An experimental study led by the University of Liverpool has generated the intriguing speculation that the anti-hypertensive drug rilmenidine might extend lifespan and slow ageing.
The researchers noted that there is considerable evidence that the ageing rate can be "markedly slowed in model organisms". So far, they said, "caloric restriction (CR) is the most robust anti-aging intervention, and CR promotes longevity across species".
However, studies of CR in humans have had equivocal results, low compliance, and many side effects, meaning that the most reasonable anti-aging target for humans would be "finding medications that can mimic the effect of caloric restriction", they said. However, "only a few compounds have been identified" that can do this.
They, therefore, searched for known compounds that elicit a similar gene expression signature to caloric restriction, and identified rilmenidine, an I1-imidazoline receptor agonist and prescription medication for the treatment of hypertension in humans.
The team's previous work had shown that rilmenidine elicited "a similar transcriptional profile to CR", with the capacity "to reprogram human cell transcription profiles to a more youthful state", and to induce a gene expression signature in the liver of mice similar to CR.
For the new study, published in Aging Cell, the researchers tested rilmenidine on the roundworm Caenorhabditis elegans and showed that at both young and older ages, it increased the animals' lifespan and improved health markers, "mimicking the effects of caloric restriction".
Drug Decelerated Decrepitude
Rilmenidine extended lifespan in C elegans whether the drug was started in early adulthood or only once the animal had aged. Furthermore, it decelerated the development of decrepitude, the researchers said, without altering developmental periods.
The study also demonstrated that the health span and lifespan benefits of rilmenidine treatment in the roundworm C elegans were mediated by the I1-imidazoline receptor nish-1, identifying this receptor as a potential longevity target.
"Consistent with the shared caloric-restriction-mimicking gene signature, supplementing rilmenidine to calorically restricted C elegans, genetic reduction of TORC1 function, or rapamycin treatment did not further increase lifespan," the team noted. In addition, rilmenidine-induced longevity required the transcription factors FOXO/DAF-16 and NRF1,2,3/SKN-1. "Furthermore, we find that autophagy, but not AMPK signaling, was needed for rilmenidine-induced longevity."
Geroprotective Effect Mimicked Calorie Restriction
They next tested rilmenidine in a mouse model and noted that "transcriptional changes similar to caloric restriction were observed in liver and kidney tissues".
The team concluded that: "Together, these results reveal a geroprotective and potential caloric restriction mimetic effect by rilmenidine that warrant fresh lines of inquiry into this compound."
This was a study in animals, and there are no guarantees that the drug would have similar effects in humans. However, the researchers noted that: "Unlike other drugs previously studied for this purpose, the widely prescribed, oral antihypertensive rilmenidine has potential for future translatability to humans, as side-effects are rare and non-severe."
Potential Benefits of Delaying Ageing 'Immense'
João Pedro Magalhães, who led the research while at the University of Liverpool and is now professor of molecular biogerontology at the University of Birmingham, said: "With a global ageing population, the benefits of delaying ageing, even if slightly, are immense. Repurposing drugs capable of extending lifespan and health span has a huge untapped potential in translational geroscience. For the first time, we have been able to show in animals that rilmenidine can increase lifespan. We are now keen to explore if rilmenidine may have other clinical applications."
Asked to comment on the study by Medscape News UK, Dr Nick Ktistakis, a senior group leader at the Babraham Institute in Cambridge, who works on autophagy, one of the processes studied in the paper, said: "The paper shows clearly that I1-imidazoline, a medicine used to treat hypertension with a known pharmacokinetic profile, is also able to extend lifespan in C elegans, a well-established model system for ageing studies.
"Significantly, this effect appears to map to the mTOR pathway, which has already been implicated in lifespan extension in many model organisms. At the same time the I1-imidazoline effect requires autophagy, another pathway that has been implicated in lifespan extension.
"Overall, this paper provides an interesting and novel way to extend lifespan via canonical routes but via drug repurposing. One question for the future is whether these effects are functionally different than the traditional route, which is to inhibit mTOR directly using rapamycin. Could I1-imidazoline treatment extend lifespan in humans but avoid any possible rapamycin side effects?"
The study was funded by the Swiss National Science Foundation, LongeCity and the Biotechnology and Biological Sciences Research Council.
