A letter describes the human evidence, not the product, the manufacturer, or the ingredient's worth.
Search by name or filter by evidence tier. Each grade reflects human RCT Randomized controlled trial: people are assigned to the treatment or a comparison by chance, so the groups differ only in what they received. It is the design that can show cause and effect. quality, dose adequacy, and replication The same finding reproduced by a separate research group. A result seen once can be chance or bias; a replicated one is harder to explain away., not marketing claims.
Muscle insulin sensitivity in prediabetic postmenopausal women, which is the use the Grade C rests on. Blood NAD+ concentration is also Grade C and is a mechanistic marker, not an outcome. Longevity, healthspan and mortality are Grade D: no human trial has tested them.
Six-minute walk in peripheral artery disease, on one unreplicated trial (C). Blood NAD+ rises reliably, a mechanistic marker that caps at C. Clamp-measured insulin sensitivity in obese men and cognition in mild cognitive impairment were tested without benefit (D Route 2). Long-COVID cognition and fatigue were also null. In early Parkinson disease, a 410-person phase 3 trial found people on NR did worse than placebo (D, harm found).
Muscle strength with resistance training in older adults
High-dose purified EPA (icosapent ethyl 4 g/day) for cardiovascular risk reduction in treated patients with raised triglycerides, which is what the Grade B rests on. REDUCE-IT moved hard cardiovascular events, but it is one industry program and no second independent icosapent outcomes trial has replicated it, so it does not reach A. Mixed EPA+DHA fish oil for primary prevention in general-risk adults is graded separately and is D. Triglyceride lowering and omega-3 index are measurements, not the graded outcome.
Use-specific. Sleep quality in primary insomnia: Grade C on three small self-report trials pooled at low to very low certainty. Cardiovascular events and all-cause mortality: Grade D, because no randomized trial has tested it
Use-specific. Fall prevention in older adults and respiratory infection prevention: Grade C, mixed randomized evidence. Fracture prevention with vitamin D3 alone: Grade D, tested and no benefit, in deficient or older adults and in adults not selected for deficiency. Vitamin D3 with calcium in older adults living in institutions: Grade B, replicated hard-endpoint benefit in institutions, null in the large community trials. Cancer and cardiovascular prevention in adults not selected for deficiency: Grade D, tested and no benefit.
Chronic heart failure as an adjunct to standard therapy
Glycemic control (fasting glucose, HbA1c) and LDL cholesterol in type 2 diabetes and dyslipidemia, on placebo-controlled trials and pooled analyses
Metabolic markers in obese men, where one 30-day crossover of 150 mg/day was positive and the independent attempts to repeat it with clamp-measured insulin sensitivity were null (C, mixed). Pooled trials find no effect on C-reactive protein, lipids, glucose or blood pressure. In older men, 250 mg/day blunted the gains in fitness, blood pressure and lipids from exercise training (D Route 2, harm found). Sirtuin activation is a mechanism, not a use
Muscle endurance and strength, on small, mixed trials: both larger trials in non-athletes missed their pre-registered primary endpoints, an elite-runner trial found no performance benefit, and a 2026 meta-analysis found the one poolable outcome, 6-minute walk distance, inconclusive. Mitochondrial and immune-cell markers moved in trials run or funded by the product's maker
Cortisol and stress or anxiety scores in stressed adults (pooled analyses disagree on perceived stress)
Blood pressure at 500 mg/day or more, where pooled trials find systolic pressure 2 to 4 mmHg lower at low to moderate certainty with very high heterogeneity (C). Lipids and glycemic control were tested and did not change (D Route 2). Senolytic use of quercetin alone has no trial on any clinical outcome (D Route 1)
Use-specific. Endothelial, vascular and inflammatory markers in type 2 diabetes: Grade C, three randomized trials agree, but the markers are not established stand-ins for a clinical outcome. Glycemic control in type 2 diabetes: Grade C, one null and two positive trials at 3 g/day. Acute 3-km running performance: Grade C, one crossover. Aging or longevity: no human randomized trial (Route 1).
Symptoms in schizophrenia as an adjunct to antipsychotics, about 2 g/day (C, mixed)
Sleep and next-day fatigue after short sleep
Sleep onset timing in delayed sleep phase disorder (B) and jet lag symptoms after flights across five or more time zones (B). In ordinary adult insomnia the effect on sleep onset is a few minutes and the adult-only pooled analysis is null, so that use is C. The antioxidant claim rests on no randomized clinical trial and carries no letter.
Plasma homocysteine lowering at 1.5 to 6 g/day, replicated across independent trials and pooled analyses
Graded by use. Activity-related joint pain in athletes and active adults: Grade B, three randomized trials agree on self-reported pain, the ceiling for self-report. Skin hydration, elasticity and wrinkles: Grade C, pooled analyses are positive overall and null in the independent and high-quality trials. None of the graded trials measured bone density
Gut microbiome diversity, immune regulation, inflammation reduction, Akkermansia support, post-antibiotic restoration
Systemic inflammatory markers (hs-CRP, IL-6) and knee osteoarthritis pain and function, both graded C. The neuroprotection and gut health uses commonly claimed for curcumin carry no citation on this record.
Cognitive test scores in older adults with mild cognitive impairment, on one small positive trial of fruiting-body powder and one partial replication. No cited trial measured nerve growth factor, nerve repair or mood
Skin moisture and elasticity, with oral astaxanthin from Haematococcus pluvialis algae at about 6 mg a day
Universal antioxidant (fat and water soluble), insulin sensitivity, peripheral neuropathy, glutathione recycling
Cognitive test performance in middle-aged and older adults
Blood pressure reduction in adults with pre-hypertension or stage 1 hypertension. This is the only use with supporting randomized trial evidence. Nattokinase has been tested for cholesterol lowering and for carotid plaque regression and did not show benefit for either
Circulation / vascular support
Cognitive scores in diagnosed mild cognitive impairment, Alzheimer's disease or diabetes with cognitive decline
Glucose control and insulin resistance in type 2 diabetes, on small short trials: one 4-week Tehran trial of 10 g/day broccoli sprout powder lowered insulin and HOMA-IR, and a Swedish trial of a concentrated sprout extract lowered fasting glucose and HbA1c in obese patients with poorly controlled diabetes, a subgroup. The same Swedish group's prediabetes trial missed its prespecified primary endpoint. NRF2 activation, the proposed mechanism, did not show in two of three randomized trials that measured it, and the one hypertension trial found no change in endothelial function or blood pressure.
LDL cholesterol, replicated across meta-analyses of randomized trials and one 12-month trial at the record's dose
Verbal learning in mild cognitive impairment: one randomized placebo-controlled pilot, 19 adults aged 60 or over, 25 mg three times a week for a year, improved Rey Auditory Verbal Learning Test performance and stable neurofilament light chain against placebo. Unreplicated, and the funder is not stated. Otherwise the evidence is observational association between low blood levels and cognitive decline.
Use-specific. In healthy older adults the primary endpoint was null in the one trial not run by the originating group, a 2-week trial sponsored by a company that holds patents on and markets glycine plus NAC products. In older adults randomized by the originating group for 16 weeks at a far higher dose, glutathione and downstream markers improved
Cognitive decline in mild cognitive impairment and Alzheimer's disease, on small randomized trials of low-dose lithium. Population studies linking trace lithium in drinking water to lower dementia rates are observational and carry no grade.
Knee osteoarthritis: structural (joint-space) and symptom evidence for crystalline glucosamine sulfate is mixed
Memory and behavior in chronic cerebral disorders of the elderly, which is the population the cited meta-analysis studied. The same review found no benefit on attention. Neuroprotection after stroke is context, not the graded claim.
Mild cognitive impairment and mild Alzheimer's disease (older pooled trials positive, the two largest trials null)
Carboxylates matrix Gla protein (MGP), a protein involved in inhibiting vascular and soft-tissue calcification
Memory in older adults with memory complaints, graded by form. The positive trials used bovine-cortex phosphatidylserine, which is no longer sold: Grade C, stated for that form. The soy-derived form sold today was tested twice without benefit: Grade D, Route 2. FDA qualified health claim (2003) acknowledges limited and not conclusive evidence.
Thyroid peroxidase antibody levels in autoimmune thyroiditis, lower across several meta-analyses and one 412-patient trial, a surrogate whose fall has not changed thyroid function, levothyroxine dose or quality of life (C). Long-term supplementation in adults who are not deficient was tested in trials of 1,312 to 35,533 people: no cancer benefit and a signal of more type 2 diabetes (D Route 2). The trials were not selected for selenium deficiency, and the Cochrane review found no clear influence of baseline status on outcomes.
Brachial artery flow-mediated dilation in older adults at 20 mg/day, a measured vascular marker that is not an established stand-in for a clinical outcome, improved in a 20-person crossover in older adults and an 18-person kidney disease pilot (C). Physical function in healthy older adults and endurance performance were tested at the same dose without benefit (D Route 2). Parkinson's disease progression was unchanged over a year at 40 to 80 mg.
Graded by use. Skin hydration, elasticity and wrinkle depth: Grade B, several 12-week randomized trials and a 7-trial meta-analysis on instrument-measured surrogates, every trial run by or with a manufacturer, stated beside the letter. Knee symptoms: Grade C, one trend with an age-subgroup signal, one null primary, one self-rating without objective change. No trial measured cartilage or joint lubrication, and no human trial supports a gut-barrier claim.
Fatigue under stress, on four small short trials of one proprietary extract, each with an author linked to its maker, against one independent registered trial in which fatigue was worse on Rhodiola than on placebo. Mixed, low-quality evidence: C. Stress resilience, cognitive performance and any anti-aging effect carry no letter
Immune support
Clinic blood pressure in hypertension, where trials disagree and the pooled effect does not appear on 24-hour or home readings
Self-reported and actigraphic sleep in small, short trials of Montmorency juice or concentrate, with the two larger recent trials null (C). Recovery of muscle strength after strenuous exercise, where pooled analyses are positive on measured strength but heterogeneous and several independent trials are null (C). The rise in urinary melatonin in one trial came from melatonin in the juice itself
Graded by use. Weight regain after diet-induced weight loss: Grade C, one maker-run trial. Insulin sensitivity and metabolic markers: Grade D, Route 2, the scale-up of the positive pilot missed its primary endpoint and a second trial found no between-group difference. No trial is independent of a product's maker.
Cognitive symptoms in mild to moderate dementia, with the standardized extract EGb 761 at 240 mg a day
Mild to moderate depression, on standard symptom scales
Erectile function in mild to moderate erectile dysfunction, on Korean red ginseng or ginseng berry extract at about 600 to 2,700 mg/day for 4 to 12 weeks: the Cochrane review found a statistically significant but trivial gain on erectile function scales, below the minimal clinically important difference, at low to moderate certainty, and more men reporting the ability to have intercourse at low certainty. No other use carries a letter.
Exercise performance: two named Cs-4 trials found no change in VO2max and one raised lactate and ventilatory thresholds in older adults
Liver enzymes in fatty liver disease, on plain silymarin at 140 mg to 700 mg three times daily: ALT falls a few units against placebo at very low certainty (Cochrane 2025, PMID 40552569). The two placebo-controlled biopsy trials missed their histologic primary endpoints. Silybin-phosphatidylcholine complexes and combination products are different agents and are not graded here.
Blood pressure, where one pooled analysis found systolic pressure 4.1 mmHg lower with a borderline interval and diastolic pressure lower only at 6 g/day or more, and another pooled analysis found no effect on brachial or aortic pressure. Exercise performance is not supported for free L-citrulline: pooled analyses of aerobic and endurance performance are null, and the small strength and repetition effects rest largely on citrulline malate, a different form.
Osteoarthritis pain and function
Osteoarthritis pain and joint function
High intensity exercise capacity, especially efforts of 1 to 4 minutes
Graded by population. Diagnosed sarcopenia: Grade C, pooled analyses disagree
Total testosterone in men with low testosterone, on small trials of standardized water extracts of the root: a 2022 meta-analysis of five randomized trials pooled a rise with very high heterogeneity, significant in men with low testosterone and not in healthy men. The largest placebo-controlled trial was funded and co-authored by the extract's maker. A hormone level is a surrogate, and no trial measured a health outcome.
Glycemic markers in adults with prediabetes or type 2 diabetes, on small mixed trials
Insulin resistance and reproductive measures in PCOS (myo-inositol)
Blood glutathione stores, where one 6-month trial of standard oral glutathione found a rise and one 4-week placebo-controlled trial found none
C-reactive protein, where a 2019 meta-analysis was null and three later meta-analyses (2024 to 2026) each report a modest pooled reduction graded moderate certainty
Fasting glucose and some lipid markers in type 2 diabetes
Fasting glucose and HbA1c in type 2 diabetes and prediabetes, across several pooled analyses of randomized trials
Graded by use. Symptom scores in healthy adults: Grade C, two trials from the maker of the product, one positive on symptom scores and one that shortened illness by about a day without changing how many people got sick. Preventing respiratory infection in adults: Grade D, tested without benefit in the maker's larger trial, an independent COVID-prevention trial and a pooled analysis.
Depressive symptoms, on small older trials of low quality
Two-hour glucose and HbA1c in one 12-week trial of 30 adults with impaired glucose tolerance, and fasting glucose in a 2023 meta-analysis of six trials that its authors rate low quality and heterogeneous. The trials studied impaired glucose tolerance, metabolic syndrome and type 2 diabetes, not healthy adults
Diabetic neuropathy symptoms: short trials report symptom-score gains, trials of a year or longer find no change in nerve function
Immune cell percentages and tumor response as an adjunct to conventional cancer treatment, in five small randomized trials of varied Ganoderma lucidum preparations pooled by Cochrane at low certainty, none measuring survival (C). Blood glucose, lipids and blood pressure were tested in type 2 diabetes and metabolic syndrome without effect (D Route 2). No single product or dose has been tested twice.
Glycemic measures in type 2 diabetes and prediabetes
Working memory and reaction measures during acute environmental or operational stress, on small short trials: positive during severe cold exposure and a military combat course, null during exercise in heat, and null on stress markers in the one recent trial. Not a daily supplement claim: the positive trials gave 2 g doses or 150 to 300 mg per kilogram, far above a typical capsule.
Sleep quality, mood and heart-rate variability in one 90-day trial of 30 overweight women starting an exercise program
Intestinal permeability markers in athletes and patients, where the pooled trials disagree with each other and one trial found permeability rose on colostrum
Glycemic and inflammatory markers in prediabetes, and antibody response to influenza vaccine in older adults
Shorter common colds in adults, using zinc acetate or gluconate lozenges that supply about 75 to 92 mg of zinc a day, started within 24 hours of the first symptoms
Glycemic control in type 2 diabetes: three meta-analyses disagree, and the signal sits in chromium picolinate above 200 mcg/day in poorly controlled diabetes
Infant information-processing speed after maternal supplementation in the third trimester (930 versus 480 mg/day, 26 mothers, no placebo arm)
Survival after curative surgery for colorectal or gastric cancer, with PSK (polysaccharide-K, a standardized prescription extract in Japan) added to older oral chemotherapy: pooled trials from the 1980s to 2000s were positive, and the three most recent trials found no benefit. Adjunctive to cancer treatment, never a substitute for it.
No established benefit. The one 12-month randomized trial, in women on tamoxifen, changed urinary estrogen metabolite ratios, a surrogate that no trial has linked to a cancer outcome, and found DIM lowered the active tamoxifen metabolites, a drug interaction signal. Its original primary endpoint, breast density, did not change.
Memory after a single oral dose of about 260 mg, in two small randomized trials from one research group (C). Daily low-dose use for memory or cognition, which is what consumer products supply, has no randomized trial (D Route 1). The one multi-week trial that measured cognition, 195 mg/day for 6 months in bipolar disorder, was null for cognition. The longevity evidence is preclinical.
Major coronary events after myocardial infarction, the primary endpoint of one large Chinese trial of one standardized extract, with cardiovascular and total mortality lower as secondary results. Monacolin K is chemically the statin lovastatin, and commercial monacolin content varies enormously.
Lipid profile improvement (LDL, triglycerides)
LDL cholesterol lowering in one trial, on top of a weight-loss diet in women with fatty liver disease
Knee osteoarthritis pain and stiffness in one industry-funded 90-day trial
Methyl donor marketed for depression and for osteoarthritis joint pain. Use-specific: as a stand-alone treatment for depression the pooled randomized trials disagree (Grade C)
Drinks of beta-hydroxybutyrate, as a ketone ester or as ketone salts, that raise blood ketones without fasting or a ketogenic diet. Single doses lower blood glucose after a meal or glucose drink, and two-week trials in heart failure raised cardiac output (both C, measured markers). Endurance performance, migraine prevention and blood pressure were tested without benefit (D Route 2).
These compounds are in the longevity conversation but lack the human randomized controlled trial People are assigned to the treatment or a comparison by chance, so the groups differ only in what they received. It is the design that can show cause and effect. evidence required for a grade above D. We track them because you will hear about them, and because the evidence could change. A well-designed human trial could move any of them up.
No randomized trial of spermidine on lifespan or mortality has been run. A 12-month randomized trial in older adults with subjective cognitive decline (SmartAge) found no effect on memory. Route 1: animal lifespan data plus observational epidemiology.
No randomized trial of fisetin as a senolytic for aging has reported results. Small randomized trials exist in other uses, including a null placebo-controlled crossover in Gulf War illness. Route 1: animal senolytic data only.
Resveratrol analogue. The single human trial's pre-specified primary outcome was lipids, and LDL cholesterol rose on pterostilbene
No human trial of oral C60 has been run
No randomized trial has tested rhamnan sulfate on plaque or vascular outcomes
No randomized trial has been run. Route 1: one open-label, uncontrolled trial of the branded formula.
PSA kinetics in biochemically relapsed prostate cancer, in two single-arm Phase II studies without a control group (D Route 1). The two placebo-controlled trials of the product, in hypertension with raised galectin-3 and in knee osteoarthritis, were both null (D Route 2). Metal-binding claims rest on uncontrolled studies by the product's developer and carry no letter.
No human randomized trial of the statin-muscle claim has reported, and no registered trial of that claim was located in this pass. Route 1 for the statin-muscle use: mechanistic and animal work. GG has now been tested in humans on other endpoints: a 150-person randomized trial found GG alone had no effect on plasma CoQ10 or on health and vitality questionnaires in healthy adults, and a 34-person fixed-order placebo-then-GG study found no change in testosterone overall. Popularity is not evidence: this is taken as a statin adjunct on the strength of a mechanism, not a trial result.
No randomized trial of Ca-AKG on an aging outcome has reported. A placebo-controlled trial of 1 g Ca-AKG on a DNA methylation clock (ABLE) has enrolled and not yet reported
No human randomized trial of standalone apigenin has been run. Route 1: cell, animal and mechanistic work only. Proposed as a CD38 inhibitor that preserves NAD+ by blocking its main degrading enzyme, and taken alongside NMN in some longevity protocols on that reasoning. The reasoning is not the evidence: a PubMed search for randomized human trials of apigenin on its own returned none
No human trial has been run, and no human dose or safety data exist. Route 1: preclinical senolytic work only. In cultured human fibroblasts, piperlongumine killed senescent cells by apoptosis, and the cited paper reports that this did not require the induction of reactive oxygen species. The authors filed a patent on piperlongumine and its analogs as anti-aging agents, and two are tied to a senolytic company.
No human trial has been published. Route 1: mouse and cell work only. The founding mouse study, now under an Expression of Concern from its journal, reported that PCC1 killed senescent cells, possibly by promoting reactive oxygen species and mitochondrial dysfunction
Proposed autophagy inducer, untested for that claim in people. The one oral trial in healthy middle-aged and older adults (100 g/day for 12 weeks) found no significant change in its primary vascular measure in the full sample, and an intravenous trial in heart attack survivors found no change in arterial inflammation.
No randomized trial has tested oral NAD+ itself on a clinical, functional or validated-scale outcome, and a 2026 systematic review found none for oral or intravenous NAD+. The one randomized trial of oral NAD+ (Kornilov 2026) tested a proprietary formulation for 5 days with blood NAD as its primary endpoint
Tested at scale for cancer prevention in six large trials. Beta-carotene alone raised lung cancer in male smokers (ATBC)
Tested at scale for cancer prevention with no benefit in any large trial. In SELECT, 400 IU/day of synthetic vitamin E significantly increased prostate cancer in healthy men on extended follow-up
Tested for colorectal adenoma recurrence in three placebo-controlled trials and a pooled analysis of 2,632 patients. No reduction. The largest trial raised the possibility of more advanced neoplasia, and its long-term follow-up found more sessile serrated lesions with extended use
Tested at scale on top of statins. Extended-release niacin alone (AIM-HIGH) and extended-release niacin with laropiprant (HPS2-THRIVE) did not reduce vascular events
Bone density and steroid hormone markers. The small controlled trials that exist were null: no effect on testosterone, lean mass or strength over 7 weeks, on bone density over 10 months, or on minerals, sex steroids or bone-turnover markers in postmenopausal women. The hormone claim traces to one non-randomized metabolic-unit study of 12 women.
Olfactory recovery after COVID-19, tested only inside a palmitoylethanolamide combination: luteolin alone is untested (D Route 1). The one trial of luteolin alone, in Gulf War illness symptoms, was null (D Route 2).
Bromelain alone has been tested in placebo-controlled trials for knee osteoarthritis pain and for inflammation markers, and showed no benefit. Positive trials of enzyme products tested bromelain inside a combination.
Swelling after oral or sinus surgery, on five small randomized trials of mixed result
Tendon, ligament and gut tissue healing. No result of a human randomized controlled trial of the compound has been published
One placebo-controlled trial of GHRH(1-29), in healthy older adults (PMID 16399214), is under review. Growth hormone and IGF-1 rose in two tiny studies from one research group, one randomizing only the order of two doses and the other uncontrolled
A buckwheat-derived scavenger of reactive lipid byproducts (isolevuglandins), for inflammation and healthy aging. No trial has tested it on a clinical outcome in healthy people. The one trial on a clinical outcome, in atrial fibrillation after ablation, found more recurrence on 2-HOBA than on placebo.
Showing 109 graded supplements. Every entry includes mechanism, dose range, drug-interaction notes, tracking metrics, and the primary human-trial reference.