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Persistent DNA damage (genotoxic stress) triggers signaling cascades that drive cells into apoptosis or senescence to avoid replicating a damaged genome. Sp1 has been found to play a role in double strand break (DSB) repair, and a link between Sp1 and aging has also been established, where Sp1 protein, but not RNA, levels decrease with age. Interestingly, inhibition ATM reverses the age-related degradation of Sp1, suggesting that DNA damage signaling is involved in senescence-related degradation of Sp1. Proteasomal degradation of Sp1 in senescent cells is mediated via sumoylation, where sumoylation of Sp1 on lysine 16 is increased in senescent cells. Taking into consideration our previous findings that Sp1 is phosphorylated by ATM in response to DNA damage and that proteasomal degradation of Sp1 at DSBs is also mediated by its sumoylation and subsequent interaction with RNF4, we investigated the potential contribution of Sp1’s role as a DSB repair factor in mediating cellular senescence. We report here that Sp1 expression is decreased with a concomitant increase in senescence markers in response to DNA damage. Mutation of Sp1 at serine 101 to create an ATM phospho-null mutant, or mutation of lysine 16 to create a sumo-null mutant, prevents the sumoylation and subsequent proteasomal degradation of Sp1 and results in a decrease in senescence. Conversely, depletion of Sp1 or mutation of Sp1 to create an ATM phosphomimetic results in premature degradation of Sp1 and an increase in senescence markers. These data link a loss of genomic stability with senescence through the action of a DNA damage repair factor.

Der Text diskutiert die Nutzbarkeit der Operationalisierten Psychodynamischen Diagnostik (OPD) zur Beschreibung der unbewussten Dynamik von Patient*innen mit psychotischen Symptomen. Die aktuell geplanten Weiterentwicklungen der Beziehungs-, Konflikt- und Strukturachse in der OPD-3 sollen der Vielfalt der Erscheinungsformen und Dynamiken psychotischer Storungen angemessener Rechnung tragen. Zur Erprobung dieser Moglichkeiten werden die stationaren Behandlungsverlaufe von zwei Patienten mit der Diagnose einer paranoiden Schizophrenie entlang der OPD eingeschatzt und beschrieben. Der Vergleich dieser beiden Falle liefert erste Hinweise, dass mit den geplanten Neuerungen der OPD ein Beziehungsverstehen psychotisch erlebender Patient*innen moglich ist und klinisch bedeutsame Gemeinsamkeiten und Unterschiede sichtbar werden, die durch die ICD / DSM-Diagnosen nicht abgebildet werden konnen. Abschliesend werden Implikationen fur die Behandlungsplanung diskutiert.

Long non-coding RNAs (lncRNAs) regulate diverse cellular processes and are associated with many age-associated diseases. However, the function of lncRNAs in cellular senescence remains largely unknown. Here we characterize the role of lncRNA H19 in senescence. We show that H19 levels decline as cells undergo senescence, and depletion of H19 results in premature senescence. We find that repression of H19 is triggered by the loss of CTCF and prolonged activation of p53 as part of the senescence pathway. Mechanistically, the loss of H19 drives senescence via increased let7b mediated targeting of EZH2. We further demonstrate that H19 is required for senescence inhibition by the mTOR inhibitor rapamycin, where it maintains lncRNA H19 levels throughout the cellular lifespan and thus prevents the reduction of EZH2 that would otherwise lead to cellular senescence. Therefore, lncRNA H19 is crucial in maintaining the balance between sustained cell growth and the onset of senescence.

In der zeitgenossischen Psychotherapieforschung findet „konzeptuelle Kompetenz“ zunehmend Erwahnung. Sie ist ein wichtiger Bestandteil der therapeutischen Arbeit in den verschiedenen Behandlungsverfahren. Allerdings fehlen bislang weitgehend die Moglichkeiten, konzeptuelle Kompetenz ausreichend gut zu beschreiben und zu erheben, um sie systematisch in klinische Praxis, Forschung sowie Aus- und Weiterbildung einzubeziehen. Im vorliegenden Beitrag findet eine Einordnung konzeptueller Kompetenz in die Themen der gegenwartigen Wirkfaktoren-Forschung statt. Darauf aufbauend werden Vorstellungen der psychotherapeutischen Arbeitsmodelle aufgenommen und in Richtung einer konzeptvergleichenden Psychotherapieforschung weiterentwickelt. Es wird das Forschungsprojekt „Working Models of Psychotherapy“ als eine Operationalisierung der Arbeitsmodelle-Konzeption vorgestellt und anhand eines klinischen Beispiels aufgezeigt, welches die Aufgaben und Moglichkeiten einer konzeptvergleichenden Forschung in der Psychotherapie sind.

Die Kombination von quantitativen und qualitativen Forschungsmethoden im Sinne einer gemeinsamen, ubergeordneten Fragestellung wird als Mixed-Methods(MM)-Forschung bezeichnet. Im vorliegenden Text wird argumentiert, dass dieser Ansatz ein bislang kaum genutztes Potenzial zur Annaherung von psychodynamischer Praxis und Psychotherapieforschung bietet. Der Autor geht von der Annahme aus, dass die wechselseitige Fremdheit, mit der klinisch-psychoanalytisches Denken und psychometrische Psychotherapieforschung zueinander stehen, auch zu tun hat, mit ihren unterschiedlichen epistemischen Grundannahmen, dass es sich um unterschiedliche Wissenskulturen handelt. Die MM-Forschung wird als moglicher „methodologischer Raum“ der wissenschaftlichen Inter- und Transkulturalitat verstanden. Der Artikel stellt gangige Typen von Studiendesigns in der MM-Forschung vor. Anschliesend werden diese mit aktuell durchgefuhrten Studien illustriert. Anhand dieser Beispiele wird die These vertreten, dass im Rahmen von MM-Studien eine psychodynamischere Psychotherapieforschung in Form einer „Psychotherapie-Beziehungs-Forschung“ moglich ist. Einerseits kann das vorliegende klinisch-konzeptuelle Wissen der Psychoanalyse genutzt werden, um bei einigen zentralen Problemen, mit denen die Therapieforschung aktuell beschaftigt ist, die Perspektive um unbewusste und anderweitig implizite Beziehungsprozesse zu erweitern. Andererseits konnte die Psychotherapieforschung auf diesem Wege mehr direkte Implikationen fur die klinisch-psychodynamische Praxis bekommen.

A key to longevity assurance is the nutrient-sensing mTOR pathway. Inhibition of mTOR extends lifespan in a variety of organisms. However, the downstream effectors of the mTOR pathway for lifespan regulation are elusive. In a recent report, we described the role of Maf1 as a critical lifespan regulator downstream of the mTOR pathway in fission yeast. Maf1 is the master negative regulator of RNA polymerase III-directed transcription (e.g. tRNAs and 5S rRNAs) and is regulated by mTOR-mediated phosphorylation. We demonstrated that Maf1 is required for lifespan extension under calorie restriction or when mTOR is inhibited. We also showed that Maf1 prevents DNA damage at tRNA genes, which appears to contribute to lifespan maintenance by Maf1. Here we highlight these observations and present additional results to discuss the role of the mTOR-Maf1-Pol III axis in promoting genomic integrity in the face of DNA replication-transcription conflicts in order to maintain normal lifespan.

Integrative Psychotherapien werden gegenwartig vermehrt diskutiert, auch im Lichte der Reform der Psychotherapeutenausbildung. In diesem Artikel sollen die verschiedenen vorgeschlagenen Strategien zur Psychotherapieintegration zusammengefasst und kritisch evaluiert werden. Eine konzeptuelle Analyse der Integrationsstrategien ergibt, dass diese notwendigerweise hinter dem haufig formulierten Anspruch einer produktiven Vereinheitlichung der theoretischen Systeme zuruckbleiben mussen. Stattdessen sehen wir die Notwendigkeit, Psychotherapieintegration anders zu denken, namlich als personliche Integration im Kontext der professionellen Entwicklung der Therapeutinnen und Therapeuten. Wir argumentieren dafur, die Vielheit der therapeutischen Grundorientierungen im Sinne eines theoretischen Eklektizismus zu erhalten. Dabei betrachten wir die vorgelegten konzeptuellen und forscherischen Bemuhungen um Psychotherapieintegration als Moglichkeit, ­gelungene Therapeutenentwicklungen hin zu vernunftigem klinischem Handeln in Abwesenheit absoluter Gewissheiten zu befordern.

ZusammenfassungDer Artikel begründet die Notwendigkeit eines genuin psychoanalytischen und gleichsam in der empirischen Psychotherapieforschung anschlussfähigen Beitrags zum Verständnis psychotischer Erkrankungen. Die sequenziell erklärende Mixed-Methods-Studie „Therapie und Psychodynamik von Patient*innen mit psychotischen Symptomen“ (T3PS-Studie) fokussiert auf die Binnendifferenzierung psychotischer Erkrankungen. Hierfür soll eine psychoanalytisch begründete Typologie dieser Patient*innen anhand messender und hermeneutischer Methoden entwickelt und validiert werden. Zur Entwicklung der Typologie sieht das Studiendesign psychodynamische, psychopathologische und weitere diagnostische Interviews mit stationären Patientinnen und Patienten (N = 100) vor. Zusätzlich werden am Ende der Behandlung Beziehungsepisodeninterviews mit Mitgliedern des Behandlungsteams geführt und Fragebogen eingesetzt. Mittels zunächst statistischer Modellierung und anschließender qualitativer Konzeptbildung sollen schließlich Prototypen psychotischer Erkrankungen entlang der in der Operationalisierten Psychodynamischen Diagnostik (OPD) erfassbaren psychoanalytischen Konzepte von Konflikt, Struktur und Beziehungsdynamik identifiziert werden. Die klinische Nützlichkeit dieser Typologie soll durch systematische Untersuchungen einzelner Behandlungsverläufe nach dem Hermeneutic Single-Case Efficacy Design (HSCED) geprüft werden.

Cellular senescence is a terminal cell fate characterized by growth arrest and a metabolically active state characterized by high glycolytic activity. Human fibroblasts were placed in a unique metabolic state using a combination of methionine restriction (MetR) and rapamycin (Rapa). This combination induced a metabolic reprogramming that prevented the glycolytic shift associated with senescence. Surprisingly, cells treated in this manner did not undergo senescence but continued to divide at a slow rate even at high passage, in contrast with either Rapa treatment or MetR, both of which extended life span but eventually resulted in growth arrest. Transcriptome-wide analysis revealed a coordinated regulation of metabolic enzymes related to one-carbon metabolism including three methyltransferase enzymes (KMT2D, SETD1B, and ASH1L), key enzymes for both carnitine synthesis and histone modification. These enzymes appear to be involved in both the metabolic phenotype of senescent cells and the chromatin changes required for establishing the senescence arrest. Targeting one of these enzymes, ASH1L, produced both a glycolytic shift and senescence, providing proof of concept. These findings reveal a mechanistic link between a major metabolic hallmark of senescence and nuclear events required for senescence.

Cellular senescence is a fundamental process that may play positive or detrimental roles for the organism. It is involved in tissue development and in tumor prevention although during aging is becoming a detrimental process contributing to the decline of tissue functions. In previous investigations, we have uncovered a better capacity to detect DNA damage in cells from long-lived mammals. Here, we report that cultured cells derived from long-lived species have a higher propensity to undergo senescence when challenged with DNA damage than cells derived from short-lived species. Using a panel of cells derived from six mammals, which range in lifespan from 3-4 years up to 120 years, we examined cell cycle response, induction of apoptosis and of cellular senescence. All species exhibited a cell cycle arrest while induction of apoptosis was variable. However, a significant positive correlation was found between the relative percent of cells, within a population which entered senescence following damage, and the lifespan of the species. We suggest that cellular senescence may have a positive role during development allowing it to contribute to the evolution of longevity. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s11357-019-00066-2) contains supplementary material, which is available to authorized users.

Aging is a major risk factor for the majority of human diseases, and the development of interventions to reduce the intrinsic rate of aging is expected to reduce the risk for age-related diseases including cardiovascular disease, cancer, and dementia. In the skin, aging manifests itself in photodamage and dermal atrophy, with underlying tissue reduction and impaired barrier function. To determine whether rapamycin, an FDA-approved drug targeting the mechanistic target of rapamycin (mTOR) complex, can reduce senescence and markers of aging in human skin, an exploratory, placebo-controlled, interventional trial was conducted in a clinical dermatology setting. Participants were greater than 40 years of age with evidence of age-related photoaging and dermal volume loss and no major morbidities. Thirty-six participants were enrolled in the study, and nineteen discontinued or were lost to follow-up. A significant (P = 0.008) reduction in p16

Aging is a major risk factor for the majority of human diseases, and the development of interventions to reduce the intrinsic rate of aging is expected to reduce the risk for age-related diseases including cardiovascular disease, cancer, and dementia. In the skin, aging manifests itself in photodamage and dermal atrophy, with underlying tissue reduction and impaired barrier function. To determine whether rapamycin, an FDA-approved drug targeting the mechanistic target of rapamycin (mTOR) complex, can reduce senescence and markers of aging in human skin, an exploratory, placebo-controlled, interventional trial was conducted in a clinical dermatology setting. Participants were greater than 40 years of age with evidence of age-related photoaging and dermal volume loss and no major morbidities. Thirty-six participants were enrolled in the study, and nineteen discontinued or were lost to follow-up. A significant (P = 0.008) reduction in p16INK4A protein levels and an increase in collagen VII protein levels (P = 0.0077) were observed among participants at the end of the study. Clinical improvement in skin appearance was noted in multiple participants, and immunohistochemical analysis revealed improvement in histological appearance of skin tissue. Topical rapamycin reduced the expression of the p16INK4A protein consistent with a reduction in cellular senescence. This change was accompanied by relative improvement in clinical appearance of the skin and histological markers of aging and by an increase in collagen VII, which is critical to the integrity of the basement membrane. These results indicate that rapamycin treatment is a potential anti-aging therapy with efficacy in humans.Trial registration ClinicalTrials.gov Identifier: NCT03103893.

Cellular senescence is a biological phenomenon that has received many interpretations since its original description by Hayflick and Moorhead in 1961. A hypothesis proposed over 40 years ago is now generally accepted: i.e. that cellular senescence is a regulated cellular program. For the majority of forms of senescence, the senescence program seems to be induced due to the prolonged presence of DNA damage [1]....

Lactase persistence (LP), the continued expression of lactase into adulthood, is the most strongly selected single gene trait over the last 10,000 years inmultiple human populations. It has been posited that the primary allele causing LP among Eurasians, rs4988235-A [1], only rose to appreciable frequencies during the Bronze and Iron Ages [2, 3], long after humans started consuming milk from domesticated animals. This rapid rise has been attributed to an influx of people from the Pontic-Caspian steppe that began around 5,000 years ago [4, 5]. We investigate the spatiotemporal spread of LP through an analysis of 14 warriors from the Tollense Bronze Age battlefield in northern Germany ( 3,200 before present, BP), the oldest large-scale conflict site north of the Alps. Genetic data indicate that these individuals represent a single unstructured Central/Northern European population.We complemented these data with genotypes of 18 individuals fromtheBronzeAge siteMokrin in Serbia ( 4,100 to 3,700 BP) and 37 individuals from Eastern Europe and the Pontic-Caspian Steppe region, predating both Bronze Age sites ( 5,980 to 3,980BP).We infer lowLPin all three regions, i.e., in northern Germany and South-eastern and Eastern Europe, suggesting that the surge of rs4988235 in Central and NorthernEuropewas unlikely caused by Steppe expansions.We estimate a selection coefficientof 0.06 and conclude that the selection was ongoing in various parts of Europe over the last 3,000 years.

Lactase persistence (LP), the continued expression of lactase into adulthood, is the most strongly selected single gene trait over the last 10,000 years in multiple human populations. It has been posited that the primary allele causing LP among Eurasians, rs4988235*T (Enattah et al. 2008), only rose to appreciable frequencies during the Bronze and Iron Ages (Mathieson et al 2015; Olalde et al. 2018), long after humans started consuming milk from domesticated animals. This rapid rise has been attributed to an influx of peoples from the Pontic-Caspian steppe that began around 5,000 years ago (Allentoft et al. 2015; Furholt et al. 2016). We investigate the spatiotemporal spread of LP through an analysis of 14 warriors from the Tollense Bronze Age battlefield in northern Germany (~3,200 BP); the oldest large-scale conflict site north of the Alps. Genetic data indicate that these individuals represent a single unstructured Central/Northern European population. We complemented these data with genotypes of 18 individuals from the Bronze Age site Mokrin in Serbia (~4,100 to ~3,700 BP) and 37 individuals from eastern Europe and the Pontic-Caspian Steppe region, predating both Bronze Age sites (~5,980 to ~4,250 BP). We infer low LP in all three regions, i.e. in northern Germany, south- eastern, and eastern Europe, suggesting that the surge of rs4988235 in Central and Northern Europe was unlikely caused by Steppe expansions. We estimate a selection coefficient of 0.06, and conclude that the selection was on-going in various parts of Europe over the last 3,000 years.

Maf1 is the master repressor of RNA polymerase III responsible for transcription of tRNAs and 5S rRNAs. Maf1 is negatively regulated via phosphorylation by the mTOR pathway, which governs protein synthesis, growth control, and lifespan regulation in response to nutrient availability. Inhibiting the mTOR pathway extends lifespan in various organisms. However, the downstream effectors for the regulation of cell homeostasis that are critical to lifespan extension remain elusive. Here we show that fission yeast Maf1 is required for lifespan extension. Maf1’s function in tRNA repression is inhibited by mTOR‐dependent phosphorylation, whereas Maf1 is activated via dephosphorylation by protein phosphatase complexes, PP4 and PP2A. Mutational analysis reveals that Maf1 phosphorylation status influences lifespan, which is correlated with elevated tRNA and protein synthesis levels in maf1∆ cells. However, mTOR downregulation, which negates protein synthesis, fails to rescue the short lifespan of maf1∆ cells, suggesting that elevated protein synthesis is not a cause of lifespan shortening in maf1∆ cells. Interestingly, maf1∆ cells accumulate DNA damage represented by formation of Rad52 DNA damage foci and Rad52 recruitment at tRNA genes. Loss of the Rad52 DNA repair protein further exacerbates the shortened lifespan of maf1∆ cells. Strikingly, PP4 deletion alleviates DNA damage and rescues the short lifespan of maf1∆ cells even though tRNA synthesis is increased in this condition, suggesting that elevated DNA damage is the major cause of lifespan shortening in maf1∆ cells. We propose that Maf1‐dependent inhibition of tRNA synthesis controls fission yeast lifespan by preventing genomic instability that arises at tRNA genes., In response to nutrient availability, mTOR inactivates Maf1 via phosphorylation. This results in hyperactivation of Pol III‐mediated transcription, leading to DNA damage due to collisions between the replication and transcription machineries. Such DNA damage may shorten lifespan. mTOR‐mediated activation of cellular processes and increased energy expenditure also negatively affect lifespan.

Inhibition of mTOR signaling using rapamycin has been shown to increase lifespan and healthspan in multiple model organisms; however, the precise mechanisms for the beneficial effects of rapamycin remain uncertain. We have previously reported that rapamycin delays senescence in human cells and that enhanced mitochondrial biogenesis and protection from mitochondrial stress is one component of the benefit provided by rapamycin treatment. Here, using two models of senescence, replicative senescence and senescence induced by the presence of the Hutchinson-Gilford progeria lamin A mutation, we report that senescence is accompanied by elevated glycolysis and increased oxidative phosphorylation, which are both reduced by rapamycin. Measurements of mitochondrial function indicate that direct mitochondria targets of rapamycin are succinate dehydrogenase and matrix alanine aminotransferase. Elevated activity of these enzymes could be part of complex mechanisms that enable mitochondria to resume their optimal oxidative phosphorylation and resist senescence. This interpretation is supported by the fact that rapamycin-treated cultures do not undergo a premature senescence in response to the replacement of glucose with galactose in the culture medium, which forces a greater reliance on oxidative phosphorylation. Additionally, long-term treatment with rapamycin increases expression of the mitochondrial carrier protein UCP2, which facilitates the movement of metabolic intermediates across the mitochondrial membrane. The results suggest that rapamycin impacts mitochondrial function both through direct interaction with the mitochondria and through altered gene expression of mitochondrial carrier proteins.

Cellular senescence is a central component of the aging process. This cellular response has been found to be induced by multiple forms of molecular damage and senescent cells increase in number with age in all tissues examined to date. We have examined the correlation with age of two key proteins involved in the senescence program, p16INK4a and HMGB2. These proteins are involved in cell cycle arrest and chromatin remodeling during senescence. Circulating levels of these markers increases with age and correlates with functional status. The levels of HMGB2 appear to be significantly correlated with functional status, whereas p16INK4a levels are more weakly associated. Interestingly, there is a strong correlation between the two proteins independent of age. In particular, a single high-functioning individual over 90 years of age displays a disproportionately low level of HGMB2. The results suggest that with improved testing methodology, it may be possible to monitor circulating protein markers of senescence in human populations.

Significance Many modern European states trace their roots back to a period known as the Migration Period that spans from Late Antiquity to the early Middle Ages. We have conducted the first population-level analysis of people from this era, generating genomic data from 41 graves from archaeological sites in present-day Bavaria in southern Germany mostly dating to around 500 AD. While they are predominantly of northern/central European ancestry, we also find significant evidence for a nonlocal genetic provenance that is highly enriched among resident Early Medieval women, demonstrating artificial skull deformation. We infer that the most likely origin of the majority of these women was southeastern Europe, resolving a debate that has lasted for more than half a century., Modern European genetic structure demonstrates strong correlations with geography, while genetic analysis of prehistoric humans has indicated at least two major waves of immigration from outside the continent during periods of cultural change. However, population-level genome data that could shed light on the demographic processes occurring during the intervening periods have been absent. Therefore, we generated genomic data from 41 individuals dating mostly to the late 5th/early 6th century AD from present-day Bavaria in southern Germany, including 11 whole genomes (mean depth 5.56×). In addition we developed a capture array to sequence neutral regions spanning a total of 5 Mb and 486 functional polymorphic sites to high depth (mean 72×) in all individuals. Our data indicate that while men generally had ancestry that closely resembles modern northern and central Europeans, women exhibit a very high genetic heterogeneity; this includes signals of genetic ancestry ranging from western Europe to East Asia. Particularly striking are women with artificial skull deformations; the analysis of their collective genetic ancestry suggests an origin in southeastern Europe. In addition, functional variants indicate that they also differed in visible characteristics. This example of female-biased migration indicates that complex demographic processes during the Early Medieval period may have contributed in an unexpected way to shape the modern European genetic landscape. Examination of the panel of functional loci also revealed that many alleles associated with recent positive selection were already at modern-like frequencies in European populations ∼1,500 years ago.

Both methionine restriction and rapamycin treatment are robust longevity-enhancing regimens for which the mechanisms remain unclear. Cellular senescence is a major contributor to the aging process, and we find that both the methionine and rapamycin regimens delay or prevent activation of the senescence program in human cells. Using a transcriptome-wide analysis, we examined the impact of methionine restriction and rapamycin treatment on senescence-associated gene expression in human cardiac fibroblasts. Our findings have been integrated into gene expression data sets from human lung and skin fibroblasts during senescence. The data demonstrate both common and tissue-specific aspects to the senescent phenotype in these cell types. For example, cardiac fibroblasts express brain naturetic peptide, a clinically relevant marker for cardiac failure, whereas senescent cells from all three tissues express at least one of the insulin-like growth factor (IGF)-binding proteins. The IGF-binding proteins are tissue-specific mediators of IGF-1, a growth factor required for proliferation of all tissues. These data suggest that senescent cells serve tissue-specific roles. Moreover, the prolongevity regimens produce distinct patterns of gene expression.

The long non-coding RNA (lncRNA) H19 is a maternally imprinted gene transcript that, in conjunction with the neighboring Igf2 gene, is critical in controlling embryonic growth. Loss of H19 results in fetal overgrowth associated with Beckwith Weidemann syndrome, while elevated H19 occurs in human cancers. In the adult, H19 functions in cancer cells where it promotes migration and is correlated with poor prognosis, and in adult stem cells where it is a key regulator of cell fate decisions during differentiation. While the function of H19 in primary somatic cells has not been defined, a reduction in the abundance of H19 has been reported during senescence in endothelial cells. Given the critical importance of H19 in cell fate decisions, it is likely that understanding the precise function of H19 in somatic cells in general and why reduced levels occur with cellular senescence will provide novel insights into both somatic cell maintenance and the senescence program. Towards this end, we examined the role of H19 in somatic cell growth using cardiac interstitial fibroblasts. Our results indicate that H19 is not only vital for somatic cell proliferation and survival, but that depletion of H19 leads to cell cycle arrest and the formation of abnormal nuclei resulting in senescent cells. We are defining both the upstream regulators of H19 and the downstream mediators of senescence following H19 depletion. Overall, these results indicate an essential role for H19 in cell cycle progression, chromatin structure, and possibly proper mitotic division.

Cellular senescence has gained much attention as a contributor to aging and susceptibility to disease. Senescent cells undergo a stable cell cycle arrest and produce pro-inflammatory cytokines. However, an additional feature of the senescence phenotype is an altered metabolic state. Despite maintaining a non-dividing state, senescent cells display a high metabolic rate. Metabolic changes characteristic of replicative senescence include altered mitochondrial function and perturbations in growth signaling pathways, such as the mTORC1-signaling pathway. Recent evidence has raised the possibility that these metabolic changes may be essential for the induction and maintenance of the senescent state. Interventions such as rapamycin treatment and methionine restriction impact key aspects of metabolism and delay cellular senescence to extend cellular lifespan. Here, we review the metabolic changes and potential metabolic regulators of the senescence program. In addition, we will discuss how lifespan-extending regimens prevent metabolic stress that accompanies and potentially regulates the senescence program.

Es wird die Therapeutenversion der Prozessskala fur imaginations- und trancebasierte tiefenpsychologische Methoden (PIT) vorgestellt und anhand einer klinischen Stichprobe validiert. Die PIT ist konzipiert als Instrument zur Erfassung von therapeutischem Vorgehen und Interventionstechniken in Katathym Imaginativer Psychotherapie (KIP), Hypnosepsychotherapie (HY) und Autogener Psychotherapie (ATP). Alle drei Verfahren sind tiefenpsychologische Methoden und zeichnen sich in ihrem therapeutischen Vorgehen durch imaginations- und trancebasierte Techniken aus. Anhand der PIT soll einerseits in zukunftigen Studien die Erfassung der Adharenz und die Anbindung von KIP, HY und ATP an die Prozess-Ergebnisforschung ermoglicht werden, andererseits bietet die Skala auch Moglichkeiten einer empirisch gestutzten Weiterentwicklung der Behandlungstechnik in den Methoden. Die PIT wurde entwickelt auf Grundlage der etablierten Comparative Psychotherapy Process Scale (CPPS) von Hilsenroth und Kollegen und ist fur den kombinierten Einsatz mit dieser vorgesehen. Die Validierung der PIT als Instrument zur Adharenzmessung erfolgte anhand von Daten aus N = 353 begonnenen und N = 161 abgeschlossenen Behandlungen. Wir konnten zeigen, dass die PIT intern konsistent ist und uber gute Itemkennwerte verfugt. Die Faktorenstruktur ist zufriedenstellend. Die Test-Retest-Reliabilitat der Items ist akzeptabel bis sehr gut. In Kombination mit der CPPS diskriminiert die PIT insgesamt sehr gut zwischen den drei untersuchten Psychotherapiemethoden. Die Ergebnisse liefern erste Hinweise, dass mit der PIT ein okonomisches und valides Instrument vorgelegt wurde, anhand dessen die Behandlungstechnik in KIP, HY und ATP aus Therapeutensicht abgebildet werden kann. Limitationen, die mit der Beschrankung auf die Therapeutenperspektive einhergehen, werden abschliesend diskutiert, gemeinsam mit Moglichkeiten zur Erweiterung der Skala.

Die Anwendung psychometrischer Ergebnisforschung auf psychoanalytisch begrundete Behandlungen wird kontrovers diskutiert. Einige Autoren argumentieren, dass auch bei psychoanalytischen Behandlungen quantitative Methoden und hinreichend grose Stichproben den Goldstandard darstellen. Andere beharren auf der Inkompatibilitat von Psychoanalyse und dieser Art von Forschung. Beide Standpunkte greifen, fur sich genommen, zu kurz. Im Folgenden wird zunachst gezeigt, inwieweit neuere Entwicklungen und Fortschritte in der psychodynamisch orientierten Psychotherapieforschung es erlauben, die These der grundsatzlichen Unvereinbarkeit von Psychoanalyse und messender Forschung zuruckzuweisen. Psychoanalytische Behandlungen konnen und sollten psychometrisch beurteilt werden. Allerdings spricht viel dafur, dass die messenden Methoden nur einen Teil der klinisch relevanten Ergebnisse von psychoanalytischen – und allen anderen – Psychotherapien erfassen konnen. Dies kann deutlich werden, wenn, im Rahmen eines pluralistischen Modells von Wissenserzeugung, zusatzlich zu den Erkenntnismitteln der psychometrischen Forschung auch die (psychoanalytisch-)klinische Hermeneutik in den Blick genommen wird. Diese erlaubt keinen Bezug zu allgemeinen Gesetzmasigkeiten, bietet aber einen Zugang zur Singularitat und Gesamtheit eines Falls. Die Frage nach dem Erfolg einer konkreten Behandlung kann ohne Berucksichtigung ihrer spezifischen Besonderheiten nicht sinnvoll beantwortet werden. Eine rein psychometrische Ergebnisforschung bleibt daher zwangslaufig unvollstandig. Moglichkeiten zur Erweiterung der Ergebnisforschung im Sinne einer pluralistischen Methodologie werden diskutiert.

Die Wirksamkeit tiefenpsychologischer Therapie ist allgemein gut belegt, allerdings ist bislang wenig uber die spezifische Wirksamkeit von integrativen Psychotherapiemethoden bekannt, die sich im Rahmen tiefenpsychologischer Behandlungen Techniken der begleiteten Imagination und der hypnotischer Trancen bedienen. In einer prospektiven naturalistischen Langsschnittstudie wurden die integrativen tiefenpsychologischen Psychotherapiemethoden Katathym Imaginative Psychotherapie (KIP) und Hypnosepsychotherapie (HY) in Bezug auf Symptomreduktion und Pradiktoren des Behandlungserfolgs untersucht. Die Stichprobe umfasste zu Beginn (T1) 300, nach 6 Monaten (T2) 183 und nach 1 Jahr (T3) 150 ambulante Patienten aus der osterreichischen Gesundheitsversorgung. Die Symptombelastung wurde mithilfe des Brief Symptom Inventory (BSI) gemessen, als mogliche Pradiktoren des Behandlungserfolgs wurden Psychological Mindedness (Psychological Mindedness Scale, PMS-D) und die Auspragung pathologischer Personlichkeitszuge (Fragebogen zur Erfassung von DSM-IV-Personlichkeitsstorungen, ADP-IV) erhoben. Es zeigte sich eine Verringerung der Symptombelastung uber die 3 Messzeitpunkte hinweg (d = 0,58). 32 % der Patienten verbesserten sich klinisch signifikant von T1 zu T3. Zwischen KIP und HY fanden sich keine signifikanten Unterschiede im Ausmas der Symptomreduktion. Psychological Mindedness und pathologische Personlichkeitszuge konnten als Moderatoren identifiziert werden. Je hoher die Psychological Mindedness der Patienten, desto starker ihre Symptomreduktion. Je starker die Personlichkeitspathologie, desto geringer die Symptomreduktion. Fur KIP und HY wurde eine Symptomreduktion nach einem Jahr Behandlung gefunden, knapp ein Drittel der Patienten zeigte eine klinisch bedeutsame Verbesserung. Psychological Mindedness erwies sich als prognostisch gunstig, ein hohes Ausmas an pathologischen Personlichkeitszugen als prognostisch ungunstig.

In evolutionary terms, life on the planet has taken the form of independently living cells for the majority of time. In comparison, the mammalian radiation is a relatively recent event. The common mammalian ancestor was probably small and short-lived. The "recent" acquisition of an extended longevity and large body mass of some species of mammals present on the earth today suggests the possibility that similar cellular mechanisms have been influenced by the forces of natural selection to create a convergent evolution of longevity. Many cellular mechanisms are potentially relevant for extending longevity; in this assay, we review the literature focusing primarily on two cellular features: (1) the capacity for extensive cellular proliferation of differentiated cells, while maintaining genome stability; and (2) the capacity to detect DNA damage. We have observed that longevity and body mass are both positively linked to these cellular mechanisms and then used statistical tools to evaluate their relative importance. Our analysis suggest that the capacity for extensive cellular proliferation while maintaining sufficient genome stability, correlates to species body mass while the capacity to correctly identify the presence of DNA damage seems more an attribute of long-lived species. Finally, our data are in support of the idea that a slower development, allowing for better DNA damage detection and handling, should associate with longer life span.

We present results from an inter-laboratory massively parallel sequencing (MPS) study in the framework of the SeqForSTRs project to evaluate forensically relevant parameters, such as performance, concordance, and sensitivity, using a standardized sequencing library including reference material, mixtures, and ancient DNA samples. The standardized library was prepared using the ForenSeq DNA Signature Prep Kit (primer mix A). The library was shared between eight European laboratories located in Austria, France, Germany, The Netherlands, and Sweden to perform MPS on their particular MiSeq FGx sequencers. Despite variation in performance between sequencing runs, all laboratories obtained quality metrics that fell within the manufacturer’s recommended ranges. Furthermore, differences in locus coverage did not inevitably adversely affect heterozygous balance. Inter-laboratory concordance showed 100% concordant genotypes for the included autosomal and Y-STRs, and still, X-STR concordance exceeded 83%. The exclusive reasons for X-STR discordances were drop-outs at DXS10103. Sensitivity experiments demonstrated that correct allele calling varied between sequencing instruments in particular for lower DNA amounts (≤ 125 pg). The analysis of compromised DNA samples showed the drop-out of one sample (FA10013B01A) while for the remaining three degraded DNA samples MPS was able to successfully type ≥ 87% of all aSTRs, ≥ 78% of all Y-STRs, ≥ 68% of all X-STRs, and ≥ 92% of all iSNPs demonstrating that MPS is a promising tool for human identity testing, which in return, has to undergo rigorous in-house validation before it can be implemented into forensic routine casework. Electronic supplementary material The online version of this article (10.1007/s00414-019-02201-2) contains supplementary material, which is available to authorized users.

The study aimed to test whether countertransference reactions contain valid information about the patient. The authors examined whether a significant part of the variance in emotional, cognitive, and motivational responses to recorded therapy sessions is attributable to the patient. Six student raters listened to 605 audiotaped sessions of 81 patients with major depression treated by 19 therapists and indicated their reactions using a modified version of the Countertransference Questionnaire. The relative amount of variance in countertransference reactions due to differences between patients, ranging from 2% to 16%, was significant for most of the countertransference dimensions. Reactions were influenced by type of treatment and severity of depression but not by comorbid personality disorder or interpersonal problems. The relative amount of variance due to differences between raters was large, averaging at 23%. The authors conclude that—albeit having a relatively low “signal-to-noise ratio” in raters without psychotherapy training—countertransference reactions contain valid clinical information.

Lines of evidence from several studies have shown that increases in life expectancy are now accompanied by increased disability rate. The expanded lifespan of the aging population imposes a challenge on the continuous increase of chronic disease. The prevalence of overweight and obesity is increasing at an alarming rate in many parts of the world. Further to increasing the onset of metabolic imbalances, obesity leads to reduced life span and affects cellular and molecular processes in a fashion resembling aging. Nine key hallmarks of the aging process have been proposed. In this review, we will review these hallmarks and discuss pathophysiological changes that occur with obesity, that are similar to or contribute to those that occur during aging. We present and discuss the idea that obesity, in addition to having disease-specific effects, may accelerate the rate of aging affecting all aspects of physiology and thus shortening life span and health span.

Across species, development and longevity are tightly linked. We discuss the relevant literature and suggest that the root for this stringent relationship is the rate of development. The basis for the relationship between rate of development and longevity lies in adaptations that have occurred through evolution at multiple levels of biological complexity: organism, organ, cellular, and molecular. Thus, the analysis of the relationship is of interest for multiple fields of biology.

Cellular senescence is a cell fate defined by an irreversible cell-cycle arrest and a pro-inflammatory secretory profile. It is a consequence of a shift in metabolism and rearrangement of chromatin. Accumulation of senescent cells is a universal hallmark of age-related pathologies suggesting these cells contribute to age-related susceptibility to disease. Here, we examine the interplay between two metabolic inhibitors of senescence: Rapamycin treatment and Methionine restriction (metR). We report that a combination of methionine restriction and rapamycin induces a metabolic reprogramming that prevents activation of the senescence program in human fibroblasts. The treated cells continue to divide at a slow rate at a high passage and lack senescence-associated markers and inflammatory cytokines. Genome-wide chromatin accessibility analysis reflects chromatin remodeling with distinctly increased accessibility of heterochromatic regions in treated cells. Further, Transcriptome-wide analysis reveals increased expression of specific methyltransferases which alter the trimethylation of H3, one of the strongest hallmarks of open chromatin. This may represent a mechanistic link between a major hallmark of senescence and nuclear events required for senescence.

Microglia support productive human immunodeficiency virus type 1 (HIV-1) infection and disturbed microglial function could contribute to the development of HIV-associated neurocognitive disorders (HAND). Better understanding of how HIV-1 infection and viral protein exposure modulate microglial function during the course of infection could lead to the identification of novel therapeutic targets for both the eradication of HIV-1 reservoir and treatment of neurocognitive deficits. This review first describes microglial origins and function in the normal central nervous system (CNS), and the changes that occur during aging. We then critically discuss how HIV-1 infection and exposure to viral proteins such as Tat and gp120 affect various aspects of microglial homeostasis including activation, cellular metabolism and cell cycle regulation, through pathways implicated in cellular stress responses including p38 mitogen-activated protein kinase (MAPK) and nuclear factor κB (NF-κB). We thus propose that the functions of human microglia evolve during both healthy and pathological aging. Aging-associated dysfunction of microglia comprises phenotypes resembling cellular senescence, which could contribute to cognitive impairments observed in various neurodegenerative diseases. In addition, microglia seems to develop characteristics that could be related to cellular senescence post-HIV-1 infection and after exposure to HIV-1 viral proteins. However, despite its potential role as a component of HAND and likely other neurocognitive disorders, microglia senescence has not been well characterized and should be the focus of future studies, which could have high translational relevance. GLIA 2016

HIV-1 causes premature aging in chronically infected patients. Despite effective anti-retroviral therapy, around 50% of patients suffer HIV-associated neurocognitive disorders (HAND), which likely potentiate aging-associated neurocognitive decline. Microglia support productive HIV-1 infection in the brain. Elevated markers of cellular senescence, including p53 and p21, have been detected in brain tissues from patients with HAND, but the potential for microglia senescence during HIV-1 infection has not been investigated. We hypothesized that HIV-1 can induce senescence in microglia. Primary human fetal microglia were exposed to single-round infectious HIV-1 pseudotypes or controls, and examined for markers of senescence. Post-infection, microglia had significantly elevated: senescence-associated β-galactosidase activity, p21 levels, and production of cytokines such as IL-6 and IL-8, potentially indicative of a senescence-associated secretory phenotype. We also found increased detection of p53-binding protein foci in microglia nuclei post-infection. Additionally, we examined mitochondrial reactive oxygen species (ROS) and respiration, and found significantly increased mitochondrial ROS levels and decreased ATP-linked respiration during HIV-1 infection. Supernatant transfer from infected cultures to naive microglia resulted in elevated p21 and caveolin-1 levels, and IL-8 production. Finally, nucleoside treatment reduced senescence markers induction in microglia. Overall, HIV-1 induces a senescence-like phenotype in human microglia, which could play a role in HAND.