Deep divefrom Episode 4Longevity2 October 202623 min

Rapamycin, Crickets and a Very Small Treadmill

A deep dive into one paper: what was known before, what the researchers did, what the numbers say and what they don't.

The paper: The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets (Scientific Reports)

MP3

Chapters

Transcript

The script the two AI voices read from. The times are worked out from the script, not heard, so a line can start a few seconds early or late.

Read the whole episode

Cold open

Host 1You heard the trailer — this is the whole story. Welcome to the Hastrup Review of Science — where artificial intelligence reads real science, so you don't have to pretend you understood the paper. One paper today: three drugs from the anti-aging field, given for two weeks to middle-aged house crickets, and then a lot of crickets on a lot of small machines.

Host 2The paper is The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets, by Gerald Yu Liao, Jenna Klug, Sherwin Dai, Swastik Singh, Elizabeth Bae and Warren Ladiges, from the Department of Comparative Medicine at the University of Washington in Seattle. It was published in Scientific Reports in September twenty twenty-six. We read the preprint version posted to bioRxiv in August twenty twenty-five, so the published version may differ in places.

Host 1And I gather the title is going to come up again.

Host 2It is. The title says all three drugs extend lifespan, and the paper's own survival table says only one of them did in this experiment. We will get there with the numbers.

Why this field exists

Host 1Start with the field. What is a gerotherapeutic?

Host 2The paper starts from what is called the geroscience hypothesis: if you slow the biological processes of aging themselves, you should delay many age-related diseases at once, rather than treating them one at a time. A gerotherapeutic is a drug aimed at those processes. The problem is testing them, because aging takes time, and in the standard mammal, the mouse, a lifespan study takes about three years.

Host 1So the pressure is towards faster animals.

Host 2As established background: yeast, nematode worms and fruit flies have been the fast workhorses of aging biology for decades, and many of the core pathways, like nutrient sensing through a protein complex called mTOR, were mapped in them. The trade-off is that they are very far from us, and their behaviour is limited. This group argues that the house cricket sits in a useful middle ground.

Host 1Why a cricket?

Host 2Acheta domesticus is the cricket sold as pet food and, increasingly, human food, so it is farmed cheaply at scale. The authors point to a short lifespan, low maintenance, and age-related decline that can be measured in its body, its movement and its behaviour. The same lab has published on cricket body shape across age and has a preprint on cognitive decline, which this paper builds on.

Host 1Is the cricket new to aging research?

Host 2Not entirely. The paper cites earlier work by Christopher Rollo's group on dietary restriction in this species, from twenty eleven. But as a drug-screening model it is young, and much of the groundwork here comes from the Ladiges lab itself, including several studies the paper lists as manuscripts in progress.

What was known before

Host 1Tell me about the three drugs.

Host 2Rapamycin blocks a protein complex called m-TOR complex one, a central sensor of nutrients and growth; blocking it pushes cells towards recycling their own components, a process called autophagy. Acarbose is a diabetes drug that slows the breakdown of starch in the gut, so glucose enters the blood more slowly, which the paper describes as mimicking caloric restriction. Phenylbutyrate is an inhibitor of histone deacetylases, enzymes that affect how tightly DNA is packed, and it is also described as supporting protein folding.

Host 1And their track record in animals?

Host 2As background: rapamycin is probably the most reproducible lifespan drug in mammals. The American Interventions Testing Program showed in twenty oh-nine that it extends mouse lifespan even when started late in life, and acarbose extends mouse lifespan too, more strongly in males. Phenylbutyrate has a thinner record; it extended lifespan in fruit flies in early work, and the paper cites it mainly for effects on protein maintenance in mammals.

Host 1Had these been tried in crickets?

Host 2The authors say continuous dosing with all three extended cricket lifespan, citing a twenty twenty-four conference abstract from their own group and a master's thesis by the first author. So the prior cricket evidence is real but not yet in full peer-reviewed form. The same lab also published a mouse study in twenty twenty-two where a short course of all three drugs as a cocktail delayed aging signs.

The open question

Host 1So what is the open question here?

Host 2Whether short, intermittent dosing works. Instead of feeding the drug for life, they give it for two weeks in mid-life, stop, and ask whether function in old age and survival afterwards are better. As background, that question matters because a transient course would be cheaper, and potentially safer, than lifelong dosing; a twenty sixteen mouse study found that three months of rapamycin in middle age extended lifespan.

Host 1And underneath that, a second question.

Host 2Yes: whether the cricket is a good enough model to answer such questions at all. A lot of this paper is about building and validating the measurement tools, not only about the drugs.

Methods: crickets and diet

Host 1Walk me through the experiment. Where do the crickets come from?

Host 2They were bought from a commercial supplier, Fluker Farms in Louisiana, and arrived at five weeks of age. They lived at twenty-nine degrees Celsius and about thirty-two percent humidity, in groups of twenty to thirty per cage, with males and females housed together. Deliberately, they were not kept in a pathogen-free facility, to resemble more natural aging.

Host 1Timeline?

Host 2Three weeks of acclimation on a control diet, then at eight weeks of age they were randomly assigned to control or one of the three drugs. The drugs were given for two weeks, ending at ten weeks of age, which the authors call the geriatric stage. Behaviour was tested at ten weeks, and a subset was kept on to measure survival until natural death.

Host 1Ten weeks is geriatric?

Host 2For this cricket, under these conditions, yes; in their survival table the control group's median survival is around a hundred days. So the treatment window covers roughly the middle of adult life.

Host 1How do you dose a cricket?

Host 2Through the food. The base diet is a standard rodent chow, ground and bound with gelatin, then dried to prevent mould. The drugs were mixed in at doses previously used in mice: rapamycin at fourteen parts per million, and acarbose and phenylbutyrate at one thousand parts per million each.

Host 1Mouse doses in a cricket.

Host 2That is a real limitation. Nobody measured how much drug ended up in the crickets' bodies, and insect metabolism is very different, so the effective dose is unknown. They did adapt the preparation to each drug's heat stability, adding rapamycin directly and dissolving the other two in water first.

Host 1How many animals?

Host 2The abstract says two hundred and seventy-four sex-matched crickets in total. Per assay the numbers are much smaller: seventy-nine in the smell test, ninety-nine in the open field, ninety-six on the treadmill, which works out at roughly ten per sex per group.

Methods: the tests

Host 1What did they measure?

Host 2Four kinds of function. Smell-guided choice in a Y-shaped maze, exploration and freezing in an open arena, endurance on a treadmill, and jumping distance. Plus body weight, body measurements, and survival.

Host 1Start with the maze.

Host 2One arm smells of vanilla, which crickets find attractive, the other of cinnamon, which they avoid. Each cricket gets ten seconds in the start arm, then thirty seconds to choose, eight trials in a row, with the scents swapped between trials. The score is the percentage of trials in which it chose vanilla, and earlier work from the lab suggests that preference fades with age.

Host 1And the open field?

Host 2Five minutes alone in a dark arena, filmed and tracked automatically with free software called ezTrack, at thirty frames per second. From the track they get distance, speed, freezing episodes, and time in the centre versus the edge. The fastest one percent of speed readings were discarded as tracking errors.

Host 1You mentioned machine learning in the abstract.

Host 2It is modest machine learning. To separate walking from running, they split each group's speed readings into two clusters with an algorithm called k-means. They checked the split against an independent measure of pixel movement, and a quality score called the silhouette came out above zero point five in every group, which conventionally means well-separated clusters.

Host 1What did the two gaits look like?

Host 2In controls, average walking speed was about two point seven centimetres per second and running about twenty-eight. Rapamycin-treated crickets had the highest averages, about two point nine walking and thirty point five running. Acarbose and phenylbutyrate groups were slower, around twenty-four running.

Host 1And the treadmill. A treadmill for crickets.

Host 2A rodent treadmill, modified: they disabled the shock grid, added dividers so crickets could not escape sideways, and installed paper catchers. A vanilla-scented paper at the far end served as motivation, the belt accelerated at zero point one metres per second squared, and each cricket had three trials, best one counted. Running time was the main endpoint, and jump distance was read off rulers on the side walls.

Host 1What were the comparison groups?

Host 2Primarily the current controls, same age, same conditions. They also compared against archived younger cohorts, juveniles and adults, and against historical geriatric controls and pooled controls from earlier experiments. Those historical comparisons fill a lot of the results section, and we will treat them with some care.

Results: smell

Host 1First result. Smell.

Host 2All three drug groups chose vanilla more often than controls, with effect sizes from about one point three to one point eight standard deviations and P-values below zero point zero one. By convention, anything above zero point eight is a large effect. The treated groups performed at adult-like levels, and rapamycin was the most consistent across the comparisons.

Host 1Any catch?

Host 2The decline in controls showed up mainly in males; among females, controls did not differ from adults. So the drugs are preserving something that, in this data, only clearly declined in one sex. And with about ten animals per subgroup, the error bars on effect sizes that large are wide.

Results: open field and gait

Host 1The open field.

Host 2Total distance was similar for controls, acarbose and rapamycin. Phenylbutyrate trended lower overall, and in males it was clearly lower, with an effect size of about one point five and a P-value just under zero point zero five. So for spontaneous activity, phenylbutyrate looks, if anything, slightly harmful in males.

Host 1And rapamycin?

Host 2Not different from controls in distance or average speed. The striking claim is a comparison to the archived cohorts: rapamycin-treated males matched juvenile activity and exceeded adults. Against the same-age controls, though, the difference was not significant.

Host 1What about the walking and running?

Host 2Acarbose-treated crickets covered more distance walking relative to running, effect size about zero point seven five. Running speed was lower with acarbose and in phenylbutyrate males. So the two non-rapamycin drugs, if anything, made aged crickets a little slower.

Host 1You said freezing.

Host 2That was the clearest drug effect in the arena. Rapamycin-treated crickets froze more than controls, in both sexes, with effect sizes from about one to two and a half, and more of that freezing happened in the centre of the arena. Acarbose increased freezing at the edges.

Host 1Is freezing good or bad?

Host 2That is the key question, and the paper answers it by interpretation. The authors read rapamycin's extra freezing as active pauses to scan the environment, not frailty, because the same crickets also spent more time in the centre. That is plausible, but freezing in an open field is also classically read as anxiety-like behaviour, and nothing in this data decides between the two readings.

A word from our sponsor

Host 1That covers the arena. Before the treadmill, a short break.

Host 2Do you have problems with staying power? Then you are in luck.

Host 2The Hastrup Review of Science is brought to you by potency supplements. Maca root capsules, taken daily, as part of a balanced routine for men who want to keep going for longer.

Host 1I take them before the treadmill. I would not say I run longer, but I do freeze less in the middle.

Host 2They come in capsules and powders, in a range of strengths, and they are very reasonably priced. They are widely available and in stock right now.

Host 1Intermittent dosing works for me. Two weeks on, then I just keep the momentum.

Host 2Potency supplements. Our referral link is in the show notes.

Results: treadmill and jumping

Host 1Back to the crickets. The treadmill.

Host 2This is the strongest functional result. Rapamycin- and phenylbutyrate-treated crickets ran longer than controls, with effect sizes between about zero point nine and two point six depending on the comparison, and the group effect in the analysis was highly significant. Both drugs brought running time back to adult or mid-age levels, and the pattern held in both sexes.

Host 1Phenylbutyrate made them walk less in the arena but run longer on the treadmill?

Host 2Yes, and the paper does not really reconcile it. One reading is that spontaneous activity and forced endurance measure different things, motivation versus capacity. Another is that, with small groups and many measures, some of these differences will be noise.

Host 1And jumping?

Host 2No difference between any treatment and controls; the effect sizes were small, from minus zero point four to plus zero point one. Against historical cohorts, rapamycin females and acarbose males jumped further, but not against the same-age controls. The authors suggest that maximal power may depend on structural changes that a short metabolic drug course does not reach.

Results: weight

Host 1Weight?

Host 2Acarbose-treated females gained more weight than control females, effect size about zero point seven five. And in all three drug groups, females gained more than males. The paper reads that as possible metabolic resilience.

Host 1How was weight change measured?

Host 2Not by following individuals. They compared each cricket's final weight to the average starting weight of its cohort, because there was no longitudinal tracking. That is a much noisier measure, and it makes the weight result one of the weaker ones.

Results: survival

Host 1Now the result in the title. Survival.

Host 2Rapamycin clearly helped. Median survival was about one hundred and thirty-six days against one hundred and four for controls, with a hazard ratio of zero point four two, meaning the rate of dying at any given time was roughly fifty-eight percent lower, and a confidence interval of zero point two five to zero point seven three. In males, rapamycin's hazard ratio was zero point four; median survival was about one hundred and thirty-three days against ninety-seven.

Host 1After only two weeks of the drug.

Host 2After two weeks, then stopping. If it holds up, that echoes the mouse finding that a short rapamycin course late in life can still extend lifespan. It is the most interesting single number in the paper.

Host 1And the other two?

Host 2Phenylbutyrate: median about one hundred days, hazard ratio zero point seven two, not significant, so no detectable benefit. Acarbose was worse than control: median ninety-one days, hazard ratio two point three overall, meaning a higher death rate, and in females a median of about ninety-four days against one hundred and twelve.

Host 1So the title is wrong.

Host 2For this experiment, yes. The results section heading itself says rapamycin extends and acarbose shortens post-treatment lifespan, yet the title, the first line of the discussion, and the caption of the survival figure all say every drug extended lifespan. The most charitable reading is that the title leans on the group's earlier continuous-dosing work, but that work is a conference abstract and a thesis, not the data in this paper.

Host 1Any other inconsistencies?

Host 2The abstract gives acarbose hazard ratios of two point nine to three point zero, the results text says two point three to two point five. And for acarbose in females, the confidence interval runs from zero point eight to eleven, which includes one, yet the adjusted P-value is reported as zero point zero one; the same happens for rapamycin in females. Intervals and P-values can come from slightly different calculations, but those mismatches are a flag that the survival statistics deserve a careful second look.

Host 1How many crickets were in the survival arm?

Host 2It was a subset. The control group had thirty-one, and the drug groups appear smaller; with sexes split, some subgroups are in the low teens or below. The paper also does not state clearly whether the survival days count from hatching or from some later point, which matters for comparing with other studies.

Why it matters

Host 1Step back. Why does this matter?

Host 2The principle being tested is that a drug can change an animal's aging trajectory without being taken continuously. For rapamycin, this paper adds a second, very distant species where a brief mid-life course was followed by longer life, and by better endurance and smell-guided choice in old age. That is a modest but real addition to the evidence that the mTOR pathway's role in aging is broadly conserved.

Host 1Who does it change things for?

Host 2Mainly for people who screen drugs. If crickets can show a lifespan signal in a few months, at the cost of rodent chow and plastic boxes, you could test many compounds or combinations cheaply before committing to a three-year mouse study. The behavioural toolkit, the maze, tracked open field, the adapted treadmill, is arguably as important a contribution as the drug results.

Host 1And the acarbose result?

Host 2Potentially useful as a warning. In mice acarbose is a fairly reliable lifespan drug, especially in males; here, short dosing followed by withdrawal was associated with worse survival in females. Whether that is about crickets, about stopping the drug, about dose, or about chance is unknown, but it is a reminder that transient and continuous dosing are not interchangeable.

Host 1What does it not mean?

Host 2It does not mean rapamycin, acarbose or phenylbutyrate slow aging in people, or that a two-week course of anything is advisable. As background, rapamycin is an immunosuppressant used in transplant medicine, and human evidence for it as an anti-aging drug is still very limited. A cricket fed rodent chow at twenty-nine degrees tells you about crickets, and at best which compounds deserve a closer look in mammals.

Caveats

Host 1The honest caveats, in one place.

Host 2First, the mismatch between the claims and the data: the title says three drugs extend lifespan, and the table supports one. Second, small groups, roughly ten crickets per sex per group for behaviour, and a smaller survival arm. The authors themselves say some assays were probably underpowered.

Host 1Third?

Host 2Many outcomes, many comparisons. Each assay is sliced by drug, by sex, and against up to four reference groups, and multiple-comparison correction is described for survival but not across the whole behavioural set. In that setting, some significant differences will be chance, and the pattern-hunting language, male-driven here, female-driven there, should be read as exploratory.

Host 1And the historical comparisons.

Host 2Many of the most appealing claims, like rapamycin males matching juveniles, come from comparing with archived cohorts tested at other times. Batch, season and supplier differences can easily produce gaps of that size. The comparisons that count are against the same-age controls run alongside, and those are more modest.

Host 1Anything about the setup itself?

Host 2Drug levels in the crickets were never measured; doses were simply carried over from mice. Food intake was not measured per animal, and the claim that it did not change rests on unpublished colony-level observations, which matters because a drug that makes food less appealing produces dietary restriction, a known lifespan intervention. And the sexes were housed together, outside pathogen-free conditions, with cannibalism mentioned as a reason to exclude some dead animals, all of which adds variance that is hard to account for.

Host 1And interpretation.

Host 2The freezing result could be curiosity or anxiety, and the paper picks the flattering reading. Weight change was estimated against cohort averages, not individuals. And there is no tissue or molecular data, so there is no evidence yet that rapamycin actually inhibited mTOR in these crickets; the mechanism is borrowed from other species.

What to watch

Host 1What should we watch for next?

Host 2A replication of the rapamycin survival effect with larger survival groups, run alongside its own controls, with measured food intake and ideally drug levels in the crickets. Also a direct test of continuous against intermittent acarbose in the same experiment, to see whether the female survival penalty is real and whether it comes from stopping the drug.

Host 1And on the model itself?

Host 2The authors list tissue work as the next step: scoring the mushroom bodies, the insect brain region used in smell learning, and muscle, to link behaviour to cellular aging. They also plan finer gait tracking, power calculations before the next study, and new candidates such as metformin, NAD precursors and S-G-L-T two inhibitors, plus combinations. The real test of the cricket as a screening model is whether compounds that work in crickets later predict which ones work in mice, and that will take years.

Sign-off

Host 1That is the deep dive: The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets, by Liao, Klug, Dai, Singh, Bae and Ladiges, from the University of Washington, published in Scientific Reports. In short: rapamycin helped, phenylbutyrate partly, acarbose shortened female survival, and the title promises more than the table delivers. The link is in the show notes.

Host 2Every Friday this same feed carries the roundup episode: five new papers as trailers, and you pick which become deep dives. This has been the Hastrup Review of Science.