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

[RapAdmin]

A recent study evaluated the effects of a two week intervention using three known geroprotective drugs on middle aged house crickets. The researchers found that transient treatment with rapamycin significantly preserved olfactory memory, restored locomotor performance to juvenile levels in males, and extended overall survival. Phenylbutyrate improved endurance, while acarbose demonstrated detrimental effects on female survival, highlighting the complexity of sex specific responses in longevity interventions.

The core challenge in longevity pharmacology is finding scalable, high throughput models that accurately mimic mammalian aging phenotypes without the lengthy lifespans of murine models. Researchers at the University of Washington School of Medicine evaluated the house cricket as a potential intermediate model for geroscience. They administered rapamycin, acarbose, and phenylbutyrate to 8 week old crickets for 14 days and then subjected them to a battery of behavioral and survival tests at 10 weeks of age.

The primary finding is that short term, late life pharmacological interventions can durably alter the aging trajectory. Rapamycin emerged as the most consistently effective compound. It preserved olfactory guided decision making across both sexes. More notably, it restored male locomotor metrics, including average speed and total distance traveled, to levels statistically indistinguishable from juvenile crickets. Rapamycin also induced a distinct shift in exploratory behavior, increasing central zone engagement and freezing responses, which suggests a modulation of risk assessment or sensory processing pathways.

Acarbose and phenylbutyrate yielded mixed results. Phenylbutyrate enhanced treadmill running endurance, aligning with its known role in promoting proteostasis and reducing neuroinflammation. However, acarbose presented a severe sex specific penalty. While it modestly improved male jumping distance, it caused a substantial reduction in post treatment survival for females.

This study validates the house cricket as a viable preclinical platform that bridges the evolutionary gap between simple invertebrates like worms and complex mammals. The data strongly suggests that continuous, lifelong dosing of gerotherapeutics is not strictly necessary to achieve significant healthspan extension. A transient pulse of mTOR inhibition during middle age appears sufficient to lock in physiological benefits that persist long after the drug is withdrawn.

Insights

For individuals interested in longevity protocols, the most interesting potential takeaway is the efficacy of short term, pulsed dosing strategies. The data indicates that continuous exposure to geroprotectants may not required to reap some systemic benefits, though this is still to be tested in humans. In this study, a brief two week exposure to rapamycin resulted in a hazard ratio of 0.40 in males and 0.48 in females. This translates to a 60 percent reduction in mortality risk for males and a 52 percent reduction for females over the observation period.

Furthermore, the effect sizes for cognitive and physical preservation were massive. For olfactory memory preservation, rapamycin produced a standardized effect size (Cohen’s d) of 1.38 to 1.61. In statistical terms, an effect size over 0.8 is considered large, meaning the treated crickets performed over 1.3 standard deviations better than the control group. For treadmill endurance, the effect size was 1.22 to 1.73. These magnitude metrics demonstrate that intermittent dosing protocols can yield profound, durable improvements in both physical endurance and cognitive function without the risks associated with chronic immunosuppression.

This study demonstrates yet another model organism successfully treated with rapamycin results in 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 so many different labs.

Full Pre-print paper: The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets | bioRxiv
Posted: August 28, 2025.
Institution: University of Washington School of Medicine.
Country: USA.

[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.

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?

[RapAdmin]

I don’t care too much about results in crickets in terms of indicating translation of results to humans (we don’t have much data to suggest that crickets are a specifically good model for successful translation of a small molecule to effectiveness in humans), but its good to see yet another model organism that rapamycin has proven successful in. Rapamycin has proven successful in extending lifespan in every organism its been tested in, from yeast, to fungi, to rotifers, to nematodes (worms), to fruit flies, to fish, to crustaceans, to mice and monkeys… and now crickets! The mTOR pathway has been conserved well over a billion years of evolution.

In a new study attempting to establish the house cricket (Acheta domesticus) as a scalable longevity model, researchers from the University of Washington tested intermittent “pulse” dosing of three top-tier geroprotective candidates: Rapamycin, Acarbose, and Phenylbutyrate. The results provide a stark warning against assuming “safe” diabetes drugs are universally beneficial across sexes.

While Rapamycin solidified its status as the “gold standard,” extending survival by nearly 60% in males and preserving juvenile-like cognitive and locomotor function, Acarbose—a drug widely considered benign in the biohacker community—dramatically reduced the lifespan of female crickets (Hazard Ratio ~3.0), effectively tripling their risk of death despite inducing weight gain. This contradicts established mouse data where Acarbose is sex-neutral or weakly beneficial in females, highlighting a potential metabolic “mismatch” or toxicity that could be relevant to specific human phenotypes.

Phenylbutyrate, often touted for its HDAC inhibition and ammonia scavenging, failed to extend lifespan significantly in the overall cohort but did show sex-specific survival benefits in females, albeit with reduced locomotor performance. This study reinforces the “Rapamycin or bust” trend in recent longevity literature while casting a shadow of uncertainty over Acarbose for females.

Source:

• Open Access Paper: The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets
• Context: University of Washington School of Medicine | Journal: Research Square (Preprint)
• Impact Evaluation: The impact score of this journal is [Unrated/Preprint]

Novelty

• Durability of “Pulse” Dosing: Most longevity studies use continuous dosing. This proves that a short, 2-week “vacation” on Rapamycin in mid-life can permanently alter the survival trajectory in an invertebrate model.
• Invertebrate Validation: Establishes the cricket as a fast, cheap screening tool that (mostly) aligns with mouse data—except for the specific Acarbose/Female divergence.

Critical Limitations

• Translational Gap (Phylogeny): Crickets are insects. They lack a closed circulatory system, a liver, and a mammalian immune system. The Acarbose toxicity could be due to insect-specific carbohydrate biology that does not apply to humans.
• Small Sample Size: N=20 is statistically fragile. A few accidental deaths could skew the Hazard Ratios significantly.
• Preprint Status: The data has not been stress-tested by peer review. The “weight gain” in Acarbose females needs histological verification to ensure it wasn’t edema or egg retention/impaction rather than “healthy fat.”

[PolishGentleman]

So we have:

• 1. Yeast
• 2. C Elegans
• 3. Fruit flies
• 4. Hydra
• 5. Killifish
• 6. freshwater cnidarian Hydra
• 7. Daphnia Magna
• 8. Mice (1. Het3, 2. B6)
• 9. rotifers
• 10. crickets

In progress:

• 1. Marmosets monkeys
• 2. Dogs

[RapAdmin]

I used Google Gemini Pro Deep Search on this issue. I would include marmosets as being successful because its been reported by Adam Salmon already, though publication is still to be done.

The Phylogeny of Longevity: An Exhaustive Analysis of Rapamycin-Induced Lifespan Extension Across the Tree of Life

1. Introduction: The Pharmacological conquest of Time

The quest to decouple biological aging from the passage of time has long been the purview of mythology, but in the last three decades, it has transitioned into a rigorous scientific discipline. Central to this paradigm shift is a compound isolated from the soil of Easter Island (Rapa Nui): rapamycin (sirolimus). Originally identified for its potent antifungal properties and subsequently developed as an immunosuppressant for organ transplantation, rapamycin has emerged as the premier “geroprotector”—a pharmacological agent capable of slowing the fundamental biological processes of aging.

The universality of rapamycin’s effects is underpinned by the evolutionary conservation of its target, the mechanistic Target of Rapamycin (mTOR). This serine/threonine kinase functions as a master nutrient sensor, integrating signals regarding amino acid availability, energy status (ATP/AMP ratio), and growth factors to dictate the cellular decision between anabolism (growth and reproduction) and catabolism (maintenance and repair). The “Hyperfunction Theory” of aging posits that aging is not merely the accumulation of damage, but the purposeless continuation of developmental growth programs into adulthood—a state of cellular over-activation driven by mTOR. By inhibiting this pathway, rapamycin effectively mimics a state of nutrient scarcity, forcing the organism into a protected mode of somatic maintenance, thereby extending lifespan.

This report provides an exhaustive, phylogenetic review of every model organism in which rapamycin has been proven to extend lifespan. Drawing from a comprehensive dataset of preclinical studies, we analyze the efficacy, mechanisms, dosing nuances, and sex-specific responses ranging from unicellular fungi to complex mammals. We also scrutinize the emerging data from pre-clinical primate and canine models, where the translational potential of this compound is currently being adjudicated.

Full report here: https://gemini.google.com/share/fb87f4e825fc

[RapAdmin]

The paper is finally through the review process and published:

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

A recent study evaluated the effects of a two week intervention using three known geroprotective drugs on middle aged house crickets. The researchers found that transient treatment with rapamycin significantly preserved olfactory memory, restored locomotor performance to juvenile levels in males, and extended overall survival. Phenylbutyrate improved endurance, while acarbose demonstrated detrimental effects on female survival, highlighting the complexity of sex specific responses in longevity interventions.

Context and Source

• Open access Paper: The gerotherapeutic drugs rapamycin, acarbose, and phenylbutyrate extend lifespan and enhance healthy aging in house crickets.
  Institution: University of Washington School of Medicine.
  Country: USA.
  Journal Name: Scientific Reports.
  Impact Evaluation: The impact score of this journal is 3.8, evaluated against a typical high-end range of 0 to 60 for top general science, therefore this is a Medium impact journal.