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Study Question: Could sperm and leukocyte telomere length (TL) be associated with sperm quality parameters and reproductive health in men from the general population?, Summary Answer: A positive association between sperm and leukocyte TL with sperm concentration and total count has been demonstrated., What Is Known Already: Male factors account for almost half of cases of couple infertility, and shorter TLs have been observed in sperm from men with impaired sperm parameters. However, evidence in men from the general population is limited., Study Design Size Duration: A total of 200 volunteers of reproductive age were recruited between February 2021 and April 2023 to participate in the Lifestyle and Environmental Determinants of Seminogram and Other Male Fertility-Related Parameters (Led-Fertyl) cross-sectional study., Participants/materials Setting Methods: TLs in sperm and leukocytes were measured using quantitative polymerase chain reaction (qPCR) in 168 and 194 participants, respectively. Sperm parameters, including concentration, total count, motility, vitality, and morphology, were analyzed using a computer-assisted sperm analysis (CASA) SCA ® system according to the World Health Organization (WHO) 2010 guidelines. Multivariable regression models were performed to assess the associations between sperm and leukocyte TL, either in tertiles or as continuous variables, and sperm quality parameters while adjusting for potential confounders., Main Results and the Role of Chance: Participants in tertiles 2 (T2) and 3 (T3) of sperm TL showed a higher sperm concentration (β: 1.09; 95% CI: 0.09-2.09 and β: 2.06; 95% CI: 1.04-3.09 for T2 and T3, respectively; P -trend < 0.001), compared to those in the reference tertile (T1). Participants in the highest tertile of sperm TL showed higher total sperm count (β: 3.83; 95% CI: 2.08-5.58 for T3 vs T1; P -trend < 0.001). Participants in the top tertile of leukocyte TL showed higher sperm concentration (β: 1.49; 95% CI: 0.44-2.54 for T3 vs T1; P -trend = 0.004), and total count (β: 3.49; 95% CI: 1.62-5.35 for T3 vs T1; P -trend < 0.001) compared with participants in T1. These results remained consistent when sperm and leukocyte TL were modelled as continuous variables., Limitations Reasons for Caution: One limitation is the impossibility of establishing a cause-effect relationship due to the cross-sectional study design. Additionally, the sample size of the study cannot be considered large., Wider Implications of the Findings: Sperm and leukocyte TLs are associated with sperm quality parameters in the general population. Additional determinations and further studies with larger sample sizes are needed to clarify the mechanisms underlying these associations and to investigate the further implications., Study Funding/competing Interests: The Led-Fertyl study was supported by the Spanish government's official funding agency for biomedical research, Instituto de Salud Carlos III (ISCIII), through the Fondo de Investigación para la Salud (FIS) and co-funded by the European Union ERDF/ESF, 'A way to make Europe'/'Investing in your future' (PI21/01447), and the Diputació de Tarragona (2021/11-No.Exp. 8004330008-2021-0022642). J.S.-S., senior author of the present study, is partially supported by ICREA under the ICREA Academia program. M.F.d.l.P. was supported by a predoctoral grant from the Rovira i Virgili University and Diputació de Tarragona (2020-PMF-PIPF-8). C.V.-H. received a predoctoral grant from the Generalitat de Catalunya (2022 FI&#95;B100108). M.Á.M. was supported by the Sara Borrell postdoctoral fellowship (CD21/00045-Instituto de Salud Carlos III (ISCIII)). All authors declare that they have no conflicts of interest., Trial Registration Number: N/A., Competing Interests: All authors declare that they have no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: Cognitive decline, a common process of brain ageing, has been associated with telomere length (TL). Delving into the identification of reliable biomarkers of brain ageing is essential to prevent accelerated cognitive impairment., Methods: We selected 317 non-smoking 'Prevención con Dieta Mediterránea-Plus' (PREDIMED-Plus) participants (mean age, 65.8 ± 5.0 years) with metabolic syndrome from two trial centres who were following a lifestyle intervention. We measured TL and cognitive function at baseline and after 3 and 4 years of follow-up, respectively. Associations between baseline or 3-year changes in TL and baseline or 4-year changes in cognitive function were analysed using multivariable regression models., Results: Baseline TL was not associated with baseline cognitive performance. Nevertheless, longer baseline TL was associated with improved 4-year changes in the Executive Function domain (β: 0.29; 95%CI: 0.12 to 0.44; P < 0.001) and the Global Cognitive Function domain (β: 0.19; 95%CI: 0.05 to 0.34; P = 0.010). Besides, a positive association was found between longer baseline TL and improved 4-year changes in the animal version of the Verbal Fluency Test (β: 0.33; 95%CI: 0.12 to 0.52; P = 0.002). By contrast, 3-year changes in TL were not associated with changes in cognitive function after 4 years., Conclusions: Longer baseline TL could protect from cognitive decline and be used as a useful biomarker of brain ageing function in an older Mediterranean population at risk of cardiovascular disease and cognitive impairment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Scope: The rosehip (Rosa canina) is a perennial shrub with a reddish pseudofruit that has demonstrated antidiabetic, antiatherosclerotic, and antiobesogenic effects in rodent models but there is low information about the molecular mechanisms underlying these effects on the onset and progression of diet-induced obesity., Methods and Results: Four-week-old C57BL/6J male mice are subjected to a high-fat diet (HFD)-supplemented or not with R. canina flesh for 18 weeks. The results indicated that the R. canina flesh exerts a preventive effect on HFD-induced obesity with a significant reduction in body-weight gain and an improvement of hyperglycemia and insulin resistance caused by a HFD. At the tissue level, subcutaneous white adipose tissue exhibits a higher number of smaller adipocytes, with decreased lipogenesis. On its side, the liver shows a significant decrease in lipid droplet content and in the expression of genes related to lipogenesis, fatty acid oxidation, and glucose metabolism. Finally, the data suggest that most of these effects agree with the presence of a putative Perosxisome proliferator-activated receptor gamma (PPARγ) antagonist in the R. canina flesh., Conclusions: R. canina flesh dietary supplementation slows down the steatotic effect of a HFD at least in part through the regulation of the transcriptional activity of PPARγ., (© 2024 The Authors. Molecular Nutrition & Food Research published by Wiley‐VCH GmbH.)

Background: Telomeres are essential for the integrity of chromosome ends during cell division and their involvement in different processes linked to aging has been established. These chromosome components are involved in spermatogenesis and seem to play an important role in fertilization and embryo development. Telomere length is shortened with each cell division. Recently, short sperm telomere length has been proposed as a potential biomarker of male infertility., Objectives: To conduct a systematic review and meta-analysis of studies exploring the association between spermatozoa and/or leukocyte telomere length with sperm quality parameters and different infertility conditions., Material and Methods: A systematic review and meta-analysis was conducted with studies from Medline-PUBMED and Cochrane Library databases until May 2022. Eligible studies included cohort, cross-sectional and case-control studies, and telomere length in spermatozoa and/or leukocytes cells was defined as the exposure. Semen quality parameters or infertility conditions (e.g., oligozoospermia, asthenozoospermia, teratozoospermia, or other spermatogenic impairment combinations) were defined as the outcomes., Results: Twenty-three observational studies were included. In the qualitative analysis, high heterogeneity was observed between studies regarding the associations between telomere length and semen parameters in different normozoospermic/fertile and oligozoospermic/infertile populations. In the meta-analysis, spermatozoa and leukocyte telomere length were shorter in infertile individuals than in fertile individuals (mean difference [95% confidence interval]: -1.43 [-1.66 to -1.21], p-value <0.001 and -1.67 [-2.02 to -1.31], p-value <0.001, respectively). Moreover, in terms of sperm telomere length, these differences were also significant between individuals with a normal seminogram and individuals with a low quantity of spermatozoa in the ejaculate (-0.97 [-1.32, -0.61], p-value <0.001)., Conclusion: The current systematic review and meta-analysis suggests the potential role of spermatozoa or leukocyte telomere length as a reliable biomarker of semen quality, which may help distinguish between infertility conditions beyond the routine semen analysis., (© 2023 The Authors. Andrology published by Wiley Periodicals LLC on behalf of American Society of Andrology and European Academy of Andrology.)

Study Question: Is ultra-processed food (UPF) consumption associated with semen quality parameters?, Summary Answer: Higher UPF consumption was inversely associated with total sperm count, sperm concentration, and total motility in men of reproductive age., What Is Known Already: The consumption of UPF, which has been rising during the last decades, has been demonstrated to be positively associated with several chronic diseases such as diabetes or cardiovascular diseases. However, the scientific evidence on its potential impact on semen quality remains notably limited., Study Design Size Duration: A cross-sectional analysis was conducted using data from 200 healthy men (mean age 28.4 ± 5.5 years) enrolled in the Led-Fertyl (Lifestyle and Environmental Determinants of Seminogram and Other Male Fertility-Related Parameters) study between February 2021 and April 2023., Participants/materials Setting Methods: UPF consumption (% of energy from UPF) was estimated according to the NOVA classification system using a validated 143-item semi-quantitative food frequency questionnaire. Total sperm count, sperm concentration, sperm vitality, total motility, progressive motility, and normal sperm forms were set as the main outcomes. Microscopic parameters were analyzed using a phase-contrast microscope and a computer-assisted sperm analysis (CASA) system. Semen samples were collected and tested according to World Health Organization 2010 standards. Multivariable linear regression models were fitted to estimate the associations between UPF tertile and semen quality parameters., Main Results and the Role of Chance: Sperm concentration ( β : -1.42 × 10 6 spz./ml; 95% CI: -2.72 to -0.12) and motility ( β : -7.83%; 95% CI: -15.16 to -0.51) were lower in participants in the highest tertile of UPF compared to the lowest. A similar association was observed for sperm count when UPF was analyzed per 10% increment of energy from UPF consumption ( β : -1.50 × 10 6 spz.; 95% CI: -2.83 to -0.17). Theoretically replacing 10% of energy from UPF consumption with 10% of energy from unprocessed or minimally processed food consumption was associated with a higher total sperm count, sperm concentration, total motility, progressive motility, and normal sperm forms., Limitations Reasons for Caution: Cross-sectional studies do not permit the drawing of causal inferences. Measurement errors and reporting bias cannot be entirely ruled out., Wider Implications of the Findings: This work suggests that consumption of UPF may have an impact on certain semen quality parameters. Furthermore, opting for unprocessed or minimally processed foods instead of UPFs could potentially benefit semen quality. If these results are replicated in future epidemiological studies with different long-term designs, these novel findings could provide valuable insights for updating or even designing preventive and interventional programs to address infertility among men of reproductive age., Study Funding/competing Interests: This study was supported by the Spanish government's official funding agency for biomedical research, ISCIII, through the Fondo de Investigación para la Salud (FIS), the European Union ERDF/ESF, 'A way to make Europe'/'Investing in your future' [PI21/01447], and the Diputació de Tarragona (2021/11-No.Exp. 8004330008-2021-0022642). J.S.-S. gratefully acknowledges the financial support of ICREA under the ICREA Academia program. C.V.-H. received a predoctoral grant from the Generalitat de Catalunya (2022 FI&#95;B100108). M.Á.M. was supported by the Sara Borrell postdoctoral fellowship (CD21/00045-Instituto de Salud Carlos III (ISCIII)). M.F.d.l.P. was supported by a predoctoral grant from the Rovira i Virgili University and Diputació de Tarragona (2020-PMF-PIPF-8). All authors have no conflict of interest to declare., Trial Registration Number: N/A., Competing Interests: All authors have no conflict of interest to declare., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background & Aims: Short telomeres have been observed in chronic disease patients. Identifying environmental and lifestyle factors that could reduce telomere attrition is crucial for disease prevention. The aim of this work was to determine whether weight-loss induced by an energy-reduced Mediterranean diet (erMedDiet) and physical activity (PA) could modify telomere length (TL)., Methods: In 317 randomized non-smoker participants (mean age, 65.8 ± 4.98 years) with metabolic syndrome from two "Prevención con Dieta Mediterránea-Plus" (PREDIMED-Plus) trial centers, we evaluated MedDiet adherence, PA, anthropometric variables and TL at baseline and after a 3-year intervention using an intensive lifestyle program (IG) with an erMedDiet and PA or an unrestricted MedDiet without PA promotion (CG)., Results: Participants in the IG displayed greater 3-year weight reductions (-3.7 ± 4 kg, P < 0.001) compared to those in the CG. No differences in TL changes between groups were observed in the cohort as a whole. However, an interaction was observed between the intervention group and sex for TL changes (p interaction  = 0.039). Women in the IG showed an increase in TL after 3-y (+0.25 ± 0.9, relative units) compared to women in the CG (-0.07 ± 1.0) (p ANCOVA  = 0.036), whereas no differences between groups were observed in men. Women in the IG had a lower risk of telomere shortening after the intervention (OR = 0.17, 95%CI: 0.05-0.64, p = 0.008) compared to women in the CG., Conclusions: A 3-year lifestyle intervention based on an erMedDiet and PA slowed telomere shortening in women but not in men., Trial Registration: ISRCTN, ISRCTN89898870. Registered 24 July 2014- Retrospectively registered, https://www.isrctn.com/ISRCTN89898870., Competing Interests: Conflict of interest All authors declare that they have no conflict of interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The associations between circulating vitamin D concentrations and total and site-specific colorectal cancer (CRC) incidence have been examined in several epidemiological studies with overall inconclusive findings. The aim of this systematic review and meta-analysis of both case-control and prospective cohort studies was to evaluate the association between CRC and circulating levels of vitamin D. The main exposure and outcome were circulating total 25(OH)D and CRC, respectively, in the overall population (i.e., all subjects). Two reviewers, working independently, screened all the literature available to identify studies that met the inclusion criteria (e.g., case-control or prospective cohort studies, published in English, and excluding non-original papers). Data were pooled by the generic inverse variance method using a random or fixed effect model, as approriate. Heterogeneity was identified using the Cochran's Q-test and quantified by the I 2 statistic. Results were stratified by study design, sex, and metabolite of vitamin D. Sensitivity and subgroup analyses were also performed. A total of 28 original studies were included for the quantitative meta-analysis. Meta-analyses comparing the highest vs lowest categories, showed a 39% lower risk between levels of total 25(OH)D and CRC risk (OR (95% CI): 0.61 (0.52; 0.71); 11 studies) in case-control studies; whereas a 20% reduced CRC risk in prospective cohort studies (HR (95% CI): 0.80 (0.66; 0.97); 6 studies). Results in women mirrored main results, whereas results in men were non-significant in both analyses. Our findings support an inverse association between circulating vitamin D levels and CRC risk.

Telomere length (TL) has been associated with aging and is determined by lifestyle. However, the mechanisms by which a dietary pattern such as the Mediterranean diet (MedDiet) affects TL homeostasis are still unknown. Our aim was to analyse the effect of an energy-restricted MedDiet with physical activity promotion (intervention group) versus an unrestricted-caloric MedDiet with no weight-loss advice (control group) on TL and 8-hydroxydeoxyguanosine (8-OHdG) plasma levels. In total, 80 non-diabetic participants with metabolic syndrome were randomly selected from the PREDIMED (PREvención con DIeta MEDiterránea)-Plus-Reus study. TL was measured by a hybridisation method and 8-OHdG levels by ELISA at baseline and after one year of intervention. Linear mixed models (LMM)-raw and after adjusting for potential confounders-were used to examine the associations between TL or 8-OHdG plasma levels by intervention group and/or time. A total of 69 subjects with available DNA samples were included in the analyses. A significant β-coefficient was found for time towards increasing values through the year of follow-up for TL (unadjusted β of 0.740 (95% CI: 0.529 to 0.951), and multivariable model β of 0.700 (95% CI: 0.477 to 0.922)). No significant βs were found, neither for the intervention group nor for the interaction between the intervention group and time. Regarding 8-OHdG plasma levels, no significant βs were found for the intervention group, time, and its interaction. Our results suggest that MedDiet could have an important role in preventing telomere shortening, but calorie restriction and exercise promotion did not provide an additional advantage concerning telomere length after one year of MedDiet intervention.

Background and Aims: Modifiable lifestyle factors, such as physical activity (PA) and Mediterranean diet (MD), decrease metabolic syndrome (MetS). The aim was to assess 1-year changes of leisure-time physical activity (LTPA), sedentary behavior, and diet quality according to MetS severity in older population at high cardiovascular risk., Methods and Results: Prospective analysis of 55-75-year-old 4359 overweight/obese participants with MetS (PREDIMED-Plus trial) categorized in tertiles according to 1-year changes of a validated MetS severity score (MetSSS). Anthropometrics, visceral adiposity index, triglycerides and glucose index, dietary nutrient intake, biochemical marker levels, dietary inflammatory index, and depression symptoms were measured. Diet quality was assessed by 17-item MD questionnaire. PAs were self-reported using the Minnesota-REGICOR Short Physical Activity Questionnaire and 30-s chair stand test. Sedentary behaviors were measured using the Spanish version of the Nurses' Health Study questionnaire. After 1-year follow-up, decreasing MetSSS was associated with an anti-inflammatory dietary pattern, high intake of vegetables, fruits, legumes, nuts, whole grain cereals, white fish, and bluefish and low intake of refined cereals, red and processed meat, cookies/sweets, and snacks/ready-to-eat-meals. It resulted in high intake of polyunsaturated fatty acids, omega-3 fatty acids, protein, fiber, vitamins B1, B6, B9, C, D, potassium, magnesium, and phosphorus and low glycemic index and saturated fatty acid, trans fatty acid, and carbohydrates intake. Regarding PA and sedentary behavior, decreasing MetSSS was associated with increased moderate-to-vigorous LTPA, chair stand test, and decreased sedentary and TV-viewing time., Conclusion: Decreasing MetSSS was associated with an anti-inflammatory dietary pattern, high LTPA, high MD adherence, low sedentary time, and low depression risk., Competing Interests: Declaration of competing interest J.S.-S. reports serving on the board of and receiving grant support through his institution from the International Nut and Dried Fruit Council, and Eroski Foundation. Reports serving in the Executive Committee of the Instituto Danone Spain and on the Scientific Committee of the Danone International Institute. He has received research support from Patrimonio Comunal Olivarero, Spain; and Borges SA, Spain. Reports receiving consulting fees or travel expenses from Danone; Eroski Foundation, Instituto Danone—Spain, and Abbot Laboratories., (Copyright © 2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Obesity, a sedentary lifestyle, high red meat consumption and alcohol, and tobacco are considered the driving factors behind colorectal cancer (CRC) worldwide. Both diet and lifestyle are recognized to play an important role in the prevention of CRC. Forty years later, the vitamin D-cancer hypothesis is considered consistent. However, the relationship between low vitamin D intake and CRC is still controversial. The aim of this meta-analysis is to determine the associations between Vitamin D intake and CRC. MEDLINE-PubMed and Cochrane databases were searched up to May 2020 for studies evaluating the association between vitamin D intake (from foods and supplements) and CRC. Two reviewers, working independently, screened all titles and abstracts to identify the studies that met the inclusion criteria (case-control or prospective cohort (PC) studies published in English). Data were pooled by the generic inverse variance method using a random or fixed effect model. Heterogeneity was identified using the Cochran Q-test and quantified by the I 2 statistic. A total of 31 original studies were included for the quantitative meta-analysis, comprising a total 47.540 cases and 70.567 controls in case-control studies, and a total of 14.676 CRC-incident cases (out of 808.130 subjects in PC studies) from 17 countries. A significant 25% lower risk was reported comparing the highest vs. the lowest dietary vitamin D consumption and CRC risk (odds ratio (95% confidence interval): 0.75 (0.67; 0.85)) in case-control studies, whereas a non-significant association was reported in case of prospective studies (hazard ratio (95% confidence interval): 0.94 (0.79; 1.11). The present meta-analysis demonstrates that high dietary vitamin D is associated to CRC prevention. However, larger and high-quality prospective studies and clinical trials are warranted to confirm this association.

Background & Aims: Ultra-processed food and drink products (UPF) consumption has been associated with obesity and its-related comorbidities. Excess of visceral fat, which appears with increasing age, has been considered as the culprit contributing to adiposity-associated adverse health outcomes. However, none of previous studies elucidated the link between UPF and directly quantified adiposity and its distribution. We aimed to prospectively investigate the association between concurrent changes in UPF consumption and objectively assessed adiposity distribution., Methods: A subsample of 1485 PREDIMED-Plus participants (Spanish men and women aged 55-75 years with overweight/obesity and metabolic syndrome) underwent body composition measurements. Consumption of UPF at baseline, 6 and 12 months was evaluated using a validated 143-item semi-quantitative Food Frequency Questionnaire. Food items (g/day) were categorized according to their degree of processing using NOVA system. Regional adiposity (visceral fat (in g) and android-to-gynoid fat ratio) and total fat mass (in g) at three time points were measured with dual-energy X-ray absorptiometry (DXA) and were normalized using sex-specific z-scores. The association of changes in UPF consumption, expressed as the percentage of total daily intake (daily g of UPF/total daily g of food and beverage intake∗100), with adiposity changes was evaluated using linear mixed-effects models., Results: On average, the consumption of UPF accounted for 8.11% (SD 7.41%) of total daily intake (in grams) at baseline. In multivariable-adjusted model, 10% daily increment in consumption of UPF was associated with significantly (all p-values <0.05) greater accumulation of visceral fat (β 0.09 z-scores, 95% CI 0.05; 0.13), android-to-gynoid fat ratio (0.05, 0.00; 0.09) and total fat (0.09, 0.06; 0.13)., Conclusion: A higher consumption of UPF was associated with greater age-related visceral and overall adiposity accumulation. Further studies are warranted to confirm these results in other populations and settings., Trial Registration: The trial was registered at the International Standard Randomized Controlled Trial (ISRCTN: http://www.isrctn.com/ISRCTN89898870) with number 89898870 and registration date of 24 July 2014, retrospectively registered., Competing Interests: Conflicts of interest E.R. reports outside the submitted work: serving on the advisory board and receiving financial support other than grants or personal fees from Cerveza y Salud, Spain; personal fees from Brewers of Europe, Belgium; personal fees from Fundación Cerveza y Salud, Spain; financial support from Instituto Cervantes, Albuquerque, USA; personal fees from Instituto Cervantes, Milan, Italy; personal fees from Instituto Cervantes, Tokyo, Japan; non-financial support from Fundación Bosch i Gimpera, Spain; grants from Spanish Institute of Health “Carlos III”; personal fees from Pernaud Richart, Mexico; personal fees from Fundación Dieta Mediterranea, Barcelona, Spain; non-financial support from ERAB, Belgium; non-financial support from Sociedad Española de Nutrición (SEN); non-financial support from Wine and Culinary International Forum; grant from Grant–Fountain Laboratories, Spain; and grant from Uriach Laboratories. The rest of the authors, JK, MM, IA, MB-R, MR-C, JVioque, SG-P, LD, JS-S(,) MF, VM, RE, JVidal, MAM-G, SC, AJJ, TF-V, RC, RO, PB-C, NB, HS, JAM, and DR, declare that they have no potential conflicts of interests., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background & Aims: The association between drinking water consumption and adiposity has been poorly explored. Therefore, we aimed to analyse the associations between the frequency of drinking water consumption and body weight and waist circumference changes in an elderly Mediterranean cohort., Methods: A total of 1832 elderly participants (aged 55-75 years) with metabolic syndrome from the PREDIMED-Plus study with baseline data on drinking water and other beverages assessed by a validated 32-item Spanish fluid-intake questionnaire and with data on body weight (BW) and waist circumference (WC) at 1-year and 2-year were included in these prospective analyses. Multivariable linear regression models were fitted to assess the β-coefficients and 95% confidence interval (CI) for BW and WC changes in terms of categories of baseline drinking water consumption (tap water and bottled water). The theoretical effect on BW and WC of replacing several beverages with drinking water was assessed using mathematical models., Results: The baseline frequency of drinking water consumption was inversely associated with 1-year and 2-year changes in BW. β-coefficients (95%CI) across categories of water consumption (<2.5, 2.5 to <5, 5 to < 7.5, ≥7.5 servings/d) expressed in % of weight changes at 2 years of follow-up were 0.0, -0.80 (-1.48, -0.12), -1.36 (-2.18, -0.54), and -1.97 (-3.09, -0.86), respectively. Individuals in the two highest categories of drinking water consumption (5 to < 7, and ≥7.5 servings/d) also showed a higher decrease in WC (expressed as % of change) after 2 years of follow-up: -1.11 (-1.96, -0.25) and -1.45 (-2.66, -0.24) compared to the reference intake (<2.5 servings/day), after adjustment for potential confounding factors. The theoretical replacement of soups, beers, spirits, hot beverages, dairy beverages, and other beverages group with drinking water was associated with greater reductions in BW at one- and two-years of follow-up., Conclusions: Drinking water consumption was inversely associated with 2-year adiposity changes in an elderly Mediterranean cohort at high cardiovascular risk. Our results also suggest that the consumption of drinking water instead of energy-containing beverages is associated with lower weight gain., The Trial Registration: ISRCTN89898870., Competing Interests: Conflict of interest JS-S serves on the board of (and is provided grant support by his institution from) the International Nut and Dried Fruit Council and the Eroski Foundation. He also serves on the Executive Committee of the Instituto Danone, Spain, and on the Scientific Committee of the Danone International Institute. He has received research support from the Patrimonio Comunal Olivarero, Spain, and Borges S.A., Spain. He receives consulting fees or travel expenses from Danone, the Eroski Foundation, the Instituto Danone, Spain, and Abbot Laboratories., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Previous studies, mainly focused on quantity rather than variety, have shown beneficial associations between the amount of fruit and vegetable consumed, diet quality and healthy lifestyle. The aim is to evaluate the association between fruit and vegetable consumption, diet quality and lifestyle in an elderly Mediterranean population, considering both variety and the combination of quantity and variety (QV)., Methods: A cross-sectional analysis of 6647 participants (51.6% of males) was conducted in the framework of the PREDIMED-Plus study. A variety score was created as the sum of vegetables and/or fruits consumed at least once per month using food frequency questionnaires. Dietary Reference Intakes (EAR and IA values) were used to estimate the prevalence of inadequate intake of dietary fiber and micronutrients. Logistic regression models were performed to examine the association between fruit and vegetable consumption and not meeting the DRIs, by tertiles of fruit and vegetable variety and QV categories., Results: Participants with higher fruit and vegetable variety score reported a significant higher intake of fiber, vitamins, minerals and flavonoids and were significantly more likely to be physically active and non-smoker. Besides, higher variety in fruit and vegetable consumption was associated with lower prevalence of having an inadequate intake of fiber [(0.13 (0.11-0.16)], two or more [(0.17 (0.14-0.21)], three or more [(0.15 (0.13-0.18)] and four or more [(0.11 (0.10-0.14)] micronutrients in our participants. Higher quantity and variety in fruit and vegetable consumption was associated with lower prevalence of having an inadequate intake of fiber [(0.05 (0.04-0.06)], two or more [(0.08 (0.06-0.10)], three or more [(0.08 (0.06-0.09)] and four or more [(0.06 (0.05-0.07)] micronutrients., Conclusion: Greater variety in fruit and vegetable intake was associated with better nutrient adequacy, diet quality and healthier lifestyle in an elderly Mediterranean population., Competing Interests: Potential conflicts of interest JS-S serves on the board of (and receives grant support through his institution from) the International Nut and Dried Fruit Council and the Eroski Foundation. He also serves on the Executive Committee of the Instituto Danone, Spain, and on the Scientifc Committee of the Danone International Institute. He has received research support from the Patrimonio Comunal Olivarero, Spain, and Borges S.A., Spain. He receives consulting fees or travel expenses from Danone, the Eroski Foundation, the Instituto Danone, Spain, and Abbot Laboratories. ER has received research funding through his institution from the California Walnut Commission, Folsom, CA, USA; was a paid member of its Health Research Advisory Group; and is a non-paid member of its Scientifc Advisory Council. RE reports grants from Cerveza y Salud, Spain and Fundación Dieta Mediterranea, Spain. Also personal fees for given lectures from Brewers of Europe, Belgium; Fundación Cerveza y Salud, Spain; Pernaud-Ricard, Mexico; Instituto Cervantes, Alburquerque, USA; Instituto Cervantes, Milano, Italy; Instituto Cervantes, Tokio, Japan; Lilly Laboratories, Spain and Wine and Culinary International Forum, Spain and non-financial support to organize a National Congress on Nutrition. Also feeding trials with product from Grand Fountain and Uriach Laboratories, Spain. LL-G, NB-T, NB, MAM-G, AD-L, DC, AG, DR, JV, AMA-G, JW, JAM, LS-M, FT, JL, XP, JAT, JL-M, AB-C, MD-R, PM-M, LD, LA-A, JV, CV, ZV-R, SC, RF, OC, MAZ, LT, MJA, CML, MM, AG-R, RC, AMG-P, JMS-L, EG, PG-S, CL, IA, IS, SE and HS have nothing to declare., (Copyright © 2021 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Purpose: We examined the association between dietary folate intake and a score of MetS (metabolic syndrome) and its components among older adults at higher cardiometabolic risk participating in the PREDIMED-Plus trial., Methods: A cross-sectional analysis with 6633 with overweight/obesity participants with MetS was conducted. Folate intake (per 100 mcg/day and in quintiles) was estimated using a validated food frequency questionnaire. We calculated a MetS score using the standardized values as shown in the formula: [(body mass index + waist-to-height ratio)/2] + [(systolic blood pressure + diastolic blood pressure)/2] + plasma fasting glucose-HDL cholesterol + plasma triglycerides. The MetS score as continuous variable and its seven components were the outcome variables. Multiple robust linear regression using MM-type estimator was performed to evaluate the association adjusting for potential confounders., Results: We observed that an increase in energy-adjusted folate intake was associated with a reduction of MetS score (β for 100 mcg/day = - 0.12; 95% CI: - 0.19 to - 0.05), and plasma fasting glucose (β = - 0.03; 95% CI: - 0.05 to - 0.02) independently of the adherence to Mediterranean diet and other potential confounders. We also found a positive association with HDL-cholesterol (β = 0.07; 95% CI: 0.04-0.10). These associations were also observed when quintiles of energy-adjusted folate intake were used instead., Conclusion: This study suggests that a higher folate intake may be associated with a lower MetS score in older adults, a lower plasma fasting glucose, and a greater HDL cholesterol in high-risk cardio-metabolic subjects.

We aimed to explore the differences in the whole transcriptome of peripheral blood mononuclear cells between elderly individuals with and without type 2 diabetes (T2D). We conducted a microarray-based transcriptome analysis of 19 individuals with T2D and 15 without. Differentially expressed genes according to linear models were submitted to the Ingenuity Pathway Analysis system to conduct a functional enrichment analysis. We established that diseases, biological functions, and canonical signaling pathways were significantly associated with T2D patients when their logarithms of Benjamini-Hochberg-adjusted p -value were >1.30 and their absolute z-scores were >2.0 (≥2.0 meant "upregulation" and ≤ -2.0 "downregulation"). Cancer signaling pathways were the most upregulated ones in T2D (z-score = 2.63, -log( p -value) = 32.3; 88.5% ( n = 906) of the total differentially expressed genes located in these pathways). In particular, integrin (z-score = 2.52, -log( p -value) = 2.03) and paxillin (z-score = 2.33, -log( p -value) = 1.46) signaling pathways were predicted to be upregulated, whereas the Rho guanosine diphosphate (Rho-GDP) dissociation inhibitor signaling pathway was predicted to be downregulated in T2D individuals (z-score = -2.14, -log( p -value) = 2.41). Our results suggest that, at transcriptional expression level, elderly individuals with T2D present an increased activation of signaling pathways related to neoplastic processes, T-cell activation and migration, and inflammation.

Background: High nut consumption has been previously associated with decreased prevalence of metabolic syndrome (MetS) regardless of race and dietary patterns., Objectives: The aim of this study was to assess whether changes in nut consumption over a 1-y follow-up are associated with changes in features of MetS in a middle-aged and older Spanish population at high cardiovascular disease risk., Methods: This prospective 1-y follow-up cohort study, conducted in the framework of the PREvención con DIeta MEDiterránea (PREDIMED)-Plus randomized trial, included 5800 men and women (55-75 y old) with overweight/obesity [BMI (in kg/m2) ≥27 and <40] and MetS. Nut consumption (almonds, pistachios, walnuts, and other nuts) was assessed using data from a validated FFQ. The primary outcome was the change from baseline to 1 y in features of MetS [waist circumference (WC), glycemia, HDL cholesterol, triglyceride (TG), and systolic and diastolic blood pressure] and excess weight (body weight and BMI) according to tertiles of change in nut consumption. Secondary outcomes included changes in dietary and lifestyle characteristics. A generalized linear model was used to compare 1-y changes in features of MetS, weight, dietary intakes, and lifestyle characteristics across tertiles of change in nut consumption., Results: As nut consumption increased, between each tertile there was a significant decrease in WC, TG, systolic blood pressure, weight, and BMI (P < 0.05), and a significant increase in HDL cholesterol (only in women, P = 0.044). The interaction effect between time and group was significant for total energy intake (P < 0.001), adherence to the Mediterranean diet (MedDiet) (P < 0.001), and nut consumption (P < 0.001). Across tertiles of increasing nut consumption there was a significant increase in extra virgin olive oil intake and adherence to the MedDiet; change in energy intake, on the other hand, was inversely related to consumption of nuts., Conclusions: Features of MetS and excess weight were inversely associated with nut consumption after a 1-y follow-up in the PREDIMED-Plus study cohort. This trial was registered at isrctn.com as ISRCTN89898870., (© The Author(s) 2020. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Background and Aims: The aim of this study was to ascertain the association between the consumption of different categories of edible olive oils (virgin olive oils and olive oil) and olive pomace oil and ankle-brachial pressure index (ABI) in participants in the PREDIMED-Plus study, a trial of lifestyle modification for weight and cardiovascular event reduction in individuals with overweight/obesity harboring the metabolic syndrome., Methods: We performed a cross-sectional analysis of the PREDIMED-Plus trial. Consumption of any category of olive oil and olive pomace oil was assessed through a validated food-frequency questionnaire. Multivariable linear regression models were fitted to assess associations between olive oil consumption and ABI. Additionally, ABI ≤1 was considered as the outcome in logistic models with different categories of olive oil and olive pomace oil as exposure., Results: Among 4330 participants, the highest quintile of total olive oil consumption (sum of all categories of olive oil and olive pomace oil) was associated with higher mean values of ABI (beta coefficient: 0.014, 95% confidence interval [CI]: 0.002, 0.027) (p for trend = 0.010). Logistic models comparing the consumption of different categories of olive oils, olive pomace oil and ABI ≤1 values revealed an inverse association between virgin olive oils consumption and the likelihood of a low ABI (odds ratio [OR] 0.73, 95% CI [0.56, 0.97]), while consumption of olive pomace oil was positively associated with a low ABI (OR 1.22 95% CI [1.00, 1.48])., Conclusions: In a Mediterranean population at high cardiovascular risk, total olive oil consumption was associated with a higher mean ABI. These results suggest that olive oil consumption may be beneficial for peripheral artery disease prevention, but longitudinal studies are needed., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Accelerated telomere shortening has been associated with several age-related diseases and/or decreased lifespan in humans. The Mediterranean diet (MedDiet) is considered to be 1 of the most recognized diets for disease prevention and healthy aging, partially due to its demonstrated anti-inflammatory and antioxidative properties which may impact on telomere length (TL). The aim of this meta-analysis was to determine the associations between MedDiet adherence and TL maintenance. MEDLINE-PubMed and Cochrane databases were searched up to December 2018 for studies evaluating the association between MedDiet adherence and TL in blood cells. Two reviewers, working independently, screened all titles and abstracts to identify studies that met the inclusion criteria [cross-sectional, case-control, and prospective cohort studies and randomized clinical trials (RCTs) published in English and excluded nonoriginal articles]. Data were pooled by the generic inverse variance method using the random effects model and expressed as standardized mean difference (SMD). Heterogeneity was identified using the Cochran Q test and quantified by the I2 statistic. A total of 8 original cross-sectional studies were included for the quantitative meta-analysis, comprising a total of 13,733 participants from 5 countries. A positive association between adherence to the MedDiet and TL was observed in all meta-analyses, with the exception of those conducted only in men: SMD (95% CI) of 0.130 (0.029; 0.231) for all subjects, 0.078 (0.005; 0.152) for women, and 0.095 (-0.005; 0.195) for men. Only 1 prospective cohort study and 1 RCT were identified, therefore, we could not undertake a meta-analysis for these study designs. The present meta-analysis of cross-sectional studies demonstrates that higher MedDiet adherence is associated with longer TL. At the same time, larger and high-quality prospective studies and clinical trials are warranted to confirm this association., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

One-year dietary quality change according to the preceding maximum weight in a lifestyle intervention program (PREDIMED-Plus trial, 55-75-year-old overweight or obese adults; n = 5695) was assessed. A validated food frequency questionnaire was used to assess dietary intake. A total of 3 groups were made according to the difference between baseline measured weight and lifetime maximum reported weight: (a) participants entering the study at their maximum weight, (b) moderate weight loss maintainers (WLM), and (c) large WLM. Data were analyzed by General Linear Model. All participants improved average lifestyle. Participants entering the study at their maximum weight were the most susceptible to improve significantly their dietary quality, assessed by adherence to Mediterranean diet, DII and both healthful and unhealthful provegetarian patterns. People at maximum weight are the most benefitted in the short term by a weight management program. Long term weight loss efforts may also reduce the effect of a weight management program.

Diet, physical activity, and other lifestyle factors have been implicated in the pathophysiology of several chronic diseases, but also in a lower total mortality and longer life expectancy. One of the mechanisms in which diet can reduce the risk of disease is with regard to its impact on telomeres. Telomere length (TL) is highly correlated to chronological age and metabolic status. Individuals with shorter telomeres are at higher risk of chronic diseases and mortality. Diet may influence TL by several mechanisms such as regulating oxidative stress and inflammation or modulating epigenetic reactions. The present systematic review aims to examine the results from epidemiologic and clinical trials conducted in humans evaluating the role of nutrients, food groups, and dietary patterns on TL. We also discuss the possible mechanisms of action that influence this process, with the perspective that TL could be a novel biomarker indicating the risk of metabolic disturbances and age-related diseases. The available evidence suggests that some antioxidant nutrients, the consumption of fruits and vegetables, and Mediterranean diet are mainly associated with longer telomeres. However, most of the evidence is based on high heterogenic observational studies and very few randomized clinical trials (RCTs). Therefore, the associations summarized in the present review need to be confirmed with larger prospective cohort studies and better-designed RCTs., (Copyright © The Author(s) 2019.)

Background: Glycolysis/gluconeogenesis and tricarboxylic acid (TCA) cycle metabolites have been associated with type 2 diabetes (T2D). However, the associations of these metabolites with T2D incidence and the potential effect of dietary interventions remain unclear., Objectives: We aimed to evaluate the association of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with insulin resistance and T2D incidence, and the potential modifying effect of Mediterranean diet (MedDiet) interventions., Methods: We included 251 incident T2D cases and 638 noncases in a nested case-cohort study within the PREDIMED Study during median follow-up of 3.8 y. Participants were allocated to MedDiet + extra-virgin olive oil, MedDiet + nuts, or control diet. Plasma metabolites were measured using a targeted approach by LC-tandem MS. We tested the associations of baseline and 1-y changes in glycolysis/gluconeogenesis and TCA cycle metabolites with subsequent T2D risk using weighted Cox regression models and adjusting for potential confounders. We designed a weighted score combining all these metabolites and applying the leave-one-out cross-validation approach., Results: Baseline circulating concentrations of hexose monophosphate, pyruvate, lactate, alanine, glycerol-3 phosphate, and isocitrate were significantly associated with higher T2D risk (17-44% higher risk for each 1-SD increment). The weighted score including all metabolites was associated with a 30% (95% CI: 1.12, 1.51) higher relative risk of T2D for each 1-SD increment. Baseline lactate and alanine were associated with baseline and 1-y changes of homeostasis model assessment of insulin resistance. One-year increases in most metabolites and in the weighted score were associated with higher relative risk of T2D after 1 y of follow-up. Lower risks were observed in the MedDiet groups than in the control group although no significant interactions were found after adjusting for multiple comparisons., Conclusions: We identified a panel of glycolysis/gluconeogenesis-related metabolites that was significantly associated with T2D risk in a Mediterranean population at high cardiovascular disease risk. A MedDiet could counteract the detrimental effects of these metabolites.This trial was registered at controlled-trials.com as ISRCTN35739639., (Copyright © The Author(s) 2020.)

Different plasma metabolites have been related to insulin resistance (IR). However, there is a lack of metabolite models predicting IR with external validation. The aim of this study is to identify a multi-metabolite model associated to the homeostatic model assessment (HOMA)-IR values. We performed a cross-sectional metabolomics analysis of samples collected from overweight and obese subjects from two independent studies. The training step was performed in 236 subjects from the SATIN study and validated in 102 subjects from the GLYNDIET study. Plasma metabolomics profile was analyzed using three different approaches: GC/quadrupole-TOF, LC/quadrupole-TOF, and nuclear magnetic resonance (NMR). Associations between metabolites and HOMA-IR were assessed using elastic net regression analysis with a leave-one-out cross validation (CV) and 100 CV runs. HOMA-IR was analyzed both as linear and categorical (median or lower versus higher than the median). Receiver operating characteristic curves were constructed based on metabolites' weighted models. A set of 30 metabolites discriminating extremes of HOMA-IR were consistently selected. These metabolites comprised some amino acids, lipid species and different organic acids. The area under the curve (AUC) for the discrimination between HOMA-IR extreme categories was 0.82 (95% CI: 0.74-0.90), based on the multi-metabolite model weighted with the regression coefficients of metabolites in the validation dataset. We identified a set of metabolites discriminating between extremes of HOMA-IR and able to predict HOMA-IR with high accuracy.

Background: Telomere attrition may play an important role in the pathogenesis and severity of type 2 diabetes (T2D), increasing the probability of β cell senescence and leading to reduced cell mass and decreased insulin secretion. Nutrition and lifestyle are known factors modulating the aging process and insulin resistance/secretion, determining the risk of T2D., Objectives: The aim of this study was to evaluate the effects of pistachio intake on telomere length and other cellular aging-related parameters of glucose and insulin metabolism., Methods: Forty-nine prediabetic subjects were included in a randomized crossover clinical trial. Subjects consumed a pistachio-supplemented diet (PD, 50 E% [energy percentage] carbohydrates and 33 E% fat, including 57 g pistachios/d) and an isocaloric control diet (CD, 55 E% carbohydrates and 30 E% fat) for 4 mo each, separated by a 2-wk washout period. DNA oxidation was evaluated by DNA damage (via 8-hydroxydeoxyguanosine). Leucocyte telomere length and gene expression related to either oxidation, telomere maintenance or glucose, and insulin metabolism were analyzed by multiplexed quantitative reverse transcriptase-polymerase chain reaction after the dietary intervention., Results: Compared with the CD, the PD reduced oxidative damage to DNA (mean: -3.5%; 95% CI: -8.07%, 1.05%; P = 0.009). Gene expression of 2 telomere-related genes (TERT and WRAP53) was significantly upregulated (164% and 53%) after the PD compared with the CD (P = 0.043 and P = 0.001, respectively). Interestingly, changes in TERT expression were negatively correlated to changes in fasting plasma glucose concentrations and in the homeostatic model assessment of insulin resistance., Conclusions: Chronic pistachio consumption reduces oxidative damage to DNA and increases the gene expression of some telomere-associated genes. Lessening oxidative damage to DNA and telomerase expression through diet may represent an intriguing way to promote healthspan in humans, reversing certain deleterious metabolic consequences of prediabetes. This study was registered at clinicaltrials.gov as NCT01441921., (Copyright © American Society for Nutrition 2019.)

Besides controlling epithelial-to-mesenchymal transition (EMT) and cell invasion, the Snail1 transcriptional factor also provides cells with cancer stem cell features. Since telomere maintenance is essential for stemness, we have examined the control of telomere integrity by Snail1. Fluorescence in situ hybridization (FISH) analysis indicates that Snail1-depleted mouse mesenchymal stem cells (MSC) have both a dramatic increase of telomere alterations and shorter telomeres. Remarkably, Snail1-deficient MSC present higher levels of both telomerase activity and the long non-coding RNA called telomeric repeat-containing RNA (TERRA), an RNA that controls telomere integrity. Accordingly, Snail1 expression downregulates expression of the telomerase gene (TERT) as well as of TERRA 2q, 11q and 18q. TERRA and TERT are transiently downregulated during TGFβ-induced EMT in NMuMG cells, correlating with Snail1 expression. Global transcriptome analysis indicates that ectopic expression of TERRA affects the transcription of some genes induced during EMT, such as fibronectin, whereas that of TERT does not modify those genes. We propose that Snail1 repression of TERRA is required not only for telomere maintenance but also for the expression of a subset of mesenchymal genes., (© The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Telomere length homeostasis is achieved by a balance of telomere shortening caused by DNA replication and nucleolytic attack and telomere lengthening by telomerase. The importance of telomere length maintenance to human health is best illustrated by dyskeratosis congenita (DC) a disease of telomere shortening caused by mutations in telomerase subunits. DC patients suffer stem cell depletion and die of bone marrow stem cell failure. Recently a new class of particularly severe DC patients was found to harbor mutations in the shelterin subunit TIN2. The DC-TIN2 mutations were clustered in small domain of unknown function. In a recently published study we showed that the DC mutation cluster in TIN2 harbored a binding site for heterochromatin protein 1 (HP1) and further, that HP1 binding to TIN2 was required for sister telomere cohesion in S phase and for telomere length maintenance by telomerase. We briefly review and discuss the implications of our findings in this Extra View, and present some new data that may shed light on how sister telomere cohesion could influence telomere elongation by telomerase.

Human telomere function is mediated by shelterin, a six-subunit complex that is required for telomere replication, protection, and cohesion. TIN2, the central component of shelterin, has binding sites to three subunits: TRF1, TRF2, and TPP1. Here we identify a fourth partner, heterochromatin protein 1γ (HP1γ), that binds to a conserved canonical HP1-binding motif, PXVXL, in the C-terminal domain of TIN2. We show that HP1γ localizes to telomeres in S phase, where it is required to establish/maintain cohesion. We further demonstrate that the HP1-binding site in TIN2 is required for sister telomere cohesion and can impact telomere length maintenance by telomerase. Remarkably, the PTVML HP1-binding site is embedded in the recently identified cluster of mutations in TIN2 that gives rise to dyskeratosis congenita (DC), an inherited bone marrow failure syndrome caused by defects in telomere maintenance. We show that DC-associated mutations in TIN2 abrogate binding to HP1γ and that DC patient cells are defective in sister telomere cohesion. Our data indicate a novel requirement for HP1γ in the establishment/maintenance of cohesion at human telomeres and, furthermore, may provide insight into the mechanism of pathogenesis in TIN2-mediated DC.

Replicated sister chromatids are held together until mitosis by cohesin, a conserved multisubunit complex comprised of Smc1, Smc3, Scc1, and Scc3, which in vertebrate cells exists as two closely related homologues (SA1 and SA2). Here, we show that cohesin(SA1) and cohesin(SA2) are differentially required for telomere and centromere cohesion, respectively. Cells deficient in SA1 are unable to establish or maintain cohesion between sister telomeres after DNA replication in S phase. The same phenotype is observed upon depletion of the telomeric protein TIN2. In contrast, in SA2-depleted cells telomere cohesion is normal, but centromere cohesion is prematurely lost. We demonstrate that loss of telomere cohesion has dramatic consequences on chromosome morphology and function. In the absence of sister telomere cohesion, cells are unable to repair chromatid breaks and suffer sister telomere loss. Our studies elucidate the functional distinction between the Scc3 homologues in human cells and further reveal an essential role for sister telomere cohesion in genomic integrity.

Previous studies in human cells indicate that sister telomeres have distinct requirements for their separation at mitosis. In cells depleted for tankyrase 1, a telomeric poly(ADP-ribose) polymerase, sister chromatid arms and centromeres separate normally, but telomeres remain associated and cells arrest in mitosis. Here, we use biochemical and genetic approaches to identify proteins that might mediate the persistent association at sister telomeres. We use immunoprecipitation analysis to show that the telomeric proteins, TRF1 (an acceptor of PARsylation by tankyrase 1) and TIN2 (a TRF1 binding partner) each bind to the SA1 ortholog of the cohesin Scc3 subunit. Sucrose gradient sedimentation shows that TRF1 cosediments with the SA1-cohesin complex. Depletion of the SA1 cohesin subunit or the telomeric proteins (TRF1 and TIN2) restores the normal resolution of sister telomeres in mitosis in tankyrase 1-depleted cells. Moreover, depletion of TRF1 and TIN2 or SA1 abrogates the requirement for tankyrase 1 in mitotic progression. Our studies indicate that sister telomere association in human cells is mediated by a novel association between a cohesin subunit and components of telomeric chromatin.

SAP18 is a highly conserved protein that was proposed to be involved in multiple cellular processes from autophagy to gene regulation and mRNA processing. In this paper we show that, in Drosophila, dSAP18 is a predominantly nuclear protein that associates to both chromosomes and the nuclear matrix. dSAP18 becomes nuclear early during development, at the onset of cellularization, and remains so all through embryo development. dSAP18 is also nuclear in salivary glands, ovaries and cultured S2 cells. Here we also show that dSAP18 forms a complex with the Drosophila homolog of pinin (dPnn), a protein factor involved in mRNA splicing. dSAP18-dPnn interaction was confirmed in vivo, through co-immunoprecipitation experiments, as well as in vitro, through GST pull-down assays. These results are discussed in the context of the possible functions played by SAP18.

SAP18, a polypeptide associated with the Sin3-HDAC co-repressor complex, was identified in a yeast two-hybrid screen as capable of interacting with the Drosophila GAGA factor. The interaction was confirmed in vitro by glutathione S-transferase pull-down assays using recombinant proteins and crude SL2 nuclear extracts. The first 245 residues of GAGA, including the POZ domain, are necessary and sufficient to bind dSAP18. In polytene chromosomes, dSAP18 and GAGA co-localize at a few discrete sites and, in particular, at the bithorax complex where GAGA binds some silenced polycomb response elements. When the dSAP18 dose is reduced, flies heterozygous for the GAGA mutation Trl67 show the homeotic transformation of segment A6 into A5, indicating that GAGA-dSAP18 interaction contributes to the functional regulation of the iab-6 element of the bithorax complex. These results suggest that, through recruitment of the Sin3-HDAC complex, GAGA might contribute to the regulation of homeotic gene expression.