Association between leukocyte telomere length and COVID-19 severity.

Background: Inter-individual variations in the clinical manifestations of SARS-CoV-2 infection are among the challenging features of COVID-19. The known role of telomeres in cell proliferation and immune competency highlights their possible function in infectious diseases. Variability in telomere length is an invaluable parameter in the heterogeneity of the clinical presentation of diseases. Result: In this study, our aim was to investigate the possible association between leukocyte telomere length (LTL) and COVID-19 severity. LTL was measured in 100 patients with moderate and severe forms of COVID-19 using the quantitative PCR (q-PCR) method. Statistical analysis confirmed a strong inverse correlation between relative LTL and COVID-19 severity. Conclusions: These findings suggest that LTL can be a useful parameter for predicting disease severity in patients, as individuals with short telomeres may have a higher risk of developing severe COVID-19. Supplementary Information: The online version contains supplementary material available at 10.1186/s43042-023-00415-z.

'Legs feed the wolf': An evolutionary perspective on psychosocial stress, physical activity, and their associations with telomere length in NCAA student-athletes and non-athletes

Psychosocial stress negatively impacts our mental and physical health, predisposing us to illness, worsened mental health, and accelerated aging. Conversely, regular physical activity, such as exercise and sports training, positively impacts our health. These opposing effects are intriguing because psychosocial stress and physical activity were inextricably linked throughout human evolution. Large populations of humans have only recently begun transitioning into more sedentary lifestyles, uncoupling psychosocial stress from physical activity. Improving our understanding of these two factors and their interactions will, in turn, improve our understanding of the mechanisms through which psychosocial stress impacts health in both modern and ancestral human populations.My dissertation examines whether physical activity moderates the association between psychosocial stress and capillary blood telomere length in NCAA student-athletes and their non- athlete counterparts in the general student population. My first paper develops an in-depth comparison of psychosocial stress in these two groups using a suite of psychosocial stress surveys and an adapted cognitive interview protocol. Student-athletes (N=65) reported lower levels of current perceived stress and anxiety symptoms (p<0.05) but similar levels of childhood psychosocial stress, recent exposure to external stressors, and depressive symptoms compared to non-athletes (N=57). My second paper utilized self-report and objective measures of physical activity (i.e., accelerometry) to compare physical activity patterns in these groups. Student- athletes (N=60) both self-reported higher levels of physical activity and recorded higher levels of activity via accelerometry (p>0.001) compared to non-athletes (N=50). Interestingly, categorical measures of activity levels (i.e., time spent in moderate-to-vigorous physical activity) identified Rowers as the most active among student-athletes, but continuous measures of activity levels (e.g., total physical activity level) identified Track and Field athletes as the most active (p>0.05 for both comparisons).My third and final paper tested whether higher physical activity weakened the association between childhood psychosocial stress and telomere length estimated from capillary blood collected on Hemaspot HF devices (N=111). Telomeres are DNA sequences that protect the ends of chromosomes. They shorten with cell replication, age, and oxidative stress, leading to functional decline with age and worsened health outcomes. Importantly, psychosocial stress is thought to accelerate TL shortening. My a priori analyses did not support a direct association between psychosocial stress, physical activity, or the interaction of these variables and telomere length. However, a post hoc analysis found that individuals who recorded higher total physical activity demonstrated a positive association between childhood psychosocial stress and telomere length (i.e., higher childhood stress predicted longer telomeres) while individuals who recorded lower total physical activity had a negative association (i.e., higher childhood psychosocial stress predicted shorter telomeres).My results do not offer explicit support for the hypothesis that physical activity moderates the effects of psychosocial stress on telomere length. However, my project adds to the literature in at least several ways. It produced a novel and much-needed comparison of psychosocial stress between NCAA student-athletes and non-athletes. It illustrated and validated several data collection techniques for psychosocial stress and physical activity. Further, my telomere findings offer an exciting direction for the future exploration of psychosocial stress- physical activity interactions. Lastly, this work improves our overall understanding of NCAA student-athletes' mental and physical health and how their unique circumstances intersect with the ongoing effects of the COVID-19 pandemic. (PsycInfo Database Record (c) 2023 APA, all rights reserved)

The Impact of Biological Ageing on Clinical Severity in Hospitalized Covid-19 Patients

Background: Previous data has suggested that shorter telomere length (TL) is associated with higher risk of adverse COVID-19 outcomes, independent of several major risk factors for COVID-19 including age. Aim(s): We aimed at further exploring the relationship between TL and COVID-19 outcome in hospitalized patients. Method(s): 257 patients with proven COVID-19 infection with or without respiratory symptoms were included. Leucocyte TL was determined using qPCR (quantitative polymerase chain reaction) in leukocytes collected at the time of hospitalization. Clinical assessment related to disease severity and progress were collected from medical records, hospitalization duration, ventilation, early warning score (EWS) and clinical improvement using the WHO-scores. Result(s): Patients with longer TL at admission had less severe outcomes and a more rapid health improvement. the odds ratios for a 1-SD increment in TL associated with hospitalization duration were 0.58 (95%Cl: 0.46-0.73: P<0.0001) unadjusted and 0.77 (95%Cl:0.59-0.99: P=0.044) adjusted for age, sex, BMI, smoking, ethnicity and comorbidities. In men, a 1-SD increment in TL was associated with lower odds (adjusted OR=0.48 95%Cl 0.30-0.77 P=0.0015) to be on ventilation, and with a lower EWS at admission (adjusted s=0.13 95%Cl:0.23-0.02 P=0.024). Finally, a 1-SD increment in TL in men was associated with a stronger decline in disease severity (based on WHOscores) after 30 days post-hospitalization(adjusted s=0.29 95%Cl:0.56-0.03 P=0.029). Conclusion(s): Biological ageing forms an additional risk factor in COVID-19 infected patients to have more disease severity and progression. TL, especially in men, may form a biological basis in these observations.

Factors associated with the humoral response after three doses of COVID-19 vaccination in kidney transplant recipients.

Introduction: Kidney transplant recipients showed a weak humoral response to the mRNA COVID-19 vaccine despite receiving three cumulative doses of the vaccine. New approaches are still needed to raise protective immunity conferred by the vaccine administration within this group of high-risk patients. Methods: To analyze the humoral response and identify any predictive factors within these patients, we designed a prospective monocentric longitudinal study of Kidney transplant recipients (KTR) who received three doses of mRNA-1273 COVID-19 vaccine. Specific antibody levels were measured by chemiluminescence. Parameters related to clinical status such as kidney function, immunosuppressive therapy, inflammatory status and thymic function were analyzed as potential predictors of the humoral response. Results: Seventy-four KTR and sixteen healthy controls were included. One month after the administration of the third dose of the COVID-19 vaccine, 64.8% of KTR showed a positive humoral response. As predictive factors of seroconversion and specific antibody titer, we found that immunosuppressive therapy, worse kidney function, higher inflammatory status and age were related to a lower response in KTR while immune cell counts, thymosin-a1 plasma concentration and thymic output were related to a higher humoral response. Furthermore, baseline thymosin-a1 concentration was independently associated with the seroconversion after three vaccine doses. Discussion: In addition to the immunosuppression therapy, condition of kidney function and age before vaccination, specific immune factors could also be relevant in light of optimization of the COVID-19 vaccination protocol in KTR. Therefore, thymosin-a1, an immunomodulatory hormone, deserves further research as a potential adjuvant for the next vaccine boosters.

RELATIVE TELOMERE LENGTH IMPACT ON MORTALITY OF COVID-19: SEX DIFFERENCES.

INTRODUCTION: Increasing age is associated with severity and higher mortality of COVID-19. Telomere shortening is associated with higher risk of infections and may be used to identify those patients who are more likely to die. We evaluated the association between relative telomere length (RTL) and COVID-19 mortality. METHODS: RTL was measured in patients hospitalized because of COVID-19. We used Kaplan-Meier method to analyze survival probabilities, and Cox regression to investigate the association between RTL and mortality (30 and 90 days). RESULTS: 608 patients were included in the analysis (mean age =72.5 years, 41.1% women, and 53.8% Caucasic). During the study period, 75 people died from COVID-19 and 533 survived. Lower RTL was associated with a higher risk of death in women either at 30 (adjusted HR (aHR)=3.33; 95%CI=1.05-10.00; p=0.040) and at 90 days (aHR=3.57; 95%CI=1.23-11.11; p=0.019). CONCLUSION: Lower RTL was associated with a higher risk of dying of COVID-19 in women. This finding suggests that RTL has an essential role in the prognosis of this subset of the population. This article is protected by copyright. All rights reserved.

Causal association of epigenetic aging and COVID-19 severity and susceptibility: A bidirectional Mendelian randomization study.

Observational data from China, the United States, France, and Italy suggest that chronological age is an adverse COVID-19 outcome risk factor, with older patients having a higher severity and mortality rate than younger patients. Most studies have gotten the same view. However, the role of aging in COVID-19 adverse effects is unclear. To more accurately assess the effect of aging on adverse COVID-19, we conducted this bidirectional Mendelian randomization (MR) study. Epigenetic clocks and telomere length were used as biological indicators of aging. Data on epigenetic age (PhenoAge, GrimAge, Intrinsic HorvathAge, and HannumAge) were derived from an analysis of biological aging based on genome-wide association studies (GWAS) data. The telomere length data are derived from GWAS and the susceptibility and severity data are derived from the COVID-19 Host Genetics Initiative (HGI). Firstly, epigenetic age and telomere length were used as exposures, and following a screen for appropriate instrumental variables, we used random-effects inverse variance weighting (IVW) for the main analysis, and combined it with other analysis methods (e.g., MR Egger, Weighted median, simple mode, Weighted mode) and multiple sensitivity analysis (heterogeneity analysis, horizontal multiplicity analysis, "leave-one-out" analysis). For reducing false-positive rates, Bonferroni corrected significance thresholds were used. A reverse Mendelian randomization analysis was subsequently performed with COVID-19 susceptibility and severity as the exposure. The results of the MR analysis showed no significant differences in susceptibility to aging and COVID-19. It might suggest that aging is not a risk factor for COVID-19 infection (P-values are in the range of 0.05-0.94). According to the results of our analysis, we found that aging was not a risk factor for the increased severity of COVID-19 (P > 0.05). However, severe COVID-19 can cause telomere lengths to become shorter (beta = -0.01; se = 0.01; P = 0.02779). In addition to this, severe COVID-19 infection can slow the acceleration of the epigenetic clock "GrimAge" (beta = -0.24, se = 0.07, P = 0.00122), which may be related to the closely correlation of rs35081325 and COVID-19 severity. Our study provides partial evidence for the causal effects of aging on the susceptibility and severity of COVID-19.

Shorter telomere length is associated with COVID-19 hospitalization and with persistence of radiographic lung abnormalities.

BACKGROUND: Age and comorbidity are the main determinants of COVID-19 outcome. Shorter leukocyte telomere length (TL), a hallmark of biological aging, has been associated with worse COVID-19 outcomes. We sought to determine TL in patients with severe COVID-19 requiring hospitalization to analyze whether clinical outcomes and post-COVID-19 manifestations are associated with shorter TL. RESULTS: We analyzed 251 patients with PCR-confirmed COVID-19, hospitalized in the first months of the pandemics. We determined TL in PBL at admission by quantitative-PCR (qPCR) analysis in patients. A healthy cohort from the same area with a similar age range (n = 169) was used to calculate TL Z-scores. After hospital discharge, 144 COVID-19 survivors were followed-up for persistent COVID-19 manifestations. A second TL determination was performed in a smaller group of 63 patients 1 year later and compared with baseline TL. Hospitalized COVID-19 patients had a decreased baseline age-adjusted TL Z-score compared to the reference group. No differences in Z-scores were observed in patients with different COVID-19 outcomes, classified as WHO ordinal scores. In 144 patients, followed for a median of 8 months, post-COVID manifestations were not associated to differences in TL. Persistence of lung radiographic abnormalities was associated with shorter baseline TL. In patients with a second TL determination, further telomere shortening (TS) was observed in 35% and telomere lengthening in 49%. Patients with further TS had suffered a more severe disease. CONCLUSION: Shorter TL is associated with COVID-19 hospitalization but not with hospital clinical outcomes nor with persistent post-COVID-19 manifestations. Delayed resolution of radiographic lung abnormalities was also associated with shorter TL.

Telomere length as a biomarker of aging and diseases

As research related to healthspan and lifespan has become a hot topic, the necessity for a reliable and practical biomarker of aging (BoA), which can provide information about mortality and morbidity risk, along with remaining life expectancy, has increased. The chromosome terminus non-coding protective structure that prevents genomic instability is called a telomere. The continual shortening of telomeres, which affects their structure as well as function, is a hallmark of agedness. The aforementioned process is a potential cause of age-related diseases (ARDs), leading to a bad prognosis and a low survival rate, which compromise health and longevity. Hence, studies scrutinizing the BoAs often include telomere length (TL) as a prospective candidate. The results of these studies suggest that TL measurement can only provide an approximate appraisal of the aging rate, and its implementation into clinical practice and routine use as a BoA has many limitations and challenges. Nevertheless, measuring TL while determining other biomarkers can be used to assess biological age. This review focuses on the importance of telomeres in health, senescence, and diseases, as well as on summarizing the results and conclusions of previous studies evaluating TL as a potential BoA.

Telomere Length Regulation.

The number of (TTAGGG)n repeats at the ends of chromosomes is highly variable between individual chromosomes, between different cells and between species. Progressive loss of telomere repeats limits the proliferation of pre-malignant human cells but also contributes to aging by inducing apoptosis and senescence in normal cells. Despite enormous progress in understanding distinct pathways that result in loss and gain of telomeric DNA in different cell types, many questions remain. Further studies are needed to delineate the role of damage to telomeric DNA, replication errors, chromatin structure, liquid-liquid phase transition, telomeric transcripts (TERRA) and secondary DNA structures such as guanine quadruplex structures, R-loops and T-loops in inducing gains and losses of telomere repeats in different cell types. Limitations of current telomere length measurements techniques and differences in telomere biology between species and different cell types complicate generalizations about the role of telomeres in aging and cancer. Here some of the factors regulating the telomere length in embryonic and adult cells in mammals are discussed from a mechanistic and evolutionary perspective.

Telomere Length and COVID-19 Outcomes: A Two-Sample Bidirectional Mendelian Randomization Study.

Observational studies have found a relationship between directly measured short leukocyte telomere length (LTL) and severe coronavirus disease 19 (COVID-19). We investigated the causal association between genetically predicted LTL and COVID-19 susceptibility or severity. A previous genome-wide association study (GWAS) of 78,592 European-ancestry participants identified single nucleotidepolymorphisms (SNPs) that can be utilized to genetically predict LTL. Summary-level data for COVID-19 outcomes were analyzed from the COVID-19 Host Genetics Initiative. A two-sample bidirectional Mendelian randomization (MR) study was designed to evaluate these causal relationships. Using an inverse-weighted MR analysis and population-based controls, genetically predicted LTL did not reveal any significant association with COVID-19 susceptibility (odds ratio (OR): 0.94; 95% CI: 0.85-1.04; p = 0.202) or severity (OR: 0.85; 95% CI: 0.70-1.03; p = 0.099). Similar results were found for five other definitions of cases/controls and/or COVID-19 outcomes. Six additional MR methods and sensitivity analyses were conducted after removing variants with potential horizontal pleiotropy and including variants at a liberal significance level, which produced similar results. Using SNPs identified for the prediction of LTL from another GWAS study, we found a non-significant association for COVID-19 susceptibility or severity with narrower CIs toward the null hypothesis. No proof of genetically predicted COVID-19 phenotypes remained causally associated with genetically predicted LTL, and the null association was consistent with a lack of significant genetic correlation. Genetic evidence does not support shorter LTL as a causal risk factor for COVID-19 susceptibility or severity.

Association between COVID-19 and telomere length: A bidirectional Mendelian randomization study.

Several traditional observational studies suggested an association between COVID-19 and leukocyte telomere length (LTL), a biomarker for biological age. However, whether there was a causal association between them remained unclear. We aimed to investigate whether genetically predicted COVID-19 is related to the risk of LTL, and vice versa. We performed bidirectional Mendelian randomization (MR) study using summary statistics from the genome-wide association studies of critically ill COVID-19 (n = 1 388 342) and LTL (n = 472 174) of European ancestry. The random-effects inverse-variance weighted estimation method was applied as the primary method with several other estimators as complementary methods. Using six single-nucleotide polymorphisms (SNPs) of genome-wide significance as instrumental variables for critically ill COVID-19, we did not find a significant association of COVID-19 on LTL (ß = 0.0075, 95% confidence interval [CI]: -0.018 to 0.021, p = 0.733). Likewise, using 97 SNPs of genome-wide significance as instrumental variables for LTL, we did not find a significant association of LTL on COVID-19 (odds ratio = 1.00, 95% CI: 0.79-1.28, p = 0.973). Comparable results were obtained using MR-Egger regression, weighted median, and weighted mode approaches. We did not find evidence to support a causal association between COVID-19 and LTL in either direction.

A cautionary note on altered pace of aging in the COVID-19 era.

Coronavirus disease 2019 (COVID-19) is highly age-dependent due to hi-jacking the molecular control of the immune cells by the severe acute respiratory syndrome-corona virus 2 (SARS-CoV-2) leading to aberrant DNA methylation (DNAm) pattern of blood in comparison to normal individuals. These epigenetic modifications have been linked to perturbations to the epigenetic clock, development of long COVID-19 syndrome, and all-cause mortality risk. I reviewed the effects of COVID-19 on different molecular age markers such as the DNAm, telomere length (TL), and signal joint T-cell receptor excision circle (sjTREC). Integrating the accumulated clinical research data, COVID-19 and novel medical management may alter the pace of aging in adult individuals (<60 years). As such, COVID-19 might be a confounder in epigenetic age estimation similar to life style diversities, pathogens and pathologies which may influence the interpretation of DNAm data. Similarly, the SARS-CoV-2 affects T-lymphocyte function with possible influence on sjTREC levels. In contrast, TL measurements performed years before the SARS-CoV-2 pandemic proved that short TL predisposes to severe COVID- 19 independently from chronological age. However, the persistence of COVID-19 epigenetic scars and the durability of the immune response after vaccination and their effect on the ongoing pace of aging are still unknown. In the light of these data, the heterogeneous nature of the samples in these studies mandates a systematic evaluation of the currrent methods. SARS-CoV-2 may modify the reliability of the age estimation models in real casework because blood is the most common biological sample encountered in forensic contexts.

Are Dyskeratosis Congenita patients at higher risk of symptomatic COVID-19?

Dyskeratosis Congenita (DC) is a rare and heterogeneous disease. This disorder is resulted from a defect in the telomere maintenance in stem cells. Telomerase RNA component, shelterin complex, and telomerase reverse transcriptase are mutated in this disease. Many studies have previously confirmed shorter leukocyte telomere length in DC. On the other hand, the association between telomere length and Coronavirus disease 2019 (COVID-19) indicated that people with a short telomere background mostly show more severe symptoms related to COVID-19, and the mortality rate among them increases as well. Because patients with DC have an abnormally short telomere length, in the current study, we hypothesized that they are at higher risk of developing symptomatic COVID-19 that requires further clinical care.

Hispanic/Latino Acculturation Profiles and Telomere Length: Latent Class Analysis on a Nationally Representative Sample.

Background: Acculturation profiles and their impact on telomere length among foreign-born Hispanics/Latinos living in the United States (US) are relatively unknown. The limited research available has linked acculturation with shortened telomere length. Objectives: To identify acculturation profiles among a US representative sample of Hispanics/Latinos and to then examine telomere length differences between profiles. Methods: We conducted a latent class analysis among a non-institutionalized US-representative sample of Hispanics/Latinos using the 1999-2002 National Health and Nutrition Examination Survey (N = 2,292). The latent variable of acculturation was assessed by length of time in the US and language used as a child, read and spoken, usually spoken at home, used to think, and used with friends (i.e., Spanish and/or English). Telomere length assessed from leukocytes was used as the distal continuous outcome. Results: We identified five profiles: (1) low acculturated [33.2% of sample]; (2) partially integrated [18.6% of sample]; (3) integrated [19.4% of sample]; (4) partially assimilated [15.1% of sample]; and (5) assimilated [13.7% of sample]. Acculturation profiles revealed nuanced differences in conditional probabilities with language use despite the length of time spent in the US. While telomere length did vary, there were no significant differences between profiles. Conclusion: Profiles identified revealed that possible life-course and generational effects may be at play in the partially assimilated and assimilated profiles. Our findings expand public health research using complex survey data to identify and assess the dynamic relationship of acculturation profiles and health biomarkers, while being among the first to examine this context using a person-centered approach.

Shorter leukocyte telomere length is associated with severity of COVID-19 infection.

The infection by COVID-19 is a serious global public health problem. An efficient way to improve this disease's clinical management would be to characterize patients at higher risk of progressing to critically severe infection using prognostic biomarkers. The telomere length could be used for this purpose. Telomeres are responsible for controlling the number of maximum cell divisions. The telomere length is a biomarker of aging and several diseases. We aimed to compare leukocyte telomere length (LTL) between patients without COVID-19 and patients with different clinical severity of the infection. Were included 53 patients who underwent SARS-CoV-2 PCR divided in four groups. The first group was composed by patients with a negative diagnosis for COVID-19 (n = 12). The other three groups consisted of patients with a confirmed diagnosis of COVID-19 divided according to the severity of the disease: mild (n = 15), moderate (n = 17) and severe (n = 9). The LTL was determined by Q-PCR. The severe group had the shortest LTL, followed by the moderate group. The negative and mild groups showed no differences. There is an increase of patients with hypertension (p = 0.0099) and diabetes (p = 0.0067) in moderate and severe groups. Severe group was composed by older patients in comparison with the other three groups (p = 0.0083). Regarding sex, there was no significant difference between groups (p = 0.6279). In an ordinal regression model, only LTL and diabetes were significantly associated with disease severity. Shorter telomere length was significantly associated with the severity of COVID-19 infection, which can be useful as a biomarker or to better understand the SARS-CoV-2 pathophysiology.

Short telomeres increase the risk of severe COVID-19.

Telomeres are non-coding DNA sequences that protect chromosome ends and shorten with age. Short telomere length (TL) is associated with chronic diseases and immunosenescence. The main risk factor for mortality of coronavirus disease 2019 (COVID-19) is older age, but outcome is very heterogeneous among individuals of the same age group. Therefore, we hypothesized that TL influences COVID-19-related outcomes. In a prospective study, we measured TL by Flow-FISH in 70 hospitalized COVID-19 patients and compared TL distribution with our reference cohort of 491 healthy volunteers. We also correlated TL with baseline clinical and biological parameters. We stained autopsy lung tissue from six non-survivor COVID-19 patients to detect senescence-associated ß-galactosidase activity, a marker of cellular aging. We found a significantly higher proportion of patients with short telomeres (<10th percentile) in the COVID-19 patients as compared to the reference cohort (P<0.001). Short telomeres were associated with a higher risk of critical disease, defined as admission to intensive care unit (ICU) or death without ICU. TL was negatively correlated with C-reactive protein and neutrophil-to-lymphocyte ratio. Finally, lung tissue from patients with very short telomeres exhibit signs of senescence in structural and immune cells. Our results suggest that TL influences the severity of the disease.