Biology subjects

Soukas, A. A.

Publications and source records attributed to Soukas, A. A..

4 recordsLinked to original sources

bioRxiv2023

Phenformin's impact on lifespan in C. elegans is resilient to environmental factors that inhibit metformin-induced longevity downstream of skn-1/Nrf and AMP-activated protein kinase

Despite being principally prescribed to treat type 2 diabetes, biguanides, especially metformin and phenformin, have been shown to extend lifespan and healthspan in preclinical models, and to reduce the impact of aging-associated diseases such as cancer. While there have been conflicting results in studies involving rodents and humans, consistent evidence from laboratories worldwide, including our own, indicates metformin and phenformins ability to significantly extend lifespan in C. elegans. However, the pro-longevity effect of metformin can vary depending on environmental conditions. Specifically, the choice of agar from different manufacturers or batches influences metformins ability to extend lifespan in C. elegans. We traced ability of certain agar batches to interfere with metformin-prompted lifespan extension to the presence of a factor that acts directly in the worm, independently of the bacterial food source, that prevents longevity promoting effects downstream of longevity effectors skn-1 and AMPK. In contrast, phenformin prompts robust lifespan extension in the face of environmental changes and exhibits broad positive effects in aging across genetically diverse Caenorhabditis species where the impact of metformin is highly variable. Thus metformin effects in aging are impacted by heretofore unappreciated environmental factors. Phenformin may represent a more robust agent with which to understand the longevity promoting mechanisms downstream of biguanides.

molecular biology↗

bioRxiv2022

Target of Rapamycin Complex 2 modulates development through Hedgehog/Patched signaling in C. elegans

Both Hedgehog (Hh) signaling and target of rapamycin complex 2 (TORC2) are central, evolutionarily conserved pathways that regulate development and metabolism. In C. elegans, loss of essential TORC2 component RICTOR (rict-1) causes delayed development, shortened lifespan, reduced brood, small size, and increased fat. Here we report that knockdown of Hedgehog-related morphogen grd-1 and its Patched-related receptor ptr-11 rescues delayed development in TORC2 loss of function mutants, indicating an unexpected role for grd-1/ptr-11 in slowing developmental rate downstream of nutrient sensing pathways. Further, we implicate chronic stress transcription factor pqm-1 as a key transcriptional effector of grd-1/ptr-11 in slowing whole-organism growth. We propose that the TORC2/grd-1/ptr-11/pqm-1 signaling relay acts as a critical executor of growth to slow development when C. elegans encounters unfavorable growth conditions. Summary statementDevelopmental rate in C. elegans is dramatically slowed in animals deficient in nutrient-sensitive target of rapamycin complex 2 signaling and slowing is effected by increased activity of a previously uncharacterized Hh-r/Ptr signaling relay.

developmental biology↗

bioRxiv2022

Riboflavin Depletion Promotes Longevity and Metabolic Hormesis in Caenorhabditis elegans

Riboflavin is an essential cofactor in many enzymatic processes and in the production of flavin adenine dinucleotide (FAD). Here we report that the partial depletion of riboflavin through knockdown of the C. elegans riboflavin transporter 1 (rft-1) promotes metabolic health by reducing intracellular flavin concentrations. Knockdown of rft-1 significantly increases lifespan in a manner dependent on FOXO/daf-16, AMP-activated protein kinase (AMPK)/aak-2, the mitochondrial unfolded protein response, and mTOR complex 2 (mTORC2). Riboflavin depletion promotes altered energetic and redox states and increases adiposity, independent of lifespan genetic dependencies. Riboflavin depleted animals also exhibit activation of caloric restriction reporters without a reduction in TORC1 signaling. Our findings indicate that riboflavin depletion activates an integrated, hormetic response that promotes lifespan and healthspan in C. elegans.

genetics↗

bioRxiv2021

Ether Lipid Biosynthesis Promotes Lifespan Extension and Enables Diverse Prolongevity Paradigms

Biguanides, including the worlds most commonly prescribed drug for type 2 diabetes, metformin, not only lower blood sugar, but also promote longevity in preclinical models. Epidemiologic studies in humans parallel these findings, indicating favorable effects of metformin on longevity and on reducing the incidence and morbidity associated with aging-related diseases. In spite of this promise, the full spectrum of molecular effectors responsible for these health benefits remains elusive. Through unbiased screening in C. elegans, we uncovered a role for genes necessary for ether lipid biosynthesis in the favorable effects of biguanides. We demonstrate that biguanides prompt lifespan extension by stimulating ether lipid biogenesis. Loss of the ether lipid biosynthetic machinery also mitigates lifespan extension attributable to dietary restriction, target of rapamycin (TOR) inhibition, and mitochondrial electron transport chain inhibition. A possible mechanistic explanation for this finding is that ether lipids are required for activation of longevity-promoting, metabolic stress defenses downstream of the conserved transcription factor Nrf2/skn-1. In alignment with these findings, overexpression of a single, key, ether lipid biosynthetic enzyme, fard-1/FAR1, is sufficient to promote lifespan extension. These findings illuminate the ether lipid biosynthetic machinery as a novel therapeutic target to promote healthy aging.

genetics↗