Telomere lengths are characteristic in each human individual

Abstract

Background. A great deal of attention has been focused on telomeres in relation to cellular aging, immortality, and cancer. However, there is no simple link between telomeres and tissue turnover. We recently proposed a hypothesis that telomere shortening with aging and telomere lengths in different organs are characteristic for human individuals.

Methods. To test this, telomere lengths were measured using DNA from cerebral cortex, myocardium, liver, renal cortex and spleen tissues obtained from human subjects ranging in age from neonates to centenarians.

Results. Regression analyses demonstrated telomere reduction rates of 29–60 base pair (bp) per year in the liver, renal cortex and spleen, but no such decrease in the cerebral cortex and myocardium. Significant correlation was found between tissues within individuals, such as cerebral cortex versus (vs) myocardium, cerebral cortex vs liver, cerebral cortex vs renal cortex, myocardium vs liver, myocardium vs renal cortex, and liver vs renal cortex. In most cases, the longest telomeres were observed in the myocardium and the shortest in the liver or renal cortex.

Conclusions. Telomere lengths did not show clear correlation with tissue renewal times in vivo, but rather were characteristic for individuals.

Introduction

Normal human cells exhibit a limited capacity for proliferation in culture (Hayflick, 1965), and this finite replicative lifespan has frequently been used as a model of human aging in mitotic tissues and organs. This phenomenon is considered to be associated with reduction in telomere length as an indicator of the number of cell divisions undergone. The human telomere is a simple repeating sequence of six bases, TTAGGG, located at the ends of chromosomes (Moyzis et al., 1988). It is thought that telomeres have multiple roles, including protection against degeneration, reconstruction, fusion, and loss (Blackburn, 1991) as well as contributing to pairing of homologous chromosomes (Levy et al., 1992). The end-to-end chromosome fusions observed in some tumors could play a role in genetic instability associated with tumorigenesis, and possibly result from telomere loss (Blackburn, 1991). Telomeric repeats of DNA sequences at chromosome ends are shortened by 33–120 base pairs (bp) with each cell division in human fibroblasts (Harley et al., 1990) and lymphocytes (Vaziri et al., 1993) in vitro, but the question of telomere shortening with aging in many other cell types and human organs in vivo remains unclear.

We conducted systematic studies to measure telomere length in various human tissues and reported telomere shortening with aging in esophageal (Takubo et al., 1999), gastric (Furugori et al., 2000) and colonic (Nakamura et al., 2000) mucosae, the liver (Takubo et al., 2000), and other sites. Although there are limited data available on tissue renewal times in human tissues, it is considered that there are very large differences among human organ and tissue renewal times. Gastrointestinal mucosal epithelial renewal is very rapid; in contrast, renewal times of hepatocytes and renal tissue are very long. However, yearly reduction rates of telomere lengths in human tissues and organs have been reported to be similar and it is about 30–60 bp. Neurons and myocardium are exceptional in that they are relatively static with respect to cell turnover (Cameron, 1970), but there have been no reports regarding their telomere status. Moreover, relationships among telomere lengths in different organs or tissues in the same individual have not been examined. Since telomere lengths, as measured by Southern blot analysis in human tissues, demonstrate very large standard deviations among individuals (Hastie et al., 1990, Allsopp et al., 1992, Takubo et al., 1999, Takubo et al., 2000, Furugori et al., 2000, Nakamura et al., 2000), attention was concentrated on study of different tissues in many subjects.

In this study we therefore measured telomere lengths by Southern blot analysis in mitotically quiescent cerebral cortex and myocardium, as well as in liver and renal cortex samples from more than 100 autopsy cases within a wide age range, from neonates to centenarians. Particular attention was paid to yearly reduction rates in these four sites and variation in telomere lengths in different organs within individuals. Telomere lengths of splenic tissues from 30 subjects were also measured. We further reviewed previously reported reduction rates of telomeres in human organs and tissues in comparison with our own data.