Metformin, a prescription diabetes medication, is the best-known candidate for slowing aging. It lowers blood sugar, delays diabetes in people with mildly raised blood sugar and produces modest, lasting weight loss; longer life and fewer heart attacks, cancers and dementia remain unproven. Digestive side effects, lower vitamin B12 and smaller training gains in older adults make trade-offs clearer than hoped-for gains for people with normal blood sugar who train hard. (Full Review)

Protocol

Trial-tested doses

850 mg twice daily

Delayed diabetes; up to 1,000 mg twice daily in the frailty trial

Lower-dose approach

500–1,000 mg daily

Used to limit side effects and exercise blunting; no human outcome data support any dose for longevity

Time of day

With meals

Extended-release once with the evening meal; active users often dose away from training sessions

Time to effect

Blood glucose

Days to weeks

HbA1c reflects about three months

Weight

6–12 months

Loss sustained for about 10 years

Aging itself

Years

Any effect has not been shown

Benefits

High: Lower blood glucose; delayed onset of type 2 diabetes; weight loss; improved blood lipids; restored ovulation in polycystic ovary syndrome

Medium: Lower risk of long-term illness after coronavirus infection; slower growth of abdominal aortic aneurysms; less knee osteoarthritis pain; lower risk of atrial fibrillation

Low: Fewer cardiovascular events; longer survival; lower cancer incidence; lower dementia risk; slower frailty progression

Speculative: Slower biological-aging markers; lower inflammatory markers

Contraindications

Severe kidney impairment, eGFR below 30 mL/min/1.73 m² (absolute contraindication); starting at eGFR 30–45 is not recommended

Acute or chronic metabolic acidosis, including diabetic ketoacidosis (absolute contraindication)

Known hypersensitivity to metformin (absolute contraindication)

Clinical or laboratory evidence of liver disease (Avoid)

Mitochondrial diseases such as MELAS and MIDD

Excessive alcohol intake

Acute low-oxygen states: acute congestive heart failure, shock, sepsis, acute heart attack (stop during the event)

Pregnancy, when the purpose is longevity

Frail or underweight older adults (direct harm to frailty outcomes is unproven)

Key Interactions

Carbonic anhydrase inhibitors (topiramate): may raise lactic acidosis risk

OCT2/MATE inhibitors (dolutegravir): raised metformin exposure; accumulation may raise lactic acidosis risk

Cimetidine: raised plasma metformin by about 50%

Proton pump inhibitors (pantoprazole): raised metformin exposure by 15–16%, with only minor effects on glucose

Trimethoprim (also in co-trimoxazole): raised metformin exposure by 37%; relevant mainly with borderline kidney function or high doses

Verapamil: blunted metformin's glucose-lowering effect

Iodinated contrast media (e.g., iohexol): metformin stopped at or before the procedure if eGFR is 30–60; eGFR re-checked after 48 hours

Dehydration or restricted food and fluid intake (e.g., prolonged fasting, ultra-endurance events): can raise lactic acidosis risk; metformin temporarily stopped

Insulin and insulin secretagogues (e.g., glipizide): raises hypoglycemia risk

Glucose-raising drugs and supplements: thiazide diuretics (e.g., hydrochlorothiazide), corticosteroids (such as prednisone), estrogens (e.g., estradiol) and nicotinic acid/niacin can cause loss of glucose control; withdrawal can cause hypoglycemia

Calcium supplements (calcium carbonate): reversed metformin-induced B12 malabsorption

Exercise training (other intervention): reduced lean-mass gains from resistance training and fitness gains from aerobic training in older adults

Theoretical (inferred from mechanism)

Berberine: additive glucose lowering, plus overlapping gastrointestinal effects

Other glucose-lowering supplements (alpha-lipoic acid): additive glucose lowering

Rapamycin (sirolimus): could compound blunted muscle growth

Risk & Side Effects

High: Gastrointestinal intolerance; vitamin B12 deficiency; blunted training adaptations

Medium: Altered offspring growth after use in pregnancy; weakness, fatigue and headache; hypoglycemia with other glucose-lowering drugs

Low: Lactic acidosis; birth defects after paternal use; Parkinson's disease; drug-induced liver injury; immune hemolytic anemia; acute pancreatitis

Speculative: Toxicity at high exposure

Monitoring

Marker	Target	Why
eGFR	Start only if ≥45; stop below 30 mL/min/1.73 m²	Sets eligibility and dose
Vitamin B12	Above 220 pmol/L	Metformin depletes it
Methylmalonic acid	Below 0.4 µmol/L	Confirms tissue B12 deficiency
Homocysteine	5–15 µmol/L	Rises with B12 deficiency
Complete blood count	Hemoglobin 13.5–17.5 g/dL men, 12.0–15.5 g/dL women	Detects anemia
HbA1c	4.0–5.6%	Falls with metformin
Fasting glucose	70–99 mg/dL	Falls with metformin
Fasting insulin	2.6–24.9 µIU/mL	Falls with improved insulin sensitivity
Alanine aminotransferase	7–56 U/L	Liver injury or liver disease stops use
Lean mass by body-composition scan	No established target; track change from own baseline	Gains may be blunted
VO2max	No established target; track change from own baseline	Gains may be blunted
Body weight	Not specified in the ER	Tracks weight change

Cadence: Glucose markers and weight at 3 months, then every 6–12 months; eGFR at least every 12 months, more often after age 65; blood counts every 12 months; vitamin B12 every 2–3 years per the label, or yearly as many practitioners prefer

Qualitative Assessment

Gastrointestinal tolerance: stool frequency, nausea, bloating
Energy and fatigue
Training progress: strength gains and endurance performance
Numbness, tingling or balance changes
Appetite and unintended weight loss, especially in older users

Metformin for Health & Longevity

Protocol

Benefits

Risk & Side Effects

Monitoring

Qualitative Assessment