“Micronuclei and Disease” special issue: Aims, scope, and synthesis of outcomes

[Abastract] The purpose of the “Micronuclei and Disease” special issue (SI) is to: (i) Determine the level of evidence for association of micronuclei (MN), a biomarker of numerical and structural chromosomal aberrations, with risk of specific diseases in humans; (ii) Define plausible mechanisms that explain association of MN with each disease; (iii) Identify knowledge gaps and research needed to translate MN assays into clinical practice. The “MN and Disease” SI includes 14 papers. The first is a review of mechanisms of MN formation and their consequences in humans. 11 papers are systematic reviews and/or meta-analyses of the association of MN with reproduction, child health, inflammation, auto-immune disease, glycation, metabolic diseases, chronic kidney disease, cardiovascular disease, eleven common cancers, ageing and frailty. The penultimate paper focuses on effect of interventions on MN frequency in the elderly. A road map for translation of MN data into clinical practice is the topic of the final paper. The majority of reviewed studies were case-control studies in which the ratio of mean MN frequency in disease cases relative to controls, i.e. the mean ratio (MR), was calculated. The mean of these MR values, estimated by meta-analyses, for lymphocyte and buccal cell MN in non-cancer diseases were 2.3 and 3.6 respectively, and for cancers they were 1.7 and 2.6 respectively. The highest MR values were observed in studies of cancer cases in which MN were measured in the same tissue as the tumour (MR = 4.9–10.8). This special issue is an important milestone in the evidence supporting MN as a reliable genomic biomarker of developmental and degenerative disease risk. These advances, together with results from prospective cohort studies, are helping to identify diseases in which MN assays can be practically employed in the clinical setting to better identify high risk patients and to prioritise them for preventive therapy

The effect of a lifestyle intervention on DNA damage and genome stability in Austrian institutionalized elderly

Der mit dem Alterungsprozess einhergehende Verlust von Muskelmasse und Muskelkraft ist stark mit einer reduzierten Lebensqualität verbunden. Um diesem Abbau entgegen zu wirken und somit Mobilität und Unabhängigkeit im Alter zu erhalten oder wiederherzustellen, ist körperliche Aktivität, insbesondere in Form von Krafttraining, wichtig. Krafttraining kombiniert mit einer optimalen Versorgung an Nährstoffen, allen voran Protein, scheint am effektivsten, um Muskelmasse und Kraft, auch bei SeniorInnen, zu erhöhen. Speziell um oxidative Schäden an der DNA und Zellmutationen zu reduzieren sind Antioxidantien sowie die Vitamine B12 und Folsäure wichtige Komponenten. Sowohl Altern, als auch der Abbau von Muskulatur sind mit Entzündungen, oxidativem Stress, DNA-Schäden und Genominstabilität verbunden. Bekanntermaßen erhöht (Kraft-) Training akut und vorübergehend die Bildung reaktiver Sauerstoff-Spezies (ROS) und bewirkt, abhängig von Trainingsstatus, Häufigkeit und relativer Intensität des Trainingsreizes, erhöhten oxidativen Stress und erhöhte Entzündungswerte im menschlichen Organismus. Allerdings ist, durch akutes körperliches Training induzierter, oxidativer Stress essentiell, um Anpassungsprozesse im menschlichen Körper nach körperlicher Belastung auszulösen und antioxidative Abwehrmechanismen zu verbessern. Das Forschungsziel der vorliegenden Arbeit war es den Einfluss von sechs Monaten Krafttraining (RT), alleine oder in Kombination mit einer Protein und Vitamin Supplementierung (RTS) und kognitivem Training (CT) auf DNA Schäden (Comet Assay) und Genomstabilität (CBMN Assay) bei institutionalisierten PensionistInnen zu untersuchen. Einhundertsiebzehn ProbandInnen wurden aus fünf Häusern des Kuratoriums Wiener Pensionisten-Wohnhäusern (KWP) rekrutiert und randomisiert den drei Interventionsgruppen zugeteilt. Es wurde in jeder Gruppe zweimal pro Woche trainiert, zusätzlich erhielt die RTS-Gruppe das Supplement täglich zum Frühstück, sowie direkt nach jedem Training. Zu Studienbeginn konnten Daten von 97 ProbandInnen (13.4% Männer, 86.6% Frauen), mit einem Durchschnittsalter von 83.0 ±6.1 Jahren, in die Berechnungen miteinbezogen werden. In der RT-Gruppe (T1-T2 +20%, p= 0.001), sowie in der RTS-Gruppe (T1-T2 +17%, p= 0.002), erhöhten sich die DNA Schäden nach dreimonatiger Intervention signifikant. Jedoch erhöhte sich die Widerstandsfähigkeit der Zellen gegenüber der Behandlung mit H2O2 nach drei und nach sechs Monaten signifikant in der RT-Gruppe (T1-T2 -24%, p= 0.030; T1-T3 -18%, p= 0.019) und der CT-Gruppe (T1-T2 -21%, p= 0.004; T1-T3 -13%, p= 0.038); lediglich eine Tendenz für einen Zeiteffekt konnte in der RTS-Gruppe beobachtet werden (Friedman-Test p= 0.093). Die Aktivität der antioxidativ wirkenden Enzyme zeigte signifikante Anstiege in den RT und RTS-Gruppen (RT +22% Catalase-activity T1-T3, p= 0.013; RTS +6% Superoxide Dismutase-activity T2-T3, p= 0.005). In dieser sehr heterogenen Altersgruppe verringerte sich die Mikrokern-Frequenz, ein Marker für Genominstabilität, in allen drei Interventionsgruppen nach sechs Monaten (RT: -13%, RTS: -10%, CT: -10%), allerdings nicht signifikant. Zwei der Parameter des CBMN-Assays, nukleoplasmatische Brücken (CT: p= 0.025) und apoptotische Zellen (RTS: p= 0.024; CT: p= 0.021), zeigten signifikante Zeiteffekte. Die Nahrungsergänzung in der RTS-Gruppe hatte einen signifikanten Effekt auf den Status der Vitamine B12 und Folsäure nach sechs Monaten (Plasma B12: +130%, p= 0.006; Folsäure - rote Blutkörperchen: +43%, p= 0.018). Diese Erhöhung des B12 Plasma Spiegels korrelierte signifikant mit einer Reduktion der Mikrokern-Frequenz in der RTS-Gruppe (RTS: r= -0.673, p= 0.002; RT: r= 0.087, p= 0.692; CT: r= -0.246, p= 0.309). Die Ergebnisse der vorliegenden Studie deuten darauf hin, dass sowohl regelmäßiges Gedächtnis-, als auch Krafttraining die Widerstandsfähigkeit gegenüber von H2O2 induzierten DNA Schäden erhöht und Chromosomenschäden bei institutionalisierten PensionistInnen reduziert. Die Daten zeigen weiters, dass bessere aerobe Fitness mit geringeren Chromosomenschäden korreliert. In dieser Altersgruppe scheint eine zusätzliche Supplementierung sinnvoll, um den Status von Vitamin B12 und Folsäure zu erhöhen.Aging and its aligned loss of muscle mass are associated with higher levels of DNA damage and deteriorated antioxidant defense. In order to improve the body´s overall resistance against DNA damage and genomic instability, maintaining a healthy and active lifestyle is desirable, especially in the elderly. Since people are getting older, many of the elderly have to change their residence from home living to an institution, which is often accompanied by malnutrition, depression and inactivity. It has been shown that exercise training – depending on the individual training status, the training frequency and intensity, and the presence of chronically increased oxidative stress and/or inflammation – acutely and transiently increases the production of free radical oxygen species (ROS). However, the exercise-induced oxidative challenge is essential for triggering the adaptation processes after physical activity in order to improve antioxidant defense mechanisms. The current study aimed at investigating the effect of a six month progressive resistance training (RT), with or without protein and vitamin supplementation (RTS), or a cognitive training (CT), on DNA strand breaks (Comet assay) and chromosomal damage (CBMN assay) in Austrian institutionalized women and men. One hundred seventeen subjects were recruited from five different houses of the Curatorship of Viennese Retirement Homes (KWP) and randomly assigned into the three intervention groups. Each group trained two times per week and the RTS group received the supplement together with their breakfast and directly after each workout. At baseline, data from 97 women and men (13.4% male, 86.6% female) were included into the calculations. The participants had a mean-age of 83.0 ±6.1 years. After six months of intervention, 80 participants completed all tests. DNA damage increased significantly in the RT group (T1-T2 +20%, p= 0.001) and the RTS group (T1-T2 +17%, p= 0.002) and showed a similar tendency in the CT group (T1-T2 +21%, p= 0.059) after three months of intervention. However, %DNA in tail, in cells exposed to H2O2 (a well-known reactive oxygen species inducer), decreased significantly in the RT (T1-T2 -24%, p= 0.030; T1-T3 -18%, p= 0.019) and CT (T1-T2 -21%, p= 0.004; T1-T3 -13%, p= 0.038) groups; only a tendency for an overall time-effect occurred in the RTS group (Friedman-Test p= 0.093). Antioxidant enzyme activity showed significant differences for time in the RT and RTS groups (RT +22% Catalase-activity T1-T3, p= 0.013; RTS +6% Superoxide Dismutase-activity T2-T3, p= 0.005). In this very heterogenic age group micronuclei (MN) frequency decreased in all intervention groups over six months (RT: -13%, RTS: -10%, CT: -10%), however not significantly. Only nucleoplasmic bridges (CT: p= 0.025) and apoptotic cells (RTS: p= 0.024; CT: p= 0.021) showed significant time effects. Vitamin status changed significantly only in the RTS group (plasma B12: +130%, p= 0.006; red blood cell folic acid: +43%, p= 0.018). We observed a significant negative correlation between the six months change of the B12 plasma level and the MN frequency in the RTS group (RTS: r= -0.673, p= 0.002; RT: r= 0.087, p= 0.692; CT: r= -0.246, p= 0.309). Our results suggest that both, cognitive and resistance training improve resistance against H2O2 induced DNA damage and decrease chromosomal damage in institutionalized elderly. To improve the status of the vitamins B12 and folic acid, a supplementation could be useful. Furthermore, our data indicate that there might be a link between aerobic fitness and chromosomal damage, by means of lower MN frequency with an elevated fitness level, even in the very oldest of our population

Super DNAging - New insights into DNA integrity, genome stability and telomeres in the oldest old

Reductions in DNA integrity, genome stability, and telomere length are strongly associated with the aging process, age-related diseases as well as the age-related loss of muscle mass. However, in people reaching an age far beyond their statistical life expectancy the prevalence of diseases, such as cancer, cardiovascular disease, diabetes or dementia, is much lower compared to “averagely” aged humans. These inverse observations in nonagenarians (90–99 years), centenarians (100–109 years) and super-centenarians (110 years and older) require a closer look into dynamics underlying DNA damage within the oldest old of our society. Available data indicate improved DNA repair and antioxidant defense mechanisms in “super old” humans, which are comparable with much younger cohorts. Partly as a result of these enhanced endogenous repair and protective mechanisms, the oldest old humans appear to cope better with risk factors for DNA damage over their lifetime compared to subjects whose lifespan coincides with the statistical life expectancy. This model is supported by study results demonstrating superior chromosomal stability, telomere dynamics and DNA integrity in “successful agers”. There is also compelling evidence suggesting that life-style related factors including regular physical activity, a well-balanced diet and minimized psycho-social stress can reduce DNA damage and improve chromosomal stability. The most conclusive picture that emerges from reviewing the literature is that reaching “super old” age appears to be primarily determined by hereditary/genetic factors, while a healthy lifestyle additionally contributes to achieving the individual maximum lifespan in humans. More research is required in this rapidly growing population of super old people. In particular, there is need for more comprehensive investigations including short- and long-term lifestyle interventions as well as investigations focusing on the mechanisms causing DNA damage, mutations, and telomere shortening