Maternal pro-inflammatory state during pregnancy and newborn leukocyte telomere length: A prospective investigation.

INTRODUCTION: Telomere biology plays a fundamental role in maintaining the integrity of the genome and cell, and shortened telomeres have been linked to several age-related diseases. The initial (newborn) telomere length (TL) represents a critically important feature of the telomere biology system. Exposure to a variety of adverse prenatal conditions such as maternal stress, suboptimal diet, obesity, and obstetric complications, is associated with shorter offspring TL at birth and in adult life. Many, if not all, of these exposures are believed to have an inflammatory component. In this context, stress-related immunological processes during pregnancy may constitute a potential additional biological pathway because they can affect telomere length and telomerase activity via transcriptions factors such as cyclic adenosine monophosphate-dependent transcription factor (ATF7) and nuclear factor-kappa B (NF-κB). Thus, in the present study we examined the hypothesis that maternal pro-inflammatory state across pregnancy, operationalized as the balance between tumor necrosis factor (TNF)-α, a major pro-inflammatory cytokine, and interleukin-10 (IL-10), the major anti-inflammatory cytokine, is associated with newborn leukocyte telomere length (LTL) at birth. METHODS AND MATERIALS: Participants were healthy women (N = 112) recruited in early pregnancy. Concentrations of TNF- α and IL-10 were quantified in early, mid and late pregnancy from maternal blood samples. Telomere length was assessed in newborn blood samples soon after birth. RESULTS: After adjusting for maternal age, maternal pre-pregnancy BMI, birth weight percentile, and infant sex, a higher mean TNF-α/IL-10 ratio across pregnancy was significantly associated with shorter newborn TL (ß = -.205, p = .030). Newborn TL was, on average, 10% shorter in offspring of women in the upper compared to lower quartile of the TNF-α/IL-10 ratio during pregnancy. DISCUSSION: These findings provide new evidence in humans for a potential "programming" mechanism linking maternal systemic pro-inflammatory processes during pregnancy with the initial (newborn) setting of her offspring's telomere system.

Telomere length and socioeconomic status at neighborhood and individual levels among 80,000 adults in the Genetic Epidemiology Research on Adult Health and Aging cohort.

BACKGROUND: Telomere length (TL) may serve as a biologic marker of aging. We examined neighborhood and individual-level socioeconomic status (SES) in relation to TL. METHODS: The study included 84,996 non-Hispanic white subjects from the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort, part of the Research Program on Genes, Environment and Health. Relative TL (T/S) was log2 transformed to improve normality and standardized to have mean 0 and variance 1. Neighborhood SES was measured using the Neighborhood Deprivation Index (NDI), and individual SES was measured by self-reported education level. We fit linear regression models of TL on age, sex, smoking, body mass index, comorbidities, NDI, and education level. We tested for differences in the associations by sex and nonlinearity in the association of NDI with TL. RESULTS: Each SD increase in NDI was associated with a decrease of 0.0192 in standardized TL, 95% confidence interval (CI) = -0.0306, -0.0078. There was no evidence of nonlinearity in the association of NDI with TL. We further found that less than high school education was associated with a decrease of 0.1371 in standardized TL, 95% CI = -0.1919, -0.0823 as compared to a college education. There were no differences in the associations by sex. CONCLUSIONS: We found evidence that both lower neighborhood SES and lower individual-level SES are associated with shorter TL among non-Hispanic whites. Our findings suggest that socioeconomic factors may influence aging by contributing to shorter TL.

Local enrichment of HP1alpha at telomeres alters their structure and regulation of telomere protection.

Enhanced telomere maintenance is evident in malignant cancers. While telomeres are thought to be inherently heterochromatic, detailed mechanisms of how epigenetic modifications impact telomere protection and structures are largely unknown in human cancers. Here we develop a molecular tethering approach to experimentally enrich heterochromatin protein HP1α specifically at telomeres. This results in increased deposition of H3K9me3 at cancer cell telomeres. Telomere extension by telomerase is attenuated, and damage-induced foci at telomeres are reduced, indicating augmentation of telomere stability. Super-resolution STORM imaging shows an unexpected increase in irregularity of telomeric structure. Telomere-tethered chromo shadow domain (CSD) mutant I165A of HP1α abrogates both the inhibition of telomere extension and the irregularity of telomeric structure, suggesting the involvement of at least one HP1α-ligand in mediating these effects. This work presents an approach to specifically manipulate the epigenetic status locally at telomeres to uncover insights into molecular mechanisms underlying telomere structural dynamics.

The Longitudinal Relationship Between Cortisol Responses to Mental Stress and Leukocyte Telomere Attrition.

Context: Chronic psychological stress has been associated with shorter telomeres, but the underlying mechanisms are poorly understood. One possibility is that the neuroendocrine responses to stress exposure are involved. Objective: To test the hypothesis that greater cortisol responsivity to acute stressors predicts more rapid telomere attrition. Design: We measured salivary cortisol responses to 2 challenging behavioral tasks. Leukocyte telomere length was measured at the time of mental stress testing and 3 years later. Participants: We studied 411 initially healthy men and women aged 54 to 76 years. Main outcome measure: Leukocyte telomere length. Results: Cortisol responses to this protocol were small; we divided participants into cortisol responders (n = 156) and nonresponders (n = 255) using a criterion (≥20% increase in cortisol concentration) previously shown to predict increases in cardiovascular disease risk. There was no significant association between cortisol responsivity and baseline telomere length, although cortisol responders tended to have somewhat shorter telomeres (ß = -0.061; standard error, 0.049). But cortisol responders had shorter telomeres and more rapid telomere attrition than nonresponders on follow-up, after controlling statistically for age, sex, socioeconomic status, smoking, time of day of stress , and baseline telomere length (ß = -0.10; standard error, 0.046; P = 0.029). The association was maintained after additional control for cardiovascular risk factors (ß = -0.11; P = 0.031). The difference between cortisol responders and nonresponders was equivalent to approximately 2 years in aging. Conclusions: These findings suggest that cortisol responsivity may mediate, in part, the relationship between psychological stress and cellular aging.

Leukocyte Telomere Length in Relation to 17 Biomarkers of Cardiovascular Disease Risk: A Cross-Sectional Study of US Adults.

BACKGROUND: Leukocyte telomere length (LTL) is a putative biological marker of immune system age, and there are demonstrated associations between LTL and cardiovascular disease. This may be due in part to the relationship of LTL with other biomarkers associated with cardiovascular disease risk. However, the strength of associations between LTL and adiposity, metabolic, proinflammatory, and cardiovascular biomarkers has not been systematically evaluated in a United States nationally representative population. METHODS AND FINDINGS: We examined associations between LTL and 17 cardiovascular biomarkers, including lipoproteins, blood sugar, circulatory pressure, proinflammatory markers, kidney function, and adiposity measures, in adults ages 20 to 84 from the cross-sectional US nationally representative 1999-2002 National Health and Nutrition Examination Survey (NHANES) (n = 7,252), statistically adjusting for immune cell type distributions. We also examine whether these associations differed systematically by age, race/ethnicity, gender, education, and income. We found that a one unit difference in the following biomarkers were associated with kilobase pair differences in LTL: BMI -0.00478 (95% CI -0.00749--0.00206), waist circumference -0.00211 (95% CI -0.00325--0.000969), percentage of body fat -0.00516 (95% CI -0.00761--0.0027), high density lipoprotein (HDL) cholesterol 0.00179 (95% CI 0.000571-0.00301), triglycerides -0.000285 (95% CI -0.000555--0.0000158), pulse rate -0.00194 (95% CI -0.00317--0.000705), C-reactive protein -0.0363 (95% CI 0.0601--0.0124), cystatin C -0.0391 (95% CI -0.0772--0.00107). When using clinical cut-points we additionally found associations between LTL and insulin resistance -0.0412 (95% CI -0.0685--0.0139), systolic blood pressure 0.0455 (95% CI 0.00137-0.0897), and diastolic blood pressure -0.0674 (95% CI -0.126--0.00889). These associations were 10%-15% greater without controlling for leukocyte cell types. There were very few differences in the associations by age, race/ethnicity, gender, education, or income. Our findings are relevant to the relationships between these cardiovascular biomarkers in the general population but not to cardiovascular disease as a clinical outcome. CONCLUSIONS: LTL is most strongly associated with adiposity, but is also associated with biomarkers across several physiological systems. LTL may thus be a predictor of cardiovascular disease through its association with multiple risk factors that are physiologically correlated with risk for development of cardiovascular disease. Our results are consistent with LTL being a biomarker of cardiovascular aging through established physiological mechanisms.

Leukocyte telomere length and mortality in the National Health and Nutrition Examination Survey, 1999-2002.

BACKGROUND: This study examined the association between leukocyte telomere length--a marker of cell aging--and mortality in a nationally representative sample of US adults ages 50-84 years. We also examined moderating effects of age, sex, race/ethnicity, and education. METHODS: Data were from the National Health and Nutrition Examination Survey, 1999-2002 (n = 3,091). Cox proportional hazards regression was used to estimate the risk of all-cause and cause- specific mortality adjusting for sociodemographic characteristics, smoking, body mass index, and chronic conditions. RESULTS: Eight hundred and seventy deaths occurred over an average of 9.5 years of follow-up. In the full sample, a decrease of 1 kilobase pair in telomere length at baseline was marginally associated with a 10% increased hazard of all-cause mortality (hazard ratio [HR]: 1.1, 95% confidence interval [CI]: 0.9, 1.4) and a 30% increased hazard of death due to diseases other than cardiovascular disease or cancer (HR: 1.3, 95% CI: 0.9, 1.9). Among African-American but not white or Mexican-American respondents, a decrease of 1 kilobase pair in telomere length at baseline was associated with a two-fold increased hazard of cardiovascular mortality (HR: 2.0, 95% CI: 1.3, 3.1). There was no association between telomere length and cancer mortality. CONCLUSIONS: The association between leukocyte telomere length and mortality differs by race/ethnicity and cause of death.

Movement-Based Behaviors and Leukocyte Telomere Length among US Adults.

INTRODUCTION: Short leukocyte telomere length (LTL) has become a hallmark characteristic of aging. Some, but not all, evidence suggests that physical activity (PA) may play an important role in attenuating age-related diseases and may provide a protective effect for telomeres. The purpose of this study was to examine the association between PA and LTL in a national sample of US adults from the National Health and Nutrition Examination Survey. METHODS: National Health and Nutrition Examination Survey data from 1999 to 2002 (n = 6503; 20-84 yr) were used. Four self-report questions related to movement-based behaviors (MBB) were assessed. The four MBB included whether individuals participated in moderate-intensity PA, vigorous-intensity PA, walking/cycling for transportation, and muscle-strengthening activities. An MBB index variable was created by summing the number of MBB an individual engaged in (range, 0-4). RESULTS: A clear dose-response relation was observed between MBB and LTL; across the LTL tertiles, respectively, the mean numbers of MBB were 1.18, 1.44, and 1.54 (Ptrend < 0.001). After adjustments (including age) and compared with those engaging in 0 MBB, those engaging in 1, 2, 3, and 4 MBB, respectively, had a 3% (P = 0.84), 24% (P = 0.02), 29% (P = 0.04), and 52% (P = 0.004) reduced odds of being in the lowest (vs highest) tertile of LTL; MBB was not associated with being in the middle (vs highest) tertile of LTL. CONCLUSIONS: Greater engagement in MBB was associated with reduced odds of being in the lowest LTL tertile.

Human telomere biology: A contributory and interactive factor in aging, disease risks, and protection.

Telomeres are the protective end-complexes at the termini of eukaryotic chromosomes. Telomere attrition can lead to potentially maladaptive cellular changes, block cell division, and interfere with tissue replenishment. Recent advances in the understanding of human disease processes have clarified the roles of telomere biology, especially in diseases of human aging and in some aging-related processes. Greater overall telomere attrition predicts mortality and aging-related diseases in inherited telomere syndrome patients, and also in general human cohorts. However, genetically caused variations in telomere maintenance either raise or lower risks and progression of cancers, in a highly cancer type-specific fashion. Telomere maintenance is determined by genetic factors and is also cumulatively shaped by nongenetic influences throughout human life; both can interact. These and other recent findings highlight both causal and potentiating roles for telomere attrition in human diseases.

Associations of cadmium and lead exposure with leukocyte telomere length: findings from National Health and Nutrition Examination Survey, 1999-2002.

Cadmium and lead are ubiquitous environmental contaminants that might increase risks of cardiovascular disease and other aging-related diseases, but their relationships with leukocyte telomere length (LTL), a marker of cellular aging, are poorly understood. In experimental studies, they have been shown to induce telomere shortening, but no epidemiologic study to date has examined their associations with LTL in the general population. We examined associations of blood lead and cadmium (n = 6,796) and urine cadmium (n = 2,093) levels with LTL among a nationally representative sample of US adults from the National Health and Nutrition Examination Survey (1999-2002). The study population geometric mean concentrations were 1.67 µg/dL (95% confidence interval (CI): 1.63, 1.70) for blood lead, 0.44 µg/L (95% CI: 0.42, 0.47) for blood cadmium, and 0.28 µg/L (95% CI: 0.27, 0.30) for urine cadmium. After adjustment for potential confounders, the highest (versus lowest) quartiles of blood and urine cadmium were associated with -5.54% (95% CI: -8.70, -2.37) and -4.50% (95% CI: -8.79, -0.20) shorter LTLs, respectively, with evidence of dose-response relationship (P for trend < 0.05). There was no association between blood lead concentration and LTL. These findings provide further evidence of physiological impacts of cadmium at environmental levels and might provide insight into biological pathways underlying cadmium toxicity and chronic disease risks.

Telomere length and the risk of atrial fibrillation: insights into the role of biological versus chronological aging.

BACKGROUND: Advanced age is the most important risk factor for atrial fibrillation (AF); however, the mechanism remains unknown. Telomeres, regions of DNA that shorten with cell division, are considered reliable markers of biological aging. We sought to examine the association between leukocyte telomere length (LTL) and incident AF in a large population-based cohort using direct LTL measurements and genetic data. To further explore our findings, we compared atrial cell telomere length and LTL in cardiac surgery patients. METHODS AND RESULTS: Mean LTL and the TERT rs2736100 single nucleotide polymorphism were assessed as predictors of incident AF in the Cardiovascular Health Study (CHS). Among the surgical patients, within subject comparison of atrial cell telomere length versus LTL was assessed. Among 1639 CHS participants, we observed no relationship between mean LTL and incident AF before and after adjustment for potential confounders (adjusted hazard ratio, 1.09; 95% confidence interval: 0.92-1.29; P=0.299); chronologic age remained strongly associated with AF in the same model. No association was observed between the TERT rs2736100 single nucleotide polymorphism and incident AF (adjusted hazard ratio: 0.95; 95% confidence interval: 0.88-1.04; P=0.265). In 35 cardiac surgery patients (26 with AF), atrial cell telomere length was longer than LTL (1.19 ± 0.20 versus 1.02 ± 0.25 [T/S ratio], P<0.001), a finding that remained consistent within the AF subgroup. CONCLUSIONS: Our study revealed no evidence of an association between LTL and incident AF and no evidence of relative atrial cell telomere shortening in AF. Chronological aging independent of biological markers of aging is the primary risk factor for AF.

An antiapoptotic role for telomerase RNA in human immune cells independent of telomere integrity or telomerase enzymatic activity.

Telomerase is a ribonucleoprotein complex that adds telomeric DNA to the ends of linear chromosomes. It contains two core canonical components: the essential RNA component, hTR, which provides the template for DNA synthesis, and the reverse transcriptase protein component, hTERT. Low telomerase activity in circulating peripheral blood mononuclear cells has been associated with a variety of diseases. It is unknown, however, whether telomerase, in addition to its long-term requirement for telomere maintenance, is also necessary for short-term immune cell proliferation and survival. We report that overexpression of enzymatically inactive hTR mutants protected against dexamethasone-induced apoptosis in stimulated CD4 T cells. Furthermore, hTR knockdown reproducibly induced apoptosis in the absence of any detectable telomere shortening or DNA damage response. In contrast, hTERT knockdown did not induce apoptosis. Strikingly, overexpression of hTERT protein caused apoptosis that was rescued by overexpression of enzymatically inactive hTR mutants. Hence, we propose that hTR can function as a noncoding RNA that protects from apoptosis independent of its function in telomerase enzymatic activity and long-term telomere maintenance in normal human immune cells. These results imply that genetic or environmental factors that alter hTR levels can directly affect immune cell function to influence health and disease.

An investigation of the effects of the core protein telomerase reverse transcriptase on Wnt signaling in breast cancer cells.

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 ß-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 ß-catenin; instead, we present evidence that anti-FLAG antibody cross-reactivity properties may explain the previously reported interaction of hTERT with ß-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.

Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study.

BACKGROUND: Telomere shortness in human beings is a prognostic marker of ageing, disease, and premature morbidity. We previously found an association between 3 months of comprehensive lifestyle changes and increased telomerase activity in human immune-system cells. We followed up participants to investigate long-term effects. METHODS: This follow-up study compared ten men and 25 external controls who had biopsy-proven low-risk prostate cancer and had chosen to undergo active surveillance. Eligible participants were enrolled between 2003 and 2007 from previous studies and selected according to the same criteria. Men in the intervention group followed a programme of comprehensive lifestyle changes (diet, activity, stress management, and social support), and the men in the control group underwent active surveillance alone. We took blood samples at 5 years and compared relative telomere length and telomerase enzymatic activity per viable cell with those at baseline, and assessed their relation to the degree of lifestyle changes. FINDINGS: Relative telomere length increased from baseline by a median of 0·06 telomere to single-copy gene ratio (T/S)units (IQR-0·05 to 0·11) in the lifestyle intervention group, but decreased in the control group (-0·03 T/S units, -0·05 to 0·03, difference p=0·03). When data from the two groups were combined, adherence to lifestyle changes was significantly associated with relative telomere length after adjustment for age and the length of follow-up (for each percentage point increase in lifestyle adherence score, T/S units increased by 0·07, 95% CI 0·02-0·12, p=0·005). At 5 years, telomerase activity had decreased from baseline by 0·25 (-2·25 to 2·23) units in the lifestyle intervention group, and by 1·08 (-3·25 to 1·86) units in the control group (p=0·64), and was not associated with adherence to lifestyle changes (relative risk 0·93, 95% CI 0·72-1·20, p=0·57). INTERPRETATION: Our comprehensive lifestyle intervention was associated with increases in relative telomere length after 5 years of follow-up, compared with controls, in this small pilot study. Larger randomised controlled trials are warranted to confirm this finding. FUNDING: US Department of Defense, NIH/NCI, Furlotti Family Foundation, Bahna Foundation, DeJoria Foundation, Walton Family Foundation, Resnick Foundation, Greenbaum Foundation, Natwin Foundation, Safeway Foundation, Prostate Cancer Foundation.

Socioeconomic status, health behavior, and leukocyte telomere length in the National Health and Nutrition Examination Survey, 1999-2002.

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.

The major reverse transcriptase-incompetent splice variant of the human telomerase protein inhibits telomerase activity but protects from apoptosis.

Human telomerase reverse transcriptase (hTERT; 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+ß- or ß-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 ß-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 ß-deletion transcript variant was associated with polyribosomes in cells. When ectopically overexpressed, ß-deletion protein competed for binding to telomerase RNA (hTR/TERC), thereby inhibiting endogenous telomerase activity. Overexpressed ß-deletion protein localized to the nucleus and mitochondria and 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 that hTERT makes multiple contributions to cancer pathophysiology.

Visualization of actin filaments and monomers in somatic cell nuclei.

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 µm(2)/s, or (2) subdiffusive, with a mobility coefficient of 0.015 µm(2)/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.

Cytomegalovirus is associated with reduced telomerase activity in the Whitehall II cohort.

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.

Cancer interception.

A common perception is that cancer risk reduction is passive, such as not smoking. However, advances in the understanding of cancer biology and in cancer treatment modalities suggest that it is now timely to consider anew cancer risk reduction by active, including pharmacologic, approaches. Risk avoidance approaches are certainly important, but other approaches are important as well, as exemplified by the irony that most new lung cancers occur in former smokers, or current avoiders. Cancer interception is the active way of combating cancer and carcinogenesis at earlier and earlier stages. A great challenge is to educate people that the development of cancers, like heart disease, typically takes years and accordingly can potentially be intercepted with risk-reducing agents in the same way that advanced cancers can be treated with drugs or that cardiovascular disease can be intercepted with antihypertensive and other risk-reducing drugs. The cancer biology behind cancer interception is increasingly solid. For example, hedgehog pathway studies of mutations in the patched homolog 1 (PTCH1) gene, which constitutively activates Smoothened (SMO), led to development of an oral SMO inhibitor active in advanced basal cell carcinoma and which, in very high-risk Gorlin syndrome patients (germ line PTCH1 mutation), is nearly completely clinically effective in intercepting basal cell neoplasia. Also, the oral immunomodulator lenalidomide, first found to be active in advanced, relapsed multiple myeloma, was highly effective in intercepting the precursor stage, high-risk smoldering multiple myeloma from progressing. These are but two exciting, recent examples of the many advances in cancer research that have created an optimal time to discover and implement cancer interception. The multifaceted roles of telomere maintenance in both fueling advanced cancers and, at early stages, keeping them at bay, also highlight how the growing knowledge of cancer biology opens avenues for cancer interception. Emerging molecular techniques, including next-generation sequencing platforms, that account for a large part of the remarkable recent advances in cancer biology are now being applied to interception of premalignancy. Keeping the medical community and public at large informed about possibilities for actively intercepting cancer will be important for gaining acceptance of this increasingly powerful approach to lessening the cancer burden.

Cumulative inflammatory load is associated with short leukocyte telomere length in the Health, Aging and Body Composition Study.

BACKGROUND: Leukocyte telomere length (LTL) is an emerging marker of biological age. Chronic inflammatory activity is commonly proposed as a promoter of biological aging in general, and of leukocyte telomere shortening in particular. In addition, senescent cells with critically short telomeres produce pro-inflammatory factors. However, in spite of the proposed causal links between inflammatory activity and LTL, there is little clinical evidence in support of their covariation and interaction. METHODOLOGY/PRINCIPAL FINDINGS: To address this issue, we examined if individuals with high levels of the systemic inflammatory markers interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and C-reactive protein (CRP) had increased odds for short LTL. Our sample included 1,962 high-functioning adults who participated in the Health, Aging and Body Composition Study (age range: 70-79 years). Logistic regression analyses indicated that individuals with high levels of either IL-6 or TNF-α had significantly higher odds for short LTL. Furthermore, individuals with high levels of both IL-6 and TNF-α had significantly higher odds for short LTL compared with those who had neither high (OR = 0.52, CI = 0.37-0.72), only IL-6 high (OR = 0.57, CI = 0.39-0.83) or only TNF-α high (OR = 0.67, CI = 0.46-0.99), adjusting for a wide variety of established risk factors and potential confounds. In contrast, CRP was not associated with LTL. CONCLUSIONS/SIGNIFICANCE: Results suggest that cumulative inflammatory load, as indexed by the combination of high levels of IL-6 and TNF-α, is associated with increased odds for short LTL. In contrast, high levels of CRP were not accompanied by short LTL in this cohort of older adults. These data provide the first large-scale demonstration of links between inflammatory markers and LTL in an older population.