Repurposing drugs capable of extending lifespan and health span has a huge untapped potential in translational geroscience. Here, we 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. We then show that treating Caenorhabditis elegans with rilmenidine at young and older ages increases lifespan. We also demonstrate that the stress-resilience, health span, and lifespan benefits of rilmenidine treatment in C. elegans are mediated by the I1-imidazoline receptor nish-1, implicating 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 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. Moreover, transcriptional changes similar to caloric restriction were observed in liver and kidney tissues in mice treated with rilmenidine. Together, these results reveal a geroprotective and potential caloric restriction mimetic effect by rilmenidine that warrant fresh lines of inquiry into this compound.
Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression
Macroautophagy/autophagy is the main intracellular catabolic pathway in neurons that eliminates misfolded proteins, aggregates and damaged organelles associated with ageing and neurodegeneration. Autophagy is regulated by both MTOR-dependent and -independent pathways. There is increasing evidence that autophagy is compromised in neurodegenerative disorders, which may contribute to cytoplasmic sequestration of aggregation-prone and toxic proteins in neurons. Genetic or pharmacological modulation of autophagy to promote clearance of misfolded proteins may be a promising therapeutic avenue for these disorders. Here, we demonstrate robust autophagy induction in motor neuronal cells expressing SOD1 or TARDBP/TDP-43 mutants linked to amyotrophic lateral sclerosis (ALS). Treatment of these cells with rilmenidine, an anti-hypertensive agent and imidazoline-1 receptor agonist that induces autophagy, promoted autophagic clearance of mutant SOD1 and efficient mitophagy. Rilmenidine administration to mutant SOD1G93A mice upregulated autophagy and mitophagy in spinal cord, leading to reduced soluble mutant SOD1 levels. Importantly, rilmenidine increased autophagosome abundance in motor neurons of SOD1G93A mice, suggesting a direct action on target cells. Despite robust induction of autophagy in vivo , rilmenidine worsened motor neuron degeneration and symptom progression in SOD1G93A mice. These effects were associated with increased accumulation and aggregation of insoluble and misfolded SOD1 species outside the autophagy pathway, and severe mitochondrial depletion in motor neurons of rilmenidine-treated mice. These findings suggest that rilmenidine treatment may drive disease progression and neurodegeneration in this mouse model due to excessive mitophagy, implying that alternative strategies to beneficially stimulate autophagy are warranted in ALS.
I think this is really interesting. It strikes me as kind of a “twofer”. Lower BP AND extend lifespan! So I’ve been looking online for rilmenidine to learn more but it seems the drug is not available in the US. I wonder why? If I want to try it out I’d have to buy it from overseas.
Personally, I think the result is from its blood pressure-lowering effects. If its effects are on autophagy, there are many other supplements and drugs to take. If you are already taking a blood pressure-lowering medication and any or all of the supplements such as fisetin, curcumin, resveratrol, quercetin, green tea extract, ashwagandha, berberine, omega-3 fatty acids, etc. that promote autophagy, I would not consider switching.
I found a seller online - looks like www.buyrilmenidine.com is expecting more stock. Not sure why I haven’t seen this site before but I’ve registered on the pricing page and will buy as soon as stock is in.
This study is interesting, having come across this recently. Only just found someone selling this specific thing on buyrilmenidine.com, think its europe based and some places don’t require a prescription for it. Has anyone seen any further research on it since the study was published in Jan 2023? Interesting to see what further research is published on animal (other than worms!) and human trials since a year ago. Rilmenidine has been around for a while so at least it has some history behind it and appears that its use has very limited side effects compared to other medication(?)
That looks like a great site, but they don’t have any reference to rilmenidine or the other brands its marketed under - you didn’t include what you were searching for in your screenshot?
FWIW:
It’s possible I suppose, but I don’t see any benefit of taking rilmenidine over telmisartan.
Rilmenidine can cause drowsiness, dry mouth, dizziness, and headache.
Telmisartan is typically well tolerated, with few side effects.
Telmisartan may have advantages over rilmenidine in terms of tolerability.
Telmisartan has beneficial effects on glucose and lipid metabolism beyond blood pressure lowering.
Rilmenidine may worsen glucose tolerance.
Telmisartan is administered once daily, while rilmenidine is typically given twice per day.
Telmisartan appears to be superior to rilmenidine overall in terms of efficacy, tolerability, metabolic effects, and convenience.
“Rilmenidine use declined in the 2000s due to concerns about withdrawal effects. It remains available but is not a first-line treatment.”
Thanks for the additional info, @desertshores !
Just for clarity, I am not advocating one over the other. Someone asked if rilmenidine was available, I happened to come across that site so I shared it with you. @Joseph , in the previous reply, stated rilmenidine 30 tablets 100mg but I was looking for 1mg per tablet. There is no reference to rilmenidine that I can find in goodrx or the other brands (Albarel, Hyperium, Iterium and Tenaxum), I did search on those but happy to be proven wrong.
I assume the scientists studying Rilmenidine have a sound basis for their focus and optimism, and I note that their publications are appropriately qualified. On the other hand, a few of the usual media sources have prematurely claimed benefits to humans, some in an exaggerated fashion.
For the time being, I’m going to stay on the sidelines for the following reasons:
As someone who takes a large number of supplements daily, including those focused on life extension, I am mindful of the potential for adverse interactions among combinations of supplements including the possibly irreversible kidney and/or liver damage. I don’t see this as a large threat, especially when framed as a risk/benefit equation but I acknowledge that I am operating in largely uncharted waters. This is one of many reasons why I am thankful for the information we share in groups like this one.
It would be difficult to put a precise number on it but the number of medical research studies on C. Elegans that end up generalizing well to humans is quite small. Numbers have been placed on the percent of medical research on mice generalizing to humans and they start around 5-10% with none being much higher. This is not to detract from important animal research, only to note that its primary benefits to human research are to suggest and refine specific paths of inquiry.
Someone may point out a better way to look at my last reason for remaining on the sideline, but I wonder why Rilmenidine is available in so few countries. I also see Rilmenidine listed on the EU(7)-PIM list of potentially inappropriate medications for older people (consented by experts from seven European countries). This lack of availability could also run the other way. I recall the US being something like 30 years behind the curve in approving metformin.
@adssx I began taking another sartan (Losartan) recently for borderline hypertension. The results greatly exceeded my expectations. I hope your results are as good. Initially, you may see a modest reduction in BP but it can take a month or more to see the full effects. My BP was in the 135-140/80 range, higher in the morning and lower in the evening. Not terribly high but I wanted to move into a healthier range. After a month, my BP has dropped to a low reading of 104/68 and a high of 124/75. Most of these reading were taking across different times each day within a minute or two after sitting down. Close enough.
To get this kind of result with no side effects of any kind was a surprise. When taking a sartan, you want to be vigilant about excess potassium intake and monitor your blood potassium one you have stabilized on the medication.
Exactly… just because something shows promise in worms, doesn’t mean its going to be effective in humans…(I suspect most don’t pan out, in fact most mice studies don’t translate to humans)… still lots of testing to be done, in mice, then in humans.
As an aside, Matt Kaeberlein has commented in the past that people making decisions to take something based just on worm (c.elegans) studies, are absolutely and completely premature… its way too early.
