt3a mutation status. These findings have implications for biological understanding and therapeutic intervention into transformation from CH to AML.
    DOI:  https://doi.org/10.1182/bloodadvances.2022006968
  3. Int J Mol Sci. 2022 Mar 27. pii: 3675. [Epub ahead of print]23(7):
    Increasing Complexity of Molecular Landscapes in Human Hematopoietic Stem and Progenitor Cells during Development and Aging.
    Suzanne M Watt, Peng Hua, Irene Roberts.
      The past five decades have seen significant progress in our understanding of human hematopoiesis. This has in part been due to the unprecedented development of advanced technologies, which have allowed the identification and characterization of rare subsets of human hematopoietic stem and progenitor cells and their lineage trajectories from embryonic through to adult life. Additionally, surrogate in vitro and in vivo models, although not fully recapitulating human hematopoiesis, have spurred on these scientific advances. These approaches have heightened our knowledge of hematological disorders and diseases and have led to their improved diagnosis and therapies. Here, we review human hematopoiesis at each end of the age spectrum, during embryonic and fetal development and on aging, providing exemplars of recent progress in deciphering the increasingly complex cellular and molecular hematopoietic landscapes in health and disease. This review concludes by highlighting links between chronic inflammation and metabolic and epigenetic changes associated with aging and in the development of clonal hematopoiesis.
    Keywords:  aging; childhood leukemias; clonal hematopoiesis of indeterminate potential; development; hematopoietic stem cells; inflamm-aging; metabolism; single-cell transcriptomics
    DOI:  https://doi.org/10.3390/ijms23073675
  4. Cells. 2022 Mar 31. pii: 1180. [Epub ahead of print]11(7):
    Regulation of Aging and Longevity by Ion Channels and Transporters.
    Kartik Venkatachalam.
      Despite significant advances in our understanding of the mechanisms that underlie age-related physiological decline, our ability to translate these insights into actionable strategies to extend human healthspan has been limited. One of the major reasons for the existence of this barrier is that with a few important exceptions, many of the proteins that mediate aging have proven to be undruggable. The argument put forth here is that the amenability of ion channels and transporters to pharmacological manipulation could be leveraged to develop novel therapeutic strategies to combat aging. This review delves into the established roles for ion channels and transporters in the regulation of aging and longevity via their influence on membrane excitability, Ca2+ homeostasis, mitochondrial and endolysosomal function, and the transduction of sensory stimuli. The goal is to provide the reader with an understanding of emergent themes, and prompt further investigation into how the activities of ion channels and transporters sculpt the trajectories of cellular and organismal aging.
    Keywords:  ER; aging; calcium; ion channels; lifespan; longevity; lysosomes
    DOI:  https://doi.org/10.3390/cells11071180
  5. Nature. 2022 Apr 13.
    The lifespan secret: why giraffes live longer than ferrets.
    Dan Fox.
      
    Keywords:  Ageing; Cancer; Genetics
    DOI:  https://doi.org/10.1038/d41586-022-01042-1
  6. Trends Biochem Sci. 2022 Apr 06. pii: S0968-0004(22)00067-6. [Epub ahead of print]
    Mitochondrial-to-nuclear communication in aging: an epigenetic perspective.
    Di Zhu, Xinyu Li, Ye Tian.
      Age-associated changes in mitochondria are closely involved in aging. Apart from the established roles in bioenergetics and biosynthesis, mitochondria are signaling organelles that communicate their fitness to the nucleus, triggering transcriptional programs to adapt homeostasis stress that is essential for organismal health and aging. Emerging studies revealed that mitochondrial-to-nuclear (mito-nuclear) communication via altered levels of mitochondrial metabolites or stress signals causes various epigenetic changes, facilitating efforts to maintain homeostasis and affect aging. Here, we summarize recent studies on the mechanisms by which mito-nuclear communication modulates epigenomes and their effects on regulating the aging process. Insights into understanding how mitochondrial metabolites serve as prolongevity signals and how aging affects this communication will help us develop interventions to promote longevity and health.
    Keywords:  UPR(mt); aging; epigenetic regulation; longevity; mitochondrial metabolites; mitochondrial–nuclear communication
    DOI:  https://doi.org/10.1016/j.tibs.2022.03.008
  7. Exp Gerontol. 2022 Apr 06. pii: S0531-5565(22)00108-5. [Epub ahead of print]163 111800
    Characterization of cellular senescence in doxorubicin-induced aging mice.
    Tianyue Sun, Lanxin Zhang, Jiali Feng, Lingyuan Bao, Jiqun Wang, Zhouzhi Song, Zhifan Mao, Jian Li, Zelan Hu.
      With a rise in the need to develop anti-aging drugs, a growing number of in vivo studies evaluating the efficacy of potential drug candidates have used doxorubicin-induced aging mice. However, changes in the biomarkers of senescent cells have not been reported in detail in these animals. To lay a foundation for the use of doxorubicin-induced aging mice, we examined the biomarkers of hepatic and renal senescent cells in these mice. We found that the 5 mg/kg doxorubicin dose is optimal to induce cellular senescence in mice. Subsequently, using this dose, we found that doxorubicin-induced an increase in senescence-associated β-galactosidase (SA-β-gal) positive cells in the kidney and lipofuscin accumulation in the liver. Some markers of senescent cells (p21WAF1/CIP1, p16INK4A, and γH2AX) were also significantly upregulated by doxorubicin and then counteracted by metformin treatment. These preliminary findings support the application of doxorubicin-induced aging mice as an animal model to evaluate the efficacy of anti-aging drug candidates.
    Keywords:  Doxorubicin; Metformin; Mice; Senescence
    DOI:  https://doi.org/10.1016/j.exger.2022.111800
  8. Eur J Pharmacol. 2022 Apr 08. pii: S0014-2999(22)00212-6. [Epub ahead of print]923 174951
    Itaconate prolongs the healthy lifespan by activating UPRmt in Caenorhabditis elegans.
    Qingqing Wang, Hongyuan Li, Gangwei Zhang, Xiaoguang Chen, Xiaohui Wang.
      Itaconate (ItA), a byproduct of the Krebs cycle, has recently emerged as an anti-inflammatory metabolite for inhibiting the overactive immune response. In addition to its immunomodulatory and antimicrobial effects, ItA may have other therapeutic avenues. Herein, the effect of ItA on aging was explored in order to better establish the therapeutic potential of this promising metabolite. ItA extended the lifespan and enhanced the stress resistance of Caenorhabditis elegans (C. elegans), even at the doses of 0.01 and 0.1 μM. Moreover, the lifespan extension effect of ItA was pronounced even for the aged worms (days 7 and 9 post adult stage). Furthermore, ItA was found to extend the healthy longevity of C. elegans in a mitochondria-dependent manner. ItA protected the mitochondrial integrity, increased ATP content, and decreased the reactive oxygen species (ROS) in C. elegans. Mechanistic investigations showed that ItA specifically activated the mitochondrial unfolded protein response (UPRmt) in worms and significantly increased the expression of activating transcription factor associated with stress-1 (ATFS-1) that senses mitochondrial stress and communicates with the nucleus during the UPRmt. ItA extended the lifespan of C. elegans in an ATFS-1-dependent manner. In summary, this study elucidates the molecular mechanism by which ItA extends the healthy lifespan and highlights the importance of mitochondrial integrity in the intervention of aging.
    Keywords:  Activating transcription factor associated with stress-1; Caenorhabditis elegans; Healthy span; Itaconate; Mitochondrial unfolded protein response
    DOI:  https://doi.org/10.1016/j.ejphar.2022.174951
  9. Int J Mol Sci. 2022 Mar 25. pii: 3612. [Epub ahead of print]23(7):
    Iron Metabolism in Aging and Age-Related Diseases.
    Yao Tian, Yuanliangzi Tian, Zhixiao Yuan, Yutian Zeng, Shuai Wang, Xiaolan Fan, Deying Yang, Mingyao Yang.
      Iron is a trace metal element necessary to maintain life and is also involved in a variety of biological processes. Aging refers to the natural life process in which the physiological functions of the various systems, organs, and tissues decline, affected by genetic and environmental factors. Therefore, it is imperative to investigate the relationship between iron metabolism and aging-related diseases, including neurodegenerative diseases. During aging, the accumulation of nonheme iron destroys the stability of the intracellular environment. The destruction of iron homeostasis can induce cell damage by producing hydroxyl free radicals, leading to mitochondrial dysfunction, brain aging, and even organismal aging. In this review, we have briefly summarized the role of the metabolic process of iron in the body, then discussed recent developments of iron metabolism in aging and age-related neurodegenerative diseases, and finally, explored some iron chelators as treatment strategies for those disorders. Understanding the roles of iron metabolism in aging and neurodegenerative diseases will fill the knowledge gap in the field. This review could provide new insights into the research on iron metabolism and age-related neurodegenerative diseases.
    Keywords:  aging; iron chelator; iron metabolism; mitochondria; neurodegenerative diseases
    DOI:  https://doi.org/10.3390/ijms23073612
  10. N Engl J Med. 2022 Apr 13.
    Covid-19 Boosters - Where from Here?
    Paul A Offit.
      
    DOI:  https://doi.org/10.1056/NEJMe2203329
  11. Nat Ecol Evol. 2022 Apr 13.
    Signs of ageing.
    Vera Domingues.
      
    DOI:  https://doi.org/10.1038/s41559-022-01751-w
  12. JAMA. 2022 Apr 12. 327(14): 1323
    Vaccine Booster Dose Appears to Reduce Omicron Hospitalizations.
    Jennifer Abbasi.
      
    DOI:  https://doi.org/10.1001/jama.2022.5156
  13. Neurochem Res. 2022 Apr 12.
    Nandrolone Supplementation Promotes AMPK Activation and Divergent 18[FDG] PET Brain Connectivity in Adult and Aged Mice.
    N R Strogulski, A Kopczynski, V G de Oliveira, R B Carteri, G Hansel, G T Venturin, S Greggio, J C DaCosta, M A De Bastiani, M S Rodolphi, L V Portela.
      Decreased anabolic androgen levels are followed by impaired brain energy support and sensing with loss of neural connectivity during physiological aging, providing a neurobiological basis for hormone supplementation. Here, we investigated whether nandrolone decanoate (ND) administration mediates hypothalamic AMPK activation and glucose metabolism, thus affecting metabolic connectivity in brain areas of adult and aged mice. Metabolic interconnected brain areas of rodents can be detected by positron emission tomography using 18FDG-mPET. Albino CF1 mice at 3 and 18 months of age were separated into 4 groups that received daily subcutaneous injections of either ND (15 mg/kg) or vehicle for 15 days. At the in vivo baseline and on the 14th day, brain 18FDG-microPET scans were performed. Hypothalamic pAMPKT172/AMPK protein levels were assessed, and basal mitochondrial respiratory states were evaluated in synaptosomes. A metabolic connectivity network between brain areas was estimated based on 18FDG uptake. We found that ND increased the pAMPKT172/AMPK ratio in both adult and aged mice but increased 18FDG uptake and mitochondrial basal respiration only in adult mice. Furthermore, ND triggered rearrangement in the metabolic connectivity of adult mice and aged mice compared to age-matched controls. Altogether, our findings suggest that ND promotes hypothalamic AMPK activation, and distinct glucose metabolism and metabolic connectivity rearrangements in the brains of adult and aged mice.
    Keywords:  18FDG-PET; Aging; Anabolic-androgen steroids; Mitochondria; Nandrolone decanoate; Neural metabolic connectivity
    DOI:  https://doi.org/10.1007/s11064-022-03592-2
  14. Ageing Res Rev. 2022 Apr 11. pii: S1568-1637(22)00063-0. [Epub ahead of print] 101621
    Pharmaceutical and nutraceutical activation of FOXO3 for healthy longevity.
    Rebecca L McIntyre, Yasmine J Liu, Man Hu, Brian J Morris, Bradley J Willcox, Timothy A Donlon, Riekelt H Houtkooper, Georges E Janssens.
      Life expectancy has increased substantially over the last 150 years. Yet this means that now most people also spend a greater length of time suffering from various age-associated diseases. As such, delaying age-related functional decline and extending healthspan, the period of active older years free from disease and disability, is an overarching objective of current aging research. Geroprotectors, compounds that target pathways that causally influence aging, are increasingly recognized as a means to extend healthspan in the aging population. Meanwhile, FOXO3 has emerged as a geroprotective gene intricately involved in aging and healthspan. FOXO3 genetic variants are linked to human longevity, reduced disease risks, and even self-reported health. Therefore, identification of FOXO3-activating compounds represents one of the most direct candidate approaches to extending healthspan in aging humans. In this work, we review compounds that activate FOXO3, or influence healthspan or lifespan in a FOXO3-dependent manner. These compounds can be classified as pharmaceuticals, including PI3K/AKT inhibitors and AMPK activators, antidepressants and antipsychotics, muscle relaxants, and HDAC inhibitors, or as nutraceuticals, including primary metabolites involved in cell growth and sustenance, and secondary metabolites including extracts, polyphenols, terpenoids, and other purified natural compounds. The compounds documented here provide a basis and resource for further research and development, with the ultimate goal of promoting healthy longevity in humans.
    Keywords:  Aging; DAF-16; FOXO3; geroprotector; nutraceutical; pharmaceutical
    DOI:  https://doi.org/10.1016/j.arr.2022.101621
  15. N Engl J Med. 2022 Apr 13.
    Fourth Dose of BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Setting.
    Ori Magen, Jacob G Waxman, Maya Makov-Assif, Roni Vered, Dror Dicker, Miguel A Hernán, Marc Lipsitch, Ben Y Reis, Ran D Balicer, Noa Dagan.
       BACKGROUND: With large waves of infection driven by the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), alongside evidence of waning immunity after the booster dose of coronavirus disease 2019 (Covid-19) vaccine, several countries have begun giving at-risk persons a fourth vaccine dose.
    METHODS: To evaluate the early effectiveness of a fourth dose of the BNT162b2 vaccine for the prevention of Covid-19-related outcomes, we analyzed data recorded by the largest health care organization in Israel from January 3 to February 18, 2022. We evaluated the relative effectiveness of a fourth vaccine dose as compared with that of a third dose given at least 4 months earlier among persons 60 years of age or older. We compared outcomes in persons who had received a fourth dose with those in persons who had not, individually matching persons from these two groups with respect to multiple sociodemographic and clinical variables. A sensitivity analysis was performed with the use of parametric Poisson regression.
    RESULTS: The primary analysis included 182,122 matched pairs. Relative vaccine effectiveness in days 7 to 30 after the fourth dose was estimated to be 45% (95% confidence interval [CI], 44 to 47) against polymerase-chain-reaction-confirmed SARS-CoV-2 infection, 55% (95% CI, 53 to 58) against symptomatic Covid-19, 68% (95% CI, 59 to 74) against Covid-19-related hospitalization, 62% (95% CI, 50 to 74) against severe Covid-19, and 74% (95% CI, 50 to 90) against Covid-19-related death. The corresponding estimates in days 14 to 30 after the fourth dose were 52% (95% CI, 49 to 54), 61% (95% CI, 58 to 64), 72% (95% CI, 63 to 79), 64% (95% CI, 48 to 77), and 76% (95% CI, 48 to 91). In days 7 to 30 after a fourth vaccine dose, the difference in the absolute risk (three doses vs. four doses) was 180.1 cases per 100,000 persons (95% CI, 142.8 to 211.9) for Covid-19-related hospitalization and 68.8 cases per 100,000 persons (95% CI, 48.5 to 91.9) for severe Covid-19. In sensitivity analyses, estimates of relative effectiveness against documented infection were similar to those in the primary analysis.
    CONCLUSIONS: A fourth dose of the BNT162b2 vaccine was effective in reducing the short-term risk of Covid-19-related outcomes among persons who had received a third dose at least 4 months earlier. (Funded by the Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute.).
    DOI:  https://doi.org/10.1056/NEJMoa2201688
  16. Kardiologiia. 2022 Mar 31. 62(3): 89-96
    [Frailty syndrome as an independent predictor of adverse prognosis in patients with chronic heart failure].
    K E Krivoshapova, E A Vegner, Olga L Barbarash.
      This review presents results of clinical studies of senile asthenia ("fragility") syndrome and chronic heart failure (CHF). Recent reports of the "fragility" prevalence in patients with CHF are described. The review presents specific features of pathophysiological pathways underlying the development of both senile asthenia syndrome and CHF; the role of "fragility" in the progression and complications of CHF is addressed. Senile asthenia syndrome associated with CHF is regarded as an independent predictor of unfavorable prognosis and high mortality in this patient category. The authors concluded that methods for "fragility" evaluation in CHF patients followed by risk stratification and selection of individual management tactics should be implemented in clinical practice.
    DOI:  https://doi.org/10.18087/cardio.2022.3.n1206
  17. Front Cell Dev Biol. 2022 ;10 664261
    Hematopoietic Stem Cell Factors: Their Functional Role in Self-Renewal and Clinical Aspects.
    Zoya Mann, Manisha Sengar, Yogesh Kumar Verma, Raja Rajalingam, Pawan Kumar Raghav.
      Hematopoietic stem cells (HSCs) possess two important properties such as self-renewal and differentiation. These properties of HSCs are maintained through hematopoiesis. This process gives rise to two subpopulations, long-term and short-term HSCs, which have become a popular convention for treating various hematological disorders. The clinical application of HSCs is bone marrow transplant in patients with aplastic anemia, congenital neutropenia, sickle cell anemia, thalassemia, or replacement of damaged bone marrow in case of chemotherapy. The self-renewal attribute of HSCs ensures long-term hematopoiesis post-transplantation. However, HSCs need to be infused in large numbers to reach their target site and meet the demands since they lose their self-renewal capacity after a few passages. Therefore, a more in-depth understanding of ex vivo HSCs expansion needs to be developed to delineate ways to enhance the self-renewability of isolated HSCs. The multifaceted self-renewal process is regulated by factors, including transcription factors, miRNAs, and the bone marrow niche. A developed classical hierarchical model that outlines the hematopoiesis in a lineage-specific manner through in vivo fate mapping, barcoding, and determination of self-renewal regulatory factors are still to be explored in more detail. Thus, an in-depth study of the self-renewal property of HSCs is essentially required to be utilized for ex vivo expansion. This review primarily focuses on the Hematopoietic stem cell self-renewal pathway and evaluates the regulatory molecular factors involved in considering a targeted clinical approach in numerous malignancies and outlining gaps in the current knowledge.
    Keywords:  Graft-versus-Host Disease (GvHD); Hematopoietic Stem Cells (HSCs); differentiation; extracellular vesicles (EVs); hematopoiesis; miRNAs; self-renewal; transcription factors
    DOI:  https://doi.org/10.3389/fcell.2022.664261
  18. Immunity. 2022 Apr 12. pii: S1074-7613(22)00139-X. [Epub ahead of print]55(4): 592-605
    Nonresolving inflammation redux.
    Carl Nathan.
      Nonresolving inflammation contributes to many diseases, including COVID-19 in its fatal and long forms. Our understanding of inflammation is rapidly evolving. Like the immune system of which it is a part, inflammation can now be seen as an interactive component of a homeostatic network with the endocrine and nervous systems. This review samples emerging insights regarding inflammatory memory, inflammatory aging, inflammatory cell death, inflammatory DNA, inflammation-regulating cells and metabolites, approaches to resolving or modulating inflammation, and inflammatory inequity.
    DOI:  https://doi.org/10.1016/j.immuni.2022.03.016
  19. Cells. 2022 Apr 04. pii: 1222. [Epub ahead of print]11(7):
    Senotherapeutics in Cancer and HIV.
    Laura Sánchez-Díaz, Asunción Espinosa-Sánchez, José-Ramón Blanco, Amancio Carnero.
      Cellular senescence is a stress-response mechanism that contributes to homeostasis maintenance, playing a beneficial role during embryogenesis and in normal adult organisms. In contrast, chronic senescence activation may be responsible for other events such as age-related disorders, HIV and cancer development. Cellular senescence activation can be triggered by different insults. Regardless of the inducer, there are several phenotypes generally shared among senescent cells: cell division arrest, an aberrant shape, increased size, high granularity because of increased numbers of lysosomes and vacuoles, apoptosis resistance, defective metabolism and some chromatin alterations. Senescent cells constitute an important area for research due to their contributions to the pathogenesis of different diseases such as frailty, sarcopenia and aging-related diseases, including cancer and HIV infection, which show an accelerated aging. Hence, a new pharmacological category of treatments called senotherapeutics is under development. This group includes senolytic drugs that selectively attack senescent cells and senostatic drugs that suppress SASP factor delivery, inhibiting senescent cell development. These new drugs can have positive therapeutic effects on aging-related disorders and act in cancer as antitumor drugs, avoiding the undesired effects of senescent cells such as those from SASP. Here, we review senotherapeutics and how they might affect cancer and HIV disease, two very different aging-related diseases, and review some compounds acting as senolytics in clinical trials.
    Keywords:  HIV; SASP; cancer; senescence; senolytic; senostatic; senotherapy
    DOI:  https://doi.org/10.3390/cells11071222
  20. J Mol Cell Cardiol. 2022 Apr 11. pii: S0022-2828(22)00069-4. [Epub ahead of print]
    Aging and HFpEF: Are we running out of time?
    Coenraad Withaar, Sunhuo Li, Laura M G Meems, Herman H W Silljé, Rudolf A de Boer.
      
    DOI:  https://doi.org/10.1016/j.yjmcc.2022.04.006
  21. Mol Omics. 2022 Apr 12.
    Metabolomics reveals the impact of the saturation of dietary lipids on the aging and longevity of C. elegans.
    Yanan Wang, Jiachen Shi, Fan Jiang, Yong-Jiang Xu, Yuanfa Liu.
      Dietary lipids play an important role in human health, but their influence on aging and longevity remains to be ascertained. This study tests the hypothesis that the consumption of fats with elevated unsaturation might slow down aging and prolong lifespan better than that with greater saturation. The metabolomic analysis of Caenorhabditis elegans (C. elegans) administrated with different dietary oils (palm oil, rapeseed oil, sunflower oil and linseed oil) revealed novel changes in lipid, carbohydrate, amino acid and purine metabolism. Elevated levels of eicosanoic acid, stearic acid, palmitic acid, L-isoleucine, L-lysine, L-tyrosine, and D-fructose, along with decreased content of arachidonic acid (ARA), eicosapentaenoic acid (EPA), and alpha-linolenic acid (ALA) were found in C. elegans with the intake of dietary oils with higher saturation. Declined gene expression levels of daf-2 and akt-1, as well as increased levels of daf-16, sod-3, hsp-16.2, hsf-1, nhr-80, fat-5, fat-6, and fat-7, were noted in the higher unsaturation dietary oil groups. Carbohydrates and amino acids showed moderate to strong correlations with daf-2 and akt-1 (negative), as well as daf-16, sod-3, hsp-16.2, and hsf-1 (positive). Otherwise, our data suggested significant positive relationships between polyunsaturated fatty acids (ARA, EPA, ALA) and nhr-80, fat-5, fat-6 and fat-7. Taken together, this study demonstrates that unsaturated dietary oils can slow down aging and prolong the lifespan of C. elegans via the insulin signaling pathway and the biosynthesis of unsaturated fatty acids.
    DOI:  https://doi.org/10.1039/d2mo00041e
  22. J Clin Invest. 2022 Apr 15. pii: e158871. [Epub ahead of print]132(8):
    Short-term senolytic treatment: a paradigm to promote fracture repair during aging.
    Isabel Beerman, Nathan Basisty, Rafael de Cabo.
      Increased age is blamed for a wide range of bone physiological changes, and although the underlying mechanisms affecting the decreased capacity for fracture healing are not fully understood, they are clearly linked to changes at the cellular level. Recent evidence suggests potential roles of senescent cells in response to most tissue injuries, including bone fractures. In this issue of the JCI, Liu, Zhang, and co-authors showed that a senolytic drug cocktail cleared senescent cells from the callus and improved bone fracture repair in aged mice. Understanding how senescent cells emerge at fracture sites and how their timely removal improves fracture healing should provide insights for effective therapeutic approaches in old age.
    DOI:  https://doi.org/10.1172/JCI158871
  23. Nutrients. 2022 Mar 29. pii: 1425. [Epub ahead of print]14(7):
    Dysmetabolism and Neurodegeneration: Trick or Treat?
    Adriana M Capucho, Ana Chegão, Fátima O Martins, Hugo Vicente Miranda, Sílvia V Conde.
      Accumulating evidence suggests the existence of a strong link between metabolic syndrome and neurodegeneration. Indeed, epidemiologic studies have described solid associations between metabolic syndrome and neurodegeneration, whereas animal models contributed for the clarification of the mechanistic underlying the complex relationships between these conditions, having the development of an insulin resistance state a pivotal role in this relationship. Herein, we review in a concise manner the association between metabolic syndrome and neurodegeneration. We start by providing concepts regarding the role of insulin and insulin signaling pathways as well as the pathophysiological mechanisms that are in the genesis of metabolic diseases. Then, we focus on the role of insulin in the brain, with special attention to its function in the regulation of brain glucose metabolism, feeding, and cognition. Moreover, we extensively report on the association between neurodegeneration and metabolic diseases, with a particular emphasis on the evidence observed in animal models of dysmetabolism induced by hypercaloric diets. We also debate on strategies to prevent and/or delay neurodegeneration through the normalization of whole-body glucose homeostasis, particularly via the modulation of the carotid bodies, organs known to be key in connecting the periphery with the brain.
    Keywords:  hypercaloric diets; insulin signaling; metabolic disorders; neurodegeneration
    DOI:  https://doi.org/10.3390/nu14071425
  24. Int J Mol Sci. 2022 Mar 23. pii: 3472. [Epub ahead of print]23(7):
    Structured Long-Chain Omega-3 Fatty Acids for Improvement of Cognitive Function during Aging.
    Ignasi Mora, Lluís Arola, Antoni Caimari, Xavier Escoté, Francesc Puiggròs.
      Although the human lifespan has increased in the past century owing to advances in medicine and lifestyle, the human healthspan has not kept up the same pace, especially in brain aging. Consequently, the role of preventive health interventions has become a crucial strategy, in particular, the identification of nutritional compounds that could alleviate the deleterious effects of aging. Among nutrients to cope with aging in special cognitive decline, the long-chain omega-3 polyunsaturated fatty acids (ω-3 LCPUFAs) docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), have emerged as very promising ones. Due to their neuroinflammatory resolving effects, an increased status of DHA and EPA in the elderly has been linked to better cognitive function and a lower risk of dementia. However, the results from clinical studies do not show consistent evidence and intake recommendations for old adults are lacking. Recently, supplementation with structured forms of EPA and DHA, which can be derived natural forms or targeted structures, have proven enhanced bioavailability and powerful benefits. This review summarizes present and future perspectives of new structures of ω-3 LCPUFAs and the role of "omic" technologies combined with the use of high-throughput in vivo models to shed light on the relationships and underlying mechanisms between ω-3 LCPUFAs and healthy aging.
    Keywords:  DHA; EPA; cell senescence; cognitive function; omega-3 PUFAs; omic technologies; structured lipids
    DOI:  https://doi.org/10.3390/ijms23073472
  25. Molecules. 2022 Apr 05. pii: 2341. [Epub ahead of print]27(7):
    Nutraceutical Role of Polyphenols and Triterpenes Present in the Extracts of Fruits and Leaves of Olea europaea as Antioxidants, Anti-Infectives and Anticancer Agents on Healthy Growth.
    Eva E Rufino-Palomares, Amalia Pérez-Jiménez, Leticia García-Salguero, Khalida Mokhtari, Fernando J Reyes-Zurita, Juan Peragón-Sánchez, José A Lupiáñez.
      There is currently a worldwide consensus and recognition of the undoubted health benefits of the so-called Mediterranean diet, with its intake being associated with a lower risk of mortality. The most important characteristics of this type of diet are based on the consumption of significant amounts of fruit, vegetables, legumes, and nuts, which provide, in addition to some active ingredients, fiber and a proportion of vegetable protein, together with extra virgin olive oil (EVOO) as the main sources of vegetable fat. Fish and meat from poultry and other small farm animals are the main sources of protein. One of the main components, as already mentioned, is EVOO, which is rich in monounsaturated fatty acids and to a lesser extent in polyunsaturated fatty acids. The intake of this type of nutrient also provides an important set of phytochemicals whose health potential is widely spread and agreed upon. These phytochemicals include significant amounts of anthocyanins, stilbenes, flavonoids, phenolic acids, and terpenes of varying complexities. Therefore, the inclusion in the diet of this type of molecules, with a proven healthy effect, provides an unquestionable preventive and/or curative activity on an important group of pathologies related to cardiovascular, infectious, and cancerous diseases, as well as those related to the metabolic syndrome. The aim of this review is therefore to shed light on the nutraceutical role of two of the main phytochemicals present in Olea europaea fruit and leaf extracts, polyphenols, and triterpenes, on healthy animal growth. Their immunomodulatory, anti-infective, antioxidant, anti-aging, and anti-carcinogenic capabilities show them to be potential nutraceuticals, providing healthy growth.
    Keywords:  animal nutrition; diet; feeding; hydroxytyrosol; maslinic acid; nutraceutical; olive tree; phytochemicals; polyphenols; triterpenes
    DOI:  https://doi.org/10.3390/molecules27072341
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