Browse
Submit Data
Databases
API
Help

Dataset Information

11 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

In utero TNF-? treatment induces telomere shortening in young adult mice in an ATF7-dependent manner.

ABSTRACT: Epidemiological studies indicate that exposure to stress during intrauterine life is associated with shorter telomeres in young adulthood, and a correlation between telomere length in early life and lifespan has been suggested. However, empirical studies evaluating these phenomena have not been performed, and the mechanism of stress-induced telomere shortening remains unknown. Since the level of tumour necrosis factor ? (TNF-?) in peripheral blood cells is increased by various psychological stresses, the effect of TNF-? administration to pregnant mice on telomere length in adulthood was examined in the present study. In utero TNF-? treatment-induced telomere shortening in adult mice. Telomere shortening was observed in certain tissues such as the bone marrow, spleen, and lung, and was detected at specific age ranges during adulthood. Telomere shortening was not observed in mice lacking the stress-responsive transcription factor ATF7, which contributes to heterochromatin formation in the absence of stress. The present study identified the conditions under which in utero TNF-? treatment induces telomere shortening in adulthood.

SUBMITTER: Liu B

PROVIDER: S-EPMC4794794 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

ATF7 mediates TNF-?-induced telomere shortening.

Project description:Telomeres maintain the integrity of chromosome ends and telomere length is an important marker of aging. The epidemiological studies suggested that many types of stress including psychosocial stress decrease telomere length. However, it remains unknown how various stresses induce telomere shortening. Here, we report that the stress-responsive transcription factor ATF7 mediates TNF-?-induced telomere shortening. ATF7 and telomerase, an enzyme that elongates telomeres, are localized on telomeres via interactions with the Ku complex. In response to TNF-?, which is induced by various stresses including psychological stress, ATF7 was phosphorylated by p38, leading to the release of ATF7 and telomerase from telomeres. Thus, a decrease of ATF7 and telomerase on telomeres in response to stress causes telomere shortening, as observed in ATF7-deficient mice. These findings give credence to the idea that various types of stress might shorten telomere.

| S-EPMC5961373 | biostudies-literature

Telomere shortening by transgenerational transmission of TNF-?-induced TERRA via ATF7.

Project description:Various stresses increase disease susceptibility and accelerate aging, and increasing evidence suggests that these effects can be transmitted over generation. Epidemiological studies suggest that stressors experienced by parents affect the longevity of their offspring, possibly by regulating telomere dynamics. Telomeres are elongated by telomerase and shortened by certain stresses as well as telomere repeat-containing RNA (TERRA), a telomere transcript. However, the mechanism underlying the transgenerational effects is poorly understood. Here, we show that TNF-?, which is induced by various psychological stresses, induces the p38-dependent phosphorylation of ATF7, a stress-responsive chromatin regulator, in mouse testicular germ cells. This caused a release of ATF7 from the TERRA gene promoter in the subtelomeric region, which disrupted heterochromatin and induced TERRA. TERRA was transgenerationally transmitted to zygotes via sperm and caused telomere shortening. These results suggest that ATF7 and TERRA play key roles in paternal stress-induced telomere shortening in the offspring.

| S-EPMC6326783 | biostudies-literature

Accelerated Telomere Shortening in Acromegaly; IGF-I Induces Telomere Shortening and Cellular Senescence.

Project description:Patients with acromegaly exhibit reduced life expectancy and increased prevalence of age-related diseases, such as diabetes, hypertension, and cardiovascular disease. However, the underlying mechanism has not been fully elucidated. Telomere shortening is reportedly associated with reduced life expectancy and increased prevalence of these age-related diseases.We measured telomere length in patients with acromegaly using quantitative PCR method. The effect of GH and IGF-I on telomere length and cellular senescence was examined in human skin fibroblasts.Patients with acromegaly exhibited shorter telomere length than age-, sex-, smoking-, and diabetes-matched control patients with non-functioning pituitary adenoma (0.62 ± 0.23 vs. 0.75 ± 0.35, respectively, P = 0.047). In addition, telomere length in acromegaly was negatively correlated with the disease duration (R2 = 0.210, P = 0.003). In vitro analysis revealed that not GH but IGF-I induced telomere shortening in human skin fibroblasts. Furthermore, IGF-I-treated cells showed increased senescence-associated ?-galactosidase activity and expression of p53 and p21 protein. IGF-I-treated cells reached the Hayflick limit earlier than GH- or vehicle-treated cells, indicating that IGF-I induces cellular senescence.Shortened telomeres in acromegaly and cellular senescence induced by IGF-I can explain, in part, the underlying mechanisms by which acromegaly exhibits an increased morbidity and mortality in association with the excess secretion of IGF-I.

| S-EPMC4598111 | biostudies-literature

Deregulated telomere transcription causes replication-dependent telomere shortening and promotes cellular senescence.

Project description:Telomeres are transcribed into non-coding TElomeric Repeat containing RNAs (TERRA). We have employed a transcriptionally inducible telomere to investigate how telomere transcription affects telomere function in Saccharomyces cerevisiae. We report that telomere shortening resulting from high levels of telomere transcription stems from a DNA replication-dependent loss of telomere tracts, which can occur independent of both telomerase inhibition and homologous recombination. We show that in order for telomere loss to occur, transcription must pass through the telomere tract itself producing a TERRA molecule. We demonstrate that increased telomere transcription of a single telomere leads to a premature cellular senescence in the absence of a telomere maintenance mechanism (telomerase and homology directed repair). Similar rapid senescence and telomere shortening are also seen in sir2? cells with compromised telomere maintenance, where TERRA levels are increased at natural telomeres. These data suggest that telomere transcription must be tightly controlled to prevent telomere loss and early onset senescence.

| S-EPMC3413150 | biostudies-literature

Cell cycle-dependent and -independent telomere shortening accompanies murine brain aging.

Project description:Replication-based telomere shortening during lifetime is species- and tissue-specific, however, its impact on healthy aging is unclear. In particular, the contribution of telomere truncation to the aging process of the CNS, where replicative senescence alone fails to explain organ aging due to low to absent mitotic activity of intrinsic populations, is undefined. Here, we assessed changes in relative telomere length in non-replicative and replicative neural brain populations and telomerase activity as a function of aging in C57BL/6 mice. Telomeres in neural cells and sub-selected neurons shortened with aging in a cell cycle-dependent and -independent manner, with preponderance in replicative moieties, implying that proliferation accelerates, but is not prerequisite for telomere shortening. Consistent with this telomere erosion, telomerase activity and nuclear TERT protein were not induced with aging. Knockdown of the Rela subunit of NF-?B, which controls both telomerase enzyme and subcellular TERT protein allocation, did also not influence telomerase activity or telomere length, in spite of its naive up-regulation selectively under aging conditions. We conclude that telomere instability is intrinsic to physiological brain aging beyond cell replication, and appears to occur independently of a functional interplay with NF-?B, but rather as a failure to induce or relocate telomerase.

| S-EPMC6286833 | biostudies-literature

Persistent NF-κB activation in muscle stem cells induces proliferation-independent telomere shortening.

Project description:During the repeated cycles of damage and repair in many muscle disorders, including Duchenne muscular dystrophy (DMD), the muscle stem cell (MuSC) pool becomes less efficient at responding to and repairing damage. The underlying mechanism of such stem cell dysfunction is not fully known. Here, we demonstrate that the distinct early telomere shortening of diseased MuSCs in both mice and young DMD patients is associated with aberrant NF-κB activation. We find that prolonged NF-κB activation in MuSCs in chronic injuries leads to shortened telomeres and Ku80 dysregulation and results in severe skeletal muscle defects. Our studies provide evidence of a role for NF-κB in regulating stem-cell-specific telomere length, independently of cell replication, and could be a congruent mechanism that is applicable to additional tissues and/or diseases characterized by systemic chronic inflammation.

| S-EPMC8183356 | biostudies-literature

Longitudinal versus cross-sectional evaluations of leukocyte telomere length dynamics: age-dependent telomere shortening is the rule.

Project description:Leukocyte telomere length (LTL) is considered a biomarker of human aging and based on cross-sectional studies it shortens with age. However, longitudinal studies reported that many adults display LTL lengthening.Using Southern blots, we compared cross-sectional rates of age-related LTL change across a ?20 year age range with those based on longitudinal evaluations in three surveys (S1, S2, and S3) with three time intervals: S1-S2 (5.8 years), S2-S3 (6.6 years), and S1-S3 (12.4 years). Hierarchical linear modeling was used to explore LTL dynamics using LTL data from S1, S2, and S3.Cross-sectionally, mean LTL shortenings were 24.6, 25.4, and 23.6 bp/y at S1, S2, and S3, respectively. Longitudinally, more variation was observed in the rate of LTL change during the shorter than longer follow-up periods. Furthermore, using simple differences in LTL, 14.4% and 10.7% of individuals displayed LTL lengthening during S1-S2 and S2-S3, respectively, but only 1.5% during S1-S3 (p < 0.001). The estimated mean rate of LTL shortening based on averaging empirical Bayes' estimates of LTL from a parsimonious hierarchical linear modeling model was 31 bp/y with a range from 23 to 47 bp/y with none of the participants showing LTL lengthening over the average 12.4 years of follow-up.As aging displays a unidirectional progression, it is unlikely that LTL elongates with age. LTL elongation in longitudinal studies primarily reflects measurement errors of LTL in relation to the duration of follow-up periods.

| S-EPMC3041470 | biostudies-literature

Telomere Shortening Impairs PGC Fate Decision

Project description:This SuperSeries is composed of the SubSeries listed below.

2022-08-31 | GSE157304 | GEO

Telomere Dysfunction Induces Sirtuin Repression that Drives Telomere-Dependent Disease.

Project description:Telomere shortening is associated with stem cell decline, fibrotic disorders, and premature aging through mechanisms that are incompletely understood. Here, we show that telomere shortening in livers of telomerase knockout mice leads to a p53-dependent repression of all seven sirtuins. P53 regulates non-mitochondrial sirtuins (Sirt1, 2, 6, and 7) post-transcriptionally through microRNAs (miR-34a, 26a, and 145), while the mitochondrial sirtuins (Sirt3, 4, and 5) are regulated in a peroxisome proliferator-activated receptor gamma co-activator 1 alpha-/beta-dependent manner at the transcriptional level. Administration of the NAD(+) precursor nicotinamide mononucleotide maintains telomere length, dampens the DNA damage response and p53, improves mitochondrial function, and, functionally, rescues liver fibrosis in a partially Sirt1-dependent manner. These studies establish sirtuins as downstream targets of dysfunctional telomeres and suggest that increasing Sirt1 activity alone or in combination with other sirtuins stabilizes telomeres and mitigates telomere-dependent disorders.

| S-EPMC6657508 | biostudies-literature