Browsing by Subject "LONGEVITY"

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  • Papaevgeniou, Nikoletta; Sakellari, Marianthi; Jha, Sweta; Tavernarakis, Nektarios; Holmberg, Carina I.; Gonos, Efstathios S.; Chondrogianni, Niki (2016)
    Aims: Proteasomes are constituents of the cellular proteolytic networks that maintain protein homeostasis through regulated proteolysis of normal and abnormal (in any way) proteins. Genetically mediated proteasome activation in multicellular organisms has been shown to promote longevity and to exert protein antiaggregation activity. In this study, we investigate whether compound-mediated proteasome activation is feasible in a multicellular organism and we dissect the effects of such approach in aging and Alzheimer's disease (AD) progression. Results: Feeding of wild-type Caenorhabditis elegans with 18 alpha-glycyrrhetinic acid (18 alpha-GA; a previously shown proteasome activator in cell culture) results in enhanced levels of proteasome activities that lead to a skinhead-1- and proteasomeactivation-dependent life span extension. The elevated proteasome function confers lower paralysis rates in various AD nematode models accompanied by decreased A beta deposits, thus ultimately decelerating the progression of AD phenotype. More importantly, similar positive results are also delivered when human and murine cells of nervous origin are subjected to 18 alpha-GA treatment. Innovation: This is the first report of the use of 18 alpha-GA, a diet-derived compound as prolongevity and antiaggregation factor in the context of a multicellular organism. Conclusion: Our results suggest that proteasome activation with downstream positive outcomes on aging and AD, an aggregation-related disease, is feasible in a nongenetic manipulation manner in a multicellular organism. Moreover, they unveil the need for identification of antiaging and antiamyloidogenic compounds among the nutrients found in our normal diet.
  • Arczewska, Katarzyna D.; Tomazella, Gisele G.; Lindvall, Jessica M.; Kassahun, Henok; Maglioni, Silvia; Torgovnick, Alessandro; Henriksson, Johan; Matilainen, Olli; Marquis, Bryce J.; Nelson, Bryant C.; Jaruga, Pawel; Babaie, Eshrat; Holmberg, Carina; Burglin, Thomas R.; Ventura, Natascia; Thiede, Bernd; Nilsen, Hilde (2013)
  • Luyten, Walter; Antal, Peter; Braeckman, Bart P.; Bundy, Jake; Cirulli, Francesca; Fang-Yen, Christopher; Fuellen, Georg; Leroi, Armand; Liu, Qingfei; Martorell, Patricia; Metspalu, Andres; Perola, Markus; Ristow, Michael; Saul, Nadine; Schoofs, Liliane; Siems, Karsten; Temmerman, Liesbet; Smets, Tina; Wolk, Alicja; Rattan, Suresh I. S. (2016)
    Human longevity continues to increase world-wide, often accompanied by decreasing birth rates. As a larger fraction of the population thus gets older, the number of people suffering from disease or disability increases dramatically, presenting a major societal challenge. Healthy ageing has therefore been selected by EU policy makers as an important priority ; it benefits not only the elderly but also their direct environment and broader society, as well as the economy. The theme of healthy ageing figures prominently in the Horizon 2020 programme , which has launched several research and innovation actions (RIA), like "Understanding health, ageing and disease: determinants, risk factors and pathways" in the work programme on "Personalising healthcare". Here we present our research proposal entitled "ageing with elegans" (AwE), funded by this RIA, which aims for better understanding of the factors causing health and disease in ageing, and to develop evidence-based prevention, diagnostic, therapeutic and other strategies. The aim of this article, authored by the principal investigators of the 17 collaborating teams, is to describe briefly the rationale, aims, strategies and work packages of AwE for the purposes of sharing our ideas and plans with the biogerontological community in order to invite scientific feedback, suggestions, and criticism.
  • Gospodaryov, Dmytro; Strilbytska, Olha M.; Semaniuk, Uliana; Perkhulyn, Natalia; Rovenko, Bohdana M.; Yurkevych, Ihor S.; Barata, Ana G.; Dick, Tobias P.; Lushchak, Oleh; Jacobs, Howard T. (2020)
    Mitochondrial alternative NADH dehydrogenase (aNDH) was found to extend lifespan when expressed in the fruit fly. We have found that fruit flies expressing aNDH from Ciona intestinalis (NDX) had 17-71% lifespan prolongation on media with different protein-tocarbohydrate ratios except NDX-expressing males that had 19% shorter lifespan than controls on a high protein diet. NDX-expressing flies were more resistant to organic xenobiotics, 2,4-dichlorophenoxyacetic acid and alloxan, and inorganic toxicant potassium iodate, and partially to sodium molybdate treatments. On the other hand, NDX-expressing flies were more sensitive to catechol and sodium chromate. Enzymatic analysis showed that NDX-expressing males had higher glucose 6-phosphate dehydrogenase activity, whilst both sexes showed increased glutathione S-transferase activity.
  • Grunewald, M.; Kumar, S.; Sharife, H.; Volinsky, E.; Gileles-Hillel, A.; Licht, T.; Permyakova, A.; Hinden, L.; Azar, S.; Friedmann, Y.; Kupetz, P.; Tzuberi, R.; Anisimov, A.; Alitalo, K.; Horwitz, M.; Leebhoff, S.; Khoma, O. Z.; Hlushchuk, R.; Djonov, Valentin G; Abramovitch, R.; Tam, J.; Keshet, E. (2021)
    Aging is an established risk factor for vascular diseases, but vascular aging itself may contribute to the progressive deterioration of organ function. Here, we show in aged mice that vascular endothelial growth factor (VEGF) signaling insufficiency, which is caused by increased production of decoy receptors, may drive physiological aging across multiple organ systems. Increasing VEGF signaling prevented age-associated capillary loss, improved organ perfusion and function, and extended life span. Healthier aging was evidenced by favorable metabolism and body composition and amelioration of aging-associated pathologies including hepatic steatosis, sarcopenia, osteoporosis, "inflammaging" (age-related multiorgan chronic inflammation), and increased tumor burden. These results indicate that VEGF signaling insufficiency affects organ aging in mice and suggest that modulating this pathway may result in increased mammalian life span and improved overall health.
  • Khan, Nahid A.; Auranen, Mari; Paetau, Ilse; Pirinen, Eija; Euro, Liliya; Forsström, Saara; Pasila, Lotta; Velagapudi, Vidya; Carroll, Christopher J.; Auwerx, Johan; Suomalainen, Anu (2014)
  • Danielsbacka, Mirkka; Tanskanen, Antti O.; Coall, David A.; Jokela, Markus (2019)
    Previous studies suggest grandparental childcare is associated with improved health and well-being of grandparents but limited information on the causal nature of this association exists. Here, we use the longitudinal Survey of Health, Ageing and Retirement in Europe (SHARE) of people aged 50 and above across 11 countries including follow-up waves between 2004 and 2015 (n = 41,713 person-observations from 24,787 unique persons of whom 11,102 had two or more measurement times). Between-person and within-person (or fixed-effect) regressions were applied, where between-person models show associations across participants and within-person models focus on each participant's variation over time. Health and well-being were measured according to self rated health, difficulties with activities of daily living (ADLs), depressive symptoms, life satisfaction and meaning of life scores. Across all analyses, childcare assistance provided by older adults to their adult children, was associated with increased health and well-being of grandparents. However, these associations were almost completely due to between-person differences and did not hold in within-person analyses that compared the same participants over time. Fewer ADL limitations for grandparents who provided childcare assistance was the only association that remained in the within-individual analyses. These findings suggest that there might be only limited causal association between grandchild care and grandparental well-being and that it may be specific to physical rather than cognitive factors. The results are discussed with regard to evolutionary psychology assumptions of altruistic behavior and positive health outcomes for the helper.
  • Mikkonen, Elisa; Haglund, Caj; Holmberg, Carina I. (2017)
    The ubiquitin-proteasome system (UPS) plays a crucial part in normal cell function by mediating intracellular protein clearance. We have previously shown that UPS-mediated protein degradation varies in a cell type-specific manner in C. elegans. Here, we use formalin-fixed, paraffin-embedded C. elegans sections to enable studies on endogenous proteasome tissue expression. We show that the proteasome immunoreactivity pattern differs between cell types and within subcellular compartments in adult wild-type (N2) C. elegans. Interestingly, widespread knockdown of proteasome subunits by RNAi results in tissue-specific changes in proteasome expression instead of a uniform response. In addition, long-lived daf-2 (e1370) mutants with impaired insulin/IGF-1 signaling (IIS) display similar proteasome tissue expression as aged-matched wild-type animals. Our study emphasizes the importance of alternate approaches to the commonly used whole animal lysate-based methods to detect changes in proteasome expression occurring at the sub-cellular, cell or tissue resolution level in a multicellular organism.
  • Bakula, Daniela; Ablasser, Andrea; Aguzzi, Adriano; Antebi, Adam; Barzilai, Nir; Bittner, Martin-Immanuel; Jensen, Martin Borch; Calkhoven, Cornelis F.; Chen, Danica; de Grey, Aubrey D. N. J.; Feige, Jerome N.; Georgievskaya, Anastasia; Gladyshev, Vadim N.; Golato, Tyler; Gudkov, Andrei V.; Hoppe, Thorsten; Kaeberlein, Matt; Katajisto, Pekka; Kennedy, Brian K.; Lal, Unmesh; Martin-Villalba, Ana; Moskalev, Alexey A.; Ozerov, Ivan; Petr, Michael A.; Reason, Matthew; Rubinsztein, David C.; Tyshkovskiy, Alexander; Vanhaelen, Quentin; Zhavoronkov, Alex; Scheibye-Knudsen, Morten (2019)
    An increasing aging population poses a significant challenge to societies worldwide. A better understanding of the molecular, cellular, organ, tissue, physiological, psychological, and even sociological changes that occur with aging is needed in order to treat age-associated diseases. The field of aging research is rapidly expanding with multiple advances transpiring in many previously disconnected areas. Several major pharmaceutical, biotechnology, and consumer companies made aging research a priority and are building internal expertise, integrating aging research into traditional business models and exploring new go-to-market strategies. Many of these efforts are spearheaded by the latest advances in artificial intelligence, namely deep learning, including generative and reinforcement learning. To facilitate these trends, the Center for Healthy Aging at the University of Copenhagen and Insilico Medicine are building a community of Key Opinion Leaders (KOLs) in these areas and launched the annual conference series titled "Aging Research and Drug Discovery (ARDD)" held in the capital of the pharmaceutical industry, Basel, Switzerland (www.agingpharma.org). This ARDD collection contains summaries from the 6th annual meeting that explored aging mechanisms and new interventions in age-associated diseases. The 7th annual ARDD exhibition will transpire 2nd-4th of September, 2020, in Basel.
  • Stelter, Robert; de la Croix, David; Myrskylä, Mikko (2021)
    When did mortality first start to decline, and among whom? We build a large, new data set with more than 30,000 scholars covering the sixteenth to the early twentieth century to analyze the timing of the mortality decline and the heterogeneity in life expectancy gains among scholars in the Holy Roman Empire. The large sample size, well-defined entry into the risk group, and heterogeneity in social status are among the key advantages of the new database. After recovering from a severe mortality crisis in the seventeenth century, life expectancy among scholars started to increase as early as in the eighteenth century, well before the Industrial Revolution. Our finding that members of scientific academies-an elite group among scholars-were the first to experience mortality improvements suggests that 300 years ago, individuals with higher social status already enjoyed lower mortality. We also show, however, that the onset of mortality improvements among scholars in medicine was delayed, possibly because these scholars were exposed to pathogens and did not have germ theory knowledge that might have protected them. The disadvantage among medical professionals decreased toward the end of the nineteenth century. Our results provide a new perspective on the historical timing of mortality improvements, and the database accompanying our study facilitates replication and extensions.
  • Zions, Michael; Meehan, Edward F.; Kress, Michael E.; Thevalingam, Donald; Jenkins, Edmund C.; Kaila, Kai; Puskarjov, Martin; McCloskey, Dan P. (2020)
    African naked mole-rats were likely the first mammals to evolve eusociality, and thus required adaptations to conserve energy and tolerate the low oxygen (O-2) and high carbon dioxide (CO2) of a densely populated fossorial nest. As hypercapnia is known to suppress neuronal activity, we studied whether naked mole-rats might demonstrate energy savings in GABAergic inhibition. Using whole-colony behavioral monitoring of captive naked mole-rats, we found a durable nest, characterized by high CO2 levels, where all colony members spent the majority of their time. Analysis of the naked mole-rat genome revealed, uniquely among mammals, a histidine point variation in the neuronal potassium-chloride cotransporter 2 (KCC2). A histidine missense substitution mutation at this locus in the human ortholog of KCC2, found previously in patients with febrile seizures and epilepsy, has been demonstrated to diminish neuronal Cl- extrusion capacity, and thus impairs GABAergic inhibition. Seizures were observed, without pharmacological intervention, in adult naked mole-rats exposed to a simulated hyperthermic surface environment, causing systemic hypocapnic alkalosis. Consistent with the diminished function of KCC2, adult naked mole-rats demonstrate a reduced efficacy of inhibition that manifests as triggering of seizures at room temperature by the GABA(A) receptor (GABA(A)R) positive allosteric modulator diazepam. These seizures are blocked in the presence of nest-like levels of CO2 and likely to be mediated through GABA(A)R activity, based on in vitro recordings. Thus, altered GABAergic inhibition adds to a growing list of adaptations in the naked mole-rat and provides a plausible proximate mechanism for nesting behavior, where a return to the colony nest restores GABA-mediated inhibition.
  • 23andMe Res Team; IPDGC; Blauwendraat, Cornelis; Heilbron, Karl; Vallerga, Costanza L.; Eerola-Rautio, Johanna; Tienari, Pentti; Singleton, Andrew B. (2019)
    Background Increasing evidence supports an extensive and complex genetic contribution to PD. Previous genome-wide association studies (GWAS) have shed light on the genetic basis of risk for this disease. However, the genetic determinants of PD age at onset are largely unknown. Objectives To identify the genetic determinants of PD age at onset. Methods Using genetic data of 28,568 PD cases, we performed a genome-wide association study based on PD age at onset. Results We estimated that the heritability of PD age at onset attributed to common genetic variation was similar to 0.11, lower than the overall heritability of risk for PD (similar to 0.27), likely, in part, because of the subjective nature of this measure. We found two genome-wide significant association signals, one at SNCA and the other a protein-coding variant in TMEM175, both of which are known PD risk loci and a Bonferroni-corrected significant effect at other known PD risk loci, GBA, INPP5F/BAG3, FAM47E/SCARB2, and MCCC1. Notably, SNCA, TMEM175, SCARB2, BAG3, and GBA have all been shown to be implicated in alpha-synuclein aggregation pathways. Remarkably, other well-established PD risk loci, such as GCH1 and MAPT, did not show a significant effect on age at onset of PD. Conclusions Overall, we have performed the largest age at onset of PD genome-wide association studies to date, and our results show that not all PD risk loci influence age at onset with significant differences between risk alleles for age at onset. This provides a compelling picture, both within the context of functional characterization of disease-linked genetic variability and in defining differences between risk alleles for age at onset, or frank risk for disease. (c) 2019 International Parkinson and Movement Disorder Society
  • Matilainen, Olli; Sleiman, Maroun S. Bou; Quiros, Pedro M.; Garcia, Susana M. D. A.; Auwerx, Johan (2017)
    Age-associated changes in chromatin structure have a major impact on organismal longevity. Despite being a central part of the ageing process, the organismal responses to the changes in chromatin organization remain unclear. Here we show that moderate disturbance of histone balance during C. elegans development alters histone levels and triggers a stress response associated with increased expression of cytosolic small heat-shock proteins. This stress response is dependent on the transcription factor, HSF-1, and the chromatin remodeling factor, ISW-1. In addition, we show that mitochondrial stress during developmental stages also modulates histone levels, thereby activating a cytosolic stress response similar to that caused by changes in histone balance. These data indicate that histone and mitochondrial perturbations are both monitored through chromatin remodeling and involve the activation of a cytosolic response that affects organismal longevity. HSF-1 and ISW-1 hence emerge as a central mediator of this multi-compartment proteostatic response regulating longevity.
  • Vannini, Nicola; Campos, Vasco; Girotra, Mukul; Trachsel, Vincent; Rojas-Sutterlin, Shanti; Tratwal, Josefine; Ragusa, Simone; Stefanidis, Evangelos; Ryu, Dongryeol; Rainer, Pernille Y.; Nikitin, Gena; Giger, Sonja; Li, Terytty Y.; Semilietof, Aikaterini; Oggier, Aurelien; Yersin, Yannick; Tauzin, Loic; Pirinen, Eija; Cheng, Wan-Chen; Ratajczak, Joanna; Canto, Carles; Ehrbar, Martin; Sizzano, Federico; Petrova, Tatiana V.; Vanhecke, Dominique; Zhang, Lianjun; Romero, Pedro; Nahimana, Aimable; Cherix, Stephane; Duchosal, Michel A.; Ho, Ping-Chih; Deplancke, Bart; Coukos, George; Auwerx, Johan; Lutolf, Matthias P.; Naveiras, Olaia (2019)
    It has been recently shown that increased oxidative phosphorylation, as reflected by increased mitochondrial activity, together with impairment of the mitochondrial stress response, can severely compromise hematopoietic stem cell (HSC) regeneration. Here we show that the NAD(+)-boosting agent nicotinamide riboside (NR) reduces mitochondrial activity within HSCs through increased mitochondrial clearance, leading to increased asymmetric HSC divisions. NR dietary supplementation results in a significantly enlarged pool of progenitors, without concurrent HSC exhaustion, improves survival by 80%, and accelerates blood recovery after murine lethal irradiation and limiting-HSC transplantation. In immune-deficient mice, NR increased the production of human leucocytes from hCD34+ progenitors. Our work demonstrates for the first time a positive effect of NAD(+)-boosting strategies on the most primitive blood stem cells, establishing a link between HSC mitochondrial stress, mitophagy, and stem-cell fate decision, and unveiling the potential of NR to improve recovery of patients suffering from hematological failure including post chemo- and radiotherapy.
  • Palombo, Flavia; Peron, Camille; Caporali, Leonardo; Iannielli, Angelo; Maresca, Alessandra; Di Meo, Ivano; Fiorini, Claudio; Segnali, Alice; Sciacca, Francesca L.; Rizzo, Ambra; Levi, Sonia; Suomalainen, Anu; Prigione, Alessandro; Broccoli, Vania; Carelli, Valerio; Tiranti, Valeria (2021)
    The generation of inducible pluripotent stem cells (iPSCs) is a revolutionary technique allowing production of pluripotent patient-specific cell lines used for disease modeling, drug screening, and cell therapy. Integrity of nuclear DNA (nDNA) is mandatory to allow iPSCs utilization, while quality control of mitochondrial DNA (mtDNA) is rarely included in the iPSCs validation process. In this study, we performed mtDNA deep sequencing during the transition from parental fibroblasts to reprogrammed iPSC and to differentiated neuronal precursor cells (NPCs) obtained from controls and patients affected by mitochondrial disorders. At each step, mtDNA variants, including those potentially pathogenic, fluctuate between emerging and disappearing, and some having functional implications. We strongly recommend including mtDNA analysis as an unavoidable assay to obtain fully certified usable iPSCs and NPCs.
  • Cayuela, Hugo; Lemaitre, Jean-Francois; Muths, Erin; McCaffery, Rebecca M.; Fretey, Thierry; Le Garff, Bernard; Schmidt, Benedikt R.; Grossenbacher, Kurt; Lenzi, Omar; Hossack, Blake R.; Eby, Lisa A.; Lambert, Brad A.; Elmberg, Johan; Merila, Juha; Gippet, Jerome M. W.; Gaillard, Jean-Michel; Pilliod, David S. (2021)
    Variation in temperature is known to influence mortality patterns in ectotherms. Even though a few experimental studies on model organisms have reported a positive relationship between temperature and actuarial senescence (i.e., the increase in mortality risk with age), how variation in climate influences the senescence rate across the range of a species is still poorly understood in free-ranging animals. We filled this knowledge gap by investigating the relationships linking senescence rate, adult lifespan, and climatic conditions using long-term capture-recapture data from multiple amphibian populations. We considered two pairs of related anuran species from the Ranidae (Rana luteiventris and Rana temporaria) and Bufonidae (Anaxyrus boreas and Bufo bufo) families, which diverged more than 100 Mya and are broadly distributed in North America and Europe. Senescence rates were positively associated with mean annual temperature in all species. In addition, lifespan was negatively correlated with mean annual temperature in all species except A. boreas. In both R. luteiventris and A. boreas, mean annual precipitation and human environmental footprint both had negligible effects on senescence rates or lifespans. Overall, our findings demonstrate the critical influence of thermal conditions on mortality patterns across anuran species from temperate regions. In the current context of further global temperature increases predicted by Intergovernmental Panel on Climate Change scenarios, a widespread acceleration of aging in amphibians is expected to occur in the decades to come, which might threaten even more seriously the viability of populations and exacerbate global decline.
  • Pispa, Johanna; Matilainen, Olli; Holmberg, Carina I. (2020)
    Variation in ambient growth temperature can cause changes in normal animal physiology and cellular functions such as control of protein homeostasis. A key mechanism for maintaining proteostasis is the selective degradation of polyubiquitinated proteins, mediated by the ubiquitin-proteasome system (UPS). It is still largely unsolved how temperature changes affect the UPS at the organismal level. Caenorhabditis elegans nematodes are normally bred at 20 °C, but for some experimental conditions, 25 °C is often used. We studied the effect of 25 °C on C. elegans UPS by measuring proteasome activity and polyubiquitinated proteins both in vitro in whole animal lysates and in vivo in tissue-specific transgenic reporter strains. Our results show that an ambient temperature shift from 20 to 25 °C increases the UPS activity in the intestine, but not in the body wall muscle tissue, where a concomitant accumulation of polyubiquitinated proteins occurs. These changes in the UPS activity and levels of polyubiquitinated proteins were not detectable in whole animal lysates. The exposure of transgenic animals to 25 °C also induced ER stress reporter fluorescence, but not the fluorescence of a heat shock responsive reporter, albeit detection of a mild induction in hsp-16.2 mRNA levels. In conclusion, C. elegans exhibits tissue-specific responses of the UPS as an organismal strategy to cope with a rise in ambient temperature.
  • Palotie, Ulla; Vehkalahti, Miira M. (2020)
    Objectives: We investigated the first re-interventions of two- and three-surface direct restorations on posterior teeth, specifically noting the type and time of the first re-intervention. Materials and methods: In 2002, altogether 5542 posterior two- and three-surface composite and amalgam restorations were done for 3051 patients aged 25-30 years at Helsinki City Public Dental Service (PDS). Based on electronic patient records, we analysed all restorations (n = 2445) having re-intervention during a 13-year follow-up. We recorded the type of tooth, restoration size, and type of first re-intervention. The time to re-intervention was the interval between the date of the placement of restoration at the year 2002 and its first re-intervention. Results: Restorative treatment was the most common (77.9%) first re-intervention, followed by endodontics (11.5%), extractions (5.2%), and other (5.4%). Males, more frequently than females, had extraction or endodontics as first re-intervention. The average time to re-intervention was 5.7 years (SD 3.8; median 5.2). Both median and mean times were shortest for cases involving endodontics or extractions. Conclusions: For the majority of two- and three-surface posterior restorations, the first re-intervention is restorative (replacement or repair of restoration). The shortest time to re-intervention is for restorations that have endodontics or extraction as the first re-intervention.