Association of accelerated dynamics of telomere sequence loss in peripheral blood leukocytes with incident knee osteoarthritis in Osteoarthritis Initiative cohort

Osteoarthritis (OA) is a chronic degenerative joint disease, being the main cause of laboral inability. Decreased telomere size in peripheral blood leukocytes (PBL) has been correlated with age-related pathologies, like knee OA. In a dynamic approach, telomere-qPCR was performed to evaluate the relative percentage of PBL telomere loss after a 6-year follow-up, in 281 subjects from the prospective osteoarthritis initiative (OAI) cohort. A radiological Kellgren-Lawrence (KL) grade ≥ 2 was indicative of knee OA. Individuals with knee OA at recruitment (n = 144) showed a higher PBL telomere loss after 6 years than those without knee OA at baseline (n = 137; p = 0.018). Moreover, individuals that developed knee OA during the follow-up (n = 39) exhibited a higher telomere loss compared to those that remained without OA (n = 98; p < 0.001). Logistic regression analysis showed that PBLs telomere loss was not significantly associated with knee OA at recruitment, but behaves as an independent risk factor associated with incidence after follow-up (OR: 1.043; p = 0.041), together with maximum KL grade (OR: 3.627; p = 0.011), body mass index-BMI (OR: 1.252; p < 0.001) and WOMAC-index (OR: 1.247; p = 0.021), at recruitment. The telomere decay in PBLs is faster in individuals with incident knee OA, possibly reflecting a systemic-global accelerated aging that enhances the cartilage degeneration.

Longer telomeres during early life predict higher lifetime reproductive success in females but not males

The mechanisms that contribute to variation in lifetime reproductive success are not well understood. One possibility is that telomeres, conserved DNA sequences at chromosome ends that often shorten with age and stress exposures, may reflect differences in vital processes or influence fitness. Telomere length often predicts longevity, but longevity is only one component of fitness and little is known about how lifetime reproductive success is related to telomere dynamics in wild populations. We examined the relationships between telomere length beginning in early life, telomere loss into adulthood and lifetime reproductive success in free-living house sparrows ( Passer domesticus ). We found that females, but not males, with longer telomeres during early life had higher lifetime reproductive success, owing to associations with longevity and not reproduction per year or attempt. Telomeres decreased with age in both sexes, but telomere loss was not associated with lifetime reproductive success. In this species, telomeres may reflect differences in quality or condition rather than the pace of life, but only in females. Sexually discordant selection on telomeres is expected to influence the stability and maintenance of within population variation in telomere dynamics and suggests that any role telomeres play in mediating life-history trade-offs may be sex specific.

Relationship between the dynamics of telomere loss in peripheral blood leukocytes from osteoarthritis patients and mitochondrial DNA haplogroup

Objective The evaluation of the evolution of telomere length from peripheral blood leukocytes (PBL) in subjects from the Osteoarthritis Initiative (OAI) cohort in relation to the incidence of osteoarthritis (OA) and explore its possible interactive influence with the mitochondrial DNA (mtDNA) haplogroup. Methods Dynamics of telomere sequence loss was quantified in PBL from initially healthy individuals, without symptoms or radiological signs, 78 carrying the mtDNA cluster HV and 47 with cluster JT, from the OAI, during a 72-month follow-up. The incidence of knee OA during this period (n=39) was radiographically established when Kellgren-Lawrence (KL) score increased from < 2 at recruitment to ≥ 2 during 72 months of follow-up. Multivariate analysis using binary logistic regression was performed to assess PBL telomere loss and mtDNA haplogroups as associated risk factors of incidence of knee OA Results Carriers of cluster HV showed an OA incidence twice that of the JT carriers (n=30 vs. n=9). Rate of PBL telomere loss was higher in cluster HV carriers and in incident individuals. Multivariate analysis showed that the dynamics of PBL telomere shortening can be a consistent risk marker of knee OA incidence. Non-incidents showed a slower telomere loss than incidents, the difference being more significant in carriers of cluster JT than in HV. Conclusion An increased telomere loss rate in PBL may reflect a systemic accelerated senescence phenotype which could be potentiated by the mitochondrial function, increasing the susceptibility of developing OA.

Telomere and Centromere Staining Followed by M-FISH Improves Diagnosis of Chromosomal Instability and Its Clinical Utility

Dicentric chromosomes are a relevant marker of chromosomal instability. Their appearance is associated with telomere dysfunction, leading to cancer progression and a poor clinical outcome. Here, we present Telomere and Centromere staining followed by M-FISH (TC+M-FISH) for improved detection of telomere dysfunction and the identification of dicentric chromosomes in cancer patients and various genetic syndromes. Significant telomere length shortening and significantly higher frequencies of telomere loss and deletion were found in the peripheral lymphocytes of patients with cancer and genetic syndromes relative to similar age-matched healthy donors. We assessed our technique against conventional cytogenetics for the detection of dicentric chromosomes by subjecting metaphase preparations to both approaches. We identified dicentric chromosomes in 28/50 cancer patients and 21/44 genetic syndrome patients using our approach, but only 7/50 and 12/44, respectively, using standard cytogenetics. We ascribe this discrepancy to the identification of the unique configuration of dicentric chromosomes. We observed significantly higher frequencies of telomere loss and deletion in patients with dicentric chromosomes (p < 10−4). TC+M-FISH analysis is superior to classical cytogenetics for the detection of chromosomal instability. Our approach is a relatively simple but useful tool for documenting telomere dysfunction and chromosomal instability with the potential to become a standard additional diagnostic tool in medical genetics and the clinic.

EXO1 resection at G-quadruplex structures facilitates resolution and replication

G-quadruplexes represent unique roadblocks to DNA replication, which tends to stall at these secondary structures. Although G-quadruplexes can be found throughout the genome, telomeres, due to their G-richness, are particularly predisposed to forming these structures and thus represent difficult-to-replicate regions. Here, we demonstrate that exonuclease 1 (EXO1) plays a key role in the resolution of, and replication through, telomeric G-quadruplexes. When replication forks encounter G-quadruplexes, EXO1 resects the nascent DNA proximal to these structures to facilitate fork progression and faithful replication. In the absence of EXO1, forks accumulate at stabilized G-quadruplexes and ultimately collapse. These collapsed forks are preferentially repaired via error-prone end joining as depletion of EXO1 diverts repair away from error-free homology-dependent repair. Such aberrant repair leads to increased genomic instability, which is exacerbated at chromosome termini in the form of dysfunction and telomere loss.