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Results for “replicative lifespan”

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PubMed1981

Altered DNA repair in fibroblasts from aged rats.

The role of DNA repair in the aging process was studied using fibroblast cultures derived from rats at the beginning (3 weeks) and at the end (2 years) of their potential lifespan. The effect of treatment of the cultures with the DNA-damaging agent, ethylnitrosourea, on the integrity of the pre-existing parental DNA and on de novo DNA synthesis was determined using the alkaline elution method. It was found that drug treatment resulted in lower levels of fragmentation of parental DNA and in decreased fractions of short daughter strands in cells derived from old relative to young animals. These results indicate an alteration of the processing of DNA damage in cells derived from aged rats.

Aging↗

PubMed1984

Increased organization of cytoskeleton accompanying the aging of human fibroblasts in vitro.

Fibroblastic cells of human origin have a limited lifespan in culture. One of the senescence-associated phenotypic changes is an increase in the abundance of cytoplasmic filaments. Human skin fibroblasts (strain 0011), derived from an 8-week-old male fetus, were passaged according to a predetermined schedule and examined at successive population doubling levels. In young rapidly growing cultures, fluorescence microscopy with NBD-Phallacidin shows a normal organization of the actin-containing fibers, microtubules and intermediate filaments, as has been described previously. At stages close to the end of the in vitro lifespan of the cell strain, large flat fibroblasts are the predominant cell type in culture. These large senescent fibroblasts contain numerous prominent actin fibers traversing the entire long axis of the cytoplasm. The fibers are often located adjacent to each other and appear to form a sheet on the ventral side of the cytoplasm. Staining of senescent cells with anti-tubulin antibody reveals an increase in the abundance of microtubules per cell and the distribution pattern is altered through the increase in the number of organization centers. Intermediate filaments are also more abundant and display tightly packed fibrillar sheets or bundles. Electron microscopic studies have confirmed the increased organization of microfilaments into bundles in senescent cells. These results suggest that during in vitro senescence, the increase in cell size is correlated with increased organization of the cytoskeleton. The presence of a rigid cytoskeletal structure may contribute in part to the inability of the senescent cell to replicate.

Cell Survival↗

PubMed2006

Dynamics of the male germline stem cell population during aging of Drosophila melanogaster.

Drosophila melanogaster has emerged as an important model system for the study of both stem cell biology and aging. Much is known about how molecular signals from the somatic niche regulate adult stem cells in the germline, and a variety of environmental factors as well as single point mutations have been shown to affect lifespan. Relatively little is known, however, about how aging affects specific populations of cells, particularly adult stem cells that may be susceptible to aging-related damage. Here we show that male germline stem cells (GSCs) are lost from the stem cell niche during aging, but are efficiently replaced to maintain overall stem cell number. We also find that the division rate of GSCs slows significantly during aging, and that this slowing correlates with a reduction in the number of somatic hub cells that contribute to the stem cell niche. Interestingly, slowing of stem cell division rate was not observed in long-lived methuselah mutant flies. We finally investigated whether two mechanisms that are thought to be used in other adult stem cell types to minimize the effects of aging were operative in this system. First, in many adult tissues stem cells exhibit markedly fewer cell cycles relative to transit-amplifying cells, presumably protecting the stem cell pool from replication-associated damage. Second, at any given time not all stem cells actively cycle, leading to 'clonal succession' from the reserve pool of initially quiescent stem cells. We find that neither of these mechanisms is used in Drosophila male GSCs.

Age Factors↗

PubMed2001

Search and selection processes in implicit and explicit word-stem completion performance in young, middle-aged, and older adults.

In the present investigation, we sought to (1) replicate previous reports of impaired word-stem completion (WSC) priming and cued recall performance in older adults, (2) gain a better understanding of the differential roles of search and selection processes in implicit and explicit WSC, and (3) determine the particular aspects of WSC performance that are influenced by age. Experiment 1 demonstrated that older adults primed and recalled fewer items on a WSC task than middle-aged adults did, who in turn primed and recalled fewer items than young adults did. A series of item analyses indicated that choice of a stem completion is influenced by two independent sources of information: the familiarity of the completion reflected by word frequency and the cue-specific match between the stem and the completion word based on the common pronunciation of the stem. Experiment 2 demonstrated that older adults utilized cue-specific matching to the same degree as young and middle-aged adults. However, the impact of target familiarity changed across the lifespan. Older adults produced and recalled high-frequency targets as well as young adults but produced and recalled fewer low-frequency targets than did young participants. The results are consistent with the view that older adults rely on familiarity to a greater degree than do young adults.

Adolescent↗

PubMed2006

The evolution of aging and age-related physical decline in mice selectively bred for high voluntary exercise.

We tested whether selective breeding for early-age high voluntary exercise behavior over 16 generations caused the evolution of lifelong exercise behavior, life expectancy, and age-specific mortality in house mice (Mus domesticus). Sixteenth-generation mice from four replicate selection lines and four replicate random-bred control lines were individually housed from weaning through death and divided between two activity treatments (either with or without running wheels). Thus, there were four treatment groups: selection versus control crossed with active versus sedentary. The effects of selective breeding on life expectancy and age-specific mortality differed between females and males. In females, sedentary selection mice had early and high initial adult mortality and thus the lowest increases in mortality with age. Active selection females had the lowest early adult mortality, had limited mortality during midlife, and exhibited rapid increases in mortality rates at the very end of life; thus, they had deferred senescence. Median life expectancy was greater for both groups of selection females than for the two complementary groups of control females. Like females, sedentary selection males had the highest early adult mortality, and slow but steadily increasing mortality over the entire lifetime. Unlike the active selection females, active control males had the lowest mortality across the lifespan (until the end of life). Interestingly, the males with the lowest median life expectancy were those in the active selection treatment group. In both sexes, running (km/week) decreased over the lifetime to very low and virtually equivalent levels at the end of life in control and selection mice. Overall, these results demonstrate an evolutionary cost of selective breeding for males, regardless of exercise level, but a benefit for females when they have an outlet for the up-selected behavior. We conclude that correlated evolution of senescence occurs in mice selectively bred for high voluntary wheel running; exercise per se is beneficial for control mice of both sexes, but the impact on the effect of selection depends on sex; and the behavioral effect of exercise selection at an early age declines throughout the life span, which demonstrates decreasing genetic correlations over age for the genes involved in increased exercise.

Aging↗

PubMed1981

Evolution of the distribution, proliferation and ultraviolet repair capacity of rat lens epithelial cells as a function of maturation and aging.

The symmetrical organization of lens epithelium was a determining factor in this study whose purpose was to investigate the growth of this tissue during development, maturation and aging. By direct observation it was possible to score all the nuclei, to determine four different zones of cellular density and to monitor them during the whole lifespan. The central zone is mainly quiescent and the proliferation at the periphery accounts for the low steady growth rate of the tissue. With aging there is a continuous decrease in the mitotic index and a cell size enlargement. These cells were able to perform unscheduled DNA synthesis in vitro after ultraviolet irradiation. There is an age-related decrease in DNA repair, but most of it occurs during development (until 59 weeks of age) and then remains constant (59-173 weeks). These results mean that in a differentiated pure cell population aging is not directly related to decline in unscheduled DNA synthesis.

Aging↗

PubMed1988

Investigations into the genotoxic potential of loxtidine, a long-acting H2-receptor antagonist.

Loxtidine, a potent, non-competitive histamine H2-receptor antagonist was evaluated for genotoxic potential using a range of short-term mutagenicity assays. Unequivocally negative results were obtained in a Salmonella/plate incorporation assay and a liquid pre-incubation assay (using S. typhimurium strains TA1535, TA100, TA1537, TA1538 and TA98), a fluctuation assay [using Escherichia coli strains WP2, WP2 uvrA (R46) and 343/113 lys60 (R46)], a gene conversion assay (using Saccharomyces cerevisiae JD1) and a human peripheral lymphocyte cytogenetic assay. All of these in vitro tests were carried out in the presence and absence of rat liver S9 mix. In addition, the major metabolites of loxtidine in the rat were also negative in the same range of microbial mutagenicity assays. Loxtidine was inactive in the mouse micronucleus test after oral administration. The potential nitrosatability of loxtidine was investigated using an expanded version of the WHO Nitrosation Assay Procedure, and detectable quantities of mutagenic nitroso-species were not formed. The subsequent appearance of carcinoid tumours within the gastric fundus of rodents treated orally with loxtidine for most of their natural lifespan, led to additional assays being carried out on this compound to determine whether the tumorigenic effects were due to alternative mutagenic mechanisms. Negative results were obtained in an in vitro unscheduled DNA synthesis assay using primary rat hepatocytes, and an assay for spindle damaging agents using Muntjac skin fibroblasts. It can be concluded from these results that loxtidine is unlikely to be a genotoxic carcinogen. The increase in carcinoid tumour incidence observed in rats and mice after loxtidine treatment was probably related to the prolonged achlorhydria produced by this potent unsurmountable histamine H2-receptor antagonist.

Animals↗

PubMed1996

Measurement of ionized magnesium with AVL 988/4 electrolyte analyzer: preliminary analytical and clinical results.

Only free magnesium has biological activity: technology for measuring the ionized fraction of magnesium is now available via ion-selective electrodes. We have evaluated an instrument (AVL 988/4) which determines ionized magnesium (cMg2+) with an ion-selective electrode based on the ionophore ETH 7025. The selectivity of the electrode is adequate for the ions normally present in plasma, except for calcium: the interference is automatically corrected by simultaneous measurements of calcium with compensation for the calcium interference to the magnesium signal. We have first verified possible interference caused by sampling procedures: known silicon interference has been avoided by use of glass tubes (BD Vacutainer with no additive, code 7626); heparin interference has been measured and found significant above 20 UI.mL-1 of plasma. Instrument evaluation according to NCCLS protocol gives the following imprecision results on 20 replicated analyses: cMg2+ (mmol.L-1) 1.29, 0.76, 0.23, CVs% (within-run) 0.67, 0.67, 3.00 and CVs% (between-run) 4.06, 3.91, 5.89 respectively. Linearity (in the range 0.23-1.60 mmol.L-1) was: measured cMg2+ = 0.981.(calculated cMg2+) + 0.009 mmol/L; r = 0.999. In healthy adults (n = 103) cMg2+ was in the range 0.46-0.74 mmol.L-1 (with a mean of 0.60 mmol/L and normal distribution). These values represent 57% to 84% of serum total magnesium concentration (TMg) (mean 71%). pH dependence of cMg2+ is present, usually to a lower extent with respect to cCa2+, but it seems different in patients with real or in vitro provoked acidosis and in hemodialyzed patients. Citrate interference on ionized magnesium measurements was found both in vitro and in vivo, whilst that due to lactate was demonstrated only in vitro. On a wide range of cMg2+ (n = 100), a good correlation is obtained both with TMg and ultrafiltrable Mg (UFMg): cMg2+ = 0.723.TMg + 0.008 mmol.L-1, r = 0.978; cMg2+ = 0.912.UFMg + 0.10 mmol.L-1, r = 0.968, respectively. The ionized magnesium in ultrafiltrate was found 25% lower than that in serum. The lifespan of the electrode, evaluated on the basis of both time from installation and on number of measured samples, was estimated longer than 4 months and able to analyze more than 1500 samples, whichever comes first. The four electrodes we used during 18 months behaved all the same way. The correlation between measurements performed in whole blood (WB-cMg2+) and in the corresponding serum (S-cMg2+) was excellent: WB-cMg2+ = 0.954.S-cMg2+ +0.02 mmol.L-1; r = 0.998; n = 60.

Adult↗

PubMed1992

Anticellular and antitumor activity of duocarmycins, novel antitumor antibiotics.

The anticellular and antitumor activities of novel antitumor antibiotics, duocarmycins (DUMs), were examined against human and murine tumor cells. DUMs consist of five compounds, A, B1, B2, C1 and C2, which possess a pharmacophore similar to that of CC-1065, a previously isolated antibiotic. Among them, DUMA exhibited ultrapotent growth-inhibitory activity with an IC50 value of 6 pM against human uterine cervix carcinoma HeLa S3 cells. DUMA and DUMB1 also inhibited the growth of adriamycin (ADM)-resistant lines of human nasopharynx carcinoma KB cells and breast carcinoma MCF-7 cells as well as their sensitive lines. DUMs inhibited the growth of s.c.-inoculated murine tumors such as B16 melanoma, sarcoma 180, M5076 sarcoma and colon 26. DUMs were also significantly effective in increasing the lifespan of i.p.-inoculated B16 melanoma-bearing mice, although their effect was marginal against other i.p.-inoculated tumors. As a whole, DUMB1 exhibited superior activity to the other four compounds. DUMB1 rapidly inhibited the incorporation of [3H]-TdR into macromolecules of HeLa S3 cells as compared with that of [3H]UR or [3H]leucine. DNA strand breaks were detected in DUMB1-treated HeLa S3 cells by agarose gel electrophoresis with a contour-clamped homogeneous electric field apparatus. These results indicate that DUMs possess interesting biological activities as DNA-targeting antitumor antibiotics.

Animals↗

PubMed2001

[The natural history of telomeres].

Telomeres are end chromosome structures, which may shorten because of DNA end replication problem and non-reparability of free-radical damage to telomeric DNA. Telomerase is an enzyme serving to maintain telomere length at a species-specific level. The absence of telomerase in somatic cells is widely believed to be the cause of the limited proliferative potential of somatic cells achieved when telomere length, which diminishes over successive cell generations, becomes critically short. However, telomeres are known to be highly heterogenous with regard to their length even in cloned cell populations. In this review data on telomer length distribution and changes in characteristics of these distributions observed over time are considered along with hypotheses about the nature of these phenomena. The following conclusions are drawn: causes of the known features of telomere length distribution are not limited to mere scattering and measurement error, and so any concepts concerning the relationships between telomere length and cell fate should take characteristics of telomere heterogeneity in consideration; the ratio of the initial telomere length and the rate of telomere shortening does not determine the proliferative potential of non-transformed cell populations and does not limit the lifespans of multicellular organisms; telomerase functions in non-germinal cells are either unnecessary or unknown; telomere heterogeneity may result from the stochastic nature of events committing cells to terminal differentiation and/or the loss of cell capacity to proliferate.

Aging↗

PubMed1998

Inhibitors of cyclin-dependent kinases induce features of replicative senescence in early passage human diploid fibroblasts.

After a limited number of population doublings (PDs), cultures of normal mammalian diploid cells undergo an irreversible growth arrest known as replicative senescence [1]. As well as contributing to cellular ageing, senescence is viewed as an important mechanism of tumour suppression by preventing the emergence of immortal cell clones [2-4]. Senescent cells have a number of characteristics that distinguish them from cycling or quiescent cells including elevated levels of two cyclin-dependent kinase (Cdk) inhibitors, p16INK4a and p21CIP1 [5-11]. Here, we demonstrate that both of these Cdk inhibitors, as well as other members of their protein families (the INK4 and CIP/KIP families, respectively [12]), induce several facets of the senescent phenotype when ectopically expressed in young human diploid fibroblasts. These include a reduced proliferative capacity, an altered size and shape, the presence of underphosphorylated retinoblastoma protein (pRb), increased expression of plasminogen activator inhibitor (PAI-1) and the appearance of senescence-associated beta-galactosidase (SA-beta-gal) activity [2,3,13-15]. A 20 amino acid peptide from p16INK4a that inhibits Cdks active in the G1 phase of the cell cycle [16] produces similar effects in a dose-dependent manner suggesting that, in primary fibroblasts, inhibition of G1-specific Cdk activity is sufficient to induce phenotypic changes that normally occur at the end of their finite lifespan.

Animals↗

PubMed2001

Conditional immortalization of freshly isolated human mammary fibroblasts and endothelial cells.

Reports differ as to whether reconstitution of telomerase activity alone is sufficient for immortalization of different types of human somatic cells or whether additional activities encoded by other "immortalizing" genes are also required. Here we show that ectopic expression of either the catalytic subunit of human telomerase (hTERT) or a temperature-sensitive mutant (U19tsA58) of simian virus 40 large-tumor antigen alone was not sufficient for immortalization of freshly isolated normal adult human mammary fibroblasts and endothelial cells. However, a combination of both genes resulted in the efficient generation of immortal cell lines irrespective of the order in which they were introduced or whether they were introduced early or late in the normal proliferative lifespan of the cultures. The order and timing of transduction, however, did influence genomic stability. Karyotype analysis indicated that introduction of both transgenes at early passage, with hTERT first, yielded diploid cell lines. Temperature-shift experiments revealed that maintenance of the immortalized state depended on continued expression of functional U19tsA58 large-tumor antigen, with hTERT alone unable to maintain growth at nonpermissive temperatures for U19tsA58 large-tumor antigen. Such conditional diploid lines may provide a useful resource for both cell engineering and for studies on immortalization and in vitro transformation.

Adult↗

PubMed2000

Reduction of Cdc25A contributes to cyclin E1-Cdk2 inhibition at senescence in human mammary epithelial cells.

Replicative senescence may be an important tumor suppressive mechanism for human cells. We investigated the mechanism of cell cycle arrest at senescence in human mammary epithelial cells (HMECs) that have undergone a period of 'self-selection', and as a consequence exhibit diminished p16INK4A levels. As HMECs approached senescence, the proportion of cells with a 2N DNA content increased and that in S phase decreased progressively. Cyclin D1-cdk4, cyclin E-cdk2 and cyclin A-cdk2 activities were not abruptly inhibited, but rather diminished steadily with increasing population age. In contrast to observations in fibroblast, p21Cip1 was not increased at senescence in HMECs. There was no increase in p27Kip1 levels nor in KIP association with targets cdks. While p15INK4B and its binding to both cdk4 and cdk6 increased with increasing passage, some cyclin D1-bound cdk4 and cdk6 persisted in senescent cells, whose inhibition could not be attributed to p15INK4B. The inhibition of cyclin E-cdk2 in senescent HMECs was accompanied by increased inhibitory phosphorylation of cdk2, in association with a progressive loss of Cdc25A. Recombinant Cdc25A strongly reactivated cyclin E-cdk2 from senescent HMECs suggesting that reduction of Cdc25A contributes to cyclin E-cdk2 inhibition and G1 arrest at senescence. Although ectopic expression of Cdc25A failed to extend the lifespan of HMECs, the exogenous Cdc25A appeared to lack activity in these cells, since it neither shortened the G1-to-S phase interval nor activated cyclin E-cdk2. In contrast, in the breast cancer-derived MCF-7 line, Cdc25A overexpression increased both cyclin E-cdk2 activity and the S phase fraction. Thus, mechanisms leading to HMEC immortalization may involve not only the re-induction of Cdc25A expression, but also activation of this phosphatase.

Adult↗

PubMed1999

A phylogenomic study of DNA repair genes, proteins, and processes.

The ability to recognize and repair abnormal DNA structures is common to all forms of life. Studies in a variety of species have identified an incredible diversity of DNA repair pathways. Documenting and characterizing the similarities and differences in repair between species has important value for understanding the origin and evolution of repair pathways as well as for improving our understanding of phenotypes affected by repair (e.g., mutation rates, lifespan, tumorigenesis, survival in extreme environments). Unfortunately, while repair processes have been studied in quite a few species, the ecological and evolutionary diversity of such studies has been limited. Complete genome sequences can provide potential sources of new information about repair in different species. In this paper, we present a global comparative analysis of DNA repair proteins and processes based upon the analysis of available complete genome sequences. We use a new form of analysis that combines genome sequence information and phylogenetic studies into a composite analysis we refer to as phylogenomics. We use this phylogenomic analysis to study the evolution of repair proteins and processes and to predict the repair phenotypes of those species for which we now know the complete genome sequence.

Adenosine Triphosphatases↗

PubMed1988

Transformation of human bronchial epithelial cells by infection with SV40 or adenovirus-12 SV40 hybrid virus, or transfection via strontium phosphate coprecipitation with a plasmid containing SV40 early region genes.

Normal human bronchial epithelial cells were infected with SV40 virus or an adenovirus 12-SV40 hybrid virus, or transfected via strontium phosphate coprecipitation with plasmids containing the SV40 early region genes. Colonies of morphologically altered cells were isolated and cultured; these cells had extended culture lifespans compared to normal human bronchial epithelial cells. All cultures eventually underwent senescence, with the exception of one which appears to have unlimited proliferative potential. Colonies arising after viral infection were screened for virus production by cocultivation with Vero cells; only viral nonproducer cultures were analyzed further. The cells retained electron microscopic features of epithelial cells, and keratin and SV40 T-antigen were detected by indirect immunofluorescence. All of the cultures were aneuploid with karyotypic abnormalities characteristic of SV40-transformed cells. No tumors formed after s.c. injection of the cells in nude mice. These cells should be useful for studies of multistage bronchial epithelial carcinogenesis.

Adenoviruses, Human↗

PubMed1989

Toxicity of an attapulgite sample studied in vivo and in vitro.

Conflicting data are found in the literature concerning the carcinogenic potency of attapulgite. We tested the carcinogenic potency of French attapulgite in rats, and compared it with 2 chrysotile samples: Rhodesian UICC (Ch A) and short Canadian fibres (Ch C). The mean length of the fibres was 0.77 micron (attapulgite), 3.21 microns (Ch A) and 1.25 microns (Ch C). The mean diameter was 0.06 micron in the 3 samples. The particles (20 mg) in saline were inoculated into the pleural cavity of Sprague-Dawley rats allowed to survive for their full lifespan. The incidence rates of mesothelioma were: 0% (saline controls), 0% (attapulgite), 19% (ChC) and 48% (Ch A). In vitro studies were carried out using cultures of rat pleural mesothelial cells (RPMC). Attapulgite and Ch C did not modify cell growth except at high doses of 10 micrograms/cm2. Unscheduled DNA synthesis (UDS) was detected using [3H]thymidine incorporation in confluent RPMC (GoG1 arrested) and a scintillation method. UDS was stimulated with either Ch A or Ch C at doses ranging from 2 to 10 micrograms/cm2. In contrast, attapulgite did not significantly enhance [3H]thymidine incorporation at doses ranging from 2 to 20 micrograms/cm2. The results show that the attapulgite tested here had no carcinogenic potency. The in vivo and in vitro reactivity of the fibres used in this experiment might perhaps be related to the fibre size; however, other parameters may also be important.

Animals↗

PubMed2005

BRAFE600-associated senescence-like cell cycle arrest of human naevi.

Most normal mammalian cells have a finite lifespan, thought to constitute a protective mechanism against unlimited proliferation. This phenomenon, called senescence, is driven by telomere attrition, which triggers the induction of tumour suppressors including p16(INK4a) (ref. 5). In cultured cells, senescence can be elicited prematurely by oncogenes; however, whether such oncogene-induced senescence represents a physiological process has long been debated. Human naevi (moles) are benign tumours of melanocytes that frequently harbour oncogenic mutations (predominantly V600E, where valine is substituted for glutamic acid) in BRAF, a protein kinase and downstream effector of Ras. Nonetheless, naevi typically remain in a growth-arrested state for decades and only rarely progress into malignancy (melanoma). This raises the question of whether naevi undergo BRAF(V600E)-induced senescence. Here we show that sustained BRAF(V600E) expression in human melanocytes induces cell cycle arrest, which is accompanied by the induction of both p16(INK4a) and senescence-associated acidic beta-galactosidase (SA-beta-Gal) activity, a commonly used senescence marker. Validating these results in vivo, congenital naevi are invariably positive for SA-beta-Gal, demonstrating the presence of this classical senescence-associated marker in a largely growth-arrested, neoplastic human lesion. In growth-arrested melanocytes, both in vitro and in situ, we observed a marked mosaic induction of p16(INK4a), suggesting that factors other than p16(INK4a) contribute to protection against BRAF(V600E)-driven proliferation. Naevi do not appear to suffer from telomere attrition, arguing in favour of an active oncogene-driven senescence process, rather than a loss of replicative potential. Thus, both in vitro and in vivo, BRAF(V600E)-expressing melanocytes display classical hallmarks of senescence, suggesting that oncogene-induced senescence represents a genuine protective physiological process.

Cell Cycle↗

PubMed2006

No association between telomere length and survival among the elderly and oldest old.

BACKGROUND: The consistent findings of a negative correlation between telomere length and replicative potential of cultured cells, as well as a decreasing telomere length in a number of different tissues in humans with age, have led to the suggestion that telomeres play a role in cellular aging in vivo and ultimately even in organismal aging. Furthermore, one small longitudinal study of elderly individuals has suggested that longer telomeres are associated with better survival. METHODS: Telomere length was measured as mean terminal restriction fragment length on blood cells from 812 persons, age 73 to 101 years, who participated in population-based surveys in 1997-1998. Among the participants were 652 twins. The participants were followed up through the Danish Civil Registration system until January 2005, at which time 412 (51%) were dead. RESULTS: Univariate Cox regression analyses revealed that longer telomeres were associated with better survival (hazard ratios = 0.89 [95% confidence interval = 0.76-1.04] per 1 kb in males and 0.79 [0.72-0.88] per 1 kb in females, respectively). However, including age in the analyses changed the estimates to 0.97 (0.83-1.14) and 0.93 (0.85-1.03), respectively. Intrapair comparison showed that among 175 twin pairs in which at least one died during follow up, it was the twin with the shorter telomere length who died first in 97 (55%) of the pairs (95% confidence interval = 48-63%). We could not confirm the recently reported negative correlation between telomere length and obesity or between telomere length and smoking. CONCLUSION: This longitudinal study of the elderly and oldest old does not support the hypothesis that telomere length is a predictor for remaining lifespan once age is controlled for.

Aged↗