A Ribosomal Perspective on Proteostasis and Aging

Steffen, Kristan K.; Dillin, Andrew

doi:10.1016/j.cmet.2016.05.013

Cited by 123 publications

(96 citation statements)

References 95 publications

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“…Reprogramming, currently an experimental tool to study development and cellular differentiation, may provide additional insights into the mechanisms of aging. Proposed drivers of physiological aging include the accumulation of DNA damage, increased ROS production, telomere shortening, cellular senescence, and defects in nuclear envelope architecture (Bernardes de Jesus and Blasco, 2013; Guarente, 2008; Haigis and Sinclair, 2009; Kennedy and Lamming, 2016; Soultoukis and Partridge, 2016; Steffen and Dillin, 2016). Multiple studies using animal models have demonstrated that the manipulation of these aging drivers leads to the manifestation of molecular hallmarks of aging that are shared between premature aging models and physiological aging (García-Prat et al, 2016; Mitchell et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming

Ocampo

Reddy

Martínez-Redondo

et al. 2016

Cell

679

701

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SUMMARY Aging is the major risk factor for many human diseases. In vitro studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age, but alteration of the aging process through reprogramming has not been directly demonstrated in vivo. Here, we report that partial reprogramming by short-term cyclic expression of Oct4, Sox2, Klf4, and c-Myc (OSKM) ameliorates cellular and physiological hallmarks of aging and prolongs lifespan in a mouse model of premature aging. Similarly, expression of OSKM in vivo improves recovery from metabolic disease and muscle injury in older wild-type mice. The amelioration of age-associated phenotypes by epigenetic remodeling during cellular reprogramming highlights the role of epigenetic dysregulation as a driver of mammalian aging. Establishing in vivo platforms to modulate age-associated epigenetic marks may provide further insights into the biology of aging.

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Section: Discussionmentioning

confidence: 99%

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming

Ocampo

Reddy

Martínez-Redondo

et al. 2016

Cell

679

701

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“…Genetic inhibition of tRNA synthetases, which may decrease mRNA translation, extends C. elegans lifespan2829. daf-2 mutants display reduced translation rates30, and reduced translation confers longevity in multiple organisms31. Thus, increased NMD activity by reduced IIS may prevent age-dependent increases in abnormal transcripts, including tRNA synthetase genes, and this may in turn contribute to the longevity of daf-2 mutants by decreasing translation.…”

Section: Discussionmentioning

confidence: 99%

RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans

et al. 2017

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Long-lived organisms often feature more stringent protein and DNA quality control. However, whether RNA quality control mechanisms, such as nonsense-mediated mRNA decay (NMD), which degrades both abnormal as well as some normal transcripts, have a role in organismal aging remains unexplored. Here we show that NMD mediates longevity in C. elegans strains with mutations in daf-2/insulin/insulin-like growth factor 1 receptor. We find that daf-2 mutants display enhanced NMD activity and reduced levels of potentially aberrant transcripts. NMD components, including smg-2/UPF1, are required to achieve the longevity of several long-lived mutants, including daf-2 mutant worms. NMD in the nervous system of the animals is particularly important for RNA quality control to promote longevity. Furthermore, we find that downregulation of yars-2/tyrosyl-tRNA synthetase, an NMD target transcript, by daf-2 mutations contributes to longevity. We propose that NMD-mediated RNA surveillance is a crucial quality control process that contributes to longevity conferred by daf-2 mutations.

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“…Due to the critical role of proteins in regulating a large variety of biological processes, protein synthesis, folding and subsequent degradation (i.e. protein homeostasis or “proteostasis”) are fundamental to maintain optimal cellular function and tissue homeostasis during normal conditions and in response to environmental stress [56, 57]. This is of particular importance to the lung, which due to its anatomical structure is in direct contact with the outside world and continuously challenged by inhaled insults including cigarette smoke.…”

Section: Discussionmentioning

confidence: 99%

Waterpipe smoking induces epigenetic changes in the small airway epithelium

Walters

Salit

et al. 2017

PLoS ONE

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Waterpipe (also called hookah, shisha, or narghile) smoking is a common form of tobacco use in the Middle East. Its use is becoming more prevalent in Western societies, especially among young adults as an alternative form of tobacco use to traditional cigarettes. While the risk to cigarette smoking is well documented, the risk to waterpipe smoking is not well defined with limited information on its health impact at the epidemiologic, clinical and biologic levels with respect to lung disease. Based on the knowledge that airway epithelial cell DNA methylation is modified in response to cigarette smoke and in cigarette smoking-related lung diseases, we assessed the impact of light-use waterpipe smoking on DNA methylation of the small airway epithelium (SAE) and whether changes in methylation were linked to the transcriptional output of the cells. Small airway epithelium was obtained from 7 nonsmokers and 7 light-use (2.6 ± 1.7 sessions/wk) waterpipe-only smokers. Genome-wide comparison of SAE DNA methylation of waterpipe smokers to nonsmokers identified 727 probesets differentially methylated (fold-change >1.5, p<0.05) representing 673 unique genes. Dominant pathways associated with these epigenetic changes include those linked to G-protein coupled receptor signaling, aryl hydrocarbon receptor signaling and xenobiotic metabolism signaling, all of which have been associated with cigarette smoking and lung disease. Of the genes differentially methylated, 11.3% exhibited a corresponding significant (p<0.05) change in gene expression with enrichment in pathways related to regulation of mRNA translation and protein synthesis (eIF2 signaling and regulation of eIF4 and p70S6K signaling). Overall, these data demonstrate that light-use waterpipe smoking is associated with epigenetic changes and related transcriptional modifications in the SAE, the cell population demonstrating the earliest pathologic abnormalities associated with chronic cigarette smoking.

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A Ribosomal Perspective on Proteostasis and Aging

Cited by 123 publications

References 95 publications

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming

In Vivo Amelioration of Age-Associated Hallmarks by Partial Reprogramming

RNA surveillance via nonsense-mediated mRNA decay is crucial for longevity in daf-2/insulin/IGF-1 mutant C. elegans

Waterpipe smoking induces epigenetic changes in the small airway epithelium

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