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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG030678-05
Application #
8417671
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Dutta, Chhanda
Project Start
2009-02-15
Project End
2013-06-30
Budget Start
2013-02-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$277,034
Indirect Cost
$89,894
Name
University of Medicine & Dentistry of NJ
Department
Pediatrics
Type
Schools of Medicine
DUNS #
623946217
City
Newark
State
NJ
Country
United States
Zip Code
07107
Ding, Zhihao; Mangino, Massimo; Aviv, Abraham et al. (2014) Estimating telomere length from whole genome sequence data. Nucleic Acids Res 42:e75
Bendix, Laila; Thinggaard, Mikael; Kimura, Masayuki et al. (2014) Association of leukocyte telomere length with fatigue in nondisabled older adults. J Aging Res 2014:403253
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
Elbers, Clara C; Garcia, Melissa E; Kimura, Masayuki et al. (2014) Comparison between southern blots and qPCR analysis of leukocyte telomere length in the health ABC study. J Gerontol A Biol Sci Med Sci 69:527-31
Steenstrup, Troels; Hjelmborg, Jacob V B; Mortensen, Laust H et al. (2013) Leukocyte telomere dynamics in the elderly. Eur J Epidemiol 28:181-7
Kark, Jeremy D; Nassar, Hisham; Shaham, Dorith et al. (2013) Leukocyte telomere length and coronary artery calcification in Palestinians. Atherosclerosis 229:363-8
Daniali, Lily; Benetos, Athanase; Susser, Ezra et al. (2013) Telomeres shorten at equivalent rates in somatic tissues of adults. Nat Commun 4:1597
Steenstrup, Troels; Hjelmborg, Jacob V B; Kark, Jeremy D et al. (2013) The telomere lengthening conundrum--artifact or biology? Nucleic Acids Res 41:e131
Aviv, Abraham; Susser, Ezra (2013) Leukocyte telomere length and the father's age enigma: implications for population health and for life course. Int J Epidemiol 42:457-62
Aviv, Abraham (2012) Genetics of leukocyte telomere length and its role in atherosclerosis. Mutat Res 730:68-74

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