Rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house cricket (BioRxiv)

[RapAdmin]

Yet another model organism successfully treated with rapamycin with positive longevity results (in addition to nematodes, flies, mice, rats and marmoset monkeys; which typically see lifespan improvement of 15% to 30%). No other drug or compound has ever consistently increased healthy lifespan in such a broad range of species, repeatedly, by many different labs.

The house cricket (Acheta domesticus) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lifespan; whether intermittent dosing offers similar benefits remains unknown. We tested 274 sex-matched crickets given 2-week intermittent dosing of each drug starting at mid-age (8-weeks), followed by behavioral testing at 10-weeks (geriatric stage). Assays included Y-maze olfactory discrimination, open-field exploration, and treadmill performance. Locomotor gaits were identified by velocity-based K-means clustering (silhouette > 0.5). A subset was monitored for post-treatment survival using Kaplan-Meier analysis. Olfactory preference was preserved by all drugs (d = -1.82 to -1.28, P < 0.01), with strongest effects in rapamycin-treated individuals. Rapamycin-treated males matched or exceeded juvenile locomotor activity; phenylbutyrate reduced male activity (d = 1.49, P < 0.05) and acarbose increased walking-to-running ratios (d = -0.75, P < 0.05). Rapamycin increased central exploration and freezing (d = -1.55, P < 0.0001), while acarbose and phenylbutyrate increased peripheral freezing (d = -0.76, P < 0.05). Rapamycin and phenylbutyrate extended maximum running time (d = -2.30 to -1.32, P < 0.0001), with sex-specific jumping gains in rapamycin-treated females and acarbose-treated males. Post-treatment lifespan was prolonged by rapamycin (HR = 0.42, P < 0.001) and reduced by acarbose in females (HR = 2.92 to 3.03, P < 0.05). Intermittent rapamycin preserved survival, cognition, and locomotion, while acarbose and phenylbutyrate produced selective benefits, supporting A. domesticus as a scalable model for geroprotective drug discovery.

Full paper: https://www.biorxiv.org/content/10.1101/2025.08.25.671822v1?ct=

AI Summary:

Here’s a detailed summary of the paper:

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The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets.

Authors

Gerald Yu Liao, Jenna Klug, Sherwin Dai, Swastik Singh, Elizabeth Bae, Warren Ladiges (Univ. of Washington School of Medicine).

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Background

• Geroscience hypothesis: interventions targeting fundamental mechanisms of aging can delay multiple age-related diseases simultaneously.

• Known drugs: Rapamycin (mTORC1 inhibitor), Acarbose (glucose metabolism modulator), and Phenylbutyrate (HDAC inhibitor/proteostasis enhancer) extend lifespan in mammals.

• Problem: mammalian studies are costly and slow.

• Solution: House crickets (Acheta domesticus) are proposed as a scalable invertebrate model because they have:

  • Short lifespans, measurable aging phenotypes (cognition, locomotion).
  • Conservation of aging mechanisms across species.
  • Suitability for behavioral and histological assays.

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Methods

• Subjects: 274 sex-matched crickets.

• Design: Intermittent 2-week mid-life (8 weeks) treatment with rapamycin (14 ppm), acarbose (1000 ppm), or phenylbutyrate (1000 ppm).

• Testing age: 10 weeks (geriatric stage).

• Assays:

  • Y-maze (olfactory discrimination).
  • Open field (exploration, freezing, locomotor behavior).
  • Treadmill + jump test (running endurance, jump distance).

• Data: Machine learning (k-means clustering of gait speeds), survival curves (Kaplan-Meier), and sex-stratified analyses.

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Key Results

1. Cognition (Olfactory discrimination)

• All three drugs preserved odor preference compared to untreated aged crickets.
• Rapamycin showed the strongest effect, especially in males.

2. Locomotion (Open-field behavior)

• Rapamycin males maintained youthful levels of locomotion (speed and activity).
• Phenylbutyrate reduced activity in males.
• Acarbose increased walking-to-running ratios (less vigorous locomotion).
• Rapamycin-treated crickets froze more in the central arena—interpreted as exploratory pauses rather than frailty.

3. Induced locomotion (Treadmill & Jumping)

• Rapamycin and phenylbutyrate extended maximum running duration.
• Sex-specific benefits: rapamycin improved female jumping, acarbose improved male jumping.
• Jumping power overall was less responsive to intervention.

4. Body weight

• Acarbose-treated females gained significantly more weight than controls.
• Across all treatments, females gained more weight than males.

5. Lifespan

• Rapamycin extended lifespan post-treatment (HR 0.42, P < 0.001), especially in males.
• Acarbose reduced female lifespan (HR ~3.0, P < 0.01).
• Phenylbutyrate showed no significant survival benefit, though females lived longer than males.

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Discussion

• Rapamycin: Most consistent benefit, preserving cognition, locomotion, and survival, even after short-term treatment.
• Acarbose: Mixed effects—modest cognitive benefit, but reduced female lifespan.
• Phenylbutyrate: Improved endurance and some cognition, but survival benefit was not robust.
• Sex-specificity: Drug effects differed by sex, echoing patterns seen in mice (e.g., rapamycin better in males, acarbose in males, phenylbutyrate in females).
• Implications: Intermittent drug dosing can remodel long-term aging outcomes, particularly with rapamycin.

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Limitations & Future Directions

• Small behavioral sample sizes (need power simulations).
• Lack of fine-grained gait/kinematic analyses.
• No histological validation of neural/muscle tissue effects.
• Future work: combinatorial treatments (rapamycin + acarbose + phenylbutyrate), early-life dosing, and other geroprotectors (metformin, NAD⁺ precursors, SGLT2 inhibitors).

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Conclusion

• House crickets are validated as a new preclinical model for geroscience.
• Rapamycin emerges as the strongest candidate, showing conserved benefits across species.
• Acarbose and phenylbutyrate show domain-specific or sex-specific benefits.
• The cricket model provides a rapid, low-cost, scalable system to screen geroprotective drugs before mammalian studies.

[A_User]

The house cricket (Acheta domesticus) is a promising preclinical geroscience model due to its short lifespan, low maintenance, age-associated functional decline, and responsiveness to geroprotective drugs. Continuous dosing with rapamycin, acarbose, and phenylbutyrate extends lifespan; whether intermittent dosing offers similar benefits remains unknown. We tested 274 sex-matched crickets given 2-week intermittent dosing of each drug starting at mid-age (8-weeks), followed by behavioral testing at 10-weeks (geriatric stage). Assays included Y-maze olfactory discrimination, open-field exploration, and treadmill performance. Locomotor gaits were identified by velocity-based K-means clustering (silhouette > 0.5). A subset was monitored for post-treatment survival using Kaplan-Meier analysis. Olfactory preference was preserved by all drugs (d’s = −1.82 to −1.28, P’s < 0.01), with strongest effects in rapamycin-treated individuals. Rapamycin-treated males matched or exceeded juvenile locomotor activity; phenylbutyrate reduced male activity (d = 1.49, P < 0.05) and acarbose increased walking-to-running ratios (d = −0.75, P < 0.05). Rapamycin increased central exploration and freezing (d = −1.55, P < 0.0001), while acarbose and phenylbutyrate increased peripheral freezing (d = −0.76, P < 0.05). Rapamycin and phenylbutyrate extended maximum running time (d’s = −2.30 to −1.32, P’s < 0.0001), with sex-specific jumping gains in rapamycin-treated females and acarbose-treated males. Post-treatment lifespan was prolonged by rapamycin (HR = 0.42, P < 0.001) and reduced by acarbose in females (HR’s = 2.92 to 3.03, P’s < 0.05). Intermittent rapamycin preserved survival, cognition, and locomotion, while acarbose and phenylbutyrate produced selective benefits, supporting A. domesticus as a scalable model for geroprotective drug discovery.

Overall survival rate:

Female:

Male:

Full pre-print paper: https://www.biorxiv.org/content/10.1101/2025.08.25.671822v1.full.pdf

AI summary:

What the study set out to do

Aging‑research labs are always looking for cheap, fast, and reliable ways to test “geroprotective” drugs—compounds that slow down the biological processes of aging rather than just treating individual diseases.
The domestic house cricket (Acheta domesticus) is an attractive test‑organism because:

• it lives only a few months, so whole‑life experiments are quick,
• it is inexpensive to raise in large numbers,
• it shows clear age‑related declines in cognition and movement that can be measured with simple behavioural tests, and
• many of the cellular pathways that drive aging in mammals (mTOR signalling, glucose metabolism, protein‑homeostasis, inflammation) are conserved in insects.

The authors asked: If we give middle‑aged crickets a short, two‑week “pulse” of three well‑studied geroprotective drugs—rapamycin, acarbose, and phenyl‑butyrate—do we see any lasting benefit to survival, brain‑function, or physical performance?

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How the experiment was done

Step	Details
Animals	274 crickets, evenly split by sex, raised under standard temperature/humidity.
Age when treatment started	8 weeks (mid‑life; a stage when subtle functional declines already appear).
Treatment	“Intermittent” dosing: the drug was mixed into the food for 2 weeks only, then removed. Doses matched those that previously extended cricket lifespan when given continuously.
Drugs	• Rapamycin – mTORC1 inhibitor (autophagy booster) • Acarbose – α‑glucosidase inhibitor (mimics calorie‑restriction‑like glucose control) • Phenyl‑butyrate – histone‑deacetylase (HDAC) inhibitor (proteostasis/epigenetic stabiliser)
Behavioural battery (tested at 10 weeks)	1. Y‑maze odor choice – vanilla vs. cinnamon; measures olfactory learning/decision‑making. 2. Open‑field arena – movement, zone preference, “freezing” (pauses). 3. Treadmill run – maximum running time and sprint‑jump distance.
Analysis	• Velocity data were split into “walking” and “running” using unsupervised K‑means clustering (silhouette > 0.5 confirmed clear separation). • Effect sizes reported as Cohen’s d (or Hedges’ g) and hazard ratios (HR) for survival.
Survival follow‑up	A subset of crickets was kept on their assigned diet until natural death; Kaplan–Meier curves were generated.

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Main findings – what each drug did (and how the effects differed between males and females)

1. Cognitive (olfactory) performance

All three drugs preserved the preference for the attractive vanilla scent compared with untreated, geriatric controls (large effect sizes d ≈ ‑1.8 to ‑1.3, p < 0.01).

• Rapamycin gave the strongest rescue, especially in males and also in females (though the female effect was slightly weaker).
• Acarbose and phenyl‑butyrate gave modest, statistically significant improvements but not as large as rapamycin.

2. General locomotion (open‑field)

Metric	Rapamycin	Acarbose	Phenyl‑butyrate
Total distance	Males matched juvenile (young) activity; females were similar to controls.	No change vs. control.	Trend toward lower distance, driven by males (d ≈ 1.5, p≈0.05).
Walking‑to‑running distance ratio	No change (similar to juveniles).	Higher ratio – crickets walked more relative to running (d ≈ ‑0.75, p < 0.05).	No effect.
Walking speed	Same as control.	Same as control.	Reduced speed, especially in males (d ≈ 0.9‑1.3, p < 0.05).
Running speed	Same as control.	Reduced running speed (d ≈ 0.9‑1.25, p < 0.05).	Same reduction as acarbose, strongest in males.
Central‑zone exploration	More central occupancy (especially males) and more freezing (both sexes).	No central‑zone boost; females showed a slight trend.	No central boost; females froze less than juveniles.
Freezing (pauses)	More freezing overall (central and peripheral) – interpreted as active scanning rather than frailty.	More peripheral freezing (especially females).	Slight increase in freezing, not as robust as rapamycin.

3. Endurance (treadmill)

Running time – the time a cricket could stay on the moving belt was significantly longer for crickets that had received rapamycin or phenyl‑butyrate (effect sizes d ≈ ‑2.6 to ‑0.9, p < 0.001). The benefit was visible in both sexes and brought performance close to that of young adults.

Maximum jump distance – none of the drugs noticeably changed this measure (d ≈ ‑0.4 to +0.13, ns), suggesting that pure power output of the hind‑legs is less plastic to metabolic/epigenetic interventions.

4. Body‑mass changes

Only acarbose‑treated females gained a modest amount of weight relative to control females (d ≈ 0.75, p < 0.05). Across all drug groups, females tended to gain more weight than males, but weight gain did not translate into shorter lifespan in any group.

5. Survival (post‑treatment)

Group	Median survival (days)	Hazard Ratio (HR) vs. control	Significance
Control	104	1.0 (reference)	–
Rapamycin	136	0.42 (≈ 58 % risk reduction)	p < 0.001
Acarbose	91	2.30 (more than double risk)	p ≈ 0.004
Phenyl‑butyrate	99.5	0.72 (non‑significant)	p = 0.20

• Sex‑specific: Rapamycin extended life particularly in males (HR ≈ 0.40, p < 0.01). Acarbose shortened life only in females (HR ≈ 3.03, p < 0.01). Phenyl‑butyrate showed a modest, non‑significant trend toward longer life in females (HR ≈ 3.22 vs. males, p < 0.01).

Key take‑away: A short, two‑week pulse of rapamycin has a lasting protective effect on both cognition and survival, even after the drug is withdrawn. By contrast, intermittent acarbose appears to be harmful to females when given only briefly, and phenyl‑butyrate gives mixed functional benefits but no clear lifespan advantage.

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Why the house cricket matters for geroscience

1. Speed & scale – Whole‑life experiments that would take years in mice can be completed in a few months in crickets, allowing rapid screening of many compounds or combinations.
2. Behavioural read‑outs – The Y‑maze, open‑field, and treadmill assays are analogous to rodent learning‑memory, anxiety‑like exploration, and endurance tests, providing translationally relevant phenotypes.
3. Conserved pathways – The same molecular targets (mTOR, glucose metabolism, HDACs) control aging in insects, flies, mice, and humans, making positive hits more likely to translate.
4. Cost‑effective – Crickets need only simple housing, no specialized vivarium, and can be housed in hundreds per cage.

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Limitations & next steps (as discussed by the authors)

Limitation	What it means	Suggested remedy
Sample size for some assays	Modest power to detect small effects, especially for sex‑by‑treatment interactions.	Use Monte‑Carlo or power‑simulation planning to determine optimal n before future studies.
Only coarse locomotor metrics (total distance, speed)	Misses subtle gait changes (e.g., stride length, coordination) that may be early indicators of sarcopenia.	Apply high‑speed video + pose‑estimation tools (DeepLabCut, OpenPose) for detailed kinematics.
No tissue‑level validation	Behavioural improvements are not directly linked to cellular or molecular changes.	Develop a standardized “geropathology” scoring system for cricket mushroom bodies, muscle fibers, gut barrier, etc., mirroring mouse frameworks.
Single‑dose regimen	Only one intermittent dose (2 wk) was tested; dose‑response and timing windows remain unknown.	Test early‑life “pulse” vs. late‑life “pulse,” and different concentrations.
Only three drugs	Many other geroprotectors (metformin, NAD⁺ precursors, SGLT2 inhibitors, senolytics) remain untested.	Expand the drug library, explore combinatorial regimens (e.g., rapamycin + acarbose).

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Bottom line for anyone interested in longevity drugs

• A short burst of rapamycin works in crickets: it protects brain‑function, keeps mice‑like endurance, and more than halves the risk of death even after the drug is stopped.
• Acarbose can be risky when given intermittently—especially for females—showing reduced lifespan despite some modest behavioural effects.
• Phenyl‑butyrate improves stamina and some exploratory behaviours but does not extend life under the intermittent schedule used.

Because crickets are cheap, fast, and show many of the same aging pathways as mammals, they represent a practical “first‑pass” platform for anyone experimenting with new anti‑aging compounds. Positive hits in crickets can be prioritized for more expensive rodent work, helping to focus resources on the most promising geroprotective interventions.

[A_User]

Oh, you posted it before. I’m surprised it didn’t generate any discussion. If it publishes that’s another animal model where rapamycin worked.

[adssx]

@Krister_Kauppi: Are crickets useful vs flies? Or should we jump from flies to mice directly? Or zebrafish in between? In terms of cost <> time tradeoff. It would be great to have a chart x = cost per experiment and y = weeks per experiment (in log?) with the various species.

[DeStrider]

I’ve always thought zebrafish were a good intermediary between C. Elegans and mice. I don’t really think C. Elegans is actually a good model. Crickets appear to be promising, though.

[relaxedmeatball]

I know nothing about crickets. I wondered whether they have blood glucose regulation system anywhere close to ours. Acarbose works in mice, but I recall it doesn’t work in C.elegans, and didn’t work here in crickets. So I asked ChatGPT (5 Pro - the $200/month version).

Short version:

• Acarbose slows starch → glucose breakdown in the mammalian small intestine. But insects digest carbohydrates differently (they rely on gut amylases and trehalases, not mammalian α-glucosidases).

• Crickets do not have blood glucose/insulin regulation like mammals. Their circulating sugar is trehalose, a disaccharide stored and released by the fat body (analogous to a liver/adipose hybrid)

• They do have insulin-like peptides (ILPs) and a conserved insulin/IGF-like signaling (IIS) pathway, but it regulates growth, reproduction, and lifespan differently than in mammals.

• Rapamycin targets mTORC1, a central growth/aging regulator present in essentially all eukaryotes (including crickets)

So basically, it’s quite reasonable that Rapa works in crickets but acarbose doesn’t.

[adssx]

So rodents are the smallest / cheapest animals with a glucose regulation system similar to ours?

[Krister_Kauppi]

@adssx I talked to one researcher at the ARDD conference and zebrafish he said is not a easy model to work with according to him. When it comes to crickets then I have not heard much about that model than that I have seen some couple of studies with it. The problem with that model is my guess it’s that it’s not so common used which makes the data around that model small. But somewhere we need to start.

@DeStrider Why do you think crickets are a promising model?