Leukocyte telomere length (LTL) is a complex genetic trait. LTL undergoes attrition with age and is associated with a host of aging related diseases and environmental conditions that diminish the human lifespan. Moreover, LTL forecasts mortality in the elderly. Cross-sectional studies have established that LTL is shorter in adult men than women and in individuals with cardiovascular diseases than in their healthy peers. LTL is also relatively short in individuals who are smokers, sedentary, overweight or of low socio-economic status. Collectively, such observations suggest that LTL is a biomarker of human aging. The two elements that contribute to leukocyte telomere dynamics are LTL and its age-dependent attrition rate. Whereas considerable information is available about LTL, little is known about the links between LTL attrition rate and aging related diseases. This project will resort to a longitudinal model in same-sex twin pairs to test the following central hypotheses: (i) Age-dependent leukocyte telomere attrition is faster in men than in women and in post-menopausal than pre- menopausal women;(ii) Leukocyte telomere attrition rate is faster under conditions of increased oxidative stress/inflammation, which are often associated with increased insulin resistance and diminished circulating IGF-1;(iii) In the elderly, LTL but not age-dependent telomere attrition rate is a predictor of mortality. This feature explains in part the longer lifespan of women than men;(iv) Age-dependent leukocyte telomere attrition is heritable. These hypotheses will be tested in two cohorts of Danish twins: the Geminakar Study and the Longitudinal Study of Aging Danish Twins (LSADT). The following are the project's specific aims: 1) Examine leukocyte telomere dynamics by Southern blots and real time-PCR measurements of telomeres, based on two occasions that span 10 years in adult twins (aged 18-63 at the baseline examination) and explore the roles of gender and menopause in telomere attrition and their links with obesity, insulin resistance, IGF-1 and indices of oxidative stress/inflammation;2) Examine the links between leukocyte telomere dynamics and mortality/survival, based on leukocyte telomere measurements on two occasions, spanning 10 years, in elderly twins (at least 73 years old at the baseline examination). We will also explore the role of CMV and EBV infections in LTL dynamics. In a subset of the elderly, we will evaluate by flow FISH telomere signal intensities in CD8+ and CD4+ cells. Findings will refine our understanding of human telomere biology and its connections with aging and lifespan.
In this study we will examine whether the rate of telomere shortening in leukocytes records the risk for the development of insulin resistance in adults and forecasts mortality in the elderly. We will also examine whether the rate of telomere attrition is faster in men than in women and in post-menopausal than pre-menopausal women. Our findings will provide a new insight into the gender gap in human longevity (women live longer than men) and the role of insulin resistance in the human lifespan.
| Aviv, Abraham; Anderson, James J; Shay, Jerry W (2017) Mutations, Cancer and the Telomere Length Paradox. Trends Cancer 3:253-258 |
| Verhulst, Simon; Dalgård, Christine; Labat, Carlos et al. (2016) A short leucocyte telomere length is associated with development of insulin resistance. Diabetologia 59:1258-65 |
| Cohen-Manheim, Irit; Doniger, Glen Michael; Sinnreich, Ronit et al. (2016) Increased attrition of leukocyte telomere length in young adults is associated with poorer cognitive function in midlife. Eur J Epidemiol 31:147-57 |
| Hjelmborg, Jacob B; Dalgård, Christine; Möller, Soren et al. (2015) The heritability of leucocyte telomere length dynamics. J Med Genet 52:297-302 |
| Boccardi, Virginia; Razdan, Neetu; Kaplunov, Jessica et al. (2015) Stn1 is critical for telomere maintenance and long-term viability of somatic human cells. Aging Cell 14:372-81 |
| Mangino, Massimo; Christiansen, Lene; Stone, Rivka et al. (2015) DCAF4, a novel gene associated with leucocyte telomere length. J Med Genet 52:157-62 |
| Dalgård, Christine; Benetos, Athanase; Verhulst, Simon et al. (2015) Leukocyte telomere length dynamics in women and men: menopause vs age effects. Int J Epidemiol 44:1688-95 |
| Aviv, Abraham; Kark, Jeremy D; Susser, Ezra (2015) Telomeres, atherosclerosis, and human longevity: a causal hypothesis. Epidemiology 26:295-9 |
| Hjelmborg, Jacob B; Dalgård, Christine; Mangino, Massimo et al. (2015) Paternal age and telomere length in twins: the germ stem cell selection paradigm. Aging Cell 14:701-3 |
| Subramanian, Subha; Liu, Chunyu; Aviv, Abraham et al. (2014) Stromal cell-derived factor 1 as a biomarker of heart failure and mortality risk. Arterioscler Thromb Vasc Biol 34:2100-5 |
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