Santina Snow Rogers Lab MDI Biological Laboratory The role of specific tissues in coordinating changes in growth, longevity and resilience to stress in response to reduced mRNA translation in C. elegans Santina Snow Rogers Lab MDI Biological Laboratory

Maintaining protein balance folding degradation synthesis

Maintaining protein balance unfolded protein refolding degradation aggregation (disease?)

Maintaining protein balance folding degradation synthesis

Translation initiation as a point of proteostatic regulation. synthesis Tight knit regulation Links nutrient availability and translation Reduce and redirect

eIF4G (ifg-1) is an essential translation component and longevity factor. Eukaryotic Initiation Factors (eIFs) eIF4G Highly conserved Essential Regulatory factor Adapted from Montero et al (2015) Control eIF4G Unpublished images by Amber Howard, Ph.D.

eIF4G (ifg-1) is an essential translation component and longevity factor. log2(fold change) ANOVA with post-hoc Tukey; *p < 0.05. Adapted from Howard et al (2016) Snow et. al. manuscript in preparation

Lowering translation activates the cytoprotective heat shock response. Part 1 Summary Lowering translation activates the cytoprotective heat shock response.

Tissues need to communicate to maintain homeostasis and viability. Too much glucose! RELEASE THE INSULIN! Brace yourself, insulin is coming…

Experimental Approach and Aims Body Wall Muscle C. elegans mutants express RNAi machinery in only tissue of interest Feed animals bacteria containing ifg-1 dsRNA Reduce translation in tissue of interest at desired life stage Intestine Hypodermis Neurons Germline Spermatheca Adapted image from Amber Howard, PhD

Reduced translation (ifg-1) in the muscle enhances fertility… Snow et. al. manuscript in preparation n=8-19; Unpaired two tailed t-test with Welch’s correction (*p<0.05, **p < 0.01, ***p < 0.001, **** p < 0.0001)

…through increased spermatogenesis. Snow et. al. manuscript in preparation n=20-70; Unpaired two tailed t-test with Welch’s correction (**p < 0.01, ***p < 0.001, **** p < 0.0001)

Reduced translation (ifg-1) in muscle accelerates development. *** Snow et. al. manuscript in preparation Error bars are SEM; n=5-16; Student’s unpaired two tailed t-test (# p < 0.05, *p < 0.01, **p < 0.001, *** p < 0.0001)

Reduced translation (ifg-1) lifespan extension is tissue dependent. 32% 16% 11% 0% 1.4% 19% Snow et. al. manuscript in preparation Lifespans were repeated at least three times; n=46-117 per lifespan.

Unfolded proteins accumulate with age, disrupting proteostasis refolding degradation aggregation (disease?)

Snow et. al. manuscript in preparation Tissue-specific reduced translation (ifg-1) possibly aids in regaining proteostasis following acute heat stress. Days of adulthood 1 2 3 4 5 6 7 8 9 10 11 12 20°C 35°C 1 2 3 4 5 Days post heat stress Snow et. al. manuscript in preparation

Parkinson’s disease model as proteotoxic stress in C. elegans Muscle specific promoter α-synuclein

Snow et. al. manuscript in preparation Reduced translation (ifg-1) in distal tissues can enhance resistance to muscular α-synuclein proteotoxicity. **** Wild Type Germline **** ** Muscle Hypodermis **** Snow et. al. manuscript in preparation Paralysis assays were repeated at least three times; n=64-124 per assay; Mantel-Cox log rank test (** p < 0.01, **** p < 0.0001)

The effect of reduced translation is tissue-specific Part 2 Summary The effect of reduced translation is tissue-specific Longevity Muscle fecundity/development Muscle proteotoxicity Not low translation, per se, that is protective Heat shock chaperone activation  

Buck Institute for Research on Aging Acknowledgements Lab members Aric Rogers, Ph.D. Jarod Rollins, Ph.D. Noah Lind Corey Henderson Former members Amber Howard, Ph.D. Bailey Blair Amruta Valiyaveetil Sarah Castor Sarah Dobbins Isaiah Mansour Elsie Washburn Paola Rivera Charles Allen Donald Brooks Collaborators Nanjing Biomedical Research Institute Di Chen, Ph.D. The Jackson Lab Steve Munger, Ph.D. University of Hamburg Zoya Ignatova, Ph.D. Frauke Adamla, Ph.D. University of Natural Resources and Life Sicences, Vienna Markus Schosserer, Ph.D. Buck Institute for Research on Aging Pankaj Kapahi, Ph.D. Funding The Ellison Medical Foundation (AG-NS-1087-13) National Institute on Aging (R00AG037621) IDeA from NIGMS of the NIH (P20GM0103423 and P20GM104318) Other Resources University of Minnesota Caenorhabditis Genetics Center (Funded by NIH ORIP P40 OD010440)

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