Frailty and the Metabolic Syndrome - Results of the Berlin Aging Study II (BASE-II).

BACKGROUND: Frailty and the metabolic Syndrome (MetS) are frequently found in old subjects and have been associated with increased risk of functional decline and dependency. Moreover, central characteristics of the MetS like inflammation, obesity and insulin resistance have been associated with the frailty syndrome. However, the relationship between MetS and frailty has not yet been studied in detail. Aim of the current analysis within the Berlin Aging Study II (BASE-II) was to explore associations between MetS and frailty taking important co-variables such as nutrition (total energy intake, dietary vitamin D intake), physical activity and vitamin D-status into account. METHODS: Complete cross-sectional data of 1,486 old participants (50.2% women, 68.7 (65.8-71.3) years) of BASE-II were analyzed. MetS was defined following the joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity in 2009. Frailty was defined according to the Fried criteria. Limitations in physical performance were assessed via questionnaire, muscle mass was measured using dual energy X-ray absorptiometry (DXA) and grip strength using a Smedley dynamometer. Adjusted regression models were calculated to assess the association between MetS and Frailty. RESULTS: MetS was prevalent in 37.6% of the study population and 31.9% were frail or prefrail according to the here calculated frailty index. In adjusted models the odds of being frail/prefrail were increased about 50% with presence of the MetS (OR1.5; 95% CI 1.2,1.9; p= 0.002). Moreover the odds of being prefrail/frail were significantly increased with low HDL-C (OR: 1.5 (95%CI: 1.0-2.3); p = 0.037); and elevated waist circumference (OR: 1.65 (95%CI: 1.1-2.3); p = 0.008). CONCLUSION: The current analysis supports an association between MetS and frailty. There are various metabolic, immune and endocrine alterations in MetS that also play a role in mechanisms underlying the frailty syndrome. To what extent cytokine alterations, inflammatory processes, vitamin D supply and hormonal changes in age and in special metabolic states as MetS influence the development of frailty should be subject of further research.

Prevalence and definition of sarcopenia in community dwelling older people. Data from the Berlin aging study II (BASE-II).

BACKGROUND: Sarcopenia describes the age-associated loss of muscle mass, strength and function. The aim of this study was to compare the prevalence of sarcopenia in a cohort of community dwelling elderly people living in Berlin, Germany, according to the criteria proposed by current consensus statements and to study the respective impact on self-reported physical performance. MATERIAL AND METHODS: This study included 1405 participants from the Berlin aging study II (BASE-II). The appendicular skeletal muscle mass index (SMI) was assessed with dual energy X-ray absorptiometry (DXA), muscle strength was measured by hand grip strength and the timed up and go" test (TUG) was performed as a functional parameter to reflect mobility. RESULTS: The prevalence of sarcopenia was 24.3 % in terms of reduced SMI only and considerably lower for sarcopenia with reduced grip strength (4.1 %) and sarcopenia with limited mobility (2.4 %). Only 0.6 % of the participants fulfilled all three criteria. Of the subjects with a normal SMI, 8.6 % had reduced grip strength and 5.1 % had limited mobility, whereas 1.3 % subjects fulfilled both criteria. Participants with reduced strength or function reported severe difficulties in performing physical tasks significantly more often than participants with normal or reduced SMI alone (p <0.029-p <0.0001). CONCLUSION: In BASE-II low skeletal muscle mass was much more frequent than reduced grip strength or poor function. Reduced strength and function were found to be associated with a greater impact on physical performance than reduced muscle mass. Low SMI does not seem to be a prerequisite for low strength or limitations in mobility.

The clinical manifestation of a defective response to DNA double-strand breaks as exemplified by Nijmegen breakage syndrome.

The autosomal recessive genetic disorder Nijmegen breakage syndrome (NBS) was first described in 1981 in patients living in Nijmegen, Holland. NBS patients display a characteristic facial appearance, microcephaly and a range of symptoms including immunodeficiency, increased cancer risk and growth retardation. In addition, NBS patient cells were found to have elevated levels of chromosomal damage and to be sensitive to ionizing irradiation (IR). This radiosensitivity had fatal consequences in some undiagnosed patients. The most dangerous DNA lesion caused by IR is considered to be the double-strand break (DSB) and indeed, NBS patient cells are sensitive to all mutagens that produce DSBs directly or indirectly. We discuss here our current understanding of how a deficiency in DSB repair manifests as the particular symptom complex of NBS.

Genetic heterogeneity for a Nijmegen breakage-like syndrome.

Nijmegen breakage syndrome (NBS) is a rare, autosomal-recessive chromosome instability disorder characterized by growth and developmental defects, immunodeficiency, high susceptibility to lymphoid malignancies, hypersensitivity to ionizing radiation and aberrant cell-cycle checkpoint control. The disease is caused by mutations in the NBS1 gene, which encodes nibrin, a component of the hMre11-Rad50-p95 complex involved in cellular response to DNA double-strand breaks. Genetic heterogeneity has been suggested in at least two patients with the NBS phenotype, but no mutation in the NBS1 gene; recently, mutations in the gene encoding the enzyme ligase IV have been identified in patients with signs of NBS. We describe a boy with an NBS clinical phenotype but no mutation in either the NBS1 or the LIG4 genes. The analysis of his cellular phenotype reveals chromosome instability and radiosensitivity, but normal cell-cycle checkpoint control. In addition, a literature review was carried out to summarize and compare data of all NBS-like patients reported to date. This case confirms genetic heterogeneity for NBS. We believe that dissecting the clinical and cellular phenotypes of this and other NBS-like patients will provide useful information for the research of new genes involved in cellular response to DNA damage and the assessment of cancer risk in NBS-like syndrome.

Spectrum of mutations in the Fanconi anaemia group G gene, FANCG/XRCC9.

FANCG was the third Faconi anaemia gene identified and proved to be identical to the previously cloned XRCC9 gene. We present the pathogenic mutations and sequence variants we have so far identified in a panel of FA-G patients. Mutation screening was performed by PCR, single strand conformational polymorphism analysis and protein truncation tests. Altogether 18 mutations have been determined in 20 families - 97% of all expected mutant alleles. All mutation types have been found, with the exception of large deletions, the large majority is predicted to lead to shortened proteins. One stop codon mutation, E105X, has been found in several German patients and this founder mutation accounts for 44% of the mutant FANCG alleles in German FA-G patients. Comparison of clinical phenotypes shows that patients homozygous for this mutation have an earlier onset of the haematological disorder than most other FA-G patients. The mouse Fancg sequence was established in order to evaluate missense mutations. A putative missense mutation, L71P, in a possible leucine zipper motif may affect FANCG binding of FANCA and seems to be associated with a milder clinical phenotype.

Isolation of a cDNA representing the Fanconi anemia complementation group E gene.

Fanconi anemia (FA) is an autosomal recessive chromosomal instability syndrome with at least seven different complementation groups. Four FA genes (FANCA, FANCC, FANCF, and FANCG) have been identified, and two other FA genes (FANCD and FANCE) have been mapped. Here we report the identification, by complementation cloning, of the gene mutated in FA complementation group E (FANCE). FANCE has 10 exons and encodes a novel 536-amino acid protein with two potential nuclear localization signals.

Expression pattern of the Nijmegen breakage syndrome gene, Nbs1, during murine development.

The Nijmegen breakage syndrome (NBS; MIM 251260), is an autosomal recessive disease characterized by microcephaly, growth retardation, immuno-deficiency and cancer predisposition. NBS cells show spontaneous chromosomal instability and hypersensitivity to ionizing radiation in combination with radioresistant DNA synthesis. At the cellular level, NBS has some features in common with ataxia teleangiectasia. In this study the murine Nbs1 gene was used for an expression study in mouse embryos at different developmental stages as well as in adult mice. A low level of expression is observed in all tissues. Highly specific expression was observed in organs with physiologic DNA double strand breakage (DSB), such as testis, thymus and spleen. Enhanced expression is also found at sites of high proliferative activity. These are the subventricular layer of the telencephalon and the diencephalon, the liver, lung, kidney and gut, as well as striated and smooth muscle cells in various organs. In the adult cerebellum the postmitotic Purkinje cells are marked specifically. These expression patterns suggest that in addition to the role of the Nbs1 gene product as part of a DNA DSB repair complex, the Nbs1 gene product may serve further functions during development.

Genomic organization of a potential human DNA-crosslink repair gene, KIAA0086.

In the present study, we describe the genomic structure of the KIAA0086 gene and the 5'-flanking sequence. The analysis is based on the alignment of the KIAA0086 cDNA and a corresponding genomic BAC sequence which was identified in a basic BLAST similarity search using the cDNA sequence as a template. The gene contains nine exons spanning approximately 20 kb. All splice sites conform to the GT-AG rule. Analysis of the upstream untranscribed region identified one GC box but no TATA box, suggesting that the KIAA0086 gene is a housekeeping gene. The promoter region contains putative recognition sites for several transcription factors, e.g., AP1, Sp1 and NFkappaB. The homology of the KIAA0086 gene to the yeast SNM1 gene, which is involved in the cellular response to DNA-interstrand crosslinks, is discussed with respect to a possible role of the KIAA0086 gene in the human disorder, Fanconi anemia.

The Fanconi anaemia group G gene FANCG is identical with XRCC9.

Fanconi anemia (FA) is an autosomal recessive disease with diverse clinical symptoms including developmental anomalies, bone marrow failure and early occurrence of malignancies. In addition to spontaneous chromosome instability, FA cells exhibit cell cycle disturbances and hypersensitivity to cross-linking agents. Eight complementation groups (A-H) have been distinguished, each group possibly representing a distinct FA gene. The genes mutated in patients of complementation groups A (FANCA; refs 4,5) and C (FANCC; ref. 6) have been identified, and FANCD has been mapped to chromosome band 3p22-26 (ref. 7). An additional FA gene has recently been mapped to chromosome 9p (ref. 8). Here we report the identification of the gene mutated in group G, FANCG, on the basis of complementation of an FA-G cell line and the presence of pathogenic mutations in four FA-G patients. We identified the gene as human XRCC9, a gene which has been shown to complement the MMC-sensitive Chinese hamster mutant UV40, and is suspected to be involved in DNA post-replication repair or cell cycle checkpoint control. The gene is localized to chromosome band 9p13 (ref. 9), corresponding with a known localization of an FA gene.

Assessment of mitomycin C sensitivity in Fanconi anemia complementation group C gene (Fac) knock-out mouse cells.

Fanconi anemia (FA) is a genetic disorder defined by cellular hypersensitivity to DNA cross-linking agents, such as mitomycin C (MMC). MMC causes increased FA cell death, chromosome breakage, and accumulation in the G2 phase of the cell cycle. Recently, Fanconi anemia complementation group C (fac) gene knock-out mice have been developed, and SV40-transformed fibroblasts were established from fac homozygous knock-out (-/-), heterozygous (+/-), and wild-type mice (+/+). MMC sensitivity of these cell lines was assessed by three methods: colony-formation assay in the presence of MMC, chromosome breakage, and cell cycle analysis to detect G2 phase arrest. The fac knock-out fibroblasts (-/-) showed a significantly higher sensitivity to MMC than did fibroblasts from wild-type (+/+) or heterozygous (+/-) mice (three experiments). In addition, we analyzed hematopoietic progenitor colony assays of bone marrow cells from fac knock-out (-/-) and heterozygous (+/-) mice. CFU-E, BFU-E, and CFU-GM colony formation from fac nullizygous mouse progenitors was markedly diminished by MMC when compared to growth of progenitors from heterozygous mice. These results show that fac knock-out mouse cells mimic the behavior of human FA-C patient cells in terms of MMC hypersensitivity. The fac knock-out mouse may be used to model some aspects of human FA and should be useful for understanding the function of the FAC protein.