Millions Take This Supplement — But It May Be Dangerous

Siim expands that clinical trials consistently show no gains in muscle mass or performance from BCAA supplementation. The only reproducible effect is a small reduction in post-exercise muscle soreness and creatine kinase. He also points out the correlation between high circulating BCAA levels and insulin resistance, though he notes that such elevations are likely a consequence of metabolic dysfunction rather than a cause. Nevertheless, intervention studies demonstrate that lowering BCAA intake improves glucose tolerance and insulin sensitivity. The risk of diabetes from BCAA supplementation likely only applies to those already metabolically compromised, but for healthy individuals, the supplements are at best useless and at worst catabolic.

Siim details a 10-year longitudinal study showing dietary calcium was not associated with coronary calcification, but supplement users had a 22% higher risk. A 2021 meta-analysis of 13 RCTs confirmed a 15% increase in heart disease risk with 1,000 mg/day in postmenopausal women. Diabetes further amplifies the risk. He suggests calcium alpha-ketoglutarate as a safer alternative because it supplies less elemental calcium and has been shown to improve bone density in postmenopausal women. The overarching message is that calcium homeostasis requires co-factors; therefore, any calcium supplementation must be balanced with K2 and magnesium to prevent harmful calcium shifts.

Siim underscores that the Interventions Testing Program—a gold-standard, multi-site mouse lifespan study—found resveratrol did not extend life in genetically diverse mice. GlaxoSmithKline’s decision to abandon its resveratrol and sirtuin program after a $720 million investment signaled the lack of translatable longevity benefits. The only lifespan extension was observed in mice fed an extremely fattening diet, echoing human data where benefits appear limited to obese/diabetic populations. Because so many longevity enthusiasts also exercise, the antagonism with exercise adaptation makes resveratrol a particularly poor choice for the biohacking crowd.

Siim argues that metformin is a net negative for the healthy because it impedes the very adaptations that exercise seeks to produce. He contrasts it with SGLT2 inhibitors (e.g., empagliflozin, dapagliflozin), which not only lower blood sugar but also extend lifespan in mice, improve kidney function, and increase VO2 max without suppressing testosterone. Given that many longevity proponents combine exercise with metformin, he deems this combination counterproductive. The absence of robust lifespan data in non-diabetic humans further weakens the case.

Siim summarizes a 2021 Cochrane review showing a possible small mortality increase with vitamin E, A, and beta-carotene, while vitamin C and selenium were neutral. He downplays the magnitude but argues that since no one needs these supplements without a deficiency, the tiny risk is enough reason to avoid them. He contrasts them with other antioxidants like NAC, astaxanthin, and melatonin, which did not show the same mortality association but still require careful timing around exercise to preserve muscle adaptations.

Siim explains that while leucine does signal mTOR to initiate protein synthesis, the process requires all nine essential amino acids as building blocks. When only the three BCAAs are supplied, the body mobilizes its own muscle tissue to obtain the missing six essential amino acids, causing net breakdown. He cites evidence that ingesting BCAAs alone reduces muscle protein synthesis and does not enhance growth; clinical trials find no effect on muscle growth or performance. The only consistent benefit is a mild reduction in muscle soreness and creatine kinase after exercise. Moreover, excess BCAAs may compete with tryptophan uptake, lowering serotonin and potentially affecting mood. Epidemiological data also link high circulating BCAA levels to insulin resistance and a 2-5 fold higher diabetes risk, though this may reflect underlying metabolic dysfunction rather than causation. Reducing BCAA intake has been shown to improve insulin sensitivity in both humans and mice.

Siim presents a 10-year follow-up study showing dietary calcium was not associated with coronary artery calcification, but calcium supplements were linked to a 22% higher risk. Excess calcium in the blood—hypercalcemia—drives calcium into the arterial walls, accelerating atherosclerosis. A 2021 meta-analysis of 13 RCTs found that 1,000 mg/day calcium supplementation increased heart disease risk by 15% in healthy postmenopausal women. The risk worsens in those with diabetes. He emphasizes that calcium should be obtained from food, and only those with low dietary intake or low blood calcium might consider supplementation. Even then, he suggests calcium alpha-ketoglutarate (lower calcium dose) paired with vitamin K2 and magnesium to direct calcium to bones and away from arteries.

Siim reports that the Interventions Testing Program found resveratrol did not extend lifespan in genetically diverse mice, a gold-standard test. GlaxoSmithKline, which paid $720 million for resveratrol and the sirtuin program, discontinued it in 2013, signaling commercial failure. The only condition where resveratrol increased lifespan was in mice on an extremely fattening diet, and some human trials show improved inflammation and metabolic markers in diabetics/obese individuals. For healthy exercisers, resveratrol blunts the improvements in lipids, metabolic markers, and cardiovascular health that typically follow exercise. It also lowers DHEA, although without affecting testosterone directly. His conclusion: unless you are obese or diabetic, resveratrol offers nothing and may harm fitness adaptations. The related compound pterostilbene similarly has no life-extension evidence and raises LDL cholesterol.

Siim explains that while metformin has a place in diabetes management, in healthy individuals it reduces VO2 max and impairs mitochondrial adaptations to exercise—meaning users get less cardiorespiratory benefit from training. Additionally, it lowers testosterone in both men and women, counteracting the natural testosterone increase that accompanies improved insulin sensitivity. He contrasts metformin with SGLT2 inhibitors, which also emerge from diabetes pharmacology but have been shown to extend lifespan in mice, improve kidney function, and even increase VO2 max without reducing testosterone. The side effect profile of SGLT2 inhibitors (mainly genital fungal infections) is considered more tolerable than metformin's for off-label anti-aging purposes. The key message: metformin is not a longevity drug for the metabolically healthy.

Siim cites a 2021 Cochrane review linking vitamin E, A, and beta-carotene to a possibly increased mortality risk (1-3%), though he considers the effect small and difficult to attribute causally. Vitamin C and selenium were not associated with increased mortality. He personally does not strongly worry about these supplements but notes that most people don't need them. Crucially, he warns that taking antioxidants like NAC immediately after exercise can blunt the hypertrophic response, as reactive oxygen species are an essential signal for muscle adaptation. Thus, antioxidant supplements should be avoided around workouts.