Tissue-specific suppression of thyroid hormone signaling in various mouse models of aging

DNA damage contributes to the process of aging, as underscored by premature aging syndromes caused by defective DNA repair. Thyroid state changes during aging, but underlying mechanisms remain elusive. Since thyroid hormone (TH) is a key regulator of metabolism, changes in TH signaling have widespread effects. Here, we reveal a significant common transcriptomic signature in livers from hypothyroid mice, DNA repair-deficient mice with severe (Csbm/m/Xpa-/-) or intermediate (Ercc1-/Δ-7) progeria and naturally aged mice. A strong induction of TH-inactivating deiodinase D3 and decrease of TH-activating D1 activities are observed in Csbm/m/Xpa-/- livers. Similar findings are noticed in Ercc1-/Δ-7, in naturally aged animals and in wild-type mice exposed to a chronic subtoxic dose of DNAdamaging agents. In contrast, TH signaling in muscle, heart and brain appears unaltered. These data show a strong suppression of TH signaling in specific peripheral organs in premature and normal aging, probably lowering metabolism, while other tissues appear to preserve metabolism. D3-mediated TH inactivation is unexpected, given its expression mainly in fetal tissues. Our studies highlight the importance of DNA damage as the underlying mechanism of changes in thyroid state. Tissue-specific regulation of deiodinase activities, ensuring diminished TH signaling, may contribute importantly to the protective metabolic response in aging

Endoscopic Administration of Mesenchymal Stromal Cells Reduces Inflammation in Experimental Colitis

Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Restricted diet delays accelerated ageing and genomic stress in DNA-repair-deficient mice

Mice deficient in the DNA excision-repair gene Ercc1 (Ercc1(Delta/-)) show numerous accelerated ageing features that limit their lifespan to 4-6 months(1-4). They also exhibit a 'survival response', which suppresses growth and enhances cellular maintenance. Such a response resembles the anti-ageing response induced by dietary restriction (also known as caloric restriction)(1,5). Here we report that a dietary restriction of 30% tripled the median and maximal remaining lifespans of these progeroid mice, strongly retarding numerous aspects of accelerated ageing. Mice undergoing dietary restriction retained 50% more neurons and maintained full motor function far beyond the lifespan of mice fed ad libitum. Other DNA-repair-deficient, progeroid Xpg(-/-) (also known as Ercc5(-/-)) mice, a model of Cockayne syndrome(6), responded similarly. The dietary restriction response in Ercc1(Delta/-) mice closely resembled the effects of dietary restriction in wild-type animals. Notably, liver tissue from Ercc1(Delta/-) mice fed ad libitum showed preferential extinction of the expression of long genes, a phenomenon we also observed in several tissues ageing normally. This is consistent with the accumulation of stochastic, transcription-blocking lesions that affect long genes more than short ones. Dietary restriction largely prevented this declining transcriptional output and reduced the number of gamma H2AX DNA damage foci, indicating that dietary restriction preserves genome function by alleviating DNA damage. Our findings establish the Ercc1(Delta/-) mouse as a powerful model organism for health-sustaining interventions, reveal potential for reducing endogenous DNA damage, facilitate a better understanding of the molecular mechanism of dietary restriction and suggest a role for counterintuitive dietary-restriction-like therapy for human progeroid genome instability syndromes and possibly neurodegeneration in general

Promises and pitfalls of Web-based experimentation in the advance of replicable psychological science: A reply to Plant (2015)

In a recent letter, Plant (2015) reminded us that proper calibration of our laboratory experiments is important for the progress of psychological science. Therefore, carefully controlled laboratory studies are argued to be preferred over Web-based experimentation, in which timing is usually more imprecise. Here we argue that there are many situations in which the timing of Web-based experimentation is acceptable and that online experimentation provides a very useful and promising complementary toolbox to available lab-based approaches. We discuss examples in which stimulus calibration or calibration against response criteria is necessary and situations in which this is not critical. We also discuss how online labor markets, such as Amazon’s Mechanical Turk, allow researchers to acquire data in more diverse populations and to test theories along more psychological dimensions. Recent methodological advances that have produced more accurate browser-based stimulus presentation are also discussed. In our view, online experimentation is one of the most promising avenues to advance replicable psychological science in the near future.Action Contro