A paradigm shift is underway in geriatrics, moving from reactive “whack-a-mole” disease management to a unified “geroprotective” strategy. This major review synthesizes evidence for nine commercially available drugs—originally approved for diabetes, cardiovascular disease, or cancer—that show distinct potential to slow biological aging. The authors argue that because aging is the primary risk factor for comorbidities like cancer and heart failure, targeting the underlying hallmarks of aging (e.g., mitochondrial dysfunction, cellular senescence, loss of proteostasis) is more effective than treating isolated symptoms.
The review highlights a “Golden Nine” list: Aspirin, Atorvastatin, Enalapril, Metformin, Canagliflozin, Liraglutide, Acarbose, N-acetylcysteine (NAC), and Dasatinib+Quercetin (D+Q). The “Big Idea” here is polypharmacology: the most effective future interventions will likely require stacking these agents to hit multiple aging targets simultaneously (e.g., combining mTOR inhibition via Canagliflozin with senolysis via D+Q). However, the report bluntly acknowledges a critical translational gap: while drugs like Canagliflozin and Acarbose deliver robust lifespan extension in mice (up to 17% in males), human data is currently limited to retrospective disease prevention rather than prospective lifespan extension.
New Open Access Research Paper: Progress in anti-ageing drug research for age-related diseases: A review
Context: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences; Published in Ageing Research Reviews (Vol. 114, 2026).
Impact Evaluation: The impact score of this journal is 12.4 (2024/2025 data), evaluated against a typical high-end range of 0–60+ for general science (e.g., Nature is ~60, specialized aging journals often ~3-5). Therefore, this is an Elite impact journal within the specialized field of gerontology.
Part 2: The Biohacker Analysis
Study Design Specifications
- Type: Systematic Review & Meta-Synthesis (Preclinical & Clinical Data).
- Subjects: Aggregated data from Caenorhabditis elegans (worms), Drosophila (flies), Mus musculus (mice; specifically Genetically Heterogeneous UM-HET3 strains), and human clinical trials (e.g., TAME, ASPREE, CANVAS).
- Key Lifespan Data (Murine Models):
- Canagliflozin (SGLT2i): 14% median lifespan extension in male mice. No significant effect in females.
- Acarbose (Alpha-glucosidase inhibitor): 17% median lifespan extension in male mice; only 5% in females.
- Aspirin: 8% increase in median survival in male mice; no effect in females.
- Metformin: Mixed results. Extended lifespan in some strains (e.g., 0.1% dietary supplementation), but toxic at higher doses. Primate data suggests slowed aging clocks but lifespan data is pending.
Mechanistic Deep Dive
The review categorizes these drugs by their ability to modulate specific “Hallmarks of Aging”:
- mTOR Inhibition (The Longevity King): Canagliflozin, Acarbose, and Metformin all converge here. Canagliflozin inhibits mTORC1 and reduces inflammation (SASP) specifically in visceral fat, mimicking caloric restriction without the hunger.
- Senolysis (Taking out the Trash): Dasatinib + Quercetin (D+Q) is distinct. It does not just suppress pathways; it physically eliminates senescent (“zombie”) cells that secrete pro-inflammatory cytokines (SASP). This addresses “Stem Cell Exhaustion” and “Chronic Inflammation” directly.
- AMPK Activation (Energy Sensing): Metformin and Aspirin activate AMPK, signaling the body to burn energy and repair cells rather than grow. This improves mitochondrial efficiency and reduces oxidative stress.
- GLP-1 Agonism (Neuroprotection): Liraglutide is highlighted not just for weight loss, but for reducing brain amyloid accumulation and neuroinflammation, suggesting it acts as a systemic anti-aging agent beyond just glycemic control.
Novelty
The paper provides a rare, direct comparison of “Standard of Care” drugs (Statins, ACE inhibitors) against “Longevity Darlings”. It elevates Canagliflozin and Acarbose to top-tier status alongside Metformin, suggesting they may be more effective for lifespan extension (particularly in males) than Metformin in rigorous mouse testing (ITP).
Critical Limitations
- The “Male Bias” Problem: Acarbose, Canagliflozin, and Aspirin show massive efficacy in male mice but fail or show weak results in females. The authors speculate this is due to sex-specific glucose handling and mTOR signaling, but for female biohackers, the data is discouragingly thin.
- Species-Specific Dosing: The mouse doses for Acarbose and Canagliflozin are massive (see Part 3). Human equivalents are often above the FDA maximum tolerated dose.
- Lack of Autophagy Targeting: The authors note a major gap: none of these repurposed drugs directly target the autophagy machinery (e.g., ATG7, LC3) with high specificity, meaning we are still missing a “cleanup” drug in this stack.
Part 3: Actionable Intelligence
1. Canagliflozin (The “SGLT2” Protocol)
- Mechanism: Blocks glucose reabsorption in kidneys; lowers insulin/glucose spikes; inhibits mTORC1.
Human Equivalent Dose (HED) Reality Check:
- Study Dose (Mouse): 180 mg/kg.
- Conversion: Mouse (3) / Human (37) 0.081 factor.
- HED Calculation: mg/kg.
- For 75kg Human: ~1,093 mg/day.
- Clinical Reality: FDA approved dose is 100 mg to 300 mg.
- Verdict: The longevity effect in mice requires 3x-10x the human clinical dose. Biohackers using standard 100mg doses are relying on mechanistic overlap, not direct lifespan data equivalence.
Safety & Toxicity:
- Genital Infections: High glucose in urine leads to yeast infections (UTIs/thrush) in ~10% of users.
- Ketoacidosis: Rare but serious risk of euglycemic diabetic ketoacidosis (DKA), especially if fasting or on a ketogenic diet. Do not combine with prolonged fasting.
Biomarker Panel:
- Efficacy: Reduced HbA1c, Reduced Fasting Insulin, Increased Urinary Glucose.
- Safety: Monitor eGFR (initial dip is normal, sustained drop is bad) and Ketones.
2. Acarbose (The “Carb Blocker” Protocol)
- Mechanism: Blocks breakdown of starch in the gut; flattens post-prandial glucose peaks; modulates gut microbiome (increases butyrate).
HED Reality Check:
- Study Dose (Mouse): 1000 ppm in chow. Approx 150 mg/kg/day.
- HED Calculation: mg/kg.
- For 75kg Human: ~911 mg/day.
- Clinical Reality: Max clinical dose is usually 300 mg/day (100mg with each meal).
- Verdict: Similar to Canagliflozin, murine longevity doses are supraphysiological.
Feasibility:
- Side Effects: Severe gas/bloating (GI distress) as undigested carbs ferment in the colon. “Socially limiting” side effects often lead to discontinuation.
3. Dasatinib + Quercetin (The “Hit-and-Run” Senolytic)
- Mechanism: Selectively induces apoptosis in senescent cells.
Protocol (Extrapolated from Clinical Trials):
- Not a daily drug. Used intermittently (e.g., 2 days on, 14 days off).
- Doses: Dasatinib (100 mg) + Quercetin (1000 mg).
Safety Warning:
- Dasatinib is a chemotherapy agent (leukemia). Known toxicities include pleural effusion (fluid around lungs), myelosuppression, and bleeding. It is not a benign supplement.
- Contraindications: History of heart disease, bleeding disorders, or liver compromise.
Part 4: The Strategic FAQ
Q1: Why do Canagliflozin and Acarbose work so well in male mice but fail in females?
A: The “Male Bias” is likely due to how females process glucose. Female mice naturally have better glucose handling and lower baseline mTOR activity than males. Therefore, drugs that lower glucose/mTOR (like Acarbose) provide less “delta” (improvement) for females. Additionally, these drugs may alter sex hormone metabolism, potentially negating benefits in females.
Q2: Can I stack Rapamycin with Acarbose or Canagliflozin?
A: Yes. The ITP (Interventions Testing Program) has tested Rapamycin + Acarbose and found synergistic effects, extending lifespan more than either drug alone. They target different nodes: Rapamycin hits mTORC1 directly; Acarbose reduces the upstream glucose signal that activates mTOR.
Q3: Is Metformin actually a “longevity” drug for healthy people?
A: The data is murky. While the TAME trial hopes to prove it, the ITP (gold standard in mice) failed to show significant lifespan extension with Metformin in non-diabetic mice. It is excellent for “squaring the curve” (healthspan) and preventing cancer/diabetes, but it may not extend maximum lifespan in already healthy, metabolically optimized individuals.
Q4: Should I take Aspirin for longevity despite the bleeding risk?
A: Probably not, unless you have specific cardiovascular risks. The ASPREE trial showed that in healthy elderly adults (>70), daily aspirin increased major hemorrhage risk (+44%) without extending disability-free survival. The risk/reward ratio has shifted to “negative” for primary prevention in the healthy elderly.
Q5: Does Canagliflozin cause muscle loss (sarcopenia)?
A: It’s a valid concern. Rapid weight loss from SGLT2 inhibitors can include lean mass. However, the study notes that Canagliflozin actually improved motor activity and exploration in aged mice, suggesting functional muscle preservation. Combining it with resistance training is non-negotiable.
Q6: What is the most dangerous drug on this list for a biohacker to self-prescribe?
A: Dasatinib. Unlike the others (which are chronic metabolic drugs), Dasatinib is a potent tyrosine kinase inhibitor with acute toxicity risks (fluid retention, heart failure). It requires strict medical supervision and intermittent dosing, not daily use.
Q7: Can I just take Berberine instead of Metformin?
A: Mechanistically, yes (both activate AMPK and improve insulin sensitivity). However, this paper focuses on pharmaceuticals with rigorously defined bioavailability. Berberine has poor oral bioavailability compared to Metformin, making the “dose-to-effect” ratio harder to manage reliably.
Q8: Are GLP-1 agonists (Liraglutide) the new “best” longevity drug?
A: They are strong contenders. Beyond weight loss, Liraglutide reduces neuroinflammation and amyloid accumulation. If you are concerned about Alzheimer’s or Parkinson’s, GLP-1s offer a neuroprotective angle that drugs like Acarbose lack.
Q9: If I’m already on a Keto diet, do I need Acarbose or Canagliflozin?
A: Likely less necessary. Acarbose blocks starch; if you aren’t eating starch, it’s useless. Canagliflozin dumps glucose; if your glucose is already baseline low from Keto, you risk euglycemic ketoacidosis (dangerous acid buildup despite normal blood sugar). Stacking SGLT2 inhibitors with strict Keto is generally contraindicated for safety.
Q10: What is the “Holy Grail” missing from this list?
A: Autophagy Inducers. The authors explicitly state that while mTOR inhibitors indirectly boost autophagy, we lack safe, specific drugs that directly activate the autophagy machinery (lysosomal cleanup). This is the next frontier in drug development.