Metformin, a extensively prescribed drug for kind 2 diabetes, not solely reduces blood sugar ranges however has additionally been proven to extend the lifespan of C. Elegans — an animal mannequin that shares comparable metabolic methods with people and are sometimes used to mannequin human illnesses.
Research Findings and Ether Lipids
New analysis led by investigators at Massachusetts General Hospital (MGH), a founding member of the Mass General Brigham healthcare system, reveals that metformin promotes longevity by stimulating the body’s manufacturing of molecules known as ether lipids, a main structural element of cell membranes.
The findings, that are revealed in eLife, counsel that boosting the manufacturing of ether lipids in people could help healthy growing older and cut back the affect of aging-related illnesses.
Experimental Methodology and Outcomes
To establish the genes required to allow lifespan extension in response to metformin and its sister drug phenformin (medication known as biguanides), the scientists silenced particular person genes within the roundworm Caenorhabditis elegans (which shares over 80% of its proteins with people and has a mean lifespan of about two weeks) and examined what occurs to the altered worms after publicity to the medicines.
The experiments reveal that genes that enhance the manufacturing of ether lipids are required to increase lifespan in response to the biguanides.
Inactivation of the genes that encode for these enzymes fully prevented the longevity-promoting results of biguanides.
Importantly, the inactivation of those genes prevented lifespan extension in a number of conditions which are additionally recognized to advertise longevity, together with dietary restriction.
Ether Lipid Synthesis and Longevity
The workforce additionally discovered that rising ether lipid synthesis alone (by overexpressing a single, key ether lipid biosynthetic enzyme known as fard-1) was enough to increase C. elegans’ lifespan, orchestrating a metabolic stress protection response by a issue known as SKN-1, which is the worm counterpart to the mammalian protein Nrf. This response altered metabolism to advertise a longer lifespan.
“Our study implicates the promotion of ether lipid biosynthesis as a novel therapeutic target to promote healthy aging. This suggests that dietary or pharmacologic intervention to promote ether lipid synthesis might one day represent a strategy to treat aging and aging-related diseases,” says senior writer Alexander A. Soukas, MD, PhD, Associate Director of the MGH Center for Genomic Medicine, an Associate Professor at Harvard Medical School and Weissman Family MGH Research Scholar 2018-2023.
“Because our research centered solely on interventions in C. elegans, additional research in mammalian fashions (akin to human cells and mice), epidemiological statement, and rigorous medical trials are required to find out the viability of selling ether lipid synthesis to advertise human health-span and lifespan.”
Reference: “Ether lipid biosynthesis promotes lifespan extension and enables diverse pro-longevity paradigms in Caenorhabditis elegans” by Lucydalila Cedillo, Fasih M Ahsan, Sainan Li, Nicole L Stuhr, Yifei Zhou, Yuyao Zhang, Adebanjo Adedoja, Luke M Murphy, Armen Yerevanian, Sinclair Emans, Khoi Dao, Zhaozhi Li, Nicholas D Peterson, Jeramie Watrous, Mohit Jain, Sudeshna Das, Read Pukkila-Worley, Sean P Curran and Alexander A Soukas, 22 August 2023, eLife.
This work was funded by NIH/NIA Grants R01AG058259 and R01AG69677 (to A.A.S.) and R01AG058610 (to S.P.C.), by the Weissman Family MGH Research Scholar Award (to A.A.S.), by a NSF GRFP Award 1000253984 (to L.C.), and by NIH/NIAID R01AI130289 (to R.P.W.), and by IRACDA NIH Grant Ok12GM106996 (to L.C.).