Average Telomere Length Research Articles

The germline p53 activation syndrome: A new patient further refines the clinical phenotype

The tumor suppressor p53 has well known roles in cancer development and germline cancer predisposition disorders, but increasing evidence supports the role of activation of this transcription factor in the pathogenesis of inherited bone marrow failure and chromosomal instability disorders. Here we report a patient with red cell aplasia, which was steroid responsive, as well as intellectual disability, seizures, microcephaly, short stature, cellular radiosensitivity, and normal telomere lengths, who had a germline heterozygous C-terminal frameshift variant in TP53 similar to others that activate the transcription factor. This is the third reported individual with a germline p53 activation syndrome, with several unique features that refine the clinical disease associated with these variants.

Telomere-length dependent T-cell clonal expansion: A model linking ageing to COVID-19 T-cell lymphopenia and mortality.

SummaryBackgroundSevere COVID-19 T-cell lymphopenia is more common among older adults and entails poor prognosis. Offsetting the decline in T-cell count during COVID-19 demands fast and massive T-cell clonal expansion, which is telomere length (TL)-dependent.MethodsWe developed a model of TL-dependent T-cell clonal expansion capacity with age and virtually examined the relation of T-cell clonal expansion with COVID-19 mortality in the general population.FindingsThe model shows that an individual with average hematopoietic cell TL (HCTL) at age twenty years maintains maximal T-cell clonal expansion capacity until the 6th decade of life when this capacity rapidly declines by more than 90% over the next ten years. The collapse in the T-cell clonal expansion capacity coincides with the steep increase in COVID-19 mortality with age.InterpretationShort HCTL might increase vulnerability of many older adults, and some younger individuals with inherently short HCTL, to COVID-19 T-cell lymphopenia and severe disease.FundingA full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Telomere length declines with age, but relates to immune function independent of age in a wild passerine.

Telomere length (TL) shortens with age but telomere dynamics can relate to fitness components independent of age. Immune function often relates to such fitness components and can also interact with telomeres. Studying the link between TL and immune function may therefore help us understand telomere–fitness associations. We assessed the relationships between erythrocyte TL and four immune indices (haptoglobin, natural antibodies (NAbs), complement activity (CA) and heterophil-lymphocyte (HL) ratio; n = 477–589), from known-aged individuals of a wild passerine (Malurus coronatus). As expected, we find that TL significantly declined with age. To verify whether associations between TL and immune function were independent of parallel age-related changes (e.g. immunosenescence), we statistically controlled for sampling age and used within-subject centring of TL to separate relationships within or between individuals. We found that TL positively predicted CA at the between-individual level (individuals with longer average TL had higher CA), but no other immune indices. By contrast, age predicted the levels of NAbs and HL ratio, allowing inference that respective associations between TL and age with immune indices are independent. Any links existing between TL and fitness are therefore unlikely to be strongly mediated by innate immune function, while TL and immune indices appear independent expressions of individual heterogeneity.

Association Between Riboflavin Intake and Telomere Length: A Cross-Sectional Study From National Health and Nutrition Examination Survey 1999-2002.

BackgroundDietary habits and dietary intake affect telomere length, a reliable marker of biological aging and a predictor of chronic disease. Riboflavin (RF) is known as a water-soluble antioxidant vitamin, but its role in telomere length maintenance has yet to be elucidated.ObjectiveThe purpose of this study was to examine the relationship between dietary RF intake and telomere length in a nationally representative sample of adults.MethodsUsing the NHANES (1999–2002), telomere data of 4,298 participants aged ≥45 years were analyzed in a cross-sectional manner. Leukocyte telomere length was measured using the quantitative real-time polymerase chain reaction (qPCR). Dietary RF intake was assessed by a trained interviewer using 24-h dietary recall method. Generalized linear regressions were performed to evaluate the association between dietary RF intake and telomere length. Subgroup analyses were performed to further explore this relationship in sex and body mass index (BMI) subgroups.ResultsAmong the 3,788 participants included, the average telomere length was longer in females (P = 0.014), while they had a lower average RF intake compared to males (P < 0.001). There was a weak positive correlation between RF intake and telomere length both when unadjusted (β = 0.011; P = 0.037) and adjusted for age, sex, and ethnicity (β = 0.013; P = 0.033). Subgroup analyses showed a positive association between RF intake and the telomere length in female after adjusting for confounding factors (β = 0.029; P = 0.046). In the female subgroup, there were significant positive relationships between telomere length and RF intake in the obese group (β = 0.086, P = 0.022).ConclusionIncreased dietary RF intake was significantly associated with longer telomere length in middle-aged and older American females, especially in low RF intake obese female.

Systemic Human Htert Aav Gene Transfer Therapy And The Effect On Telomere Length And Biological Age, A Case Report

A single adult female human was treated with AAV hTERT gene transfer therapy on two separate occasions 5 years apart. Follow-up is 5.8 years. The first dose administered on 9.16.2015 consisted of a total intravenous dose of 3e15 AAV hTERT. The second dose administered on 9.24.2020 consisted of a total intravenous dose of 3e15 AAV hTERT. Before and after each therapy and periodically in between the doses, Human Leucocyte telomere analysis was performed. The initial telomere length measurements collected on 9.15.2015 at the initiation of the AAV hTERT gene transfer therapy demonstrated a baseline average telomere length of 6.71kb which corresponded to a telomere percentage relative to age and population at the 30th percentile. The most recent telomere length measurements collected on 7.13.2021 demonstrated an average telomere length of 8.94kb which corresponded to a telomere percentage relative to age and population at the 89th percentile. The results demonstrate the progressive lengthening of the recipient’s telomeres from 6.71kb to 8.94kb despite advancing 5.8 years in chronological age. Associated age as related to telomere length (also known as biological age) was calculated and compared to chronological age. Initially on 9.15.2015, and prior to the first AAV hTERT gene transfer therapy, the associated age was calculated to be 62 years. The latest telomere analysis dated 7.13.2021 demonstrated a calculated associated age of 25 years. This decrease in associated, or biological age, decreased at a rate of 5.3 years per year of chronological age advancement.

Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects

AbstractInherited bone marrow failure syndromes (IBMFSs) are a group of disorders typified by impaired production of 1 or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant, Høyeraal-Hreidarsson (HH) syndrome, are rare IBMFSs characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. We identified biallelic variants in the gene encoding the 5′-to-3′ DNA exonuclease Apollo/SNM1B in 3 unrelated patients presenting with a DC/HH phenotype consisting of early-onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly, and/or intrauterine growth retardation. All 3 patients carry a homozygous or compound heterozygous (in combination with a null allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080 cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS that combines clinical hallmarks of DC/HH with normal telomere length. Medscape Continuing Medical Education online▪In support of improving patient care, this activity has been planned and implemented by Medscape, LLC and the American Society of Hematology. Medscape, LLC is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.Medscape, LLC designates this Journal-based CME activity for a maximum of 1.00 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.Successful completion of this CME activity, which includes participation in the evaluation component, enables the participant to earn up to 1.0 MOC points in the American Board of Internal Medicine's (ABIM) Maintenance of Certification (MOC) program. Participants will earn MOC points equivalent to the amount of CME credits claimed for the activity. It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting ABIM MOC credit.All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal CME activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 75% minimum passing score and complete the evaluation at http://www.medscape.org/journal/blood; and (4) view/print certificate. For CME questions, see page 2575. DisclosuresAssociate Editor Irene Roberts declares no competing financial interests. CME questions author Laurie Barclay owns stock, stock options, or bonds from the following ineligible company: AbbVie Inc (former). Learning objectivesUpon completion of this activity, participants will: 1Describe clinical features of 3 unrelated patients with biallelic variants in the gene encoding the 5′-to-3′ DNA exonuclease Apollo/SNM1B (Apollo), according to a case series2Determine genetic features of 3 unrelated patients with biallelic Apollo variants, according to a case series3Identify clinical and research implications of clinical and genetic features of 3 unrelated patients with biallelic Apollo variants, according to a case seriesRelease date: April 21, 2022; Expiration date: April 21, 2023

Telogator: a method for reporting chromosome-specific telomere lengths from long reads.

Telomeres are the repetitive sequences found at the ends of eukaryotic chromosomes and are often thought of as a 'biological clock,' with their average length shortening during division in most cells. In addition to their association with senescence, abnormal telomere lengths are well known to be associated with multiple cancers, short telomere syndromes and as risk factors for a broad range of diseases. While a majority of methods for measuring telomere length will report average lengths across all chromosomes, it is known that aberrations in specific chromosome arms are biomarkers for certain diseases. Due to their repetitive nature, characterizing telomeres at this resolution is prohibitive for short read sequencing approaches, and is challenging still even with longer reads. We present Telogator: a method for reporting chromosome-specific telomere length from long read sequencing data. We demonstrate Telogator's sensitivity in detecting chromosome-specific telomere length in simulated data across a range of read lengths and error rates. Telogator is then applied to 10 germline samples, yielding a high correlation with short read methods in reporting average telomere length. In addition, we investigate common subtelomere rearrangements and identify the minimum read length required to anchor telomere/subtelomere boundaries in samples with these haplotypes. Telogator is written in Python3 and is available at github.com/zstephens/telogator. Supplementary data are available at Bioinformatics online.

A standalone approach to utilize telomere length measurement as a surveillance tool in oral leukoplakia.

Oral squamous cell carcinoma (OSCC) is often preceded by a white patch on a surface of the mouth, called oral leukoplakia (OL). As accelerated telomere length (TL) shortening in dividing epithelial cells may lead to oncogenic transformation, telomere length measurement could serve as a predictive biomarker in OL. However, due to high variability and lack of a universal reference, there has been a limited translational application. Here, we describe an approach of evaluating TL using paired peripheral blood mononuclear cells (PBMC) as an internal reference and demonstrate its translational relevance. Oral brush biopsy and paired venous blood were collected from 50 male OL patients and 44 male healthy controls (HC). Relative TL was measured by quantitative PCR. TL of each OL or healthy sample was normalized to the paired PBMC sample (TL ratio). In OL patients, the mean TL ratio was significantly smaller not only in the patch but also in distal normal oral tissue, relative to healthy controls without a high‐risk oral habit. Dysplasia was frequently associated with a subgroup that showed a normal TL ratio at the patch but significantly smaller TL ratio at a paired normal distal site. Our data suggest that evaluation of TL attrition using a paired PBMC sample eliminates the requirement of external reference DNA, makes data universally comparable and provides a useful marker to define high‐risk OL groups for follow‐up programs. Larger studies will further validate the approach and its broader application in other premalignant conditions.

Association of telomere length with diabetes mellitus and idiopathic dilated cardiomyopathy in a South Indian population: A pilot study

Telomere shortening has been associated with ageing and with many age-related diseases including cancer, coronary artery disease, heart failure and diabetes. We sought to investigate the link between telomere shortening and age-related diseases like type 2 diabetes mellitus (DM) (without any complications: DM; with neuropathic complication: DN) and idiopathic dilated cardiomyopathy (IDCM) in south Indian population. We compared telomere lengths of blood lymphocytes taken from patients with associated age-related diseases, namely DM (n = 47), DN (n = 52) and IDCM (n = 34) and controls (n = 46). In addition, we evaluated the relationship between echocardiographic left ventricular ejection fraction (LVEF), left ventricular end diastolic and systolic diameters (LVEDd and LVESd) and telomere length in IDCM patients. Telomere length negatively correlated with age in the cohorts with diabetes and IDCM, and in controls. Average telomere length in diabetes and IDCM patients was significantly shorter than that of controls either before or after adjustments for age and sex. Duration of diabetes in patients with type 2 diabetes did not correlate with telomere length. No correlation was found between the length of telomeres and echocardiography parameters like LVEF, LVEDd and LVESd in IDCM patients. Though echocardiographic characteristics of IDCM did not correlate with telomere length, telomere shortening was found to be accelerated in diabetes (both DM and DN) and IDCM in a south Indian population. Neuropathic complication in diabetes had no effect on telomere shortening. While telomere shortening is a cause or a consequence of diabetic and cardiac pathology remains further investigation, the current study substantiates the usefulness of telomere length measurements as a marker in conjunction with other biochemical markers of age-related diseases.

Renal Senescence, Telomere Shortening and Nitrosative Stress in Feline Chronic Kidney Disease.

Kidney tissues from cats with naturally occurring chronic kidney disease (CKD) and adult and senior cats without CKD were assessed to determine whether telomere shortening and nitrosative stress are associated with senescence in feline CKD. The histopathologic assessment of percent global glomerulosclerosis, inflammatory infiltrate, and fibrosis was performed. Senescence and nitrosative stress were evaluated utilizing p16 and iNOS immunohistochemistry, respectively. Renal telomere length was evaluated using telomere fluorescent in situ hybridization combined with immunohistochemistry. CKD cats were found to have significantly increased p16 staining in both the renal cortex and corticomedullary junction compared to adult and senior cats. Senior cats had significantly increased p16 staining in the corticomedullary junction compared to adult cats. p16 staining in both the renal cortex and corticomedullary junction were found to be significantly correlated with percent global glomerulosclerosis, cortical inflammatory infiltrate, and fibrosis scores. p16 staining also correlated with age in non-CKD cats. Average telomere length was significantly decreased in CKD cats compared to adult and senior cats. CKD cats had significantly increased iNOS staining compared to adult cats. Our results demonstrate increased renal senescence, telomere shortening, and nitrosative stress in feline CKD, identifying these patients as potential candidates for senolytic therapy with translational potential.

Telomere dynamics in the first year of life, but not later in life, predict lifespan in a wild bird.

Telomeres are protective, nucleoprotein structures at the end of chromosomes that have been associated with lifespan across taxa. However, the extent to which these associations can be attributed to absolute length vs. the rate of telomere shortening prior to sampling remains unresolved. In a longitudinal study, we examined the relationship between lifespan, telomere length and the rate of telomere shortening in wild, purple-crowned fairy-wrens (Malurus coronatus coronatus). To this end, we measured telomere length using quantitative polymerase chain reaction in the blood of 59 individuals sampled as nestlings and 4-14months thereafter, and in 141known-age individuals sampled on average three times across adulthood. We applied within-subject centring analyses to simultaneously test for associations between lifespan and average telomere length and telomere shortening. We reveal that the rate of telomere shortening and to a lesser extent telomere length in the first year of life independently predicted lifespan, with individuals with faster shortening rates and/or shorter telomeres living less long. In contrast, in adulthood neither telomere shortening nor telomere length predicted lifespan, despite a considerably larger data set. Our results suggest that telomere length measured very early in life (during development) and longitudinal assessments of telomere shortening during the first year of life constitute more useful biomarkers of total life expectancy than either telomere length measured after development, or telomere shortening later in adulthood.

Telomere length variation does not correspond with the growth disturbances in the rainbow trout (Oncorhynchus mykiss)

Somatic growth is considered to affect pace of the telomere attrition in vertebrates. As normally developed and dwarf fish differ in the body size we have decided to compare telomere length in the rainbow trout (Oncorhynchus mykiss) with normal growth and with growth reduced due to the dwarf condition. Examined 1-year-old fish with normal and dwarf appearance were siblings originated from androgenetic fully homozygous doubled haploid (DH) line of rainbow trout. Particular dwarf individuals had body deformities such as humpback, kyphosis, and lordosis. Somatic cells of examined rainbow trout had an average telomere length between 17 and 20 kb, comparable in females and males. Dwarf rainbow trout exhibited significantly lower body length and weight than their normally developed siblings even though no differences in the telomere length were found between these fishes. Statistical analysis did not exhibit any correlation between body size and the telomere length. Equal length of telomeres observed in the studied normal and dwarf rainbow trout suggests morphological and physiological differences in fish with different growth rates do not affect dynamics of telomeric DNA. Or any variation in the telomere length might have been levelled by telomerase that in rainbow trout is active in all tissues irrespective of the individual developmental stage.

T-Cell Telomere Length As a Biomarker to Predict Outcome in Patients Receiving CAR-T Immunotherapy

Introduction: CAR T-cells remain in a quiescent or dormant state when unstimulated, showing no proliferative activity. In contrast, upon specific antigen stimulation (i.e., CD19) CAR T-cells divide both in-vitro and in-vivo, initiate immune responses and can kill their target cells in the body. However, one of the major physiological immune changes with increased age is the progressive impairment of T-cell responses. This process termed immunosenescence (which may be similar T-cell exhaustion) is associated with the shortening of telomeres, specific DNA repeated sequences that protect the end of linear chromosomes from degradation and fusion with neighbor chromosomes. We aim to investigate change in T-cell telomere length with CAR-T cell therapy and its potential impact on outcome in patients receiving CART immunotherapy.Methods: We enrolled adult patients (age range: 30-80 years old) receiving CART immunotherapy for diffuse large B cell lymphoma (DLBCL), multiple myeloma (MM), mantle cell lymphoma (MCL), or follicular lymphoma (FL). We collected peripheral blood at two time points: i) pre-lymphodepletion therapy and ii) two weeks post CAR-T cell infusion. Peripheral blood mononuclear cells were isolated from blood via density gradient and T-cells isolated from PBMC with magnetic beads (negative selection). Telomere lengths are quantified from T-cells by using a highly sensitive technique called TeSLA (Telomere Shortest Length Assay) that allows absolute quantification of both the average telomere length and the lengths of critically short telomeres, which are believed to play a major role in promoting cell cycle arrest and T-cell exhaustion.Results: We identified 7 patients receiving CAR T cell therapy for hematological malignancies at University of Texas Southwestern Medical Center. The cohort included 7 patients, 2 patients with DLBCL and 1 patient with MCL receiving CD19 CAR-T Cell therapy and 4 patients with MM receiving BCMA CAR-T cell therapy. Median age of patient was 65 yrs. Median follow up was 273 days post CAR T-cell therapy with all patients being alive at last follow-up. Two patients experienced Grade I Cytokine release syndrome (CRS), two patients with Grade 2 CRS and one patient with Grade 2 ICANS. Our initial analysis shows that patients telomere lengths changes pre and post CAR T-cell infusion. Regarding change in critically short telomere (<1.6kb); 6 out of 7 patients had reduction the shorter telomere from BL to post CAR-T. We are currently evaluating the effect of change in telomere length on outcomes.Conclusions: CAR T-cell therapy is a game-changer for hematological malignancies; however, disease still relapse. Understanding the mechanics of poor response or relapse after CAR T-cell therapy is critical in advancing the field. Initial results suggest T-cell telomere length are significantly affected during CAR T-cell manufacturing process and post infusion. These results are potentially important as telomere length can be utilized as a biomarker to predict CAR T-cell therapy outcomes. [Display omitted] DisclosuresAnderson: Celgene, BMS, Janssen, GSK, Karyopharm, Oncopeptides, Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Awan: Verastem: Consultancy; Incyte: Consultancy; Cardinal Health: Consultancy; Dava Oncology: Consultancy; BMS: Consultancy; ADCT therapeutics: Consultancy; Beigene: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Kite pharma: Consultancy; Gilead sciences: Consultancy; Johnson and Johnson: Consultancy; Abbvie: Consultancy; Janssen: Consultancy; Astrazeneca: Consultancy; Genentech: Consultancy. Madanat: Onc Live: Honoraria; Blue Print Pharmaceutical: Honoraria; Geron Pharmaceutical: Consultancy; Stem line pharmaceutical: Honoraria. Patel: Celgene-BMS: Membership on an entity's Board of Directors or advisory committees; PVI: Honoraria; Agios: Membership on an entity's Board of Directors or advisory committees. Sweetenham: EMA Wellness: Membership on an entity's Board of Directors or advisory committees. Kansagra: Alynylam, Celgene/BMS, Cota Health, GSK, Janssen, Karyopharm, Oncopeptide, Pfizer, Takeda, Sanofi: Membership on an entity's Board of Directors or advisory committees.

An Inducible Leukemia-Associated Transcription Factor Facilitates Large-Scale Ex Vivo Generation of Functional Human Macrophages

Long-term ex vivo expansion of human CD34+ hematopoietic stem and progenitor cells (HSPCs) proves to be unfeasible as cellular differentiation occurs when HSPCs are detached from their supporting bone marrow stem cell niche. This issue renders it difficult to make use of the proliferation capacity of HSPCs to subsequently produce functional blood cells in relevant numbers, e.g. for cell therapy approaches. To circumvent this challenge, leukemia-associated chimeric transcription factors, including MLL fusion proteins, can be exploited for their pronounced ability to propel cell proliferation while preserving cell immaturity. By designing the protein's activity controllable, the immature state can be abolished at an arbitrary point in time enabling terminal differentiation.In this study, we employed the fusion gene mixed lineage leukemia/eleven nineteen leukemia (MLL-ENL) for engineering an inducible protein switch. For this purpose, we fused the coding sequence of an FK506-Binding Protein 12 (FKBP12)-derived destabilization domain (DD) to the transcription factor MLL-ENL and subsequently expressed the protein switch (DD-MLL-ENL) in human CD34+ HSPCs derived from adult healthy donors. In the presence of the specific ligand Shield1, DD-mediated protein degradation is prevented leading to massive and long-term expansion of HSPC-derived late monocytic precursors in the presence of IL-3, IL-6, SCF, FLT3-L, TPO and GM-CSF. The cells do not exhibit additional driver mutations, feature a normal karyotype and telomere length, and sustain immaturity that is strictly dependent on Shield1 supplementation every other day even after two years of ex vivo culture. Upon Shield1 deprivation, the cells completely lost self-renewal and colony-forming properties and spontaneously differentiated. By changing the cytokines to GM-CSF in combination with IFN-γ and LPS we differentiated the progenitor cells into macrophages (MΦ) (Fig. 1 A, B). Immunophenotypic characterization revealed upregulation of the monocyte/macrophage-associated surface markers CD14, CD80, CD86, CD163 and MHC class I and II, concordant with monocytic morphology as judged by cytospin preparations. Analysis of the transcription of selected inflammatory genes, including IL-6 and IL-10, revealed overlapping M1 and M2 macrophage characteristics. Furthermore, mRNA expression profiles using nCounter Systems technology covering a total of 770 myeloid innate immunity-related genes proves the cells' identity as differentiated phagocytes shown by upregulation of gene clusters involved in Fc receptor signaling, TLR signaling, antigen presentation and T cell activation. In functional assays, we demonstrated the ability of the obtained cells to migrate towards the chemokine CCL2 in a 3D chemotaxis assay, attach to VCAM-1 under flow and shear stress and produce reactive oxygen species. Regarding the cells' phagocytic capability, we could verify the uptake of bacterial particles as well as apoptotic cells in efferocytosis assays. Finally, we demonstrated IgG Fc region recognition and binding by the expressed Fcγ receptors enabling phagocytosis of lymphoblastic tumor cells, including Daudi, Raji and patient-derived MCL cells in an antibody-dependent manner using rituximab (RTX), daratumumab (Dara) and trastuzumab (Trast) as a negative control (Fig. 1C).Overall, we could demonstrate the conversion of a harmful leukemic transcription factor into a useful molecular tool for large-scale ex vivo production of functional blood cells. Such engineered controllable protein switches might have the potential to be employed as molecular tools to produce functional immune cells for cell-based immunotherapeutic approaches. [Display omitted] DisclosuresRedondo Monte: Minaris Regenerative Medicine: Current Employment. Beier: Alexion: Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees; Jazz: Other: Travel reembursement. Weigert: Janssen: Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Greif: AstraZeneca: Honoraria.

Pilot Study of Absolute Telomere Lengths in Preterm Infants.

Annually, approximately 15 million babies are born preterm (<37 weeks gestational age) globally. In the neonatal intensive care unit (NICU) environment, infants are exposed to repeated stressful or painful procedures as part of routine lifesaving care. These procedures have been associated with epigenetic alterations that may lead to an increased risk of neurodevelopmental disorders. Telomere length has been negatively associated with adverse life experiences in studies of adults. This pilot study aimed to describe telomere length in a sample of preterm infants at NICU discharge and examine any associations with pain, feeding method, and neurodevelopment. This descriptive pilot study sample includes baseline absolute telomere length (aTL) of 36 preterm infants immediately prior to discharge. Quantitative polymerase chain reaction was used to determine aTL. Infant demographics, pain/stress, type of feeding, antibiotic use, neurodevelopment, and buccal swab data were collected. Descriptive data analysis was used to describe the telomere length using graphs. Among our preterm infant samples, the mean aTL was far greater than the average adult telomere length. Although no significant associations were found between aTL and pain, feeding method, and neurodevelopment, a trend between sex was noted where male telomere lengths were shorter than females as they aged. This is one of few studies to evaluate preterm infant telomere length. Although other researchers have used relative telomere length, we used the more accurate aTL. We found nonsignificant shorter telomere lengths among males. Additional large-scale, longitudinal studies are needed to better identify the predictors of telomere length at the time of discharge from NICU.

Maternal Vitamin D and Newborn Telomere Length.

Nutrition is important during pregnancy for offspring health. Gestational vitamin D intake may prevent several adverse outcomes and might have an influence on offspring telomere length (TL). In this study, we want to assess the association between maternal vitamin D intake during pregnancy and newborn TL, as reflected by cord blood TL. We studied mother–child pairs enrolled in the Maternal Nutrition and Offspring’s Epigenome (MANOE) cohort, Leuven, Belgium. To calculate the dietary vitamin D intake, 108 women were asked to keep track of their diet using the seven-day estimated diet record (EDR) method. TL was assessed in 108 cord blood using a quantitative real-time PCR method. In each trimester of pregnancy, maternal serum 25-hydroxyvitamin D (25-OHD) concentration was measured. We observed a positive association (β = 0.009, p-value = 0.036) between newborn average relative TL and maternal vitamin D intake (diet + supplement) during the first trimester. In contrast, we found no association between average relative TL of the newborn and mean maternal serum 25-OHD concentrations during pregnancy. To conclude, vitamin D intake (diet + supplements), specifically during the first trimester of pregnancy, is an important factor associated with TL at birth.

Association of Childhood Socioeconomic Status with Leukocyte Telomere Length Among African Americans and the Mediating Role of Behavioral and Psychosocial Factors: Results from the GENE-FORECAST Study

PurposeWe examined if childhood socioeconomic status (SES) was related to adult leucocyte telomere length (TL) using the data of 361 African American (AA) participants from the GENE-FORECAST Study. We also assessed the mediating role of behavioral and psychosocial factors in the association between childhood SES and adult TL.MethodsChildhood SES was assessed individually by using participant’s mother’s education and occupation, father’s education and occupation, parental home ownership, and family structure. TL was assessed using the quantitative polymerase chain reaction method. Information on potential confounders and mediators were collected. The associations of childhood SES with TL were assessed using multivariable linear regression models. We used path analysis to quantify and test the share of these associations that was statistically explained by each of the mediators (participant’s educational attainment, smoking status, physical activity, dietary habit, perceived stress, and depressive symptoms).ResultsMother’s education was associated with longer average TL (β: 0.021; 95% CI: 0.001, 0.04, p=0.038) in confounder adjusted models. Once mediators were introduced in the model, the estimates were reduced and remained marginally significant (β: 0.017; 95% CI: −0.003, 0.038, p=0.061). According to path model, approximately 19% of the effect of mother’s education on TL (β: 0.004; 95% CI: −0.001, 0.01, p < 0.10) was mediated through participant’s own education level. No significant mediation effect was observed for any other mediators.ConclusionsThese data provide evidence that participant’s mother’s education was positively linked to adult TL in AA population. Participant’s own educational level partially explained this association.

Heritable variation in telomere length predicts mortality in Soay sheep

Telomere length (TL) is considered an important biomarker of whole-organism health and aging. Across humans and other vertebrates, short telomeres are associated with increased subsequent mortality risk, but the processes responsible for this correlation remain uncertain. A key unanswered question is whether TL-mortality associations arise due to positive effects of genes or early-life environment on both an individual's average lifetime TL and their longevity, or due to more immediate effects of environmental stressors on within-individual TL loss and increased mortality risk. Addressing this question requires longitudinal TL and life history data across the entire lifetimes of many individuals, which are difficult to obtain for long-lived species like humans. Using longitudinal data and samples collected over nearly two decades, as part of a long-term study of wild Soay sheep, we dissected an observed positive association between TL and subsequent survival using multivariate quantitative genetic models. We found no evidence that telomere attrition was associated with increased mortality risk, suggesting that TL is not an important marker of biological aging or exposure to environmental stress in our study system. Instead, we find that among-individual differences in average TL are associated with increased lifespan. Our analyses suggest that this correlation between an individual's average TL and lifespan has a genetic basis. This demonstrates that TL has the potential to evolve under natural conditions, and suggests an important role of genetics underlying the widespread observation that short telomeres predict mortality.

Telomere length is highly heritable and independent of growth rate manipulated by temperature in field crickets.

Many organisms are capable of growing faster than they do. Restrained growth rate has functionally been explained by negative effects on lifespan of accelerated growth. However, the underlying mechanisms remain elusive. Telomere attrition has been proposed as a causal agent and has been mostly studied in endothermic vertebrates. We established that telomeres exist as chromosomal-ends in a model insect, the field cricket Gryllus campestris, using terminal restriction fragment and Bal 31 methods. Telomeres comprised TTAGGn repeats of 38kb on average, more than four times longer than the telomeres of human infants. Bal 31 assays confirmed that telomeric repeats were located at the chromosome-ends. We tested whether rapid growth between day 1, day 65, day 85, and day 125 is achieved at the expense of telomere length by comparing nymphs reared at 23°C with their siblings reared at 28°C, which grew three times faster in the initial 65days. Surprisingly, neither temperature treatment nor age affected average telomere length. Concomitantly, the broad sense heritability of telomere length was remarkably high at ~100%. Despite high heritability, the evolvability (a mean-standardized measure of genetic variance) was low relative to that of body mass. We discuss our findings in the context of telomere evolution. Some important features of vertebrate telomere biology are evident in an insect species dating back to the Triassic. The apparent lack of an effect of growth rate on telomere length is puzzling, suggesting strong telomere length maintenance during the growth phase. Whether such maintenance of telomere length is adaptive remains elusive and requires further study investigating the links with fitness in the wild.

Mathematical modelling of ageing acceleration of the human follicle due to oxidative stress and other factors.

There is a gradual telomere shortening due to the inability of the replication machinery to copy the very ends of chromosomes. Additionally, other factors such as high levels of oxidation (free radicals or reactive oxygen species (ROS)), e.g. due to cumulated stress, inflammation or tobacco smoke, accelerate telomere shortening. In humans, the average telomere length is about 10-15 kb at birth and telomeres shorten at a pace of 70 bp per year. However, when cells are exposed to ROS, telomere attrition happens at a faster pace, generating a wide variety of telomere size distribution in different length percentiles, which are different to what is expected just by age. In this work, the generational age of a cell is associated with its telomere length (TL), from certain maximum to the minimal TL that allows replication. In order to study the accumulation of aged granulosa cells in human follicles, from preantral to preovulatory size, a mathematical model is proposed, regarding different degrees of accelerated telomere shortening, which reflect the action of ROS in addition to the telomere shortening that happens after cell division. In cases of cells with TL shorter than cells with average TL, with low telomerase activity and accelerated telomere shortening, the mathematical model predicts an aged outcome in preovulatory follicles. The model provides a plausible explanation for what has been observed in oocytes from older women, which have been exposed to ROS for a longer period of time and have bad outcomes after in vitro fertilization.