Compare Supplements

Side-by-side comparison of 2 supplements

Mfn4.0

Metformin

Limited safety

Pio4.0

Pioglitazone (Actos)

Limited safety

Evidence

Mostly mechanism / observational

Evidence Score4/10

Studies: 8

Meta-analyses: 1

Mostly mechanism / observational

Evidence Score4/10

Studies: 6

Meta-analyses: 1

Dosage & timing

Dosage:

Off-label longevity use mirrors diabetes dosing (commonly 500–1500 mg/day of extended-release with meals) under a clinician. Not an approved longevity regimen, and unnecessary in well-controlled non-diabetics without a clear rationale.

Best Time:

With meals · with food

Take with food

Form:

Extended-release tablet

Dosage:

Off-label metabolic use mirrors diabetes dosing (e.g. 15–45 mg once daily) under a clinician. A prescription drug; not an approved longevity regimen.

Best Time:

Morning

Can take on empty stomach

Form:

Oral tablet (pioglitazone)

What you'll notice

📉 Glycemic controlpositive

Weeks

📊 Possible mortality benefit (epidemiology)positive

Years

🏃 May blunt exercise adaptationtrade-off

Weeks of training

📉 Improved insulin sensitivitypositive

Weeks to months

🧠 Reduced recurrent stroke / MIpositive

Months to years

🫁 NASH / liver histology improvementpositive

Months

Safety

Limited safety

Contraindications:

Severe renal impairment (eGFR < 30)
Acute metabolic acidosis
Conditions predisposing to lactic acidosis (severe hypoxia, decompensated heart failure)

Drug Interactions:

Iodinated contrast
Alcohol (excessive)

Side Effects:

GI upset (diarrhea, nausea)Vitamin B12 depletionLactic acidosis

Limited safety

Contraindications:

Symptomatic heart failure (NYHA III–IV)
Active or history of bladder cancer
Active liver disease / significant hepatic impairment

Drug Interactions:

Insulin
Gemfibrozil (CYP2C8 inhibitor)
Insulin secretagogues (sulfonylureas)

Side Effects:

Weight gainFluid retention / edemaBone fracture (especially women)

How they work together

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