Telomere length is a critical determinant for survival in multiple myeloma

The variable clinical outcomes of Multiple Myeloma (MM) patients are incompletely defined by current prognostication tools. We examined the clinical utility of high‐resolution telomere length analysis as a prognostic marker in MM. Cohort stratification, using a previously determined length threshold for telomere dysfunction, revealed that patients with short telomeres had a significantly shorter overall survival (P < 0·0001; HR = 3·4). Multivariate modelling using forward selection identified International Staging System (ISS) stage as the most important prognostic factor, followed by age and telomere length. Importantly, each ISS prognostic subset could be further risk‐stratified according to telomere length, supporting the inclusion of this parameter as a refinement of the ISS. Despite the introduction of novel therapeutic modalities, patients with multiple myeloma (MM) display a heterogeneous clinical course, with survival ranging from a few months to over 10 years. Therefore, there is a requirement for reliable prognostic and predictive markers in this disease to allow for risk stratification and rational clinical decision‐making. The most commonly used prognostic system in MM is the International Staging System (ISS) that is based on serum levels of both β2‐micoglobulin and albumin (Greipp et al, 2005). Recently the ISS has been improved upon by the inclusion of cytogenetic information to take into account the level of lactate dehydrogenase and the considerable genetic heterogeneity known to occur in this disease (Palumbo et al, 2015). Hyperdiploidy and the loss of whole chromosome arms is frequently detected in MM, which includes, amongst others, gains of 1q in 30% of cases and the loss of 17p in 7% of cases (Walker et al, 2010). Short dysfunctional telomeres are susceptible to DNA repair activities that can result in chromosomal fusion and the initiation of cycles of anaphase‐bridging, breakage and fusion that can drive genomic instability and clonal evolution (Artandi et al, 2000; Roger et al, 2013; Jones et al, 2014). Telomere dysfunction has been documented in numerous haematological malignancies (Jones et al, 2012), and is one putative mechanism that may lead to the genetic and clinical heterogeneity observed in MM (Wu et al, 2003) and may relate to changes in the 3D telomeric architecture that have been documented in MM cells (Klewes et al, 2013). Recently, we have shown that high‐resolution telomere analysis, combined with a functional definition of telomere length, can provide powerful prognostic information in several tumour types, including chronic lymphocytic leukaemia (CLL)(Lin et al, 2014), myelodysplasia (unpublished observations) and breast cancer (Simpson et al, 2015). Here we sought to apply these technologies to examine the prognostic utility of telomere length in MM

Lifelong leukocyte telomere dynamics and survival in a free-living mammal

Telomeres play a fundamental role in the maintenance of genomic integrity at a cellular level, and average leukocyte telomere length (LTL) has been proposed as a biomarker of organismal aging. However, studies tracking LTL across the entire life course of individuals are lacking. Here, we examined lifelong patterns of variation in LTL among four birth cohorts of female Soay sheep (Ovis aries) that were longitudinally monitored and sampled from birth to death. Over the first 4 months of life, there was within‐individual loss of LTL, consistent with findings in the human and primate literature, but there was little evidence of consistent LTL loss associated with age after this point. Overall, we observed only weak evidence of individual consistency in LTL across years and over the entire lifespan: Within‐individual variation was considerable, and birth cohorts differed markedly in their telomere dynamics. Despite the high levels of LTL variation within the lifetimes of individuals, there remained significant associations between LTL and longevity. Detailed analysis of the longitudinal data set showed that this association was driven by improved survival of individuals with longer LTL over the first 2 years of life. There was no evidence that LTL predicted survival in later adulthood. Our data provide the first evidence from a mammal that LTL can predict mortality and lifespan under natural conditions, and also highlight the potentially dynamic nature of LTL within the lifetimes of individuals experiencing a complex and highly variable environment

Longitudinal telomere length shortening and cognitive and physical decline in later life:The Lothian Birth Cohorts 1936 and 1921

Telomere length is hypothesised to be a biological marker of both cognitive and physical ageing. Here we measure telomere length, and cognitive and physical abilities at mean ages 70, 73 and 76 years in the Lothian Birth Cohort 1936 (LBC1936), and at mean ages 79, 87, 90 and 92 years in the Lothian Birth Cohort 1921 (LBC1921). We investigate whether telomere length change predicts change in cognitive and physical abilities. In LBC1936 telomere length decreased by an average of 65 base pairs per year and in LBC1921 by 69 base pairs per year. However, change in telomere length did not predict change in cognitive or physical abilities. This study shows that, although cognitive ability, walking speed, lung function and grip strength all decline with age, they do so independently of telomere length shortening

Cross-sectional associations of sex hormones with leucocyte telomere length, a marker of biological age, in a community-based cohort of older men

Context: Telomeres protect chromosomes from damage, and shorter leucocyte telomere length (LTL) is a marker of advancing biological age. The association between testosterone (T) and its bioactive metabolites, dihydrotestosterone (DHT) and oestradiol (E2) with telomere length, particularly in older men, is uncertain. The study aimed to clarify associations of sex hormones with LTL in older men. Participants and methods: We used cross‐sectional data from 2913 men aged 76.7 ± 3.2 years with morning blood samples assayed for T, DHT, E2 (mass spectrometry), and sex hormone‐binding globulin (SHBG, immunoassay), to correlate sex hormones with LTL measured using PCR and expressed as T/S ratio in multivariable linear regression models adjusted for age, cardiometabolic risk factors and cardiovascular disease history. Results: Average difference per decade of age was T −0.46 nmol/L, DHT −0.11 nmol/L, E2 −7.5 pmol/L, SHBG +10.2 nmol/L and LTL (T/S ratio) −0.065. E2 correlated with T/S ratio (r = 0.038, P = 0.039) and SHBG was inversely correlated (r = −0.053, P = 0.004). After multivariable adjustment, E2 was associated with T/S ratio (per 1 SD increase E2: coefficient 0.011, P = 0.043), T and DHT were not associated. When E2 and SHBG were simultaneously included, E2 remained positively (coefficient 0.014, P = 0.014) and SHBG inversely (coefficient −0.013, P = 0.037) associated with T/S ratio. Conclusions: In older men, neither T nor DHT is associated with LTL while E2 is independently associated with LTL and SHBG is inversely associated, thus relating sex hormone exposure to lower biological age. Further research is needed to determine causality and clarify the role of sex hormones in male ageing