workshop report: aging (from molecules to populations)
A recent workshop was held in Denmark some time (May) this year, and a report from that workshop was on the journal Mechanisms of Ageing and Development (Volume 129, Issue 10, October 2008, Pages 614-623). It was hosted by the University of Copenhagen Faculty of Health Sciences, in conjunction with the International Alliance of Research Universities (IARU), and was entitled Aging—From Molecules to Populations.
“One of the goals of IARU is to bring together an international group of researchers with different strengths, areas of expertise and resources, to promote research on human aging and longevity.”
Three collaborative efforts were described:
“DARC – Danish Aging Research Center (DARC). Formation of DARC was made possible by the support of the Velux Foundation. The DARC member universities include The Section of Social Medicine, Department of Public Health at the University of Copenhagen, the Danish Centre for Molecular Gerontology at the University of Aarhus, and the Aging Research Center at the University of Southern Denmark. DARC will exploit the distinct strengths of these research programs, which span from molecular biology to epidemiology, demography and social sciences. In particular, Aarhus University has strong expertise in molecular gerontology, University of Copenhagen has strong expertise in social epidemiology, and Southern Denmark University has strong expertise in genetic epidemiology. DARC will perform studies primarily using five existing Danish cohorts: The Danish Twin Registry, The Danish 1905 Cohort; Danish Centenarian Studies (1985 and 1905), The Metropolit Study 1953, and The 1914 Glostrup Cohort. At this workshop, Kaare Christensen (University of Southern Denmark) reported on recent collaborative research projects carried out by DARC.
CAMB – Copenhagen Aging and Midlife Biobank (CAMB). A new initiative whose goal is to establish a midlife biobank in order to study biological, cognitive and social variables that influence aging over the entire life course. CAMB will establish a biological and cognitive data base for subsamples of the Metropolit Study (born 1953) (Osler et al., 2004), the Copenhagen Perinatal Cohort (born 1959–1961) (Zachau-Christiansen, 1972) and The Danish Longitudinal Study on Work, Unemployment and Health (born 1949, 1959) (Christensen et al., 2004). Each of these cohorts has unique advantages as well as specific limitations. By using all three study groups, CAMB will provide the opportunity to link biological and neuropsychological data with existing data from registers and questionnaires. Data collection for CAMB will take place 2009–2011. Kirsten Avlund (University of Copenhagen) presented a progress report on this project.
The Medical Research Council (MRC) National Survey of Health and Development 1946 Birth Cohort is a database of information on the health and development of 5362 British men and women, all born in one week in March 1946. The individuals in this cohort have been followed-up 21 times since birth. Collection of clinical data on this cohort is now underway. Initial clinical studies will focus on cardiovascular disease and musculoskeletal function.”
BLM helicase as a mousetrap
Robert Brosh, Jr. wrote an article on Nature about the BLM helicase [Nature 456, 453-454 (27 November 2008) | doi:10.1038/456453a; Published online 26 November 2008]. His introductory paragraph goes:
“Bloom’s syndrome, which is characterized by severe growth retardation, immunodeficiency, anaemia, reduced fertility and predisposition to cancer1, is caused by mutations in the gene BLM. At the cellular level, the hallmark of this genetic disorder is a high rate of sister-chromatid exchange — the swapping of homologous stretches of DNA between a chromosome and its identical copy generated during DNA replication2. Understanding how mutations in BLM lead to this chromosomal abnormality has been of considerable interest to both scientists and clinicians. So the latest clue to solving the mystery of Bloom’s syndrome, which Xu et al.3 and Singh et al.4 report in Genes & Development, is a welcome advance.”
The BLM protein complex consists of several components, much like a mousetrap. With all the parts properly assembled, the mousetrap will operate efficiently and catch the mouse. In this case, a DNA structure called a double Holliday junction is caught in the BLM complex. Xu et al.3 and Singh et al.4 report the discovery of a component of this complex, RMI2, which stabilizes and orchestrates the action of the BLM complex, ensuring resolution of the double Holliday junction, and so promoting chromosomal stability
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endocycling cells
Sonam Mehrotra and colleagues reported that endocycling cells in Drosophila melanogaster do not apoptose in response to DNA rereplication genotoxic stress. Below is the abstract of their recent paper published in Genes and Development journal [doi: 10.1101/gad.1710208; Genes & Dev. 2008. 22: 3158-3171]:
Initiation of DNA replication at origins more than once per cell cycle results in rereplication and has been implicated in cancer. Here we use Drosophila to examine the checkpoint responses to rereplication in a developmental context. We find that increased Double-parked (Dup), the Drosophila ortholog of Cdt1, results in rereplication and DNA damage. In most cells, this rereplication triggers caspase activation and apoptotic cell death mediated by both p53-dependent and -independent pathways. Elevated Dup also caused DNA damage in endocycling cells, which switch to a G/S cycle during normal development, indicating that rereplication and the endocycling DNA reduplication program are distinct processes. Unexpectedly, however, endocycling cells do not apoptose regardless of tissue type. Our combined evidence suggests that endocycling apoptosis is repressed in part because proapoptotic gene promoters are silenced. Normal endocycling cells had DNA lesions near heterochromatin, which increased after rereplication, explaining why endocycling cells must constantly repress the genotoxic apoptotic response. Our results reveal a novel regulation of apoptosis in development and new insights into the little-understood endocycle. Similar mechanisms may operate during vertebrate development, with implications for cancer predisposition in certain tissues.
Figure S6. Over-expression of grim but not hid induces cell death in endocycle follicle cells of the ovary. Stage 10A endocycling follicle cells labeled with DAPI (blue) from hsp70:grim females one hour after a single heat induction (A) or without heat induction (B). Scale bar: 50 μm. (C) Quantification of mitotic cycling (M) and endocycling (E) follicle cell death in hsp70:grim and hsp70:Hid strains one hour after heat induction. Mitotic cycling cell data was derived from stages 1-5 and endocycling cell data from stages 9-10 egg chambers. Data was derived from 11 ovarioles for hsp70:grim (number of cells >/=�000 for (M), >/= 15,000 for (E) and 8 ovarioles for hsp70:Hid (number of cells >/= 700 for (M) and >/= 12,000 for (E).
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the zinc-finger protein Zelda
Hsiao-Lan Liang and colleagues published a paper recently describing the zinc-finger protein Zelda [Nature 456, 400-403 (20 November 2008) | doi:10.1038/nature07388; Received 20 June 2008; Accepted 29 August 2008; Published online 19 October 2008]. Below is the abstract:
In all animals, the initial events of embryogenesis are controlled by maternal gene products that are deposited into the developing oocyte. At some point after fertilization, control of embryogenesis is transferred to the zygotic genome in a process called the maternal-to-zygotic transition. During this time, many maternal RNAs are degraded and transcription of zygotic RNAs ensues1. There is a long-standing question as to which factors regulate these events. The recent findings that microRNAs2, 3 and Smaug4 mediate maternal transcript degradation have shed new light on this aspect of the problem. However, the transcription factor(s) that activate the zygotic genome remain elusive. The discovery that many of the early transcribed genes in Drosophila share a cis-regulatory heptamer motif, CAGGTAG and related sequences5, 6, collectively referred to as TAGteam sites5 raised the possibility that a dedicated transcription factor could interact with these sites to activate transcription. Here we report that the zinc-finger protein Zelda (Zld; Zinc-finger early Drosophila activator) binds specifically to these sites and is capable of activating transcription in transient transfection assays. Mutant embryos lacking zld are defective in cellular blastoderm formation, and fail to activate many genes essential for cellularization, sex determination and pattern formation. Global expression profiling confirmed that Zld has an important role in the activation of the early zygotic genome and suggests that Zld may also regulate maternal RNA degradation during the maternal-to-zygotic transition.
rDNA and epigenetic regulation
Antero Salminen and Kai Kaarnirant wrote a mini review on rDNA and sirtuins — Biochemical and Biophysical Research Communications journal (received 3 November 2008, available online 14 November 2008). They stated that transcription and silencing of rRNA genes are controlled by several forms of epigenetic regulation. They further noted that SIRT1 could be a yin-yang type of anti-aging factor. It could improve chronological longevity of post-mitotic cells by repressing rRNA transcription. It could also support replication by maintaining rDNA stability thru repression of rDNA recombination.
Fig. 1. A schematic presentation depicting the yin-yang role of SIRT1 in the regulation of replicative and organismal aging via epigenetic complexes which can repress either rDNA locus recombination or rRNA gene transcription.
biogerontology congress
6th European Congress of Biogerontology 2008
“ Ageing and individual life history”
November 30 – December 3
Conference Centre NH Leeuwenhorst, Noordwijkerhout (close to Leiden and Amsterdam)
ageing symposium
The Salk Institute, Nature, Nature Reviews Molecular Cell Biology and the Fondation IPSEN are pleased to announce the third annual Symposium on Biological Complexity:
Processes of Aging
January 8-10, 2009, Salk Institute for Biological Studies, La Jolla, California.
- Early registration deadline December 10th 2008
- Industry $600
- Academia $400
- Students and Locals $200
- Salk Scientists $0
- Late registration (after December 10th 2008)
- Industry $700
- Academia $500
- Students and Locals $300
- Salk Scientists $0
- Your registration to the Symposium will give you:
- - access to all sessions
- - admission to poster displays
- - breakfast services, coffee breaks and lunch boxes
- - dinner on January 10
- - abstract book
- Registration fee does not include Lodging and Transportation
- To register please go to: http://sni-symp.kintera.org/2009
- Abstract submission deadline December 10th 2008
- To submit an abstract please go to: http://sni-symp09.kintera.org/abstracts09
WRN protects against cytotoxicity of topotecan but not etoposide
Markus Christmann and colleagues recently reported their findings on whether DNA helicases, like WRN, are involved in the repair of topoisomerase inhibitor-induced DNA damage.
“Although the interplay between topo I and WRN has been reported and some early publications are available on WRN and resistance against topo II poisons, there is no systematic analysis of the role of WRN in the sensitivity against topo I and topo II poisons in human cancer cells.”
“… we utilized human U2-OS osteosarcoma cells stably transfected with siRNA specific for the wrn gene. Using this isogenic cell system, we studied for the first time comparatively the role of WRN in cellular resistance to topo I and topo II inhibitors and its involvement in the repair or processing of topo I inhibitor-induced DNA damage.”
Using three different methods (WST assay, colony forming assay, and quantification of apoptosis), they showed that the WRN helicase protects against the cytotoxic effects of the topo I inhibitor topotecan (TPT) but not the topo II inhibitor etoposide (ETO).
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Fig. 4. Formation and repair of SSBs and DSBs following TPT treatment. (A) To analyze the TPT-induced formation and repair of DNA strand breaks, wrn-wt and wrn-kd cells were exposed to 1 μg/ml TPT (left panel) or etoposide (right panel). At the indicated time points, the formation of DNA single-strand breaks was detected via alkaline SCGE. OTM, olive tail moment. Data of the mean ± S.D. of three independent experiments are shown. (B) Determination of DSBs by neutral SCGE in wrn-wt and wrn-kd cells at various times after exposure to 1 μg/ml TPT. Data of at least three independent experiments are shown. (C) To determine the amount of H2AX phosphorylation, wrn-wt and wrn-kd cells were exposed to 1 μg/ml TPT. At different times after exposure, cells were harvested, protein extracts were prepared and 25 μg were subjected to Western blot analysis. The membrane was incubated with γH2AX specific antibodies. For loading control, ERK2 was detected. To quantify the amount H2AX phosphorylation, the intensity of the strongest band was set to 100%. (D) To determine the formation of γH2AX foci, wrn-wt and wrn-kd cells were exposed to 1 μg/ml TPT. After the indicated time points, cells were fixed, and the γH2AX foci were visualized using γH2AX specific antibodies using fluorescence microscopy. For each time point, foci in 40 cells were counted and the results of three independent experiments ± S.D. is shown (left panel). A representative experiment is provided in the right panel.
intelligent people live longer?
Ian Deary wrote an essay in Nature (13 November 2008) about intelligence and ageing. At the outset, he stressed the validity of intelligence tests:
“Scores from cognitive-ability tests (also known as intelligence tests or IQ tests) have validity that is almost unequalled in psychology (Deary, 2001).”
He highlighted four non-exclusive possibilities for the link between intelligence and death:
“First, what occurs to many people as an obvious pathway of explanation, is that intelligence is associated with more education, and thereafter with more professional occupations that might place the person in healthier environments.”
“Second, people with higher intelligence might engage in more healthy behaviours.”
“Third, mental test scores from early life might act as a record of insults to the brain that have occurred before that date.”
“Fourth, mental test scores obtained in youth might be an indicator of a well-put-together system.”
He wrote further:
“Although intelligence plays a part in health behaviours and health outcomes that contribute to specific causes of death, a clear chain of causation from intelligence to health outcomes and then to death has not emerged. Different types of mortality, including cardiovascular disease, homicide and suicide, seem to demand their own explanations for being associated with early-life intelligence. Those who found the intelligence–death association ‘obvious’ must think again.”
In the end, he asked:
“Why do we die when we do, and to what extent is this question tractable?”
Deary, I. J. Intelligence: A Very Short Introduction (Oxford Univ. Press, 2001).
