Un estudio realizado en monos durante 3 años revela que la metformina (antidiabético) retarda su envejecimiento (especialmente del cerebro e hígado). La actividad neuronal se pareció a la de monos 6 años más jóvenes (equivalente a 18 años humanos)
El cerebro envejece más lentamente en los monos a los que se administra un fármaco barato para la diabetes
Un medicamento de bajo coste para la diabetes retrasa el envejecimiento de los monos macho y es especialmente eficaz para retrasar los efectos del envejecimiento en el cerebro, según un pequeño estudio en el que se realizó un seguimiento de los animales durante más de tres años1. Los resultados plantean la posibilidad de que la metformina, un medicamento muy extendido, pueda utilizarse algún día para retrasar el envejecimiento en humanos.
Los monos que recibieron metformina a diario mostraron un deterioro cerebral asociado a la edad más lento que los que no recibieron el fármaco. Además, su actividad neuronal se asemejaba a la de monos unos seis años más jóvenes (equivalente a unos 18 años humanos) y los animales tenían una cognición mejorada y una función hepática preservada.
Este estudio, publicado en Cell el 12 de septiembre, contribuye a sugerir que, aunque morir es inevitable, "envejecer, tal como lo conocemos, no lo es", afirma Nir Barzilai, geocientífico del Albert Einstein College of Medicine de Nueva York, que no participó en el estudio.
Un medicamento básico
La metformina se utiliza desde hace más de 60 años para reducir los niveles de azúcar en sangre de los diabéticos de tipo 2, y es el segundo medicamento más recetado en Estados Unidos. Desde hace tiempo se sabe que el fármaco tiene efectos que van más allá del tratamiento de la diabetes, lo que ha llevado a los investigadores a estudiarlo contra afecciones como el cáncer, las enfermedades cardiovasculares y el envejecimiento.
Data from worms, rodents, flies and people who have taken the drug for diabetes suggest the drug might have anti-ageing effects. But its effectiveness against ageing had not been tested directly in primates, and it is unclear whether its potential anti-ageing effects are achieved by lowering blood sugar or through a separate mechanism.
This led Guanghui Liu, a biologist who studies ageing at the Chinese Academy of Sciences in Beijing, and his colleagues to test the drug on 12 elderly male cynomolgus macaques (Macaca fasciucularis); another 16 elderly monkeys and 18 young or middle-aged animals served as a control group. Every day, treated monkeys received the standard dose of metformin that is used to control diabetes in humans. The animals took the drug for 40 months, which is equivalent to about 13 years for humans.
Over the course of the study, Liu and his colleagues took samples from 79 types of the monkeys’ tissues and organs, imaged the animals’ brains and performed routine physical examinations. By analysing the cellular activity in the samples, the researchers were able to create a computational model to determine the tissues’ ‘biological age’, which can lag behind or exceed the animals’ age in years since birth.
Slowing the clock
The researchers observed that the drug slowed the biological ageing of many tissues, including from the lung, kidney, liver, skin and the brain’s frontal lobe. They also found that it curbed chronic inflammation, a key hallmark of ageing. The study was not intended to see whether the drug extended the animals’ lifespans; previous research has not established an impact on lifespan2 but has shown lengthened healthspan3 — the number of years an organism lives in good health.
This means that metformin can “effectively rewind organ age” in monkeys, Liu says. The authors also identified a potential pathway by which the drug protects the brain: it activates a protein called NRF2, which safeguards against cellular damage triggered by injury and inflammation.
This study is the “most quantitative, thorough examination of metformin action that I’ve seen beyond mice”, says Alex Soukas, a molecular geneticist at Massachusetts General Hospital in Boston. “It was a surprise to see how comprehensive [the drug’s] effects were across tissue types.”
Low-cost drug, high-cost trial
Although these results are encouraging, much more research will be necessary to study the drug before it’s validated as an anti-ageing compound in humans, Liu says.
The fraught quest to account for sex in biology research
For one, only 12 monkeys received the drug. Soukas says he would therefore like to see a replication of this effort or a study that includes more animals. Furthermore, the researchers tested only male animals, which Rafael de Cabo, a translational geroscientist at the National Institute on Aging in Baltimore, Maryland, says is concerning. He acknowledges that it is extremely expensive to run this type of long-term experiment, but adds that it is crucial to understand ageing in females as well, given that there are often large differences between the sexes.
In the meantime, Liu and his colleagues have launched a 120-person trial in collaboration with the biopharmaceutical company Merck in Darmstadt, Germany, which developed and manufactures metformin, to test whether the drug delays ageing in humans.
Barzilai has even bigger ambitions: he and his colleagues have been spearheading an effort to raise US$50 million to study the drug in a trial of 3,000 people aged 65–79 over 6 years. Research into metformin and other anti-ageing candidates could one day mean that doctors will be able to focus more on keeping people healthy for as long as possible rather than on treating diseases, he says.
doi: https://doi.org/10.1038/d41586-024-02938-w
References
Yang, Y. et al. Cell https://doi.org/10.1016/j.cell.2024.08.021 (2024).
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