Exposure to environmental radionuclides associates with tissue-specific impacts on telomerase expression and telomere length

ABSTRACTTelomere length reflects cellular ageing. Increased telomere shortening in leukocytes is associated with a range of neurodegenerative and cardiovascular diseases, the onset and progression of which may be mediated by behavioural traits such as anxiety and stress reactivity. However, the effects of the hypothalamus-pituitary-adrenal axis stress response are shown to be tissue specific. As such, leukocyte telomere length may not give an accurate measure of the relationship between stress-reactivity and telomere length in disease relevant tissues. To test the hypothesis that stress-reactivity contributes to age-related telomere shortening in a tissue specific manner, we examined the correlation between telomere length in heart and brain tissue and stress-reactivity in a population of young (6-9 month) and ageing (18 month) zebrafish. Stress-reactivity was assessed by tank diving, a zebrafish version of the rodent open-field test, and through gene expression. Telomere length was assessed using quantitative polymerase chain reaction. We show that ageing zebrafish have shorter telomeres in both heart and brain. Telomere length is inversely related to stress-reactivity in heart but not brain of ageing individuals. These data support the hypotheses that an anxious predisposition contributes to telomere shortening in heart tissue, and by extension age-related heart disease, and that stress-reactivity contributes to age-related telomere shortening in a tissue-specific manner.

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SUN-017 Developmental Programming: Prenatal Testosterone Treatment Induced Metabolic Defects May Involve Premature Cellular Senescence

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1749 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Muraly Puttabyatappa ◽

Joseph Norman Ciarelli ◽

Vasantha Padmanabhan

Keyword(s):

Oxidative Stress ◽

Telomere Length ◽

Cellular Senescence ◽

Premature Aging ◽

Large Magnitude ◽

Tissue Specific ◽

Metabolic Defects ◽

Female Sheep ◽

Magnitude Increase ◽

And Oxidative Stress

Abstract Prenatal exposure to excess testosterone (T) programs peripheral insulin resistance and dyslipidemia along with tissue-specific increases in ectopic lipid accumulation, oxidative stress and insulin resistance in liver and muscle of the early adult female sheep. Prenatal T increased inflammation and oxidative stress in the visceral (VAT) but not subcutaneous (SAT) adipose tissue, with no effect on insulin sensitivity in both depots. These systemic and tissue-specific metabolic changes are reminiscent of defects such as non-alcoholic fatty liver disease (NFLAD) common among aged individuals. Because it is known that gestational insults can program premature aging of reproductive organs and chronic cardiovascular abnormalities, we hypothesized that programming of premature cellular senescence is one of the ways through which gestational T induces premature aging of metabolic systems during early adulthood. To test this hypothesis, mitochondrial oxidative phosphorylation (OXPHOS) and telomere length, as measure of cellular senescence, were assessed in liver, muscle, VAT and SAT collected from control and prenatal T- (100mg T propionate twice a week from days 30-90 of gestation) -treated female sheep at 21 months of age. Genomic DNA was subjected to TeloTAGG Telomere Length Assay (Sigma-Aldrich, St Louis, MO) and whole tissue protein lysates analyzed by immunoblot using Total OXPHOS Human WB Antibody Cocktail (ab110411, Abcam, Cambridge, MA). Data were analyzed by Student’s t test and Cohen’s effect size analysis. Prenatal T-treatment induced 1) a trend (p = 0.09) towards a large magnitude increase in shorter telomere fragments (0.08 -3.6 KB) in the liver and 2) a non-significant large magnitude decrease in shorter telomere fragments in muscle and SAT without having any effect in the VAT. Prenatal T also induced a large magnitude increase in mitochondrial OXPHOS protein complexes II and IV in liver, without having an effect at the level of the muscle, VAT and SAT. These findings are suggestive that prenatal T-treatment induced hepatic defects may involve premature cellular senescence. The relevance of parallel increase in mitochondrial OXPHOS in the liver is unclear and remains to be explored. The defects observed in the muscle and SAT may occur independent of cellular senescence or alterations in mitochondrial function. The lack of change in telomere length and mitochondrial OXPHOS in spite of increased inflammation and oxidative stress in the VAT is suggestive of a potential protective function in play, consistent with maintenance of the insulin sensitivity in this tissue. This study, therefore, raises the possibility that metabolic defects programmed by gestational insults may involve premature aging of metabolic organs in a tissue-specific manner and have translational bearing in conditions associated with hyperandrogenic states.

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Chronological Aging Standard Curves of Telomere Length and Mitochondrial DNA Copy Number in Twelve Tissues of C57BL/6 Male Mouse

Cells ◽

10.3390/cells8030247 ◽

2019 ◽

Vol 8 (3) ◽

pp. 247 ◽

Cited By ~ 11

Author(s):

Ji Baek ◽

Hyeonwi Son ◽

Young-Hoon Jeong ◽

Sang Park ◽

Hyun Kim

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dna ◽

Telomere Length ◽

Copy Number ◽

Accelerated Aging ◽

Male Mice ◽

Dna Copy Number ◽

Tissue Specific ◽

Chronological Aging ◽

Mitochondrial Dna Copy Number

The changes in telomere length and mitochondrial DNA copy number (mtDNAcn) are considered to be aging markers. However, many studies have provided contradictory or only fragmentary information about changes of these markers in animal models, due to inaccurate analysis methods and a lack of objective aging standards. To establish chronological aging standards for these two markers, we analyzed telomere length and mtDNAcn in 12 tissues—leukocytes, prefrontal cortex, hippocampus, pituitary gland, adrenal gland, retina, aorta, liver, kidney, spleen, skeletal muscle, and skin—from a commonly used rodent model, C57BL/6 male mice aged 2–24 months. It was found that at least one of the markers changed age-dependently in all tissues. In the leukocytes, hippocampus, retina, and skeletal muscle, both markers changed age-dependently. As a practical application, the aging marker changes were analyzed after chronic immobilization stress (CIS) to see whether CIS accelerated aging or not. The degree of tissue-aging was calculated using each standard curve and found that CIS accelerated aging in a tissue-specific manner. Therefore, it is expected that researchers can use our standard curves to objectively estimate tissue-specific aging accelerating effects of experimental conditions for least 12 tissues in C57BL/6 male mice.

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