Design and Analysis of Pharmacological Studies in Aging

Clay, Khalyd J.; Petrascheck, Michael

doi:10.1007/978-1-0716-0592-9_7

Cited by 4 publications

(5 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…al. 29 Each permutation (strain‐drug) was tested in trials of 50‐100 animals in each trial. These numbers have sufficient power to detect differences in lifespan of 20% or more in more than 95% of the time.…”

Section: Methodsmentioning

confidence: 99%

Multiple Targets, One Goal: Compounding life‐extending effects through Polypharmacology

Avchaciov,

Clay,

Denisov

et al. 2024

Preprint

View full text Add to dashboard Cite

Analysis of lifespan‐extending compounds suggested the most effective geroprotectors target multiple biogenic amine receptors. To test this hypothesis, we used graph neural networks to predict such polypharmacological compounds and evaluated them inC. elegans. Over 70% of the selected compounds extended lifespan, with effect sizes in the top 5% compared to the DrugAge database. This reveals that rationally designing polypharmacological compounds enables the design of geroprotectors with exceptional efficacy.Key takeawaysThe most effective known geroprotectors act by polypharmacological mechanisms.Graph neural networks predicted polypharmacological geroprotectors with a hit rate of 70%.The predicted polypharmacological geroprotectors are exceptionally effective.The predicted polypharmacological mechanism was experimentally confirmed.Rationally designing polypharmacological compounds results in geroprotectors with exceptional efficacy.

show abstract

Section: Methodsmentioning

confidence: 99%

Multiple Targets, One Goal: Compounding life‐extending effects through Polypharmacology

Avchaciov,

Clay,

Denisov

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Age-synchronized C. elegans were prepared in a liquid medium, as described above, and seeded into flat-bottom, optically clear 96-well plates (Corning, 351172) containing 150 µL total volume per well, as previously described ( Clay and Petrascheck, 2020 ). Plates contained ~10 animals per well in 6 mg/mL γ-irradiated OP50.…”

Section: Methodsmentioning

confidence: 99%

Proteostasis is differentially modulated by inhibition of translation initiation or elongation

Clay,

Yang,

Clark

et al. 2023

eLife

Self Cite

View full text Add to dashboard Cite

Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Here, we use chemical inhibitors targeting discreet steps of translation to compare how lowering the concentration of all or only translation initiation-dependent proteins rescues Caenorhabditis elegans from proteotoxic stress. We systematically challenge proteostasis and show that pharmacologically inhibiting translation initiation or elongation elicits a distinct protective profile. Inhibiting elongation protects from heat and proteasome dysfunction independently from HSF-1 but does not protect from age-associated protein aggregation. Conversely, inhibition of initiation protects from heat and age-associated protein aggregation and increases lifespan, dependent on hsf-1, but does not protect from proteotoxicity caused by proteasome dysfunction. Surprisingly, we find that the ability of the translation initiation machinery to control the concentration of newly synthesized proteins depends on HSF-1. Inhibition of translation initiation in wild-type animals reduces the concentration of newly synthesized proteins but increases it in hsf-1 mutants. Our findings suggest that the HSF-1 pathway is not only a downstream target of translation but also directly cooperates with the translation initiation machinery to control the concentration of newly synthesized proteins to restore proteostasis.

show abstract

“…Age–synchronized C. elegans were prepared in liquid medium, as described above, and seeded into flat-bottom, optically clear 96–well plates (Corning, 351172) containing 150uL total volume per well, as previously described (Clay and Petrascheck, 2020). Plates contained ~10 animals per well in 6 mg/mL γ–irradiated OP50.…”

Section: Competing Interestsmentioning

confidence: 99%

Proteostasis is differentially modulated by inhibition of translation initiation or elongation

Clay

Yang

Petrascheck

2022

Preprint

Self Cite

View full text Add to dashboard Cite

Recent work has revealed an increasingly important role for mRNA translation in maintaining proteostasis. Inhibiting translation protects from various proteostatic insults, including heat, expression of aggregation-prone proteins, or aging. However, multiple studies have come to differing conclusions about the mechanisms underlying the protective effects of translation inhibition. Here, we systematically lower translation either by pharmacologically inhibiting translation initiation or elongation and show that each step activates distinct protective responses in Caenorhabditis elegans. Targeting initiation triggers an HSF?1 dependent mechanism that protects from heat and age-associated protein misfolding but not from proteotoxicity caused by proteasome dysfunction. Conversely, targeting elongation triggers an HSF-1 independent mechanism that protects from heat and proteasome dysfunction but not from age-associated protein aggregation. Furthermore, while inhibiting translation initiation increases lifespan in wild-type worms, inhibiting translation elongation only extends lifespan when the animals exhibit preexisting proteotoxic stress—either as a result of aggregation-prone protein expression or hsf-1 deficiency. Together our findings suggest that organisms evolved complementary mechanisms that the mRNA translation machinery can trigger to restore proteostasis.

show abstract

Design and Analysis of Pharmacological Studies in Aging

Cited by 4 publications

References 26 publications

Multiple Targets, One Goal: Compounding life‐extending effects through Polypharmacology

Multiple Targets, One Goal: Compounding life‐extending effects through Polypharmacology

Proteostasis is differentially modulated by inhibition of translation initiation or elongation

Proteostasis is differentially modulated by inhibition of translation initiation or elongation

Contact Info

Product

Resources

About