Rilmenidine dosage and evidence

What is Rilmenidine?

How does Rilmenidine work?

It acts on a spot in the brain that helps control blood pressure. It lowers blood pressure with less sleepiness than clonidine, an older pill of the same kind. The ageing idea is that it turns up the cell's clean-up system, called autophagy, and makes cells act like the body is eating less. In worms, the longer life needed one specific receptor, two stress-handling genes, and a working clean-up system. It did not need the cell's main energy sensor. The mouse nerve disease work shows the other side of the same idea. The clean-up really was switched on, and it could be measured. In those mice, too much clearing of the power plants inside nerve cells seems to be what did the harm.

What have studies in people found about Rilmenidine?

Many years of use as a blood pressure pill where it is sold. One study in 18 people with Huntington's disease that looked at safety only. Nothing in people on ageing.

• Sold as a blood pressure pill in France and several other European countries, with the normal safety record that comes with that.
• One 2 year study in 18 people with Huntington's disease. It checked whether people could handle the drug, not whether it helped. 12 finished, and it made no claim of benefit.
• No study in people has measured lifespan, biological age or any sign of ageing on this drug.
• In mice, the hard results point the wrong way twice. In two mouse models of a muscle-wasting nerve disease, the drug did what it was meant to inside cells, and the mice did worse.

What this does not tell you: A worm is not a mammal, and the mouse work on this drug shows why that matters. The mouse data in the ageing paper is about genes in the liver and kidney, not about living longer. The only mouse survival result for this drug is a shorter life, in a model of nerve disease. Nobody has tested whether it helps normal ageing mice live longer.

The state of the research

The evidence, in charts

The studies we cite

• Study in people2017
  An open-label study to assess the feasibility and tolerability of rilmenidine for the treatment of Huntington's disease

  This study was never built to find out whether the drug works. 18 people with mild to moderate Huntington's disease took 1 mg of rilmenidine a day for six months, then 2 mg for another eighteen. 12 finished. Everyone knew they were getting the drug and there was no group to compare against. Three serious events happened, including a hospital admission for depression, none judged drug related. What was measured was dropouts and harms, not benefit.

  The only sustained human study in a neurological population. 18 non-demented patients with mild to moderate Huntington's disease took 1 mg daily for 6 months then 2 mg for a further 18 months. 12 completed. Three serious adverse events were recorded including hospitalisation for depression, none judged drug related. The primary outcome was withdrawals and serious adverse events, not efficacy, and the authors state that changes in secondary outcomes were comparable to untreated observational cohorts without formal statistical comparison.

  PMID 29075837 Journal of Neurology
• Animal study2023
  Rilmenidine extends lifespan and healthspan in Caenorhabditis elegans via a nischarin I1-imidazoline receptor

  In worms. Rilmenidine made tiny worms live longer and handle stress better, whether they started young or old. It only worked through one specific receptor and the cell's clean-up system. It added nothing for worms already eating less or on rapamycin. In mice, it changed genes in the liver and kidney to look like eating less, but the mice's lifespan was not measured. Two authors have business interests in longevity.

  The paper that put rilmenidine into geroscience. Identified by searching for compounds with a caloric-restriction-like expression signature. Increased lifespan in C. elegans when given at young and older ages, with the stress resilience, healthspan and lifespan benefits all dependent on the I1-imidazoline receptor nish-1, on DAF-16 and SKN-1, and on autophagy but not AMPK. Adding it to calorically restricted worms, reduced TORC1 function or rapamycin produced no further gain. Mice treated with rilmenidine showed caloric-restriction-like transcriptional changes in liver and kidney, which is a gene expression finding and not a lifespan finding. Two authors disclose commercial longevity interests.

  PMID 36670049 Aging Cell
• Animal study2010
  Rilmenidine attenuates toxicity of polyglutamine expansions in a mouse model of Huntington's disease

  In mice and in a dish. Rilmenidine turned on the cell's clean-up system in mice and in nerve cells grown in a dish. In mice bred to get Huntington's disease, it eased signs of the disease and cut the level of the harmful protein.

  The result that made rilmenidine interesting to the autophagy field. It was found in a screen of approved drugs for mTOR-independent autophagy induction, induced autophagy in mice and in primary neuronal culture, attenuated disease signs in a Huntington's disease mouse model and reduced levels of the mutant huntingtin fragment.

  PMID 20190273 Human Molecular Genetics
• Animal study2018
  Rilmenidine promotes MTOR-independent autophagy in the mutant SOD1 mouse model of amyotrophic lateral sclerosis without slowing disease progression

  In mice. In mice bred to get a muscle-wasting nerve disease, rilmenidine switched on cell clean-up in the spinal cord as planned. The harmful protein went down. But the nerve cells died faster and the mice got sicker faster. The authors blame too much clearing of the power plants inside nerve cells.

  Autophagy and mitophagy were induced in the spinal cord as intended and soluble mutant SOD1 fell, and despite that rilmenidine worsened motor neuron degeneration and symptom progression in SOD1G93A mice. The authors attribute the harm to excessive mitophagy and severe mitochondrial depletion in motor neurons.

  PMID 28980850 Autophagy
• Animal study2021
  Stimulation of mTOR-independent autophagy and mitophagy by rilmenidine exacerbates the phenotype of transgenic TDP-43 mice

  In mice. In a second mouse model of the same kind of nerve disease, rilmenidine again switched on cell clean-up. This time the mice died sooner and lost nerve cells faster. A key protein was also pulled out of the cell centre. This is a lifespan result pointing the wrong way.

  The second and harder negative. In TDP-43WTxQ331K double transgenic mice, rilmenidine induced robust spinal cord autophagy and exacerbated the phenotype: truncated lifespan, accelerated motor neuron loss and pronounced clearance of TDP-43 from nuclei. A lifespan result in mice pointing the wrong way.

  PMID 33798740 Neurobiology of Disease