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categories: ["longevity", "society"]categories: ["longevity", "society"]tags: ["supplements", "regulation", "vitamins", "clinical trials", "consumer health", "antioxidants"]tags: ["supplements", "regulation", "vitamins", "clinical trials", "consumer health", "antioxidants"]summary: "Vitamins, minerals, botanicals, and other compounds sold without pre-market approval, whose large randomized trials have repeatedly failed to show benefit in well-nourished adults."summary: "Vitamins, minerals, botanicals, and other compounds sold without pre-market approval, whose large randomized trials have repeatedly failed to show benefit in well-nourished adults."updated: "2026-10-27"updated: "2026-10-29"humanEvidence: "Correcting a documented deficiency is established medicine, but large randomized trials in well-nourished adults have been null for cancer and cardiovascular endpoints, and beta-carotene and vitamin E raised cancer incidence in some groups."humanEvidence: "Correcting a documented deficiency is established medicine, but large randomized trials in well-nourished adults have been null for cancer and cardiovascular endpoints, and beta-carotene and vitamin E raised cancer incidence in some groups."access: "Sold without prescription in supermarkets, pharmacies, and online almost everywhere; in the United States no product needs approval before sale, and monthly cost ranges from a few dollars to several hundred."access: "Sold without prescription in supermarkets, pharmacies, and online almost everywhere; in the United States no product needs approval before sale, and monthly cost ranges from a few dollars to several hundred."reversibility: "reversible"reversibility: "reversible"lines 49–67 → 49–6734 unchanged lines not shown
## The regulatory bargain## The regulatory bargain The Dietary Supplement Health and Education Act of 1994 (DSHEA) defines a dietary supplement as aThe Dietary Supplement Health and Education Act of 1994 (DSHEA) defines a dietary supplement as afood rather than a drug or a food additive.[^dshea] The consequences are structural. Afood rather than a drug or a food additive.[^dshea] The classification has structural consequences.manufacturer is responsible for concluding that its product is safe, but need not demonstrate thatA manufacturer is responsible for concluding that its product is safe, but need not demonstrate thatconclusion to anyone before selling it, and need not show any benefit at all. To remove a product,conclusion to anyone before selling it, and need not show any benefit at all. To remove a product,the Food and Drug Administration must establish that it presents a significant or unreasonablethe Food and Drug Administration must establish that it presents a significant or unreasonable risk,risk — after it is on the market and often after people have been hurt. Ingredients not sold in theand it must do so after the product is on the market, often after people have been hurt. IngredientsUnited States before October 1994 require a pre-market notification rather than an approval, andnot sold in the United States before October 1994 require a pre-market notification rather than ancompliance with even that is widely acknowledged to be partial.approval, and compliance with even that is widely acknowledged to be partial. Labels may carry structure/function claims ("supports immune health") but not disease claimsLabels may carry structure/function claims ("supports immune health") but not disease claims("prevents colds"), and must state that the product is not intended to diagnose, treat, cure, or("prevents colds"), and must state that the product is not intended to diagnose, treat, cure, orprevent any disease. Good manufacturing practice rules issued in 2007 and phased in over theprevent any disease. Good manufacturing practice rules issued in 2007 and phased in over thefollowing years bind manufacturers on identity, purity, and record-keeping. Those rules governfollowing years bind manufacturers on identity, purity, and record-keeping. Those rules governprocess, not effect: a product can be made exactly as specified and still do nothing.process rather than effect, so a product can be made exactly as specified and still do nothing. Other jurisdictions police claims more tightly without changing the underlying deal. The EuropeanOther jurisdictions police claims more tightly without changing the underlying deal. The EuropeanUnion harmonized permitted vitamin and mineral sources in 2002 and requires health claims to beUnion harmonized permitted vitamin and mineral sources in 2002 and requires health claims to belines 97–122 → 97–12029 unchanged lines not shown
## The trial record## The trial record The antioxidant hypothesis gave the field its central prediction. If aging reflects accumulatedThe antioxidant hypothesis gave the field its central prediction. If aging reflects accumulatedoxidative damage, supplementing antioxidants should slow it — an idea still embedded in consumeroxidative damage, supplementing antioxidants should slow it. The idea is still embedded in consumermarketing long after it stopped being how biogerontologists describe the [[hallmarks-of-aging]].marketing long after it stopped being how biogerontologists describe the [[hallmarks-of-aging]].Tested at scale, it did worse than null. In the Finnish ATBC trial, male smokers givenTested at scale, it did worse than null. In the Finnish ATBC trial, male smokers given beta-carotenebeta-carotene developed more lung cancer than those given placebo.[^atbc1994] CARET, testingdeveloped more lung cancer than those given placebo.[^atbc1994] CARET, testing beta-carotene withbeta-carotene with vitamin A in smokers and asbestos-exposed workers, was stopped early for thevitamin A in smokers and asbestos-exposed workers, was stopped early for the same reason and forsame reason and for higher overall mortality.[^omenn1996] Extended follow-up of the SELECT prostatehigher overall mortality.[^omenn1996] Extended follow-up of the SELECT prostate cancer preventioncancer prevention trial found significantly more prostate cancer in the men who had receivedtrial found significantly more prostate cancer in the men who had received vitamin E.[^klein2011]vitamin E.[^klein2011] Three large trials, three findings of harm from compounds sold asAll three large trials found harm from compounds sold as protective.protective. The nutrients with the strongest observational associations have fared no better underThe nutrients with the strongest observational associations have fared no better underrandomization. VITAL enrolled more than 25,000 older US adults and tested vitamin D and marinerandomization. VITAL enrolled more than 25,000 older US adults and tested vitamin D and marineomega-3 against placebo; neither reduced the primary cancer or cardiovascularomega-3 against placebo; neither reduced the primary cancer or cardiovascularendpoints.[^manson2019] An ancillary study in the same cohort found no reduction in fracturesendpoints.[^manson2019] An ancillary study in the same cohort found no reduction in fractureseither.[^leboff2022] A separate European trial of vitamin D, omega-3, and a home exerciseeither.[^leboff2022] A separate European trial of vitamin D, omega-3, and a home exercise programmeprogramme in older adults found no benefit on itsin older adults found no benefit on its co-primary clinical endpoints, though a later analysis ofco-primary clinical endpoints, though a later analysis of stored samples reported that vitamin Dstored samples reported that vitamin D slightly slowed several DNA-methylation age estimates. Thatslightly slowed several DNA-methylation age estimates. That last result is worth naming precisely:last result needs to be stated precisely: a shift in an [[epigenetic-clock]] reading is a change ina shift in an [[epigenetic-clock]] reading is a change in a prediction, not in an outcome, and noa prediction rather than in an outcome, and no regulator accepts one as a surrogate.regulator accepts one as a surrogate. Reviewing this literature in 2022, the US Preventive Services Task Force found the evidenceReviewing this literature in 2022, the US Preventive Services Task Force found the evidenceinsufficient to recommend multivitamins or most single nutrients to healthy adults for preventinginsufficient to recommend multivitamins or most single nutrients to healthy adults for preventinglines 129–135 → 127–1346 unchanged lines not shown
> on cognitive substudies of a later cocoa and multivitamin trial reporting modestly slower decline> on cognitive substudies of a later cocoa and multivitamin trial reporting modestly slower decline> on test batteries in older adults. Critics answer that the effects are small and measured on> on test batteries in older adults. Critics answer that the effects are small and measured on> continuous test scores rather than diagnoses. Defenders answer that the products are cheap and> continuous test scores rather than diagnoses. Defenders answer that the products are cheap and> safe and that real-world nutrient intakes are not uniformly adequate. Unresolved as of 2026.> safe and that real-world nutrient intakes are not uniformly adequate. The question is unresolved> as of 2026. ## Where supplementation is established medicine## Where supplementation is established medicine lines 149–164 → 148–16413 unchanged lines not shown
## The longevity shelf## The longevity shelf A distinct commercial layer sells compounds for healthy aging rather than for deficiency. ItA distinct commercial layer sells compounds for healthy aging rather than for deficiency. Itincludes [[nad-precursors]]; resveratrol, promoted through the sirtuin research programmeincludes [[nad-precursors]]; resveratrol, promoted through the sirtuin research programme associatedassociated with [[david-sinclair]] and since substantially deflated; flavonoids such as fisetin andwith [[david-sinclair]] and since substantially deflated; flavonoids such as fisetin and quercetin,quercetin, marketed on their [[senolytics|senolytic]] activity againstmarketed on their [[senolytics|senolytic]] activity against [[cellular-senescence|senescent cells]][[cellular-senescence|senescent cells]] in mice; spermidine, sold as an inducer of [[autophagy]]in mice; spermidine, sold as an inducer of [[autophagy]] and a mimetic of [[caloric-restriction]],and a mimetic of [[caloric-restriction]], which produced no cognitive benefit in a randomized trialwhich produced no cognitive benefit in a randomized trial in older adults with subjective memoryin older adults with subjective memory complaints; urolithin A, sold on mitophagy andcomplaints; urolithin A, sold on mitophagy and [[mitochondrial-dysfunction|mitochondrial decline]],[[mitochondrial-dysfunction|mitochondrial decline]], with small randomized trials in adultswith small randomized trials in adults reporting changes in muscle endurance measures;reporting changes in muscle endurance measures; [[magnesium-l-threonate|magnesium L-threonate]], sold for memory and sleep on the strength of rat studies and a few small human trials funded by the ingredient's licensees; and taurine, after a 2023 report in *Science* that[[magnesium-l-threonate|magnesium L-threonate]], sold for memory and sleep on the strength of ratsupplementation extended median lifespan in mice, with human evidence limited to observationalstudies and a few small human trials funded by the ingredient's licensees; and taurine, after a 2023associations.report in *Science* that supplementation extended median lifespan in mice, with human evidencelimited to observational associations. The pattern repeats: a mechanism in cells, a result in mice, a small human trial reporting aThe pattern repeats: a mechanism in cells, a result in mice, a small human trial reporting abiomarker, and a product. The missing step in every case is a randomized trial with a functionalbiomarker, and a product. The missing step in every case is a randomized trial with a functionallines 170–192 → 170–1925 unchanged lines not shown
recommended product in the same interface.recommended product in the same interface. The boundary with drugs is not stable either. [[metformin]] and [[rapamycin]] are prescriptionThe boundary with drugs is not stable either. [[metformin]] and [[rapamycin]] are prescriptionmedicines used off-label toward the same goal; [[nootropics]] straddle the line; and US lawmedicines used off-label toward the same goal; [[nootropics]] straddle the line; and US law excludesexcludes from the supplement definition a compound authorized for investigation as a new drugfrom the supplement definition a compound authorized for investigation as a new drug before it wasbefore it was sold as a supplement, the clause at the centre of the dispute over NMN. The contrastsold as a supplement, the clause at the centre of the dispute over NMN. The useful contrast is withworth holding is [[glp-1-receptor-agonists|the GLP-1 drugs]] — an approved class with[[glp-1-receptor-agonists|the GLP-1 drugs]], an approved class with cardiovascular outcome trials,cardiovascular outcome trials, which is what the supplement market has never had to produce.evidence the supplement market has never had to produce. ## Content, contamination, and harm## Content, contamination, and harm Independent testing repeatedly finds products that do not match their labels. Botanical productsIndependent testing repeatedly finds products that do not match their labels. Botanical productshave been found substituted or diluted, most publicly in a 2015 New York attorney general actionhave been found substituted or diluted, most publicly in a 2015 New York attorney general actionagainst major retailers, though that investigation's DNA-barcoding method drew criticism fromagainst major retailers, though that investigation's DNA-barcoding method drew criticism fromanalytical chemists because extraction destroys much of the DNA it looks for. Quantities deviate:analytical chemists because extraction destroys much of the DNA it looks for. Quantities deviate: anan analysis of melatonin gummies sold in the United States, a product taken foranalysis of melatonin gummies sold in the United States, a product taken for[[sleep-and-longevity|sleep]], found large discrepancies between labelled and measured content. The most serious failure is undeclared pharmaceuticals — sildenafil analogues in[[sleep-and-longevity|sleep]], found large discrepancies between labelled and measured content. Thesexual-performance products, sibutramine in weight-loss products, unapproved stimulants in sportsmost serious failure is undeclared pharmaceuticals: sildenafil analogues in sexual-performanceproducts. One study found banned drugs still present in supplements bought months after FDAproducts, sibutramine in weight-loss products, unapproved stimulants in sports products. One studyrecalls.[^cohen2014]found banned drugs still present in supplements bought months after FDA recalls.[^cohen2014] Harm is not hypothetical. Supplement-related adverse events are a documented cause of emergencyHarm is not hypothetical. Supplement-related adverse events are a documented cause of emergencydepartment visits in the United States, concentrated in cardiac symptoms among young adults takingdepartment visits in the United States, concentrated in cardiac symptoms among young adults takinglines 213–224 → 213–22420 unchanged lines not shown
The scientifically useful trials would look different from the ones already run: functionalThe scientifically useful trials would look different from the ones already run: functionalendpoints such as mobility, infection, or cognition rather than cancer incidence; populationsendpoints such as mobility, infection, or cognition rather than cancer incidence; populationsselected for plausible insufficiency rather than well-nourished volunteers; and durations longselected for plausible insufficiency rather than well-nourished volunteers; and durations longenough to matter. Whether any compound on the longevity shelf survives that test is open. Theenough to matter. Whether any compound on the longevity shelf survives that test is open. The recordrecord for the compounds already examined at scale is that they did not, and that two of them,for the compounds already examined at scale is that they did not, and that two of them,beta-carotene and vitamin E, harmed some of the people who took them. The interventions with thebeta-carotene and vitamin E, harmed some of the people who took them. The interventions with thebest functional evidence for [[healthspan|staying healthy longer]],best functional evidence for [[healthspan|staying healthy longer]],[[exercise-and-aging|structured exercise]] above all, remain the ones nobody can bottle.[[exercise-and-aging|structured exercise]] above all, cannot be sold in a bottle. Of all theSupplements are the most widely consumed application of the [[geroscience-hypothesis]] and theapplications of the [[geroscience-hypothesis]], supplements are the most widely consumed and theleast tested.least tested. ## See also## See alsoremoved, struck through added, underlinedLine numbers count the serialised markdown of each revision, frontmatter included.
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