Telomere length predicts replicative capacity of human fibroblasts.

Abstract

When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explae by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes, shorten throughout the life-span of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m = -0.2 doubling per yr; r = -0.42; P = 0.02) and between telomeric DNA and donor age (m = -15 base pairs per yr; r = -0.43; P = 0.02). However, there was a stiking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublngs per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent slglcantiy fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker ofsomatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age ofthe donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.The cellular senescence model of aging was founded by landmark experiments of Hayflick and Moorhead (1), who firmly established that normal human fibroblasts have a finite life-span in vitro. Although much evidence supports this model (2-8), the mechanism accounting for the finite division capacity of normal somatic cells remains a mystery. Olovnikov (9, 10) suggested that the cause of cellular senescence is the gradual loss of telomeres due to the end-replication problem-i.e., the inability of DNA polymerase to completely replicate the 3' end of linear duplex DNA (11) (for review, see refs. 12 and 13).Telomeres play a critical role in chromosome structure and function. They prevent aberrant recombination (14-16) and apparently function in the attachment ofchromosome ends to the nuclear envelope (17 (31)(32)(33). These observations have led to the telomere hypothesis of cellular aging (13), in which loss of telomeres due to incomplete DNA replication and absence of telomerase provides a mitotic clock that ultimately signals cell cycle exit, limiting the replicative capacity of somatic cells. To further explore this hypothesis, we have examined the relationship between telomere length, in vivo age, and replicative capacity of fibroblasts from normal donors and subjects with the Hutchinson-Gilford syndrome of premature aging (34,35). We have also determined the relationship between telomere length in sperm DNA and donor age.MATERIALS AND MET...

Normal growth and regenerating ability of myoblasts from unaffected muscles of facioscapulohumeral muscular dystrophy patients

“…As a mean (7.53), they did not differ from that of the two controls (6.970.2 and 7.470.3), and all telomere sizes kept within the range of normal values (6.5-8.5), as published. [42][43][44] Number of D4Z4 repeats…”

Human cord blood-derived primitive progenitors are enriched in CD34+c-kit− cells: correlation between long-term culture-initiating cells and telomerase expression

“…2,6 Since telomerase activity is absent in most somatic cells, telomere shortening occurs in these cells. [7][8][9][10] In contrast, immortal tumor cell lines and germ cell tissues show high levels of telomerase activity, resulting in a stable telomere length and unlimited proliferation. 7,11 It was recently reported that human hematopoietic stem/progenitor cells and activated lymphocytes exhibit low levels of telomerase activity.…”

“…[7][8][9][10] In contrast, immortal tumor cell lines and germ cell tissues show high levels of telomerase activity, resulting in a stable telomere length and unlimited proliferation. 7,11 It was recently reported that human hematopoietic stem/progenitor cells and activated lymphocytes exhibit low levels of telomerase activity. [12][13][14] However, telomere shortening is observed in these cells, implying that the level of activity is insufficient to maintain stable telomere length and that the proliferative potential of these cells is limited.…”

Induction of bovine articular chondrocyte senescence with oxidized low‐density lipoprotein through lectin‐like oxidized low‐density lipoprotein receptor 1

“…The telomere hypothesis is generally accepted as the explanation for the mechanism that underlies cell senescence (26,27). Structures of telomeres, the terminal, guanine-rich sequences of chromosomes (TTAGGG repeats in humans and other vertebrates), work to stabilize the chromosome during replication by protecting the chromosome end against exonucleases.…”

“…Structures of telomeres, the terminal, guanine-rich sequences of chromosomes (TTAGGG repeats in humans and other vertebrates), work to stabilize the chromosome during replication by protecting the chromosome end against exonucleases. Telomere length decreases with replication, and when this has decreased to a critical length, the cell is signaled to stop dividing and to enter cellular senescence (replicative senescence) (26,27). Telomerase is an RNAdependent DNA polymerase that synthesizes telomeric DNA sequences.…”