Accelerated telomere shortening in rheumatic diseases: cause or consequence?

Accelerated aging of the immune system (immune aging), represented by telomere shortening, has been implicated in a variety of rheumatic diseases. Studies addressing telomere shortening in rheumatic diseases so far yielded controversial results. The current review aims to provide an overview on the role of immune aging in a plethora of immune-mediated conditions including systemic sclerosis, rheumatoid arthritis, systemic lupus erythematosus and osteoarthritis. The main question this review aims to answer is whether rheumatic diseases cause accelerated aging or that accelerated aging drives rheumatic diseases.     

Immunosenescence and rheumatoid arthritis: does telomere shortening predict impending disease?

The pathogenesis of RA, a disabling autoimmune disease, is incompletely understood. Early in the development of RA there appears to be loss of immune homeostasis and regulation, and premature immunosenescence. While identification of risk factors and understanding of the phases of RA pathogenesis are advancing, means of accurately predicting an individual's risk of developing RA are currently lacking. Telomere length has been proposed as a potential new biomarker for the development of RA that could enhance prediction of this serious disease. Studies examining telomere length in relation to RA have found that telomere erosion appears to proceed more rapidly in subjects with RA than in healthy controls, and that telomere lengths are shorter in those with the RA-risk HLA-shared epitope genes. These studies have been small, however, with retrospective or cross-sectional designs. The potential role of telomere shortening as an independent biomarker for future RA risk, perhaps strongly genetically determined by HLA-SE genes, after controlling for known risk factors such as smoking, body mass index and immunosuppressant medication use, as well as systemic inflammation, is an unanswered question.     

Large-scale parent�Cchild comparison confirms a strong paternal influence on telomere length

Telomere length is documented to have a hereditary component, and both paternal and X-linked inheritance have been proposed. We investigated blood cell telomere length in 962 individuals with an age range between 0 and 102 years. Telomere length correlations were analyzed between parent–child pairs in different age groups and between grandparent–grandchild pairs. A highly significant correlation between the father''s and the child''s telomere length was observed (r=0.454, P<0.001), independent of the sex of the offspring (father–son: r=0.465, P<0.001; father–daughter: r=0.484, P<0.001). For mothers, the correlations were weaker (mother–child: r=0.148, P=0.098; mother–son: r=0.080, P=0.561; mother–daughter: r=0.297, P=0.013). A positive telomere length correlation was also observed for grandparent–grandchild pairs (r=0.272, P=0.013). Our findings indicate that fathers contribute significantly stronger to the telomere length of the offspring compared with mothers (P=0.012), but we cannot exclude a maternal influence on the daughter''s telomeres. Interestingly, the father–child correlations diminished with increasing age (P=0.022), suggesting that nonheritable factors have an impact on telomere length dynamics during life.     

Can telomere alterations predict biochemical recurrence in prostate adenocarcinoma? A preliminary study

Telomeres function in human somatic tissues to stabilize chromosome ends. Telomere shortening can be one of the ways that cause chromosomal instability in the pathogenesis of prostatic carcinoma. In the current study, we evaluated telomere length (TL) in normal and malignant prostate tissues, and its association with prognostic factors and with time to biochemical tumor recurrence. Tissue microarrays constructed from paraffin blocks from radical prostatectomy specimens containing 61 randomly selected cases were used. Sections were hybridized with a Cy3-labeled telomere-specific peptide nucleic acid probe. TL, proportional to probe fluorescence intensity, was visually evaluated. Statistical analysis was done to relate TL clinical and pathological prognostic variables. The majority (49/61) of prostate cancers displayed abnormally short telomeres. Univariate analysis revealed inverse correlation between telomere shortening in tumor and Gleason scores (p = 0.017). Multivariate analyses pointed to TL as an independent predictor in addition to serum pre-operative PSA for reduced biochemical progression-free survival (p = 0.035). Telomere shortening is a common alteration in prostatic adenocarcinoma. Normal or long telomeres are rarely seen and, when present, seem to provide a growth advantage for the tumor as being an advocate for poor differentiation.     

Stable telomere length and telomerase expression from naïve to memory B-lymphocyte differentiation

Telomere length and telomerase activity play important roles in regulating replicative lifespan of cells. The length of telomeres also serves as a marker for the replicative history and for the remaining replicative potential of cells. Differential telomere length has been reported in human na?ve and memory T cells but not in na?ve versus memory B-lymphocytes. We report here an analysis of telomere length and induced telomerase expression in na?ve (CD27(-)) and memory (CD27(+)) B cells from normal adults. Although both na?ve and memory B cells lose telomere repeats with age, there is no consistent difference in telomere length between these two B cell subsets. Furthermore, both na?ve and memory B cells are capable of inducing telomerase activity at similar levels after in vitro stimulation independent of donor's age. Finally, there is a slow increase of memory B cells in peripheral blood with age. Together, these findings suggest that B cells are capable of maintaining telomere length during differentiation from na?ve to memory B cells and this ability is maintained through age.     

Nutrition, oxidative damage, telomere shortening, and cellular senescence: individual or connected agents of aging?

There is substantial and long-standing literature linking the level of general nutrition to longevity. Reducing nutrition below the amount needed to sustain maximum growth increases longevity in a wide range of organisms. Oxidative damage has been shown to be a major feature of the aging process. Telomere shortening is now well established as a key process regulating cell senescence in vitro. There is some evidence that the same process may be important for aging in vivo. Very recently it has been found that oxidative damage accelerates telomere shortening. It is therefore possible for us to propose as an outline hypothesis that the level of nutrition determines oxidative damage which in turn determines telomere shortening and cell senescence and that this pathway is important in determining aging and longevity in vivo. We also propose that telomeres in addition to their well-recognized role in "counting" cell divisions are also, through their GGG sequence, important monitors of oxidative damage over the life span of a cell. This may explain the evolutionary conservations of this triplet in the repeat telomere sequence unit.     

Meta-analysis of telomere length in 19?713 subjects reveals high heritability,stronger maternal inheritance and a paternal age effect

Telomere length (TL) has been associated with aging and mortality, but individual differences are also influenced by genetic factors, with previous studies reporting heritability estimates ranging from 34 to 82%. Here we investigate the heritability, mode of inheritance and the influence of parental age at birth on TL in six large, independent cohort studies with a total of 19 713 participants. The meta-analysis estimate of TL heritability was 0.70 (95% CI 0.64–0.76) and is based on a pattern of results that is highly similar for twins and other family members. We observed a stronger mother–offspring (r=0.42; P-value=3.60 × 10⁻⁶¹) than father–offspring correlation (r=0.33; P-value=7.01 × 10⁻⁵), and a significant positive association with paternal age at offspring birth (β=0.005; P-value=7.01 × 10⁻⁵). Interestingly, a significant and quite substantial correlation in TL between spouses (r=0.25; P-value=2.82 × 10⁻³⁰) was seen, which appeared stronger in older spouse pairs (mean age ≥55 years; r=0.31; P-value=4.27 × 10⁻²³) than in younger pairs (mean age<55 years; r=0.20; P-value=3.24 × 10⁻¹⁰). In summary, we find a high and very consistent heritability estimate for TL, evidence for a maternal inheritance component and a positive association with paternal age.     

T-cell mean telomere lengths changes in treatment naïve HIV-infected patients randomized to G-CSF or placebo simultaneously with initiation of HAART

The effect of highly active antiretroviral therapy (HAART) and granulocyte colony stimulating factor (G‐CSF) on mean telomere restriction fragment (TRF) length of peripheral blood mononuclear cells (PBMC) was examined in 11 treatment naïve human immunodeficiency virus (HIV)‐infected individuals with a CD4⁺ T‐cell count < 350cells/mm³. Patients were randomized to HAART combined with G‐CSF thrice weekly for 12 weeks (n = 6) or placebo (n = 5). An increase in the mean TRF lengths was observed in PBMC of patients on HAART after 24 weeks of treatment mainly owing to increased mean CD8⁺ T‐cell TRF lengths. However, in the group of patients on HAART combined with G‐CSF no changes of PBMC mean TRF length was observed during treatment or during 12 weeks of follow‐up. The mean CD4⁺ T‐cell TRF length did not change in any of the two groups. These results confirm that HAART induces mainly the lengthening of the mean CD8⁺ T‐cell TRF length. However, G‐CSF given simultaneously with HAART induces an inhibition of the expected lengthening in mean TRF length. These results do therefore not support the use of adjuvant G‐CSF treatment simultaneously when initiating HAART and should further be evaluated before use in non‐neutropenic HIV‐infected patients.     

Does cellular aging relate to patterns of allostasis?: An e`xamination of basal and stress reactive HPA axis activity and telomere length

Long-term exposure to stress and its physiological mediators, in particular cortisol, may lead to impaired telomere maintenance. In this study, we examine if greater cortisol responses to an acute stressor and/or dysregulated patterns of daily cortisol secretion are associated with shorter telomere length. Twenty-three postmenopausal women comprising caregivers for dementia partners (n=14) and age- and BMI-matched non-caregivers provided home sampling of cortisol-saliva samples at waking, 30 min after waking, and bedtime, and a 12-hour overnight urine collection. They were also exposed to an acute laboratory stressor throughout which they provided saliva samples. Peripheral blood mononuclear cells were isolated from a fasting blood sample and assayed for telomere length. As hypothesized, greater cortisol responses to the acute stressor were associated with shorter telomeres, as were higher overnight urinary free cortisol levels and flatter daytime cortisol slopes. While robust physiological responses to acute stress serve important functions, the long-term consequences of frequent high stress reactivity may include accelerated telomere shortening.     

Prolonged exposure of naïve CD8+ T cells to interleukin-7 or interleukin-15 stimulates proliferation without differentiation or loss of telomere length

Interleukin (IL)‐7 and IL‐15 are cytokines implicated in homeostatic control of the peripheral CD8 T‐cell pool. We compared the effects of IL‐7 and IL‐15 on survival and proliferation of purified human CD8⁺ T‐cell subsets. Low concentrations of either cytokine reduced the spontaneous apoptosis of all subsets, and enhancement of survival corresponded to the extent of Bcl‐2 up‐regulation. Surprisingly, although minimal proliferation of naïve CD8⁺ T cells was observed during the first week of culture with cytokines, a marked expansion of these cells occurred at later time points, particularly in response to IL‐15. This occurred largely without phenotypic change or acquisition of effector function, indicating a dissociation of differentiation from proliferation. Notably, progression of naïve CD8⁺ T cells through several cell divisions resulted in up‐regulation of telomerase and the maintenance of telomere length. These data show that IL‐7 and IL‐15 induce cell proliferation and rescue from apoptosis in a concentration, time and subset‐dependent manner, and have implications for the homeostatic expansion of the naïve CD8⁺ T‐cell pool.