From the philosopher’s stone to modern “longevity drugs,” for millennia humans have sought to discover and develop treatments that hold the power to prevent or delay death. According to recently published research, we now have another candidate to add to the list: the antihypertensive drug rilmenidine, which study authors Bennett et al. show extends lifespan in nematode worms (C. elegans). Do we have reason to believe this drug may offer real benefits for human longevity, independent of its effects on hypertension, or is this just another dead end?
The research group had previously identified rilmenidine as a longevity candidate by screening for drugs that elicited similar gene expression patterns as those observed with calorie restriction (CR). As I’ve discussed on various occasions on the podcast (e.g., with Dr. Matt Kaeberlein and Dr. Steve Austad), CR has repeatedly been shown to extend lifespan in animal studies, but these results are unlikely to translate to human applications due to negative effects on muscle mass and immune function and the difficulty of maintaining experimental levels of CR in a real-world setting. Therefore, the investigators sought compounds which might mimic the cellular effects associated with CR without the need for reduced macronutrient intake (so called “CR mimetics”).
They found a high degree of overlap between the gene expression profiles of CR and rilmenidine, a drug which is commonly prescribed for blood pressure management and thus has an established safety and bioavailability profile in humans. Given these observations, Bennett et al. tested rilmenidine’s efficacy in extending lifespan in the model species C. elegans, reporting their findings earlier this year.
What did the study show?
The researchers treated wild-type, larval C. elegans with rilmenidine and observed an extension in lifespan of 19% relative to worms treated with a control solution. Additionally, worms treated with rilmenidine at either the early adult or late adult stage exhibited approximately 33% lifespan extension compared to controls.
Bennett et al. then sought to determine whether the observed effects on lifespan were mediated by pathways also associated with CR. Eat–2 mutants, which possess a genetic defect that limits food consumption, were used as a C. elegans model of CR. While eat-2 mutants treated with control solution and wild-type worms treated with rilmenidine demonstrated extended lifespan relative to wild-type control worms, the two variables together did not yield any additive effect. That is, treating eat-2 mutants with rilmenidine did not extend lifespan to a greater extent than observed with either eat-2 mutation or rilmenidine treatment alone, indicating that the drug acts through common pathways with CR. Using other mutant lines, the investigators further show that the longevity effects of rilmenidine likely involve inhibition of mTOR activity and upregulation of autophagy pathways, both of which are also associated with CR.
Are these lifespan data biologically significant?
At face value, a 33% increase in lifespan is certainly an eye-popping result. But as Dr. Kaeberlein explained in AMA #35, longevity studies can often be misleading if lifespans among control worms are unusually short or exhibit high variability.
Control lifespans in this study were not, on average, shorter than values typically reported in literature, but variability in lifespan for both control-treated wild-type worms and rilmenidine-treated wild-type worms across experiments was extremely high. For instance, in one experiment assessing optimal rilmenidine dosing, control-treated wild-type worms survived an average of 21.85 days. In experiments assessing autophagy pathways, wild-type worms with the same control treatment survived an average of 28.01 days – a 28% discrepancy between two groups of worms that were nominally identical and received the same intervention. In some cases, the mean lifespan of rilmenidine-treated wild-type worms fell within this 22-28 day range.
Indeed, this level of variability exceeds the between-group differences observed in most experiments, indicating that a large proportion of the apparent “difference” between groups in a given experiment could in fact be accounted for by experimental margin of error, despite showing within-experiment statistical significance. In other words, it’s possible that the interventions did not have biological significance, or at least had a much smaller true effect than they appeared to have. A lack of biological relevance for a 28% between-group difference is especially plausible when we compare to another mutation – in the gene daf-2 – which has been shown to double C. elegans lifespan. Manipulation of daf-2 gene analogs in other species have failed to produce effects that come anywhere close to the magnitude of those observed with C. elegans, suggesting that this particular model species may have unique properties that support an unusually malleable lifespan.
How relevant are these results to human longevity?
Nematode worms, of course, do have very different biology and life cycles from humans. This is always a major concern when predicting how results from animal studies – and particularly invertebrate animal studies – will translate to humans. For instance, unlike humans, C. elegans can enter a so-called “dauer” state of dormancy and arrested development when environmental conditions are unsuitable for growth, and we can easily imagine how such an ability could impact overall lifespan. Still, animal studies serve an important purpose in elucidating mechanisms of action, as in Bennett et al.’s experiments on CR-associated pathways.
Unfortunately, the investigators’ use of genetic mutants for nearly all mechanistic experiments limits our ability to draw reliable conclusions. Since many of these mutations affected multi-functional signaling pathways (e.g., mTOR), it’s unclear what additional, relevant processes may have been impacted by these mutations or whether rilmenidine may have affected these mutants in ways that were distinct from wild-types.
Take, for example, the results from eat-2 mutants. The authors point out that rilmenidine showed no additive effect with CR on lifespan in eat-2s, but the data show that the rilmenidine-treated mutants’ lifespans were in fact no longer than wild-type controls – significantly shorter than mutants treated with control solution or wild-types treated with rilmenidine. This observation can be explained in one of two ways: 1) rilmenidine has no significant effect on longevity and differences seen in some experiments are, as suggested above, entirely within the experimental margin of error, or 2) the mutants worms responded to rilmenidine in some undefined, negative way, illustrating the unknowns inherent with mutant models and thus the uncertainty in mechanistic conclusions from these studies.
The Bottom Line
Rilmenidine is approved as a blood pressure medication only in select countries (and the U.S. isn’t among them), and human trials to date have not investigated its effects on lifespan and mortality. There’s a chance that taking rilmenidine for the treatment of hypertension may extend lifespan simply through its effects on cardiovascular and kidney health, as is the case with many antihypertensive drugs.
However, the study by Bennett et al. raises the possibility that this medication may have other, independent benefits for lifespan and cellular aging processes. Based on their data, I’m not convinced this treatment works in nematode worms, let alone having promise for humans. With any luck, further work may prove me wrong, but until then, rilmenidine as a longevity drug seems like the latest in a long line of “fountain of youth” myths.
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