Intervention against aging?
Is a diabetes drug the new miracle drug to prolong life and even delay aging-associated diseases?
Maria Ermolaeva / FLI
The first clinical testing of a potential life-prolonging effect of metformin in aged humans without diabetes has been initiated by the American Federation for Aging Research (AFAR). However, the long-term effects of metformin in a non-diabetic cohort at different age have not been investigated yet. Researchers at the Leibniz Institute on Aging – Fritz Lipmann Institute (FLI) in Jena, and their colleagues from the Friedrich Schiller University Jena (FSU), Germany, have now addressed these questions. They used the nematode C. elegans and human primary cells to investigate the metabolic response of young and old non-diabetic organisms to metformin treatment in detail. The current study has now been published in the journal Nature Metabolism.
Metformin - therapy against aging?
Metformin affects blood glucose levels by increasing the effect of the body's own insulin, and it is currently the most frequently prescribed drug for the diabetes type 2. Type 2 diabetes is an aging-related disease, and many patients begin metformin treatment at an advanced age. Based on the increased survival and reduced prevalence of aging-associated diseases in diabetes patients under metformin treatment, it was proposed that the longevity benefits of metformin could be extended to metabolically healthy older people.
"Upon discovering the life-prolonging effect of metformin in metabolic healthy worms and mice, a real hype arose about this diabetes drug as a possible miracle medicine against aging" says Dr. Maria Ermolaeva, head of the junior research group "Stress Tolerance and Homeostasis" at FLI. Her group uses the nematode C. elegans as well as mammalian cell cultures and the short-lived turquoise killifish to identify changes in metabolism and stress responses during aging.
Metformin treatment shortens the life span of old organisms
"In our current study we were able to uncover important limitations for the use of metformin as longevity medicine," says Dr. Ermolaeva. In contrast to the positive longevity effects in young organisms that received metformin, lifespan is shortened through metformin intake at an older age. "Previous studies that provided evidence of an extended longevity by metformin usually examined animals treated with metformin from young adult or middle age until the end of life. In contrast, we have looked at treatment windows covering the entire life span, or restricted to early life or to late life". The study also utilized a human cell culture model of replicative aging to assess human responses to metformin at a cellular level and compare them to organismal responses of the worms.
Metformin longevity benefits are reversed with age
The research team led by Dr. Ermolaeva found that the very same metformin treatment that prolonged life when C. elegans worms were treated at young age, was highly toxic when animals of old age were treated. Up to 80% of the population treated at old age were killed by metformin within the first 24 hours of treatment. Consistently, human primary cells demonstrated a progressive decrease in metformin tolerance as they approached replicative senescence. The researchers were able to link this detrimental phenotype to the reduced ability of old cells and old nematodes to adapt to metabolic stressors like metformin. Under these circumstances, the exact same dose of the drug that increased longevity of young-treated organisms by triggering adaptive stress responses was harmful in animals treated at old age, which were unable to activate such protective signals.
Rapamycin alleviates metformin toxicity
Using proteome and lipid metabolism analysis, the team showed that metformin treatment initiated at an advanced age induces a cascade of metabolic failures culminating in lethal mitochondrial decline, exhaustion of ATP and ultimately in cell death. Interestingly, the toxic effect of metformin in old animals was reduced by simultaneous administration of rapamycin, an immunosuppressive drug found by the authors to stabilize the ATP levels in metformin-treated cells - a possibility to alleviate metformin toxicity in older organisms and advance the idea of metformin as an anti-aging drug.
"Our study, performed in C. elegans and human primary fibroblasts shows that there is an age-related decrease in metformin tolerance, which in later life leads to toxicity of all metformin doses tested. This shows possible safety risks of late life administration of metformin to individuals without diabetes," explains Ermolaeva. "Our data raises serious questions about the suitability of metformin as an anti-aging drug for older individuals without diabetes," says Dr. Ermolaeva about the results.
This work links the reversal of metformin benefits in late life to a decline of key metabolic activities (mitochondria, glycolysis, lipid turnover) in old animals, describing the unique molecular and genetic mechanism of the age-specific adverse effects of metformin. It underlines the emerging importance of personalized approaches to longevity treatments and warrants further detailed studies in mammals to probe the suitability of metformin as an intervention to promote healthy aging in non-diabetic humans.
Other news from the department science
Start-up Colossal Biosciences Joins Biorescue In Its Mission To Save The Northern White Rhino From Extinction
Colossal will assist the rescue mission by leveraging genome sequencing and gene editing methods to save the endangered species
"For the first time, we have systematically measured the size and abundance of cells across all major tissues and organs"
What's that smell? New gut microbe produces smelly toxic gas but protects against pathogens
Taurine-degrading bacteria influence intestinal microbiome
Wastewater treatment plants as drivers for the energy transition
Technical add-on module can, in principle, turn any wastewater treatment plant into a CO2 sink and decentralized methane production plant
At which age we are at our happiest
An evaluation of over 400 samples shows how subjective well-being develops over the course of a lifespan
New approach to testing for long Covid
Blood vessels in the eye altered with persistent coronavirus symptoms
Researchers create pioneering approaches for the detection of viral antigens
Sybodies: a revolution in biological recognition
New SARS-CoV-2 variant Eris on the rise
SARS-CoV-2 lineage EG.5.1 has an advantage at evading neutralizing antibodies
Does the human brain have an Achilles heel that ultimately leads to Autism?
CHOOSEn fate: one brain organoid’s tale on Autism
Co-crystal improves the water-solubility of ASA
This could benefit patients diagnosed with suspected acute myocardial infarction
Observing nanoparticles with unprecedented precision
Illuminated: Researchers investigate new physical phenomena on the nanoscale with microstructured fibers
Falling Walls announces Science Breakthrough of the Year 2023 laureates
“These outstanding breakthroughs will change the face of the world and impressively prove what ingenuity, curiosity and courage can achieve”
Most read news
Cells with an ear for music release insulin
For the first time, researchers are using music, including Queen's global hit "We will rock you," to stimulate insulin release from cells
"Anti-obesity drugs" normalises brain in obesity
Anti-obesity drug improves associative learning in people with obesity
Microbe of the Year 2023: Bacillus subtilis – for health and technology
Already, Bacillus subtilis is indispensable in many industries, and many more innovations are expected
Younger generation gets sick earlier and more often than older generation
In spite of their advanced age, they are in the middle of life, healthy, active and mentally alert – they are referred to as the “young old”
How sleep deprivation can harm the brain
Sleep deprivation decreases the amount of a factor that protects neurons
A whole new order of bacteria could hold the key to improving biogas production
The discovery was made by researchers from Germany, Spain and the Netherlands
How to inactivate common cold viruses
In the cold season, cold viruses are everywhere. But we can do something about it
How minimal genetic differences can turn healthy food into a deadly danger
You are what you eat - this old saying could take on a new dimension according to latest research results
New approach to testing for long Covid
Blood vessels in the eye altered with persistent coronavirus symptoms
More news from our other portals
Major breakthrough in the development of electric vehicle batteries
New study finds ways to suppress lithium plating in automotive batteries for faster charging electric vehicles
Blender Bites launches at Walmart USA
The products are to be introduced in about 1,600 stores across the country
Benchtop NMR spectroscopy can accurately analyse pyrolysis oils
More accessible analysis could help develop the potential of bio-oils as an alternative to fossil fuels
Green methanol for shipping and industry: € 10.4 Mio. for the "Leuna100" project
A consortium of two Fraunhofer institutes, DBI-Gastechnologisches Institut Freiberg, Technical University of Berlin and C1 makes industrial history at the Leuna site
Clean water from fog
A property known as photocatalytic memory ensures that this also functions when skies are overcast and at night
Green, sweet and crisp - New apple variety Pia41 approved
The apple bred at the Julius Kühn Institute receives variety protection
Research shows table salt could be the secret ingredient for better chemical recycling
Table salt as the key to the plastics recycling revolution?
Sugar: Small increase in production despite record prices
EU sugar market more than in need of reform to keep medium-sized processing companies competitive
Graphene discovery could help generate hydrogen cheaply and sustainably
Microscopic insights into electrochemical interfaces
Stanford study shows how the meat and dairy sector resists competition from alternative animal products
Scientists use quantum device to slow down simulated chemical reaction 100 billion times
What happens in femtoseconds in nature can now be observed in milliseconds in the lab
New battery holds promise for green energy
Redox-flow battery eliminates costly and inefficient membrane
Fondant under the magnifying glass
New insights into the properties of sweet coating: The results could be used to optimize the industrial production process in the future
Leipzig-based start-up converts CO₂ into green chemicals with patented plasma catalysis
CO₂ recycling as a useful complement to carbon capture and storage
A microchip for Parmigiano Reggiano cheese
Consorzio del Parmigiano Reggiano, p-Chip Corporation, and Kaasmerk Matec Partner to Launch Breakthrough in Food-Safe Digital Tracking Technology
Cleaning water with ‘smart rust’ and magnets
New method for pollutants such as crude oil, glyphosate, microplastics and hormones
A Second Life for Electric Car Batteries
Scientists develop a decision model for retired lithium-ion batteries