Using molecular similarity to discover bioactive small molecules with novel chemical scaffolds can be computationally demanding. We describe Ultra-fast Shape Recognition with Atom Types (UFSRAT), an efficient algorithm that considers both the 3D distribution (shape) and electrostatics of atoms to score and retrieve molecules capable of making similar interactions to those of the supplied query.
Computational optimization and pre-calculation of molecular descriptors enables a query molecule to be run against a database containing 3.8 million molecules and results returned in under 10 seconds on modest hardware. UFSRAT has been used in pipelines to identify bioactive molecules for two clinically relevant drug targets; FK506-Binding Protein 12 and 11β-hydroxysteroid dehydrogenase type 1. In the case of FK506-Binding Protein 12, UFSRAT was used as the first step in a structure-based virtual screening pipeline, yielding many actives, of which the most active shows a KD, app of 281 µM and contains a substructure present in the query compound. Success was also achieved running solely the UFSRAT technique to identify new actives for 11β-hydroxysteroid dehydrogenase type 1, for which the most active displays an IC50 of 67 nM in a cell based assay and contains a substructure radically different to the query. This demonstrates the valuable ability of the UFSRAT algorithm to perform scaffold hops.
Availability and Implementation
A web-based implementation of the algorithm is freely available at http://opus.bch.ed.ac.uk/ufsrat/.
Telomeres play a central role in cellular aging, and shorter telomere length has been associated with age-related disorders including diabetes. However, a causal link between telomere shortening and diabetes risk has not been established. In a well-characterized longitudinal cohort of American Indians participating in the Strong Heart Family Study, we examined whether leukocyte telomere length (LTL) at baseline predicts incident diabetes independent of known diabetes risk factors. Among 2,328 participants free of diabetes at baseline, 292 subjects developed diabetes during an average 5.5 years of follow-up. Compared with subjects in the highest quartile (longest) of LTL, those in the lowest quartile (shortest) had an almost twofold increased risk of incident diabetes (hazard ratio [HR] 1.83 [95% CI 1.26–2.66]), whereas the risk for those in the second (HR 0.87 [95% CI 0.59–1.29]) and the third (HR 0.95 [95% CI 0.65–1.38]) quartiles was statistically nonsignificant. These findings suggest a nonlinear association between LTL and incident diabetes and indicate that LTL could serve as a predictive marker for diabetes development in American Indians, who suffer from disproportionately high rates of diabetes.
The spatiotemporal organization and dynamics of chromatin play critical roles in regulating genome function. However, visualizing specific, endogenous genomic loci remains challenging in living cells. Here, we demonstrate such an imaging technique by repurposing the bacterial CRISPR/Cas system. Using an EGFP-tagged endonuclease-deficient Cas9 protein and a structurally optimized small guide (sg) RNA, we show robust imaging of repetitive elements in telomeres and coding genes in living cells. Furthermore, an array of sgRNAs tiling along the target locus enables the visualization of non-repetitive genomic sequences. Using this method, we have studied telomere dynamics during elongation or disruption, the subnuclear localization of the MUC4 loci, the cohesion of replicated MUC4 loci on sister chromatids, and their dynamic behaviors during mitosis. This CRISPR imaging tool has potential to significantly improve the capacity to study the conformation and dynamics of native chromosomes in living human cells.
We tested whether leukocyte telomere length maintenance, which underlies healthy cellular aging, provides a link between sugar-sweetened beverage (SSB) consumption and risk of cardiometabolic disease. We examined cross-sectional associations between consumption of SSBs, diet soda and fruit juice and telomere length in a nationally representative sample of healthy adults.
The study population included 5,309 adults, aged 20 to 65 years, with no prior history of diabetes or cardiovascular disease, from the 1999–2002 National Health and Nutrition Examination Surveys. Leukocyte telomere length was assayed from DNA specimens. Diet was assessed using 24-hour dietary recalls. Associations were examined using multivariate linear regression for the outcome of log-transformed telomere length.
After adjustment for sociodemographic and health-related characteristics, sugar-sweetened soda consumption was associated with shorter telomeres (β=−0.010, 95% CI −0.020, −0.001, P=0.04). Consumption of 100% fruit juice was marginally associated with longer telomeres (β= 0.016, 95% CI −0.000, 0.033). No significant associations were observed between consumption of diet sodas or non-carbonated sugar-sweetened beverages and telomere length.
Regular consumption of sugar-sweetened sodas may influence metabolic disease development through accelerated cell aging.
Studies in humans suggest that leukocyte telomere length may act as a marker of biological aging. We investigated whether individuals in the Nicoya region of Costa Rica, known for exceptional longevity, had longer telomere length than those in other parts of the country. After controlling for age, age squared, rurality, rainy season and gender, mean leukocyte telomere length in Nicoya was substantially longer (81 base pairs, p<0.05) than in other areas of Costa Rica, providing evidence of a biological pathway to which this notable longevity may be related. This relationship remains unchanged (79 base pairs, p<0.05) after statistically controlling for nineteen potential biological, dietary and social and demographic mediators. Thus the difference in mean leukocyte telomere length that characterizes this unique region does not appear to be explainable by traditional behavioral and biological risk factors. More detailed examination of mean leukocyte telomere length by age shows that the regional telomere length difference declines at older ages.
telomere length; Costa Rica; aging; biomarkers; socioeconomic; longevity
Peripheral blood leukocyte telomere length is increasingly being used as a biomarker of aging, but its natural variation in human populations is not well understood. Several other biomarkers show seasonal variation, as do several determinants of leukocyte telomere length. We examined whether there was monthly variation in leukocyte telomere length in Costa Rica, a country with strong seasonal differences in precipitation and infection.
We examined a longitudinal population based cohort of 581 Costa Rican adults age 60 and above, from which blood samples were drawn between October 2006 and July 2008. Leukocyte telomere length was assayed from these samples using the quantitative PCR method. Multivariate regression models were used to examine correlations between month of blood draw and leukocyte telomere length.
Telomere length from peripheral blood leukocytes varied by as much as 200 base pairs depending on month of blood draw, and this difference is not likely to be due to random variation. A moderate proportion of this association is statistically accounted for by month and region specific average rainfall. We found shorter telomere length associated with greater rainfall.
There are two possible explanations of our findings. First, there could be relatively rapid month-to-month changes in leukocyte telomere length. This conclusion would have implications for understanding the natural population dynamics of telomere length. Second, there could be seasonal differences in constituent cell populations. This conclusion would suggest that future studies of leukocyte telomere length use methods to account for the potential impact of constituent cell type.
telomere length; seasonality; lymphocytes; infection; rainfall
Telomerase canonically maintains telomeres, but recent reports have suggested that the core protein mammalian telomerase reverse transcriptase (TERT) component, together with the chromatin remodeling factor BRG1 and β-catenin, may also bind to and promote expression of Wnt target genes. However, this proposed noncanonical role of TERT in Wnt signaling has been controversial. Here, we investigated the effects of human TERT (hTERT) on Wnt signaling in human breast cancer lines and HeLa cells. We failed to find evidence for physical association of hTERT with BRG1 or β-catenin; instead, we present evidence that anti-FLAG antibody cross-reactivity properties may explain the previously reported interaction of hTERT with β-catenin. Furthermore, altering hTERT levels in four different breast cancer cell lines caused minimal and discordant effects on Wnt target and Wnt pathway gene expression. Although hTERT's role in Wnt signaling was addressed only indirectly, no significant representation of Wnt target genes was detected in chromatin immunoprecipitation-sequencing (ChIP-seq) and chromatin isolation by RNA purification and sequencing (ChIRP-seq) loci cooccupied in HeLa S3 cells by both BRG1 and hTR. In summary, our evidence fails to support the idea of a biologically consistent hTERT interaction with the Wnt pathway in human breast cancer cells, and any detectable influence of hTERT depended on cell type and experimental system.
hTERT (TERT), the catalytic protein subunit of telomerase, is subjected to numerous alternative splicing events, but the regulation and function of these splice variants is obscure. Full-length hTERT includes conserved domains that encode reverse transcriptase activity, RNA binding and other functions. The major splice variant termed α+β− or β-deletion is highly expressed in stem and cancer cells, where it codes for a truncated protein lacking most of the reverse transcriptase domain but retaining the known RNA binding motifs. In a breast cancer cell panel, we found that β-deletion was the hTERT transcript that was most highly expressed. Splicing of this transcript was controlled by the splice regulators SRSF11, HNRNPH2 and HNRNPL and the β-deletion transcript variant was associated with polyribosomes in cells. When ectopically overexpressed, β-deletion protein competed for binding to hTR (TERC) RNA, thereby inhibiting endogenous telomerase activity. Overexpressed β-deletion protein localized to the nucleus and mitochondria and it protected breast cancer cells from cisplatin-induced apoptosis. Our results reveal that a major hTERT splice variant can confer a growth advantage to cancer cells independent of telomere maintenance, suggesting hTERT makes multiple contributions to cancer pathophysiology.
Telomerase; hTERT; alternative splicing; apoptosis; breast cancer cells
The purpose of this study was to examine the association between socioeconomic status (SES) and leukocyte telomere length (LTL) – a marker of cell aging that has been linked to stressful life circumstances – in a nationally representative, socioeconomically and ethnically diverse sample of US adults aged 20–84. Using data from the National Health and Nutrition Examination Survey (NHANES), 1999–2002, we found that respondents who completed less than a high school education had significantly shorter telomeres than those who graduated from college. Income was not associated with LTL. African-Americans had significantly longer telomeres than whites, but there were no significant racial/ethnic differences in the association between education and telomere length. Finally, we found that the association between education and LTL was partially mediated by smoking and body mass index but not by drinking or sedentary behavior.
socioeconomic status; cell aging; telomere length; health behavior; United States
Shorter leukocyte telomere length (LTL) has been associated with a wide range of age-related disorders including cardiovascular disease (CVD) and diabetes. Obesity is an important risk factor for CVD and diabetes. The association of LTL with obesity is not well understood. This study for the first time examines the association of LTL with obesity indices including body mass index, waist circumference, percent body fat, waist-to-hip ratio, and waist-to-height ratio in 3,256 American Indians (14-93 years old, 60% women) participating in the Strong Heart Family Study. Association of LTL with each adiposity index was examined using multivariate generalized linear mixed model, adjusting for chronological age, sex, study center, education, lifestyle (smoking, alcohol consumption, and total energy intake), high-sensitivity C-reactive protein, hypertension and diabetes. Results show that obese participants had significantly shorter LTL than non-obese individuals (age-adjusted P=0.0002). Multivariate analyses demonstrate that LTL was significantly and inversely associated with all of the studied obesity parameters. Our results may shed light on the potential role of biological aging in pathogenesis of obesity and its comorbidities.
obesity; Leukocyte telomere length; American Indians; strong heart family study
Short leukocyte telomere length (LTL) has been associated with atherosclerosis in cross-sectional studies, but the prospective relationship between telomere shortening and risk of developing carotid atherosclerosis has not been well-established. This study examines whether LTL at baseline predicts incidence and progression of carotid atherosclerosis in American Indians in the Strong Heart Study. The analysis included 2,819 participants who were free of overt cardiovascular disease at baseline (2001-2003) and were followed through the end of 2006-2009 (average 5.5-yr follow-up). Discrete atherosclerotic plaque was defined as focal protrusion with an arterial wall thickness ≥50% the surrounding wall. Carotid progression was defined as having a higher plaque score at the end of study follow-up compared to baseline. Associations of LTL with incidence and progression of carotid plaque were examined using Cox proportional hazard regression, adjusting for standard coronary risk factors. Compared to participants in the highest LTL tertile, those in the lowest tertile had significantly elevated risk for both incident plaque (HR, 1.49; 95% CI, 1.09–2.03) and plaque progression (HR, 1.61; 95% CI, 1.26–2.07). Our results provide initial evidence for a potential prognostic utility of LTL in risk prediction for atherosclerosis.
leukocyte telomere length; carotid atherosclerosis; risk prediction; American Indians; Strong Heart Study
Telomere length and telomerase activity have received increased attention
as markers of cellular aging, but the determinants of inter-individual variation
in these markers are incompletely understood. Cytomegalovirus (CMV) infection
may be particularly important for telomere and telomerase dynamics due to its
dramatic impact on peripheral blood lymphocyte composition, i.e., increasing the
number and proportions of highly differentiated T cells that are characterized
by shorter telomere length (TL) and lowered telomerase activity (TA). However,
the possible relationship between CMV infection and leukocyte TL and TA has not
been well-examined in vivo. This study examined the
associations of CMV seropositivity and CMV IgG antibodies with leukocyte (TL)
and (TA) in a sample of 434 healthy individuals (ages 53–76) from the
Whitehall II cohort. Positive CMV serostatus was significantly associated with
lower TA among women, and higher CMV IgG antibody levels were associated with
lower TA in the overall sample. However, neither CMV seropositivity nor CMV IgG
antibody levels (reflecting subclinical reactivation) among the seropositive
were significantly associated with TL. These associations were robust to
adjustment for age, employment grade, BMI, and smoking status. The results
demonstrate that CMV seropositivity and subclinical reactivation predict lower TA. Future longitudinal studies should test whether the association of CMV
with lower TA contributes to accelerated telomere shortening over time.
telomeres; telomerase; cytomegalovirus; infections; Whitehall II
Short telomere length, a marker of biological aging, has been associated with age-related metabolic disorders. Telomere attrition induces profound metabolic dysfunction in animal models, but no study has examined the metabolome of telomeric aging in human. Here we studied 423 apparently healthy American Indians participating in the Strong Family Heart Study. Leukocyte telomere length (LTL) was measured by qPCR. Metabolites in fasting plasma were detected by untargeted LC/MS. Associations of LTL with each metabolite and their combined effects were examined using generalized estimating equation adjusting for chronological age and other aging-related factors. Multiple testing was corrected using the q-value method (q<0.05). Of the 1,364 distinct m/z features detected, nineteen metabolites in the classes of glycerophosphoethanolamines, glycerophosphocholines, glycerolipids, bile acids, isoprenoids, fatty amides, or L-carnitine ester were significantly associated with LTL, independent of chronological age and other aging-related factors. Participants with longer (top tertile) and shorter (bottom tertile) LTL were clearly separated into distinct groups using a multi-marker score comprising of all these metabolites, suggesting that these newly detected metabolites could be novel metabolic markers of biological aging. This is the first study to interrogate the human metabolome of telomeric aging. Our results provide initial evidence for a metabolic control of LTL and may reveal previously undescribed new roles of various lipids in the aging process.
metabolic profiles; metabolomics; telomeric age; telomere length; American Indians
Shorter telomeres have been associated with poor health behaviors, age-related diseases, and early mortality. Telomere length is regulated by the enzyme telomerase, and is linked to exposure to proinflammatory cytokines and oxidative stress. In our recent randomized controlled trial, omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation lowered the concentration of serum proinflammatory cytokines. This study assessed whether n-3 PUFA supplementation also affected leukocyte telomere length, telomerase, and oxidative stress. In addition to testing for group differences, changes in the continuous n-6:n-3 PUFA ratio were assessed to account for individual differences in adherence, absorption, and metabolism. The double-blind 4-month trial included 106 healthy sedentary overweight middle-aged and older adults who received (1) 2.5 g/day n-3 PUFAs, (2) l.25 g/day n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Supplementation significantly lowered oxidative stress as measured by F2-isoprostanes (p=0.02). The estimated geometric mean log-F2-isoprostanes values were 15% lower in the two supplemented groups compared to placebo. Although group differences for telomerase and telomere length were nonsignificant, changes in the n-6:n-3 PUFA plasma ratios helped clarify the intervention’s impact: telomere length increased with decreasing n-6:n-3 ratios, p=0.02. The data suggest that lower n-6:n-3 PUFA ratios can impact cell aging. The triad of inflammation, oxidative stress, and immune cell aging represents important pre-disease mechanisms that may be ameliorated through nutritional interventions. This translational research broadens our understanding of the potential impact of the n-6:n-3 PUFA balance. ClinicalTrials.gov identifier: NCT00385723
omega-3; omega-6; telomeres; inflammation; cell aging; nutritional neuroscience; oxidative stress; F2-isoprostanes; fish oil
In adults, one of the major determinants of leukocyte telomere length (LTL), a predictor of age-related diseases and mortality, is cumulative psychosocial stress exposure. More recently we reported that exposure to maternal psychosocial stress during intrauterine life is associated with LTL in young adulthood. The objective of the present study was to determine how early in life this effect of stress on LTL is apparent by quantifying the association of maternal psychosocial stress during pregnancy with newborn telomere length.
In a prospective study of N = 27 mother-newborn dyads maternal pregnancy-specific stress was assessed in early gestation and cord blood peripheral blood mononuclear cells were subsequently collected and analyzed for LTL measurement.
After accounting for the effects of potential determinants of newborn LTL (gestational age at birth, weight, sex, and exposure to antepartum obstetric complications), there was a significant, independent, linear effect of pregnancy-specific stress on newborn LTL that accounted for 25% of the variance in adjusted LTL (β = −0.099; P = .04).
Our finding provides the first preliminary evidence in human beings that maternal psychological stress during pregnancy may exert a “programming” effect on the developing telomere biology system that is already apparent at birth, as reflected by the setting of newborn LTL.
fetal/developmental programming of health and disease risk; maternal psychosocial stress; newborn telomere biology
Morbidity and mortality are greater among socially disadvantaged racial/ethnic groups and those of lower socioeconomic status (SES). Greater chronic stress exposure in disadvantaged groups may contribute to this by accelerating cellular aging, indexed by shorter age-adjusted telomere length. While studies consistently relate shorter leukocyte telomere length (LTL) to stress, the few studies, mostly from the UK, examining associations of LTL with SES have been mixed. The current study examined associations between educational attainment and LTL among 2,599 high-functioning black and white adults age 70-79 from the Health, Aging and Body Composition Study. Multiple regression analyses tested associations of race/ethnicity, educational attainment and income with LTL, adjusting for potential confounders. Those with only a high school education had significantly shorter mean LTL (4806 basepairs) than those with post-high school education (4926 basepairs; B=125, SE= 47.6, p = .009). A significant interaction of race and education (B = 207.8, SE = 98.7, p = .035) revealed more beneficial effects of post-high school education for blacks than for whites. Smokers had shorter LTL than non-smokers, but the association of education and LTL remained significant when smoking was covaried (B = 119.7, SE = 47.6, p = .012). While higher income was associated with longer LTL, the effect was not significant (p > .10). This study provides the first demonstration of an association between educational attainment and LTL in a US population where higher education appears to have a protective effect against telomere shortening, particularly in blacks.
Socioeconomic status; education; telomere length; race; health disparities
The enzyme telomerase lengthens telomeres—protective structures containing repetitive DNA sequences at chromosome ends. Telomere shortening is associated with diseases of ageing in mammals. Chronic stress has been related to shorter immune-cell telomeres, but telomerase activity under stress may be low, permitting telomere loss, or high, partially attenuating it. We developed an experimental model to examine the impacts of extended unpredictable stress on telomerase activity in male rats. Telomerase activity was 54 per cent higher in stressed rats than in controls, and associated with stress-related physiological and behavioural outcomes. This significant increase suggests a potential mechanism for resilience to stress-related replicative senescence.
chronic stress; telomere; telomerase; ageing; resilience
Major depressive disorder (MDD) has been associated with reduced leukocyte telomere length (LTL). It is not known, however, whether psychosocial and behavioral protective factors moderate this association. In the current study, we examine whether multisystem resiliency – defined by healthy emotion regulation, strong social connections, and health behaviors (sleep and exercise) – predicts LTL and mitigates previously demonstrated associations between depression diagnosis and LTL. LTL was measured, using a quantitative PCR assay, in 954 patients with stable cardiovascular disease in the Heart and Soul Study. In a fully adjusted model, high multisystem resiliency predicted longer LTL (b = 80.00, SE = 27.17, p = .003), whereas each individual factor did not. Multisystem resiliency significantly moderated the MDD-LTL association (p = .02). Specifically, MDD was significantly related to LTL at 1 SD below the mean of multisystem resiliency (b = −142.86, SE = 56.46, p = .01), but not at 1 SD above the mean (b = 49.07, SE = 74.51, p = .51). This study suggests that MDD associations with biological outcomes should be examined within a psychosocial–behavioral context, because this context shapes the nature of the direct relationship. Further research should explore the cognitive, neural, and other physiological pathways through which multisystem resiliency may confer biological benefit.
Major depressive disorder; Telomeres; Cell aging; Resiliency; Social connections; Emotion regulation; Physical activity
Telomere attrition is a novel risk factor for cardiovascular disease. Studies of telomere length in relation to kidney function are limited. We explored the association of kidney function with telomere length and telomere shortening.
The Heart and Soul study is a longitudinal study of patients with stable coronary heart disease (CHD). Measures of baseline kidney function included: serum creatinine, creatinine-derived estimated glomerular filtration rate (eGFRCKD-EPI), 24-hour urine measured creatinine clearance, cystatin C, cystatin C-derived estimated glomerular filtration rate (eGFRcys) and urine albumin to creatinine ratio. Telomere length was measured from peripheral blood leukocytes at baseline (N=954) and 5 years later (N=608). Linear regression models were used to test the association of kidney function with i) baseline telomere length and ii) change in telomere length over 5 years.
At baseline, mean eGFRCKD-EPI was 72.6 (± 21.5) ml/min/1.73 m2, eGFRcys was 71.0 (± 23.1) ml/min/1.73 m2 and ACR was 8.6 (±12.3) mg/gm. Only lower baseline eGFRCKD-EPI was associated with shorter baseline telomere length (9.1 [95% CI 1.2–16.9] fewer base pairs for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). Lower baseline eGFRCKD-EPI (and all other measures of kidney function) predicted more rapid telomere shortening (10.8 [95% CI 4.3–17.3] decrease in base pairs over 5 years for every 5 ml/min/1.73 m2 lower eGFRCKD-EPI). After adjustment for age, these associations were no longer statistically significant.
In patients with CHD, reduced kidney function is associated with i) shorter baseline telomere length and ii) more rapid telomere shortening over 5 years, however these associations are entirely explained by older age.
kidney; CKD; telomere
Obesity and shorter telomeres are commonly associated with elevated risk for age-related diseases and mortality. Whether telomere length (TL) may be associated with obesity or variations in adiposity is not well established. Therefore, we set out to test the hypothesis that TL may be a risk factor for increased adiposity using data from a large population-based cohort study.
Levels of adiposity were assessed in 6 ways (obesity status, body mass index or BMI, the percentage of body fat or % body fat, leptin, visceral and subcutaneous fat mass) in 2,721 elderly subjects (42% black and 58% white). Associations between TL measured in leukocytes at baseline and adiposity traits measured at baseline and 3 of these traits after 7 years of follow-up were tested using regression models adjusting for important covariates. Additionally, we look at weight changes and relative changes in BMI and % body fat between baseline and follow-up.
At baseline, TL was negatively associated with % body fat (β = −0.35 ± 0.09, p = 0.001) and subcutaneous fat (β = −2.66 ± 1.07, p = 0.01), and positively associated with leptin after adjusting for % body fat (β = 0.32 ± 0.14, p = 0.001), but not with obesity, BMI or visceral fat. Prospective analyses showed that longer TL was associated with positive percent change between baseline and 7-year follow-up for both BMI (β = 0.48 ± 0.20, p = 0.01) and % body fat (β = 0.42 ± 0.23, p = 0.05).
Our study suggests that shorter TL may be a risk factor for increased adiposity. Coupling with previous reports on their reversed roles, the relationship between adiposity and TL may be complicated and warrant more prospective studies.
Obesity; telomere length; adiposity; telomeres
Telomeres play a central role in cellular senescence and are associated with a variety of age-related disorders such as dementia, Alzheimer's disease and atherosclerosis. Telomere length varies greatly among individuals of the same age, and is heritable. Here we performed a genome-wide linkage scan to identify quantitative trait loci (QTL) influencing leukocyte telomere length (LTL) measured by quantitative PCR in 3,665 American Indians (aged 14 – 93 years) from 94 large, multi-generational families. All participants were recruited by the Strong Heart Family Study (SHFS), a prospective study to identify genetic factors for cardiovascular disease and its risk factors in American Indians residing in Oklahoma, Arizona and Dakota. LTL heritability was estimated to be between 51% and 62%, suggesting a strong genetic predisposition to interindividual variation of LTL in this population. Significant QTLs were localized to chromosome 13 (Logarithm of odds score (LOD) = 3.9) at 13q12.11, to 18q22.2 (LOD = 3.2) and to 3p14.1 (LOD = 3.0) for Oklahoma. This is the first study to identify susceptibility loci influencing leukocyte telomere variation in American Indians, a minority group suffering from a disproportionately high rate of type 2 diabetes and other age-related disorders.
leukocyte telomere length; genome-wide linkage scan; quantitative trait loci; American Indians
Fluorescent nuclear actin reporters are used to determine the distribution of nuclear actin in live somatic cells and evaluate its potential functions. They reveal distinct monomeric and filamentous actin populations in nuclei of live somatic cells and implicate nuclear actin in mRNA processing and organization of the nucleoplasm.
In addition to its long-studied presence in the cytoplasm, actin is also found in the nuclei of eukaryotic cells. The function and form (monomer, filament, or noncanonical oligomer) of nuclear actin are hotly debated, and its localization and dynamics are largely unknown. To determine the distribution of nuclear actin in live somatic cells and evaluate its potential functions, we constructed and validated fluorescent nuclear actin probes. Monomeric actin probes concentrate in nuclear speckles, suggesting an interaction of monomers with RNA-processing factors. Filamentous actin probes recognize discrete structures with submicron lengths that are excluded from chromatin-rich regions. In time-lapse movies, these actin filament structures exhibit one of two types of mobility: 1) diffusive, with an average diffusion coefficient of 0.06–0.08 μm2/s, or (2) subdiffusive, with a mobility coefficient of 0.015 μm2/s. Individual filament trajectories exhibit features of particles moving within a viscoelastic mesh. The small size of nuclear actin filaments is inconsistent with a role in micron-scale intranuclear transport, and their localization suggests that they do not participate directly in chromatin-based processes. Our results instead suggest that actin filaments form part of a large, viscoelastic structure in the nucleoplasm and may act as scaffolds that help organize nuclear contents.
RNA is an essential component of telomerase. It plays roles in the polymerization cycle that replicates telomeric DNA repeats and recruits proteins involved in telomere regulation.
Telomerase is a eukaryotic ribonucleoprotein (RNP) whose specialized reverse transcriptase action performs de novo synthesis of one strand of telomeric DNA. The resulting telomerase-mediated elongation of telomeres, which are the protective end-caps for eukaryotic chromosomes, counterbalances the inevitable attrition from incomplete DNA replication and nuclease action. The telomerase strategy to maintain telomeres is deeply conserved among eukaryotes, yet the RNA component of telomerase, which carries the built-in template for telomeric DNA repeat synthesis, has evolutionarily diverse size and sequence. Telomerase shows a distribution of labor between RNA and protein in aspects of the polymerization reaction. This article first describes the underlying conservation of a core set of structural features of telomerase RNAs important for the fundamental polymerase activity of telomerase. These include a pseudoknot-plus-template domain and at least one other RNA structural motif separate from the template-containing domain. The principles driving the diversity of telomerase RNAs are then explored. Much of the diversification of telomerase RNAs has come from apparent gain-of-function elaborations, through inferred evolutionary acquisitions of various RNA motifs used for telomerase RNP biogenesis, cellular trafficking of enzyme components, and regulation of telomerase action at telomeres. Telomerase offers broadly applicable insights into the interplay of protein and RNA functions in the context of an RNP enzyme.
Chronic psychological stressis a risk factor formultiple diseases of aging. Accelerated cellular aging as indexed by short telomere length has emerged as a potential common biological mechanism linking various forms of psychological stress and diseases of aging. Stress appraisals determine the degree and type of biological stress responses and altered stress appraisals may be a common psychological mechanism linking psychological stress and diseases of aging. However, no previous studies have examined the relationship between stress appraisals and telomere length. We exposed chronically stressed female caregivers and non-caregiving controls (N= 50; M age = 62.14±6.10) to a standardized acute laboratory stressor and measured their anticipatory and retrospective threat and challenge appraisals of the stressor. We hypothesized that threat and challenge appraisals would be associated with shorter and longer telomere length respectively, and that chronic care giving stress would influence telomere length through altered stress appraisals. Higher anticipatory threat appraisals were associated with shorter age-adjusted telomere length (β = −.32, p = .03), but challenge appraisals and retrospective threat appraisals showed no independent association with telomere length. Caregivers reported significantly higher anticipatory (β = −.36, p = .006)and retrospective (β = −.29, p = .03) threat appraisals than controls, but similar challenge appraisals. Although there was no significant main effect of caregiver status on telomere length, care giving had a significant indirect effect on telomere length through anticipatory threat appraisals. Exaggerated anticipatory threat appraisals may be a common and modifiable psychological mechanism of psychological stress effects on cellular aging.
cellular aging; challenge; chronic stress; stress appraisals; threat; telomere length