Publications by authors named "Keith Blackwell"

129 Publications

Neuronal SKN-1B modulates nutritional signalling pathways and mitochondrial networks to control satiety.

PLoS Genet 2021 03 4;17(3):e1009358. Epub 2021 Mar 4.

School of Biosciences, University of Kent, Canterbury, United Kingdom.

The feeling of hunger or satiety results from integration of the sensory nervous system with other physiological and metabolic cues. This regulates food intake, maintains homeostasis and prevents disease. In C. elegans, chemosensory neurons sense food and relay information to the rest of the animal via hormones to control food-related behaviour and physiology. Here we identify a new component of this system, SKN-1B which acts as a central food-responsive node, ultimately controlling satiety and metabolic homeostasis. SKN-1B, an ortholog of mammalian NF-E2 related transcription factors (Nrfs), has previously been implicated with metabolism, respiration and the increased lifespan incurred by dietary restriction. Here we show that SKN-1B acts in two hypothalamus-like ASI neurons to sense food, communicate nutritional status to the organism, and control satiety and exploratory behaviours. This is achieved by SKN-1B modulating endocrine signalling pathways (IIS and TGF-β), and by promoting a robust mitochondrial network. Our data suggest a food-sensing and satiety role for mammalian Nrf proteins.
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http://dx.doi.org/10.1371/journal.pgen.1009358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7932105PMC
March 2021

Global profiling of distinct cysteine redox forms reveals wide-ranging redox regulation in C. elegans.

Nat Commun 2021 03 3;12(1):1415. Epub 2021 Mar 3.

State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing, China.

Post-translational changes in the redox state of cysteine residues can rapidly and reversibly alter protein functions, thereby modulating biological processes. The nematode C. elegans is an ideal model organism for studying cysteine-mediated redox signaling at a network level. Here we present a comprehensive, quantitative, and site-specific profile of the intrinsic reactivity of the cysteinome in wild-type C. elegans. We also describe a global characterization of the C. elegans redoxome in which we measured changes in three major cysteine redox forms after HO treatment. Our data revealed redox-sensitive events in translation, growth signaling, and stress response pathways, and identified redox-regulated cysteines that are important for signaling through the p38 MAP kinase (MAPK) pathway. Our in-depth proteomic dataset provides a molecular basis for understanding redox signaling in vivo, and will serve as a valuable and rich resource for the field of redox biology.
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http://dx.doi.org/10.1038/s41467-021-21686-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930113PMC
March 2021

Safety of fibula free flap in patients following total knee replacement.

Head Neck 2021 02 21;43(2):585-589. Epub 2020 Oct 21.

Department of Otolaryngology - Head and Neck Surgery, Oregon Health and Sciences University, Portland, Oregon, USA.

Background: Fibula free flap (FFF) is the preferred osteocutaneous flap for reconstruction of large head and neck composite defects. There is a paucity of data whether FFF can be performed safely in patients with knee replacement (total knee arthroplasty [TKA]).

Methods: Multi-institutional review of outcomes following FFF in patients who had prior TKA.

Results: Ten surgeons reported successful FFF in 53 patients with prior TKA. The most common preoperative imaging was a CT angiogram of the bilateral lower extremities. There was no evidence of intraoperative vascular abnormality. Physical therapy began between postoperative day 1 to postoperative day 3. At 1 month postoperatively, 40% of patients were using a cane or walker to ambulate, but by 3 months all had returned to baseline ambulatory status. At >1 year, there were no gait complications.

Conclusion: FFF appears safe in patients with prior knee replacement without an increased risk of complications compared to baseline.
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http://dx.doi.org/10.1002/hed.26519DOI Listing
February 2021

Vasodilation by Verapamil-Nitroglycerin Solution in Microvascular Surgery.

Otolaryngol Head Neck Surg 2021 01 7;164(1):104-109. Epub 2020 Jul 7.

Department of Otolaryngology-Head and Neck Surgery, University of California-Los Angeles, Los Angeles, California, USA.

Objective: Papaverine is a topical vasodilator commonly used during microvascular surgery to inhibit undesired vasoconstriction. A previous national shortage of papaverine prompted evaluation of an alternative, effective vasodilator. This study aims to assess the experience of a solution of verapamil and nitroglycerin (VG) as a potential alternative pharmacologic vasodilator.

Study Design: Retrospective case series.

Setting: Two tertiary academic medical centers.

Subjects And Methods: Among 298 patients, 306 consecutive free tissue transfers performed between 2014 and 2017 for head and neck defect reconstruction utilized a VG solution. Patient and flap characteristics, intraoperative patient and flap complications, and postoperative complications were reviewed. Diameter of the cervical recipient artery was measured intraoperatively before and after topical application of the VG solution in a subset of 43 patients (44 flaps).

Results: Flaps included fibula, radial forearm, subscapular system, and anterolateral thigh. In total, 3 (0.98%) flaps failed with varied etiology unrelated to the VG solution (venous thrombosis, arterial anastomosis thrombosis, physical damage to the perforator). Specific to topical application of the VG solution, the mean recipient artery diameter increased from 2.1 to 3.1 mm, a 48% increase ( < .01). There were no intraoperative cardiac events or complications attributable to the VG solution.

Conclusion: We describe the use of a VG solution for pharmacologic vasodilation during microvascular free tissue transfer. Its use was associated with an acceptable incidence of adverse events, none of which were directly attributable to the VG solution. Apparent and sustained vasodilation was demonstrated. The VG solution represents a safe and efficacious alternative to papaverine in microvascular surgery.
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http://dx.doi.org/10.1177/0194599820937991DOI Listing
January 2021

TOR Signaling in Development, Metabolism, and Aging.

Genetics 2019 10;213(2):329-360

Department of MCDB, University of Colorado at Boulder, and

The arget f apamycin (TOR or mTOR) is a serine/threonine kinase that regulates growth, development, and behaviors by modulating protein synthesis, autophagy, and multiple other cellular processes in response to changes in nutrients and other cues. Over recent years, TOR has been studied intensively in mammalian cell culture and genetic systems because of its importance in growth, metabolism, cancer, and aging. Through its advantages for unbiased, and high-throughput, genetic and studies, has made major contributions to our understanding of TOR biology. Genetic analyses in the worm have revealed unexpected aspects of TOR functions and regulation, and have the potential to further expand our understanding of how growth and metabolic regulation influence development. In the aging field, has played a leading role in revealing the promise of TOR inhibition as a strategy for extending life span, and identifying mechanisms that function upstream and downstream of TOR to influence aging. Here, we review the state of the TOR field in , and focus on what we have learned about its functions in development, metabolism, and aging. We discuss knowledge gaps, including the potential pitfalls in translating findings back and forth across organisms, but also describe how TOR is important for biology, and how work has developed paradigms of great importance for the broader TOR field.
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http://dx.doi.org/10.1534/genetics.119.302504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6781902PMC
October 2019

A triple drug combination targeting components of the nutrient-sensing network maximizes longevity.

Proc Natl Acad Sci U S A 2019 10 30;116(42):20817-20819. Epub 2019 Sep 30.

Institute of Healthy Ageing, Department of Genetics, Evolution and Environment, University College London, WC1E 6BT London, United Kingdom;

Increasing life expectancy is causing the prevalence of age-related diseases to rise, and there is an urgent need for new strategies to improve health at older ages. Reduced activity of insulin/insulin-like growth factor signaling (IIS) and mechanistic target of rapamycin (mTOR) nutrient-sensing signaling network can extend lifespan and improve health during aging in diverse organisms. However, the extensive feedback in this network and adverse side effects of inhibition imply that simultaneous targeting of specific effectors in the network may most effectively combat the effects of aging. We show that the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, the mTOR complex 1 (mTORC1) inhibitor rapamycin, and the glycogen synthase kinase-3 (GSK-3) inhibitor lithium act additively to increase longevity in Remarkably, the triple drug combination increased lifespan by 48%. Furthermore, the combination of lithium with rapamycin cancelled the latter's effects on lipid metabolism. In conclusion, a polypharmacology approach of combining established, prolongevity drug inhibitors of specific nodes may be the most effective way to target the nutrient-sensing network to improve late-life health.
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http://dx.doi.org/10.1073/pnas.1913212116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6800352PMC
October 2019

Invasive Oral Tongue Mucormycosis Rapidly Presenting After Orthotopic Liver Transplant.

Ear Nose Throat J 2019 Jun 13;98(5):268-270. Epub 2019 May 13.

1 Department of Head and Neck Surgery, UCLA David Geffen School of Medicine, Los Angeles, CA, USA.

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http://dx.doi.org/10.1177/0145561319840535DOI Listing
June 2019

Dietary Restriction Extends Lifespan through Metabolic Regulation of Innate Immunity.

Cell Metab 2019 05 21;29(5):1192-1205.e8. Epub 2019 Mar 21.

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address:

Chronic inflammation predisposes to aging-associated disease, but it is unknown whether immunity regulation might be important for extending healthy lifespan. Here we show that in C. elegans, dietary restriction (DR) extends lifespan by modulating a conserved innate immunity pathway that is regulated by p38 signaling and the transcription factor ATF-7. Longevity from DR depends upon p38-ATF-7 immunity being intact but downregulated to a basal level. p38-ATF-7 immunity accelerates aging when hyperactive, influences lifespan independently of pathogen exposure, and is activated by nutrients independently of mTORC1, a major DR mediator. Longevity from reduced insulin/IGF-1 signaling (rIIS) also involves p38-ATF-7 downregulation, with signals from DAF-16/FOXO reducing food intake. We conclude that p38-ATF-7 is an immunometabolic pathway that senses bacterial and nutrient signals, that immunity modulation is critical for DR, and that DAF-16/FOXO couples appetite to growth regulation. These conserved mechanisms may influence aging in more complex organisms.
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http://dx.doi.org/10.1016/j.cmet.2019.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6506407PMC
May 2019

Total Glossectomy With Free Flap Reconstruction: Twenty-Year Experience at a Tertiary Medical Center.

Laryngoscope 2019 05 22;129(5):1087-1092. Epub 2019 Jan 22.

Department of Head and Neck Surgery, Los Angeles, California.

Objectives/hypothesis: To characterize the demographics, clinicopathologic characteristics, and treatment and reconstructive outcomes of patients who underwent total glossectomy STUDY DESIGN: Retrospective chart review at an academic tertiary-care medical center.

Methods: All patients who had undergone total glossectomy (as an individual procedure or as part of a more extensive resection) between January 1, 1995 and December 31, 2014 were included in the analysis. Patient characteristics and clinical outcomes were reviewed.

Results: Forty-eight patients underwent total glossectomy for oral tongue and base of tongue cancer. The mean age of the patients was 56 (range, 29-92 years). History of tobacco and heavy alcohol use was found in 76% and 11% of patients, respectively. The majority of patients had advanced cancer (91.7% at stage IV), and 60.4% had salvage therapy for recurrent disease. T4 disease comprised 81% of patients. Sixty percent had clinical or radiographic evidence of nodal metastasis. Reconstruction of the defect was performed with free flaps from the rectus abdominus (40%), fibula (25%), anterolateral thigh (23%), and other donor tissues. One- and 5-year survival rates were 42% and 26%, with locoregional and distant recurrence reported at 36% and 25%, respectively.

Conclusions: Total glossectomy for oncologic control is most commonly performed in patients who have stage IV cancers. Despite high reconstructive success rates, the likelihood of locoregional and distance recurrence was high. Most patients can communicate intelligibly and achieve decannulation, but swallowing outcomes remain guarded, especially considering previous irradiation and resection of the base of tongue.

Level Of Evidence: 4 Laryngoscope, 129:1087-1092, 2019.
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http://dx.doi.org/10.1002/lary.27579DOI Listing
May 2019

Mitochondrial unfolded protein response transcription factor ATFS-1 promotes longevity in a long-lived mitochondrial mutant through activation of stress response pathways.

BMC Biol 2018 12 18;16(1):147. Epub 2018 Dec 18.

Department of Genetics, Harvard Medical School, Boston, MA, USA.

Background: The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway activated by disruption of proteostasis in the mitochondria. This pathway has been proposed to influence lifespan, with studies suggesting that mitoUPR activation has complex effects on longevity.

Results: Here, we examined the contribution of the mitoUPR to the survival and lifespan of three long-lived mitochondrial mutants in Caenorhabditis elegans by modulating the levels of ATFS-1, the central transcription factor that mediates the mitoUPR. We found that clk-1, isp-1, and nuo-6 worms all exhibit an ATFS-1-dependent activation of the mitoUPR. While loss of atfs-1 during adulthood does not affect lifespan in any of these strains, absence of atfs-1 during development prevents clk-1 and isp-1 worms from reaching adulthood and reduces the lifespan of nuo-6 mutants. Examining the mechanism by which deletion of atfs-1 reverts nuo-6 lifespan to wild-type, we find that many of the transcriptional changes present in nuo-6 worms are mediated by ATFS-1. Genes exhibiting an ATFS-1-dependent upregulation in nuo-6 worms are enriched for transcripts that function in stress response and metabolism. Consistent, with this finding, loss of atfs-1 abolishes the enhanced stress resistance observed in nuo-6 mutants and prevents upregulation of multiple stress response pathways including the HIF-1-mediated hypoxia response, SKN-1-mediated oxidative stress response and DAF-16-mediated stress response.

Conclusions: Our results suggest that in the long-lived mitochondrial mutant nuo-6 activation of the mitoUPR causes atfs-1-dependent changes in the expression of genes involved in stress response and metabolism, which contributes to the extended longevity observed in this mutant. This work demonstrates that the mitoUPR can modulate multiple stress response pathways and suggests that it is crucial for the development and lifespan of long-lived mitochondrial mutants.
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http://dx.doi.org/10.1186/s12915-018-0615-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298126PMC
December 2018

Readmission after surgery for oropharyngeal cancer: An analysis of rates, causes, and risk factors.

Laryngoscope 2019 04 19;129(4):910-918. Epub 2018 Sep 19.

Department of Head and Neck Surgery, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California.

Objectives/hypothesis: Determine the rate, diagnoses, and risk factors associated with 30-day nonelective readmissions for patients undergoing surgery for oropharyngeal cancer.

Study Design: Retrospective cohort study.

Methods: We analyzed the Nationwide Readmissions Database for patients who underwent oropharyngeal cancer surgery between 2010 and 2014. Rates and causes of 30-day readmissions were determined. Multivariate logistic regression was used to identify risk factors for readmission.

Results: Among 16,902 identified cases, the 30-day, nonelective readmission rate was 10.2%, with an average cost per readmission of $14,170. The most common readmission diagnoses were postoperative bleeding (14.1%) and wound complications (12.6%) (surgical site infection [8.6%], dehiscence [2.3%], and fistula [1.7%]). On multivariate regression, significant risk factors for readmission were major ablative surgery (which included total glossectomy, pharyngectomy, and mandibulectomy) (odds ratio [OR]: 1.29, 95% confidence interval [CI]: 1.06-1.60), advanced Charlson/Deyo comorbidity (OR: 2.00, 95% CI: 1.43-2.79), history of radiation (OR: 1.58, 95% CI: 1.15-2.17), Medicare (OR: 1.34, 95% CI: 1.06-1.69) or Medicaid (OR: 1.82, 95% CI: 1.32-2.50) payer status, index admission from the emergency department (OR: 1.19, 95% CI: 1.02-1.40), and length of stay ≥6 days (OR: 1.57, 95% CI: 1.19-2.08).

Conclusions: In this large database analysis, we found that approximately one in 10 patients undergoing surgery for oropharyngeal cancer is readmitted within 30 days. Procedural complexity, insurance status, and advanced comorbidity are independent risk factors, whereas postoperative bleeding and wound complications are the most common reasons for readmission.

Level Of Evidence: 4. Laryngoscope, 129:910-918, 2019.
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http://dx.doi.org/10.1002/lary.27461DOI Listing
April 2019

Sentinel lymph node biopsy in cutaneous melanoma of the head and neck using the indocyanine green SPY Elite system.

Am J Otolaryngol 2018 Sep - Oct;39(5):485-488. Epub 2018 May 17.

Department of Head and Neck Surgery, UCLA David Geffen School of Medicine, 10833 Le Conte Ave, 62-132, Los Angeles, CA 90095, USA. Electronic address:

Purpose: Lymph node status is the single most important prognostic factor for patients with early-stage cutaneous melanoma. Sentinel lymph node biopsy (SLNB) has become the standard of care for intermediate depth melanomas. Modern SLNB implementation includes technetium-99 lymphoscintigraphy combined with local administration of a vital blue dye. However, sentinel lymph nodes may fail to localize in some cases and false-negative rates range from 0 to 34%. Here we demonstrate the feasibility of a new sentinel lymph node biopsy technique using indocyanine green (ICG) and the SPY Elite near-infrared imaging system.

Materials And Methods: Cases of primary cutaneous melanoma of the head and neck without locoregional metastasis, underwent SLNB at a single quaternary care institution between May 2016 and June 2017. Intraoperatively, 0.25 mL of ICG was injected intradermal in 4 quadrants around the primary lesion. 10-15 minute circulation time was permitted. SPY Elite identified the sentinel lymph node within the nodal basin marked by lymphoscintigraphy. Target first echelon lymph nodes were confirmed with a gamma probe and ICG fluorescence.

Results: 14 patients were included with T1a to T4b cutaneous melanomas. Success rates for sentinel lymph node identification using lymphoscintigraphy and the SPY Elite system were both 86%. Zero false negatives occurred. Median length of follow-up was 323 days.

Conclusions: In this pilot study, Indocyanine green near-infrared fluorescence demonstrates a safe, and facile method of sentinel lymph node biopsy for cutaneous melanoma of the head and neck compared with lymphoscintigraphy and vital blue dyes.
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http://dx.doi.org/10.1016/j.amjoto.2018.05.006DOI Listing
December 2018

Oxidative Stress Assays (arsenite and tBHP) in .

Bio Protoc 2017 Jul;7(13)

Department of Genetics, Harvard Medical School, Boston, Massachusetts, USA.

Cells and organisms face constant exposure to reactive oxygen species (ROS), either from the environment or as a by-product from internal metabolic processes. To prevent cellular damage from ROS, cells have evolved detoxification mechanisms. The activation of these detoxification mechanisms and their downstream responses represent an overlapping defense response that can be tailored to different sources of ROS to adequately adapt and protect cells. In this protocol, we describe how to measure the sensitivity to oxidative stress from two different sources, arsenite and tBHP, using the nematode .
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http://dx.doi.org/10.21769/BioProtoc.2365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809133PMC
July 2017

Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling.

Cell 2017 Dec 16;171(7):1545-1558.e18. Epub 2017 Nov 16.

Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065, USA; Department of Pharmacology, Weill Cornell Medicine, New York, NY 10065, USA. Electronic address:

mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling. Mechanistically, SRPK2 promotes SR protein binding to U1-70K to induce splicing of lipogenic pre-mRNAs. Inhibition of this signaling pathway leads to intron retention of lipogenic genes, which triggers nonsense-mediated mRNA decay. Genetic or pharmacological inhibition of SRPK2 blunts de novo lipid synthesis, thereby suppressing cell growth. These results thus reveal a novel role of mTORC1-SRPK2 signaling in post-transcriptional regulation of lipid metabolism and demonstrate that SRPK2 is a potential therapeutic target for mTORC1-driven metabolic disorders.
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http://dx.doi.org/10.1016/j.cell.2017.10.037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920692PMC
December 2017

Triclosan Disrupts SKN-1/Nrf2-Mediated Oxidative Stress Response in C. elegans and Human Mesenchymal Stem Cells.

Sci Rep 2017 10 3;7(1):12592. Epub 2017 Oct 3.

Department of Internal Medicine, Brody School of Medicine at East Carolina University, Greenville, NC, 27834, USA.

Triclosan (TCS), an antimicrobial chemical with potential endocrine-disrupting properties, may pose a risk to early embryonic development and cellular homeostasis during adulthood. Here, we show that TCS induces toxicity in both the nematode C. elegans and human mesenchymal stem cells (hMSCs) by disrupting the SKN-1/Nrf2-mediated oxidative stress response. Specifically, TCS exposure affected C. elegans survival and hMSC proliferation in a dose-dependent manner. Cellular analysis showed that TCS inhibited the nuclear localization of SKN-1/Nrf2 and the expression of its target genes, which were associated with oxidative stress response. Notably, TCS-induced toxicity was significantly reduced by either antioxidant treatment or constitutive SKN-1/Nrf2 activation. As Nrf2 is strongly associated with aging and chemoresistance, these findings will provide a novel approach to the identification of therapeutic targets and disease treatment.
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http://dx.doi.org/10.1038/s41598-017-12719-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5626723PMC
October 2017

Untangling Longevity, Dauer, and Healthspan in Caenorhabditis elegans Insulin/IGF-1-Signalling.

Gerontology 2018 22;64(1):96-104. Epub 2017 Sep 22.

Eidgenössische Technische Hochschule (ETH) Zürich, Health Sciences and Technology, Schwerzenbach, Switzerland.

The groundbreaking discovery that lower levels of insulin/IGF-1 signaling (IIS) can induce lifespan extension was reported 24 years ago in the nematode Caenorhabditis elegans. In this organism, mutations in the insulin/IGF-1 receptor gene daf-2 or other genes in this pathway can double lifespan. Subsequent work has revealed that reduced IIS (rIIS) extends lifespan across diverse species, possibly including humans. In C. elegans, IIS also regulates development into the diapause state known as dauer, a quiescent larval form that enables C. elegans to endure harsh environments through morphological adaptation, improved cellular repair, and slowed metabolism. Considerable progress has been made uncovering mechanisms that are affected by C. elegans rIIS. However, from the beginning it has remained unclear to what extent rIIS extends C. elegans lifespan by mobilizing dauer-associated mechanisms in adults. As we discuss, recent work has shed light on this question by determining that rIIS can extend C. elegans lifespan comparably through downstream processes that are either dauer-related or -independent. Importantly, these two lifespan extension programs can be distinguished genetically. It will now be critical to tease apart these programs, because each may involve different longevity-promoting mechanisms that may be relevant to higher organisms. A recent analysis of organismal "healthspan" has questioned the value of C. elegans rIIS as a paradigm for understanding healthy aging, as opposed to simply extending life. We discuss other work that argues strongly that C. elegans rIIS is indeed an invaluable model and consider the likely possibility that dauer-related processes affect parameters associated with health under rIIS conditions. Together, these studies indicate that C. elegans and analyses of rIIS in this organism will continue to provide unexpected and exciting results, and new paradigms that will be valuable for understanding healthy aging in humans.
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http://dx.doi.org/10.1159/000480504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828946PMC
October 2018

Intraosseous mucoepidermoid carcinoma: Outcome review.

Laryngoscope 2018 05 22;128(5):1083-1092. Epub 2017 Aug 22.

Department of Head and Neck Surgery, University of California Irvine, Irvine.

Objective: Identify the effect of patient characteristics, disease traits, and treatment modality on patient outcomes in the rare disease process of intraosseous mucoepidermoid carcinoma.

Study Design: Retrospective review of institutional case records and literature.

Methods: This study includes one case report, a literature review of the MEDLINE database from 1950 through June 2017 using keywords "intraosseous" and "mucoepidermoid," and a query of the University of California, Los Angeles, Department of Pathology database for all documented cases of intraosseous mucoepidermoid carcinoma of the head and neck.

Results: Indicators of poorer prognosis were male gender (P = 0.0071) and higher histological grade (P = 0.0095). Lesion site, size, association with odontogenic cyst, and treatment type did not have a statistically significant correlation with patient outcomes. There also was no statistically significant correlation observed between treatment modality and recurrent or progressive disease when stratified by histological grade of the cancer.

Conclusion: This study identified male gender and high histological tumor grade as poor prognostic indicators; however, it did not reveal a statistically significant relationship between treatment modality and patient outcomes. Data regarding patient outcomes following treatment was limited due to loss to follow-up, suggesting that further investigation is required. Based on this review, decisions regarding treatment should be clinically guided and individually tailored to the patient's baseline health, disease severity, and the patient's treatment goals. A multi-disciplinary conference, as was utilized in the presented case report, may be the best approach to treatment planning for these patients at this time.

Level Of Evidence: 4. Laryngoscope, 128:1083-1092, 2018.
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http://dx.doi.org/10.1002/lary.26832DOI Listing
May 2018

Three novel ANO5 missense mutations in Caucasian and Chinese families and sporadic cases with gnathodiaphyseal dysplasia.

Sci Rep 2017 02 8;7:40935. Epub 2017 Feb 8.

Beijing Institute of Dental Research, Beijing Stomatological Hospital, Capital Medical University, Beijing, China.

Gnathodiaphyseal dysplasia (GDD; MIM#166260) is an autosomal dominant syndrome with characteristic cemento-osseous lesions of jawbones, bone fragility, and diaphyseal sclerosis of tubular bones. To date, only five mutations in the proposed calcium-activated chloride channel ANO5/TMEM16E gene have been identified. In this study, we describe two families and two singular patients with three new mutations. One Caucasian family with seven affected members exhibited frequent bone fractures and florid osseous dysplasia (p.Cys356Tyr), while one Chinese family with two affected members suffered from cementoma and purulent osteomyelitis (p.Cys360Tyr). In addition, two different novel mutations (p.Gly518Glu and p.Arg215Gly) were identified in sporadic patients without family history. In vitro studies overexpressing GDD mutations (p.Cys356Tyr and p.Cys360Tyr) showed significantly reduced ANO5 protein. It appears that all GDD mutations known so far locate in an extracellular domain following the first transmembrane domain or in the 4 putative transmembrane domain. Both wild-type and mutant ANO5 protein localize to the endoplasmic reticulum. After Ano5 gene knock-down with shRNA in MC3T3-E1 osteoblast precursors we saw elevated expression of osteoblast-related genes such as Col1a1, osteocalcin, osterix and Runx2 as well as increased mineral nodule formation in differentiating cells. Our data suggest that ANO5 plays a role in osteoblast differentiation.
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http://dx.doi.org/10.1038/srep40935DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5296836PMC
February 2017

NADPH oxidase-mediated redox signaling promotes oxidative stress resistance and longevity through in .

Elife 2017 01 13;6. Epub 2017 Jan 13.

Friedrich Miescher Institute for Biomedical Research, University of Basel, Basel, Switzerland.

Transient increases in mitochondrially-derived reactive oxygen species (ROS) activate an adaptive stress response to promote longevity. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases produce ROS locally in response to various stimuli, and thereby regulate many cellular processes, but their role in aging remains unexplored. Here, we identified the orthologue of mammalian mediator of ErbB2-driven cell motility, MEMO-1, as a protein that inhibits BLI-3/NADPH oxidase. MEMO-1 is complexed with RHO-1/RhoA/GTPase and loss of results in an enhanced interaction of RHO-1 with BLI-3/NADPH oxidase, thereby stimulating ROS production that signal via p38 MAP kinase to the transcription factor SKN-1/NRF1,2,3 to promote stress resistance and longevity. Either loss of or increasing BLI-3/NADPH oxidase activity by overexpression is sufficient to increase lifespan. Together, these findings demonstrate that NADPH oxidase-induced redox signaling initiates a transcriptional response that protects the cell and organism, and can promote both stress resistance and longevity.
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http://dx.doi.org/10.7554/eLife.19493DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5235354PMC
January 2017

Metformin: Restraining Nucleocytoplasmic Shuttling to Fight Cancer and Aging.

Cell 2016 12;167(7):1670-1671

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston MA 02115, USA. Electronic address:

In this issue of Cell, Wu et al. employed C. elegans and human cell experiments to identify a pathway through which metformin increases lifespan and inhibits growth. A key transcriptional target, ACAD10, is activated when metformin induces nuclear exclusion of the GTPase RagC, thereby inhibiting mTORC1 through an unexpected mechanism.
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http://dx.doi.org/10.1016/j.cell.2016.11.058DOI Listing
December 2016

MicroRNA mir-34 provides robustness to environmental stress response via the DAF-16 network in C. elegans.

Sci Rep 2016 12 1;6:36766. Epub 2016 Dec 1.

Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, The Netherlands.

Diverse stresses and aging alter expression levels of microRNAs, suggesting a role for these posttranscriptional regulators of gene expression in stress modulation and longevity. Earlier studies demonstrated a central role for the miR-34 family in promoting cell cycle arrest and cell death following stress in human cells. However, the biological significance of this response was unclear. Here we show that in C. elegans mir-34 upregulation is necessary for developmental arrest, correct morphogenesis, and adaptation to a lower metabolic state to protect animals against stress-related damage. Either deletion or overexpression of mir-34 lead to an impaired stress response, which can largely be explained by perturbations in DAF-16/FOXO target gene expression. We demonstrate that mir-34 expression is regulated by the insulin signaling pathway via a negative feedback loop between miR-34 and DAF-16/FOXO. We propose that mir-34 provides robustness to stress response programs by controlling noise in the DAF-16/FOXO-regulated gene network.
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http://dx.doi.org/10.1038/srep36766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131338PMC
December 2016

Cysteine Sulfenylation Directs IRE-1 to Activate the SKN-1/Nrf2 Antioxidant Response.

Mol Cell 2016 08;63(4):553-566

Research Division, Joslin Diabetes Center, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address:

Emerging evidence suggests that many proteins may be regulated through cysteine modification, but the extent and functions of this signaling remain largely unclear. The endoplasmic reticulum (ER) transmembrane protein IRE-1 maintains ER homeostasis by initiating the unfolded protein response (UPR(ER)). Here we show in C. elegans and human cells that IRE-1 has a distinct redox-regulated function in cytoplasmic homeostasis. Reactive oxygen species (ROS) that are generated at the ER or by mitochondria sulfenylate a cysteine within the IRE-1 kinase activation loop. This inhibits the IRE-1-mediated UPR(ER) and initiates the p38/SKN-1(Nrf2) antioxidant response, thereby increasing stress resistance and lifespan. Many AGC-family kinases (AKT, p70S6K, PKC, ROCK1) seem to be regulated similarly. The data reveal that IRE-1 has an ancient function as a cytoplasmic sentinel that activates p38 and SKN-1(Nrf2) and indicate that cysteine modifications induced by ROS signals can direct proteins to adopt unexpected functions and may coordinate many cellular processes.
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http://dx.doi.org/10.1016/j.molcel.2016.07.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4996358PMC
August 2016

Natural thioallyl compounds increase oxidative stress resistance and lifespan in Caenorhabditis elegans by modulating SKN-1/Nrf.

Sci Rep 2016 Feb 22;6:21611. Epub 2016 Feb 22.

Department of Molecular Biotechnology, Graduate School of Advanced Sciences of Matter, Hiroshima University, Higashi-Hiroshima 739-8530, Japan.

Identification of biologically active natural compounds that promote health and longevity, and understanding how they act, will provide insights into aging and metabolism, and strategies for developing agents that prevent chronic disease. The garlic-derived thioallyl compounds S-allylcysteine (SAC) and S-allylmercaptocysteine (SAMC) have been shown to have multiple biological activities. Here we show that SAC and SAMC increase lifespan and stress resistance in Caenorhabditis elegans and reduce accumulation of reactive oxygen species (ROS). These compounds do not appear to activate DAF-16 (FOXO orthologue) or mimic dietary restriction (DR) effects, but selectively induce SKN-1 (Nrf1/2/3 orthologue) targets involved in oxidative stress defense. Interestingly, their treatments do not facilitate SKN-1 nuclear accumulation, but slightly increased intracellular SKN-1 levels. Our data also indicate that thioallyl structure and the number of sulfur atoms are important for SKN-1 target induction. Our results indicate that SAC and SAMC may serve as potential agents that slow aging.
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http://dx.doi.org/10.1038/srep21611DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4761942PMC
February 2016

An unusual initial presentation of mantle cell lymphoma arising from the lymphoid stroma of warthin tumor.

Diagn Pathol 2015 Dec 3;10:209. Epub 2015 Dec 3.

Department of Pathology and Laboratory Medicine, UCLA David Geffen School of Medicine, UCLA Path & Lab Med, AL-134 CHS, BOX 951732, Los Angeles, CA, 90095-1732, USA.

Background: Warthin tumors presenting concomitantly with a lymphoma is vanishingly rare with only 15 reported cases in English literature. Herein, we report an unusual initial presentation of a mantle cell lymphoma involving the lymphoid stroma of a Warthin tumor.

Case Presentation: A seventy-seven year old otherwise healthy gentleman with a 50-pack year smoking history presents with a slowly enlarging left cheek mass. CT scan of the neck demonstrated a left parotid gland tumor measuring 3.4 cm in greatest dimension. He underwent a left superficial parotidectomy, with subsequent histopathologic examination revealing a Warthin tumor with extensive expansion of the lymphoid stroma. Flow cytometric, immunohistochemical, and cytogenetic studies of the stromal component of the tumor confirmed the presence of a mantle cell lymphoma. Clinical staging demonstrated stage IVa disease, and was considered to be at low to intermediate risk due to the slow growth of the parotid lesion. The patient is undergoing close follow up with repeat PET-CT scans at six months.

Conclusion: To the best of our knowledge, this is the first well documented collision tumor between mantle cell lymphoma and a Warthin tumor. This case also brings to light the significance of thorough evaluation of the lymphoid component of Warthin tumor.
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http://dx.doi.org/10.1186/s13000-015-0444-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4669604PMC
December 2015

Hyponatremia and perioperative complications in patients with head and neck squamous cell carcinoma.

Head Neck 2016 04 18;38 Suppl 1:E1370-4. Epub 2015 Sep 18.

Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, California.

Background: Recent studies suggest that hyponatremia is associated with perioperative morbidity and mortality after general surgical procedures, as well as mortality among medical inpatients. We investigated the association of hyponatremia with perioperative complications in patients undergoing surgical resection of head and neck squamous cell carcinoma (HNSCC).

Methods: All patients with pathologically confirmed HNSCC undergoing either primary or salvage surgical resection from March 1, 2013, until May 31, 2014, at a single tertiary care academic center were included in this retrospective review. The primary outcome was 30-day mortality. Secondary outcomes included postoperative complications (respiratory, cardiac, renal, and wound), hospital and intensive care unit (ICU) length of stay, and need for blood transfusion.

Results: Two hundred fourteen surgical patients with HNSCC were identified for analysis. Patient ages ranged from 22 to 100 years (mean, 67 years). One hundred thirty-eight men and 76 women were included. Primary tumor sites were oral cavity (47.7%), oropharynx (18.7%), larynx (12.6%), salivary glands (7.9%), cutaneous (7.5%), sinonasal (2.8%), and hypopharynx (2.3%). Surgical resections were balanced between primary (48.1%) and salvage (51.9%). Thirty-five patients (16.4%) carried a presurgical diagnosis of diabetes. Fifteen patients (7.0%) demonstrated preoperative hyponatremia, and 46 (24.9%) had postoperative hyponatremia. Within the primary outcome measure, no difference in mortality was identified. Complications were noted in 58 patients (27.1%), and were more frequent in hyponatremic patients, both preoperatively and postoperatively (60.0% and 41.3%, respectively). Binomial logistic regression demonstrated risk of complications significantly associated with preoperative hyponatremia (odds ratio [OR] = 4.374; 95% confidence interval [CI] = 1.231-15.545; p = .023), increasing age (OR = 1.385; 95% CI = 1.032-1.857; p = .030), and increasing length of surgery (OR = 1.234; 95% CI = 1.046-1.455; p = .013). Postoperative hyponatremia was associated with increased hospital length of stay (p = .034).

Conclusion: Hyponatremia is a frequent electrolyte abnormality in patients with HNSCC. Both preoperative and postoperative hyponatremia are associated with perioperative morbidity, thus meriting intensive postoperative medical monitoring and treatment. Additional investigation is warranted to identify the pathophysiologic mechanisms behind this association. © 2015 Wiley Periodicals, Inc. Head Neck 38: E1370-E1374, 2016.
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http://dx.doi.org/10.1002/hed.24229DOI Listing
April 2016

Assessment of Fibula Flap Skin Perfusion in Patients Undergoing Oromandibular Reconstruction: Comparison of Clinical Findings, Fluorescein, and Indocyanine Green Angiography.

JAMA Facial Plast Surg 2015 Nov-Dec;17(6):422-6

Department of Head and Neck Surgery, David Geffen School of Medicine at University of California, Los Angeles.

Importance: Complications of partial flap necrosis contribute substantially to morbidity in patients who undergo head and neck reconstructive surgery.

Objective: To assess the usefulness of clinical findings, intraoperative fluorescein angiography, and intraoperative indocyanine green angiography (ICGA) for evaluation of flap skin paddle perfusion in patients undergoing oromandibular reconstruction who are at high risk of partial skin paddle necrosis.

Design, Setting, And Participants: Retrospective medical record review from May 21, 1996, to May 27, 2015, at a tertiary care academic medical center. Participants were 73 patients who underwent reconstruction of through-and-through defects of the mucosa, mandible, and skin using fibula free flaps that contained large bilobed skin paddles.

Main Outcomes And Measures: The rates of partial skin paddle necrosis and revision reconstructive surgery.

Results: The rates of partial flap necrosis were 8% (n = 2) among 25 patients in whom the skin paddle was trimmed based on ICGA and 33% (n = 16) among 48 patients in whom the skin paddle was trimmed according to clinical findings (P = .02). The rates of revision reconstructive surgery were 20% (5 of 25) when flap skin paddles were trimmed using ICGA and 42% (20 of 48) when trimmed per clinical findings (P = .06).

Conclusions And Relevance: The use of ICGA may reduce the risk of partial skin flap necrosis in free flaps used in patients undergoing head and neck reconstruction who are at high risk of developing flap necrosis. Indocyanine green angiography imaging should be considered in any flap in which skin paddle viability is uncertain based on clinical findings and in patients in whom the skin paddle extends beyond the primary and adjacent angiosomes.

Level Of Evidence: 3.
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http://dx.doi.org/10.1001/jamafacial.2015.0961DOI Listing
April 2016

SKN-1/Nrf, stress responses, and aging in Caenorhabditis elegans.

Free Radic Biol Med 2015 Nov 5;88(Pt B):290-301. Epub 2015 Aug 5.

Research Division, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA; Department of Genetics and Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02215, USA.

The mammalian Nrf/CNC proteins (Nrf1, Nrf2, Nrf3, p45 NF-E2) perform a wide range of cellular protective and maintenance functions. The most thoroughly described of these proteins, Nrf2, is best known as a regulator of antioxidant and xenobiotic defense, but more recently has been implicated in additional functions that include proteostasis and metabolic regulation. In the nematode Caenorhabditis elegans, which offers many advantages for genetic analyses, the Nrf/CNC proteins are represented by their ortholog SKN-1. Although SKN-1 has diverged in aspects of how it binds DNA, it exhibits remarkable functional conservation with Nrf/CNC proteins in other species and regulates many of the same target gene families. C. elegans may therefore have considerable predictive value as a discovery model for understanding how mammalian Nrf/CNC proteins function and are regulated in vivo. Work in C. elegans indicates that SKN-1 regulation is surprisingly complex and is influenced by numerous growth, nutrient, and metabolic signals. SKN-1 is also involved in a wide range of homeostatic functions that extend well beyond the canonical Nrf2 function in responses to acute stress. Importantly, SKN-1 plays a central role in diverse genetic and pharmacologic interventions that promote C. elegans longevity, suggesting that mechanisms regulated by SKN-1 may be of conserved importance in aging. These C. elegans studies predict that mammalian Nrf/CNC protein functions and regulation may be similarly complex and that the proteins and processes that they regulate are likely to have a major influence on mammalian life- and healthspan.
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http://dx.doi.org/10.1016/j.freeradbiomed.2015.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4809198PMC
November 2015

Lipid-mediated regulation of SKN-1/Nrf in response to germ cell absence.

Elife 2015 Aug 24;4. Epub 2015 Aug 24.

Research Division, Joslin Diabetes Center, Boston, United States.

In Caenorhabditis elegans, ablation of germline stem cells (GSCs) extends lifespan, but also increases fat accumulation and alters lipid metabolism, raising the intriguing question of how these effects might be related. Here, we show that a lack of GSCs results in a broad transcriptional reprogramming in which the conserved detoxification regulator SKN-1/Nrf increases stress resistance, proteasome activity, and longevity. SKN-1 also activates diverse lipid metabolism genes and reduces fat storage, thereby alleviating the increased fat accumulation caused by GSC absence. Surprisingly, SKN-1 is activated by signals from this fat, which appears to derive from unconsumed yolk that was produced for reproduction. We conclude that SKN-1 plays a direct role in maintaining lipid homeostasis in which it is activated by lipids. This SKN-1 function may explain the importance of mammalian Nrf proteins in fatty liver disease and suggest that particular endogenous or dietary lipids might promote health through SKN-1/Nrf.
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http://dx.doi.org/10.7554/eLife.07836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4541496PMC
August 2015

Accidental dropping or misplacement of free flaps.

Laryngoscope 2015 Aug 15;125(8):1807-10. Epub 2015 Apr 15.

Department of Otolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, Pennsylvania, U.S.A.

Objectives/hypothesis: Standard operating procedures have been developed in many surgical practices to ensure quality of care as it relates to specimens removed from the body. Most of these specimens are sent to pathology. Some, such as calvarial bone harvested during craniotomy are replaced in the body. Free tissue transfer involves harvesting tissue from one body site, storage for a variable period of time outside of the body, and then insertion in another location. As with any system there is ample opportunity for accidental "misplacement." We undertook a multi-institutional study to examine the incidence, etiology, and opportunity for process improvement.

Study Design: Retrospective review.

Methods: A retrospective review was performed at five institutions (8,382 free flaps).

Results: Thirteen (0.15%) flaps were dropped or wrapped in a towel/sponge and placed in a waste bucket. Eight radial forearm, three fibula, one latissimus dorsi, and one anterolateral thigh flap were misplaced. All flaps were retrieved, washed in saline/betadine, and implanted into the patient. All flaps survived; no altered outcomes were encountered. The etiology of the misplacement of the free tissue from the sterile field included miscommunication among nursing staff (seven), miscommunication among medical staff (two), and dropping the flap (four). As a result of these events, changes in the handling procedures were instituted including standard labeling methodologies and communication strategies.

Conclusions: Inadvertent misplacement of free tissue from the sterile field does occur in a sporadic fashion. Process improvement evaluation at all institutions led to improved strategies for prevention. No long-lasting altered outcomes were encountered.

Level Of Evidence: 4
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http://dx.doi.org/10.1002/lary.25282DOI Listing
August 2015

Dauer-independent insulin/IGF-1-signalling implicates collagen remodelling in longevity.

Nature 2015 Mar 15;519(7541):97-101. Epub 2014 Dec 15.

1] Joslin Diabetes Center, One Joslin Place, Boston, Massachusetts 02215, USA [2] Harvard Stem Cell Institute, 7 Divinity Avenue, Cambridge, Massachusetts 02138, USA [3] Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, Massachusetts 02215, USA.

Interventions that delay ageing mobilize mechanisms that protect and repair cellular components, but it is unknown how these interventions might slow the functional decline of extracellular matrices, which are also damaged during ageing. Reduced insulin/IGF-1 signalling (rIIS) extends lifespan across the evolutionary spectrum, and in juvenile Caenorhabditis elegans also allows the transcription factor DAF-16/FOXO to induce development into dauer, a diapause that withstands harsh conditions. It has been suggested that rIIS delays C. elegans ageing through activation of dauer-related processes during adulthood, but some rIIS conditions confer robust lifespan extension unaccompanied by any dauer-like traits. Here we show that rIIS can promote C. elegans longevity through a program that is genetically distinct from the dauer pathway, and requires the Nrf (NF-E2-related factor) orthologue SKN-1 acting in parallel to DAF-16. SKN-1 is inhibited by IIS and has been broadly implicated in longevity, but is rendered dispensable for rIIS lifespan extension by even mild activity of dauer-related processes. When IIS is decreased under conditions that do not induce dauer traits, SKN-1 most prominently increases expression of collagens and other extracellular matrix genes. Diverse genetic, nutritional, and pharmacological pro-longevity interventions delay an age-related decline in collagen expression. These collagens mediate adulthood extracellular matrix remodelling, and are needed for ageing to be delayed by interventions that do not involve dauer traits. By genetically delineating a dauer-independent rIIS ageing pathway, our results show that IIS controls a broad set of protective mechanisms during C. elegans adulthood, and may facilitate elucidation of processes of general importance for longevity. The importance of collagen production in diverse anti-ageing interventions implies that extracellular matrix remodelling is a generally essential signature of longevity assurance, and that agents promoting extracellular matrix youthfulness may have systemic benefit.
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http://dx.doi.org/10.1038/nature14021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4352135PMC
March 2015
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