Functional Impairment of Endothelial Colony Forming Cells (ECFC) in Patients with Severe Atherosclerotic Cardiovascular Disease (ASCVD).

Endothelial dysfunction is a key factor in atherosclerosis. However, the link between endothelial repair and severity of atherosclerotic cardiovascular disease (ASCVD) is unclear. This study investigates the relationship between ASCVD, markers of inflammation, and circulating endothelial progenitor cells, namely hematopoietic cells with paracrine angiogenic activity and endothelial colony forming cells (ECFC). Two hundred and forty-three subjects from the TELARTA study were classified according to the presence of clinical atherosclerotic disease. ASCVD severity was assessed by the number of involved vascular territories. Flow cytometry was used to numerate circulating progenitor cells (PC) expressing CD34 and those co-expressing CD45, CD34, and KDR. Peripheral blood mononuclear cells ex vivo culture methods were used to determine ECFC and Colony Forming Unit- endothelial cells (CFU-EC). The ECFC subpopulation was analyzed for proliferation, senescence, and vasculogenic properties. Plasma levels of IL-6 and VEGF-A were measured using Cytokine Array. Despite an increased number of circulating precursors in ASCVD patients, ASCVD impaired the colony forming capacity and the angiogenic properties of ECFC in a severity-dependent manner. Alteration of ECFC was associated with increased senescent phenotype and IL-6 levels. Our study demonstrates a decrease in ECFC repair capacity according to ASCVD severity in an inflammatory and senescence-associated secretory phenotype context.

Telomeres: New players in immune-mediated inflammatory diseases?

Telomeres are repetitive DNA sequences located at the ends of linear chromosomes that preserve the integrity and stability of the genome. Telomere dysfunctions due to short telomeres or altered telomere structures can ultimately lead to replicative cellular senescence and chromosomal instability, both mechanisms being hallmarks of ageing. Chronic inflammation, oxidative stress and finally telomere length (TL) dynamics have been shown to be involved in various age-related non-communicable diseases (NCDs). Immune-mediated inflammatory diseases (IMIDs), including affections such as inflammatory bowel disease, psoriasis, rheumatoid arthritis, spondyloarthritis and uveitis belong to this group of age-related NCDs. Although in recent years, we have witnessed the emergence of studies in the literature linking these IMIDs to TL dynamics, the causality between these diseases and telomere attrition is still unclear and controversial. In this review, we provide an overview of available studies on telomere dynamics and discuss the utility of TL measurements in immune-mediated inflammatory diseases.

Telomere length tracking in children and their parents: implications for adult onset diseases.

Adults with comparatively short or long leukocyte telomere length (LTL) typically continue to display comparatively short or long LTL throughout life. This LTL tracking stems from the inability of person-to-person variation in age-dependent LTL shortening during adulthood to offset the wide interindividual LTL variation established prior to adult life. However, LTL tracking in children is unstudied. This study aimed to examine LTL shortening rates and tracking in children and their parents. Longitudinal study in children (n = 67) and their parents (n = 99), whose ages at baseline were 11.4 ± 0.3 and 43.4 ± 0.4 yr, respectively. LTL was measured by Southern blotting at baseline and ∼14 yr thereafter. LTL displayed tracking in both children [intraclass correlation coefficient (ICC) = 0.905, P < 0.001] and their parents (ICC = 0.856, P < 0.001). The children's rate of LTL shortening was twice that of their parents (40.7 ± 2.5 bp/yr; 20.3 ± 2.1 bp/yr, respectively; P < 0.0001). LTL tracking applies not only to adulthood but also to the second decade of life. Coupled with previous work showing that the interindividual variation in LTL across newborns is as wide as in their parents, these findings support the thesis that the LTL-adult disease connection is principally determined before the second decade of life, perhaps mainly at birth.-Benetos, A., Verhulst, S., Labat, C., Lai, T.-P., Girerd, N., Toupance, S., Zannad, F., Rossignol, P., Aviv, A. Telomere length tracking in children and their parents: implications for adult onset diseases.

Short Leukocyte Telomere Length Precedes Clinical Expression of Atherosclerosis: The Blood-and-Muscle Model.

RATIONALE: Short telomere length (TL) in leukocytes is associated with atherosclerotic cardiovascular disease (ASCVD). It is unknown whether this relationship stems from having inherently short leukocyte TL (LTL) at birth or a faster LTL attrition thereafter. LTL represents TL in the highly proliferative hematopoietic system, whereas TL in skeletal muscle represents a minimally replicative tissue. OBJECTIVE: We measured LTL and muscle TL (MTL) in the same individuals with a view to obtain comparative metrics for lifelong LTL attrition and learn about the temporal association of LTL with ASCVD. METHODS AND RESULTS: Our Discovery Cohort comprised 259 individuals aged 63±14 years (mean±SD), undergoing surgery with (n=131) or without (n=128) clinical manifestation of ASCVD. In all subjects, MTL adjusted for muscle biopsy site (MTLA) was longer than LTL and the LTL-MTLA gap similarly widened with age in ASCVD patients and controls. Age- and sex-adjusted LTL (P=0.005), but not MTLA (P=0.90), was shorter in patients with ASCVD than controls. The TL gap between leukocytes and muscle (LTL-MTLA) was wider (P=0.0003), and the TL ratio between leukocytes and muscle (LTL/MTLA) was smaller (P=0.0001) in ASCVD than in controls. Findings were replicated in a cohort comprising 143 individuals. CONCLUSIONS: This first study to apply the blood-and-muscle TL model shows more pronounced LTL attrition in ASCVD patients than controls. The difference in LTL attrition was not associated with age during adulthood suggesting that increased attrition in early life is more likely to be a major explanation of the shorter LTL in ASCVD patients. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02176941.

Telomere length and age-dependent telomere attrition: the blood-and-muscle model 1.

Short telomere length (TL) is associated with atherosclerotic cardiovascular disease (ACVD) and other age-related diseases. It is unclear whether these associations originate from having inherently short TL or a faster TL attrition before or during disease development. We proposed the blood-and-muscle model to assess TL dynamics throughout life course. Our objective was to measure TL in leukocytes (LTL) and in skeletal muscle (MTL), which served as a proxy of TL at birth. The delta (MTL-LTL) represented life-long telomere attrition. Blood draws and skeletal muscle biopsies were performed on 35 Lebanese individuals undergoing surgery. Following DNA extraction, LTL and MTL were measured by Southern blot. In every individual aged between 30 and 85 years, MTL was longer than LTL. With age, MTL and LTL decreased, but the delta (MTL-LTL) increased by 14 bp/year. We validated the blood-and-muscle model that allowed us to identify TL, TL at birth, and lifelong TL attrition in a cross-sectional study. This model can be used in larger cross-sectional studies to evaluate the association of telomere dynamics with age-related diseases onset and progression.

A short leucocyte telomere length is associated with development of insulin resistance.

AIMS/HYPOTHESIS: A number of studies have shown that leucocyte telomere length (LTL) is inversely associated with insulin resistance and type 2 diabetes mellitus. The aim of the present longitudinal cohort study, utilising a twin design, was to assess whether shorter LTL predicts insulin resistance or is a consequence thereof. METHODS: Participants were recruited between 1997 and 2000 through the population-based national Danish Twin Registry to participate in the GEMINAKAR study, a longitudinal evaluation of metabolic disorders and cardiovascular risk factors. Baseline and follow-up measurements of LTL and insulin resistance over an average of 12 years were performed in a subset of the Registry consisting of 338 (184 monozygotic and 154 dizygotic) same-sex twin pairs. RESULTS: Age at baseline examination was 37.4 ± 9.6 (mean ± SD) years. Baseline insulin resistance was not associated with age-dependent changes in LTL (attrition) over the follow-up period, whereas baseline LTL was associated with changes in insulin resistance during this period. The shorter the LTL at baseline, the more pronounced was the increase in insulin resistance over the follow-up period (p < 0.001); this effect was additive to that of BMI. The co-twin with the shorter baseline LTL displayed higher insulin resistance at follow-up than the co-twin with the longer LTL. CONCLUSIONS/INTERPRETATION: These findings suggest that individuals with short LTL are more likely to develop insulin resistance later in life. By contrast, presence of insulin resistance does not accelerate LTL attrition.

Longer Telomere Length in Balkan Endemic Nephropathy Patients Undergoing Chronic Hemodialysis is Associated with Lower Cardiovascular Mortality.

BACKGROUND: Balkan endemic nephropathy (BEN) is characterized with later onset and milder forms of hypertension, and with lower pulse wave velocity (PWV) than other end-stage kidney disease (ESKD). Longer telomeres are associated with better cardiovascular (CV) prognosis. Therefore, we hypothesized that telomere length (TL) could be longer in BEN patients compared to other ESKD patients. METHODS: A total of 124 patients undergoing hemodialysis (HD) (68 BEN, 56 non-BEN) were enrolled and followed-up for 72 months. TL was measured in leukocytes by Southern blot at inclusion. RESULTS: Age and sex-adjusted TL was significantly longer in the BEN group (p<0.001). TL was negatively associated with carotid-femoral PWV in BEN patients. BEN patients had significantly lower CV mortality than non-BEN ESKD patients (p<0.001). In the BEN group shorter TL (1kb change) was the only determinant of shorter survival (HR 0.11). Using the TL threshold defined by ROC analysis (TL < 6.21 kb), we showed in both groups significantly higher CV mortality in the presence of short telomeres (Log-rank (Mantel-p<0.001). CONCLUSIONS: Longer telomeres are associated with less CV mortality in patients undergoing chronic HD. BEN patients had longer TL and longer survival than other ESKD patients. In BEN patients, TL was negatively associated with arterial stiffness and positively associated with survival. This study confirmed our hypothesis that BEN is associated with slower vascular aging and that longer TL may partially explain this phenomenon.

Buildup from birth onward of short telomeres in human hematopoietic cells.

Telomere length (TL) limits somatic cell replication. However, the shortest among the telomeres in each nucleus, not mean TL, is thought to induce replicative senescence. Researchers have relied on Southern blotting (SB), and techniques calibrated by SB, for precise measurements of TL in epidemiological studies. However, SB provides little information on the shortest telomeres among the 92 telomeres in the nucleus of human somatic cells. Therefore, little is known about the accumulation of short telomeres with age, or whether it limits the human lifespan. To fill this knowledge void, we used the Telomere-Shortest-Length-Assay (TeSLA), a method that tallies and measures single telomeres of all chromosomes. We charted the age-dependent buildup of short telomeres (<3 kb) in human hematopoietic cells from 334 individuals (birth-89 years) from the general population, and 18 patients with dyskeratosis congenita-telomere biology disorders (DC/TBDs), whose hematopoietic cells have presumably reached or are close to their replicative limit. For comparison, we also measured TL with SB. We found that in hematopoietic cells, the buildup of short telomeres occurs in parallel with the shortening with age of mean TL. However, the proportion of short telomeres was lower in octogenarians from the general population than in patients with DC/TBDs. At any age, mean TL was longer and the proportion of short telomeres lower in females than in males. We conclude that though converging to the TL-mediated replicative limit, hematopoietic cell telomeres are unlikely to reach this limit during the lifespan of most contemporary humans.

Longitudinal Association of Telomere Dynamics with Obesity and Metabolic Disorders in Young Children.

In adults, short leukocyte telomere length (LTL) is associated with metabolic disorders, such as obesity and diabetes mellitus type 2. These associations could stem from early life interactions between LTL and metabolic disorders. To test this hypothesis, we explored the associations between LTL and metabolic parameters as well as their evolution over time in children with or without obesity at baseline. Seventy-three (n = 73) children attending our Outpatient Clinic for the Prevention and Management of Overweight and Obesity in Childhood and Adolescence, aged 2-10 years (mean ± SD: 7.6 ± 2.0 years), were followed for 2 to 4 years. Anthropometric, clinical, and biological (including LTL by Southern blot) measurements were performed annually. Baseline LTL correlated negatively with BMI (p = 0.02), fat percentage (p = 0.01), and blood glucose (p = 0.0007). These associations persisted after adjustments for age and sex. No associations were found between LTL attrition during the follow-up period and any of the metabolic parameters. In young children, obesity and metabolic disturbances were associated with shorter telomeres but were not associated with more pronounced LTL attrition. These results suggest that short telomeres contribute to the development of obesity and metabolic disorders very early in life, which can have a major impact on health.

Anti-spike IgG antibody kinetics following the second and third doses of BNT162b2 vaccine in nursing home residents.

BACKGROUND: Duration of post-vaccination protection against COVID-19 in nursing home (NH) residents is a critical issue. The objective of this study was to estimate the duration of the IgG(S) response to the mRNA BNT162b2 vaccine in NH residents with (COV-Yes) or without (COV-No) history of SARS-CoV-2 infection. METHODS: A 574 COV-Yes and COV-No NH residents were included in 2 cohorts: Main (n = 115, median age 87 years) or Confirmatory (n = 459, median age 89 years). IgG(S) quantification was carried out at three different time points following the BNT162b2 vaccine: three (1st) and seven (2nd) months after the 2nd dose, and 1 month after the 3rd dose (3rd quantification) in the Main cohort, and twice (2nd and 3rd) in the Confirmatory cohort. The seroneutralization capacity according to COVID-19 history was also measured in a subgroup of patients. RESULTS: Neutralization capacity was strongly correlated with IgG(S) levels (R2 :76%) without any difference between COV-Yes and COV-No groups for the same levels of IgG(S). After the 2nd dose, duration of the assumed robust protection (IgG(S) >264 BAU/ml) was two-fold higher in the COV-Yes vs. COV-No group: 12.60 (10.69-14.44) versus 5.76 (3.91-8.64) months, with this advantage mainly due to the higher IgG(S) titers after the 2nd dose and secondary to a slower decay over time. After the 3rd dose, duration of robust protection was estimated at 11.87 (9.88-14.87) (COV-Yes) and 8.95 (6.85-11.04) (COV-No) months. These results were similar in both cohorts. CONCLUSIONS AND RELEVANCE: In old subjects living in NH, history of SARS-CoV-2 infection provides a clear advantage in the magnitude and duration of high IgG(S) titers following the 2nd dose. Importantly, the 3rd dose induces a much more pronounced IgG(S) response than the 2nd dose in COV-No subjects, the effect of which should be able to ensure a prolonged protection against severe forms of COVID-19 in these subjects.

Ovarian Telomerase and Female Fertility.

Women's fertility is characterized both quantitatively and qualitatively mainly by the pool of ovarian follicles. Monthly, gonadotropins cause an intense multiplication of granulosa cells surrounding the oocyte. This step of follicular development requires a high proliferation ability for these cells. Telomere length plays a crucial role in the mitotic index of human cells. Hence, disrupting telomere homeostasis could directly affect women's fertility. Strongly expressed in ovaries, telomerase is the most effective factor to limit telomeric attrition and preserve ovarian reserve. Considering these facts, two situations of infertility could be correlated with the length of telomeres and ovarian telomerase activity: PolyCystic Ovary Syndrome (PCOS), which is associated with a high density of small antral follicles, and Premature Ovarian Failure (POF), which is associated with a premature decrease in ovarian reserve. Several authors have studied this topic, expecting to find long telomeres and strong telomerase activity in PCOS and short telomeres and low telomerase activity in POF patients. Although the results of these studies are contradictory, telomere length and the ovarian telomerase impact in women's fertility disorders appear obvious. In this context, our research perspectives aimed to explore the stimulation of ovarian telomerase to limit the decrease in the follicular pool while avoiding an increase in cancer risk.

Telomere Length in Valve Tissue Is Shorter in Individuals With Aortic Stenosis and in Calcified Valve Areas.

BACKGROUND: Short telomere length (TL) is associated with age-related diseases, in particular cardiovascular diseases. However, whether the onset and course of aortic stenosis (AS) is linked to TL in aortic valves remains unknown. OBJECTIVES: To assess telomere dynamics (TL and telomerase activity) in aortic valves and the possible implication of TL in onset and course of AS. METHODS: DNA was extracted from aortic valves obtained from 55 patients (78.2% men; age, 37-79 years), who had undergone replacement surgery due to AS (AS group, n = 32), aortic valve regurgitation and aortic dilation (Non-AS group, n = 23). TL was measured by telomere restriction fragment analysis (TRF) in calcified and non-calcified aortic valve areas. Telomerase activity was evaluated using telomerase repeat amplification protocol (TRAP) in protein extracts from non-calcified and calcified areas of valves obtained from 4 additional patients (50% men; age, 27-70 years). RESULTS: TL was shorter in calcified aortic valve areas in comparison to non-calcified areas (n = 31, 8.58 ± 0.73 kb vs. 8.12 ± 0.75 kb, p < 0.0001), whereas telomerase activity was not detected in any of those areas. Moreover, patients from AS group displayed shorter telomeres in non-calcified areas than those from the Non-AS group (8.40 ± 0.64 kb vs. 8.85 ± 0.65, p = 0.01). CONCLUSIONS: Short telomeres in aortic valves may participate in the development of AS, while concurrently the calcification process seems to promote further local decrease of TL in calcified areas of valves.

Number and Replating Capacity of Endothelial Colony-Forming Cells are Telomere Length Dependent: Implication for Human Atherogenesis.

Background Short leukocyte telomere length (TL) is associated with atherosclerotic cardiovascular disease. Endothelial repair plays a key role in the development of atherosclerosis. The objective was to examine associations between TL and proliferative dynamics of endothelial colony-forming cells (ECFCs), which behave as progenitor cells displaying endothelial repair activity. Methods and Results To isolate ECFCs, we performed a clonogenic assay on blood samples from 116 participants (aged 24-94 years) in the TELARTA (Telomere in Arterial Aging) cohort study. We detected no ECFC clones in 29 (group 1), clones with no replating capacity in other 29 (group 2), and clones with replating capacity in the additional 58 (group 3). Leukocyte TL was measured by Southern blotting and ECFCs (ECFC-TL). Age- and sex-adjusted leukocyte TL (mean±SEM) was the shortest in group 1 (6.51±0.13 kb), longer in group 2 (6.69±0.13 kb), and the longest in group 3 (6.78±0.09 kb) (P<0.05). In group 3, ECFC-TL was associated with the number of detected clones (P<0.01). ECFC-TL (7.98±0.13 kb) was longer than leukocyte TL (6.74±0.012 kb) (P<0.0001) and both parameters were strongly correlated (r=0.82; P<0.0001). Conclusions Individuals with longer telomeres display a higher number of self-renewing ECFCs. Our results also indicate that leukocyte TL, as a proxy of TL dynamics in ECFCs, could be used as a surrogate marker of endothelial repair capacity in clinical and laboratory practice because of easy accessibility of leukocytes. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT02176941.

A genetic determinant of VEGF-A levels is associated with telomere attrition.

Telomere length (TL) is a hallmark of cellular aging and is associated with chronic diseases development. The vascular endothelial growth factor A (VEGF-A), a potent angiogenesis factor, is implicated in the pathophysiology of many chronic diseases. The aim of the present study was to investigate the associations between VEGF-A and TL. TL in leukocytes (LTL) and skeletal muscle (MTL) were measured, 10 VEGF-related polymorphisms genotyped, and VEGF-A plasma concentrations determined in 402 individuals from the TELARTA cohort. LTL/MTL ratio was calculated as an estimate of lifelong TL attrition. Associations between VEGF-A variants and levels, and TL parameters were investigated. We identified one significant association between the minor allele (T) of rs6993770 variant and LTL/MTL ratio (P=0.001143, ß=0.0148, SE=0.004516). The rs6993770 is an intronic variant of the ZFPM2 gene, which is involved in haematopoiesis and the identified association with increased telomere attrition could be due to increased haematopoiesis. No significant epistatic interaction was identified, and no association was found between levels of VEGF-A and any of assessed phenotypes. We identified a potential common genetic regulation between VEGF-A and telomere length attrition that could be explained by mechanisms of increased hematopoiesis and production of platelets. VEGF-A and TL could play an important role in personalized medicine of chronic diseases and identification of molecular links between them can promote the understanding of their complex implications.

The Nexus Between Telomere Length and Lymphocyte Count in Seniors Hospitalized With COVID-19.

Profound T-cell lymphopenia is the hallmark of severe coronavirus disease 2019 (COVID-19). T-cell proliferation is telomere length (TL) dependent and telomeres shorten with age. Older COVID-19 patients, we hypothesize, are, therefore, at a higher risk of having TL-dependent lymphopenia. We measured TL by the novel Telomere Shortest Length Assay (TeSLA), and by Southern blotting (SB) of the terminal restriction fragments in peripheral blood mononuclear cells of 17 COVID-19 and 21 non-COVID-19 patients, aged 87 ± 8 (mean ± SD) and 87 ± 9 years, respectively. TeSLA tallies and measures single telomeres, including short telomeres undetected by SB. Such telomeres are relevant to TL-mediated biological processes, including cell viability and senescence. TeSLA yields 2 key metrics: the proportions of telomeres with different lengths (expressed in %) and their mean (TeSLA mTL), (expressed in kb). Lymphocyte count (109/L) was 0.91 ± 0.42 in COVID-19 patients and 1.50 ± 0.50 in non-COVID-19 patients (p < .001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kb (p = .005) and positively correlated with TeSLA mTL (p = .03). Lymphocyte count was not significantly correlated with SB mTL in either COVID-19 or non-COVID-19 patients. We propose that compromised TL-dependent T-cell proliferative response, driven by short telomere in the TL distribution, contributes to COVID-19 lymphopenia among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons. Clinical Trials Registration Number: NCT04325646.

Telomere length in granulosa cells and leukocytes: a potential marker of female fertility? A systematic review of the literature.

In the context of a continuously increased delay of motherhood and of an increase of the incidence of premature ovarian failure, it is of the greatest interest to dispose of a predictive marker of the duration of the fertility window. Unfortunately, current available markers of women's fertility (hormonal rates or echography count of small follicles) have a poor predictive value of premature ovarian failure. In the last ten years, some studies have suggested that telomere length may be correlated with premature ovarian failure, but the results of these studies are contradictory.In accordance with guidelines from Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), this systematic review of the literature selected studies evaluating telomere length or telomerase activity in granulosa cells and/or in leukocytes as a premature ovarian failure marker.Five publications (252 premature ovarian failure patients) were included in this review of experimental evidence. Two of them studied telomere length and/or telomerase activity in granulosa cells and 4 in leukocytes in women with premature ovarian failure. For each study, authors determined if there was a positive or a negative correlation between telomeric parameters and premature ovarian failure.3 studies (178 premature ovarian failure patients) found shorter telomere length in granulosa cells and/or leukocytes and/or lower telomerase activity in premature ovarian failure patients. 2 studies (74 premature ovarian failure patients) presented contradictory results about the correlation of leucocyte telomere length with premature ovarian failure.Shorter telomeres and diminished telomerase activity in granulosa cells appear to be associated with ovarian insufficiency. However, the number of studies and of subjects within are low and the methodology questionable. The confirmation of these results is essential with more subjects, better defined populations and more adapted methodology, in order to consider telomere length in granulosa cells and/or in leucocytes as an early and reliable marker for the decline of ovarian function.

TERC Variants Associated with Short Leukocyte Telomeres: Implication of Higher Early Life Leukocyte Telomere Attrition as Assessed by the Blood-and-Muscle Model.

Short leukocyte telomere length (LTL) is associated with atherosclerotic cardiovascular disease (ASCVD). Mendelian randomisation studies, using single nucleotide polymorphisms (SNPs) associated with short LTL, infer a causal role of LTL in ASCVD. Recent results, using the blood-and-muscle model, indicate that higher early life LTL attrition, as estimated by the ratio between LTL and skeletal muscle telomere length (MTL), rather than short LTL at conception, as estimated by MTL, should be responsible of the ASCVD-LTL connection. We combined LTL and MTL measurements and SNPs profiling in 402 individuals to determine if 15 SNPs classically described as associated with short LTL at adult age were rather responsible for higher LTL attrition during early life than for shorter LTL at birth. Two of these SNPs (rs12696304 and rs10936599) were associated with LTL in our cohort (p = 0.027 and p = 0.025, respectively). These SNPs, both located on the TERC gene, were associated with the LTL/MTL ratio (p = 0.007 and p = 0.037, respectively), but not with MTL (p = 0.78 and p = 0.32 respectively). These results suggest that SNPs located on genes coding for telomere maintenance proteins may contribute to a higher LTL attrition during the highly replicative first years of life and have an impact later on the development of ASCVD.

A Mechanism for Severity of Disease in Older Patients with COVID-19: The Nexus between Telomere Length and Lymphopenia.

BACKGROUND: Lymphopenia due to a plummeting T-cell count is a major feature of severe COVID-19. T-cell proliferation is telomere length (TL)-dependent and TL shortens with age. Older persons are disproportionally affected by severe COVID-19, and we hypothesized that those with short TL have less capacity to mount an adequate T-cell proliferative response to SARS-CoV-2. This hypothesis predicts that among older patients with COVID-19, shorter telomeres of peripheral blood mononuclear cells (PBMCs) will be associated with a lower lymphocyte count. METHODS: Our sample comprised 17 COVID-19 and 21 non-COVID-19 patients, aged 87(8) (mean(SD)) and 87 (9) years, respectively. We measured TL by the Telomere Shortest Length Assay, a novel method that measures and tallies the short telomeres directly relevant to telomere-mediated biological processes. The primary analysis quantified TL as the proportion of telomeres shorter than 2 kilobases. For comparison, we also quantified TL by Southern blotting, which measures the mean length of telomeres. RESULTS: Lymphocyte count (109/L) was 0.91 (0.42) in COVID-19 patients and 1.50(0.50) in non-COVID-19 patients (P < 0.001). In COVID-19 patients, but not in non-COVID-19 patients, lymphocyte count was inversely correlated with the proportion of telomeres shorter than 2 kilobases (P = 0.005) and positively correlated with the mean of telomeres measured by TeSLA (P = 0.03). Lymphocyte counts showed no statistically significant correlations with Southern blotting results in COVID-19 or non-COVID-19 patients. CONCLUSIONS: These results support the hypothesis that a compromised TL-dependent T-cell proliferative response contributes to lymphopenia and the resulting disproportionate severity of COVID-19 among old adults. We infer that infection with SARS-CoV-2 uncovers the limits of the TL reserves of older persons.

The individual's signature of telomere length distribution.

Mean telomere length in human leukocyte DNA samples reflects the different lengths of telomeres at the ends of the 23 chromosomes and in an admixture of cells. However, only rudimentary information is available regarding the distribution of telomere lengths in all chromosomes and the different cell types in leukocyte samples. Understanding the configuration of leukocyte telomere length distribution (LTLD) could be helpful in capturing intrinsic elements that are not provided by the mean leukocyte telomere length (mLTL). The objective of this study was to analyse LTLD and its temporal variation in adults. Leukocyte samples were donated on two occasions (8 years apart) by 72 participants in the ADELAHYDE study. Telomere length was measured by Southern blotting of the terminal restriction fragments. Individuals with comparable mLTLs displayed different shapes of LTLDs. Inter-individual variation in LTLD shape was much larger than intra-individual variation in LTLD shape between baseline and follow-up leukocyte samples. These results show an important individual stability of LTLD shape over time indicating that each individual has a characteristic LTLD signature.