Every molecule that applies for inclusion in our formulas passes through the same evaluation framework. Most do not make it through. Not because they lack scientific interest, but because scientific interest alone is not sufficient justification for a formula intended for a human being.
Selecting a bioactive is an act of rigor, not an act of marketing. The supplement market operates on an inverse logic: popularity often precedes evidence. Molecules present in countless products have never demonstrated robust human clinical efficacy. Some carry risk signals that the industry consistently minimizes.
This article is an inventory of what we have chosen not to include, organized by reason for exclusion.
Insufficient bioavailability:
Insufficient clinical evidence:
Unfavorable benefit/risk ratio:
The three selection filters
Before entering a precision formula, a bioactive must clear three successive barriers.
The first filter is documented bioavailability. A molecule with remarkable laboratory properties produces no effect if it cannot reach its biological target in active form after oral ingestion. Pharmacokinetics (what happens to a molecule once ingested: absorption, transformation, distribution, elimination) is often the first point of failure.
The second filter is human clinical evidence. Animal models and cell culture experiments explore mechanisms. They do not prove that an effect exists in humans. A randomized controlled clinical trial, with human participants, comparison groups, and predefined measurable health outcomes, is the only level of evidence that matters for a formulation.
The third filter is a favorable benefit/risk ratio. Even an effective molecule can be excluded if its documented adverse effects create a risk signal that outweighs the expected benefit, particularly in unselected populations.
Most candidates fail at the first filter.
Insufficient bioavailability: the first wall
Quercetin and fisetin
Quercetin is one of the best-selling antioxidants in the world. It displays impressive antioxidant activity in cellular models and a theoretical capacity to reduce inflammation. Its oral bioavailability in standard formulations is below 2% (PubMed).
The mechanism is identical to that of resveratrol (described in our dedicated article on that molecule): the liver conjugates quercetin into glucuronides and sulfates on first pass, producing metabolites with limited biological activity. What cells encounter in the laboratory is not what the body receives after a capsule.
Fisetin (a flavonoid found in strawberries and apples) shows promising senolytic properties (capable of eliminating senescent cells, meaning aged cells that stop dividing but persist in tissues) in murine models. Its human data consist of a handful of small pilot studies. Oral bioavailability and human pharmacokinetics remain insufficiently characterized to justify formulation.
Green tea EGCG
Epigallocatechin gallate (EGCG, the primary polyphenol in green tea) has accumulated preclinical data on inflammation, metabolism, and neuroprotection. Its oral bioavailability ranges from approximately 2 to 13%, depending on the individual and dietary conditions (PubMed).
This degree of variability is problematic for a precision formula. It makes real systemic exposure unpredictable. Added to this are documented drug interactions with anticoagulants (warfarin) and drugs transported by P-glycoprotein (a cellular transporter that regulates the absorption of many molecules).
Green tea also contains L-theanine, an amino acid whose oral bioavailability reaches approximately 100% and whose human clinical literature is substantial. It is possible to extract the documented benefit of a plant without carrying along its pharmacokinetic limitations.
Oral glutathione
Glutathione is the body's primary intracellular antioxidant. Supplementing it directly via the oral route seems logical. It runs into a fundamental biochemical obstacle: gastrointestinal peptidases (digestive enzymes) break down the tripeptide glutathione (composed of three amino acids: glycine, cysteine, and glutamic acid) before it reaches the bloodstream (PubMed).
N-acetylcysteine (NAC), a direct precursor of glutathione, has superior oral bioavailability and a substantial human clinical literature. This is a rational substitution: when the direct target is inaccessible, the precursor with a documented pathway is selected.
Pterostilbene
Pterostilbene is a stilbenoid structurally similar to resveratrol but with two methoxy groups replacing the hydroxy groups. This structural difference confers higher oral bioavailability (approximately 80% in some animal models) (PubMed). Human pharmacokinetic data remain limited, however, and controlled clinical trials on primary health outcomes are still insufficient to justify formulation. A molecule to watch.
Insufficient human clinical evidence: the second filter
Astragaloside IV and TA-65
Astragaloside IV (the primary saponin from astragalus root) is presented in certain circles as a telomerase activator (the enzyme that lengthens telomeres, the protective ends of chromosomes). TA-65, its patented derivative, sells for several thousand euros per year.
The literature is unambiguous: no randomized clinical trial has demonstrated measurable benefit on longevity, telomere length, or any other primary health outcome in humans. Available studies are observational or trials without robust control groups (PubMed). The mechanistic hypothesis is interesting. The clinical proof is absent.
No randomized controlled clinical trial has demonstrated a benefit of astragaloside IV on a primary health outcome in humans to date.
Ergothioneine
Ergothioneine is a sulfur-containing amino acid found in mushrooms and certain microorganisms. It is actively absorbed via a specific transporter and accumulates in tissues with high oxidative demand. Epidemiological data show a correlation between plasma ergothioneine levels and reduced all-cause mortality (PubMed).
Correlation is not causation. These observational studies cannot distinguish whether ergothioneine actively protects or whether it is simply a marker of a diet rich in vegetables and mushrooms. Controlled intervention trials in humans are essentially absent. A molecule to monitor, not to formulate.
Apigenin
Apigenin is a flavone found in parsley, chamomile, and celery. Preclinical data on neuroprotection and circadian rhythm modulation (the 24-hour biological clock) are promising. In vitro studies also suggest activity on the CD38/NAD+ axis (a NAD+ degradation pathway, where NAD+ is the central coenzyme of cellular energy metabolism).
Controlled human clinical trials are virtually nonexistent. The biohacking community has preceded clinical validation by several years. This gap between preclinical enthusiasm and clinical proof is a pattern we know well.
Acetyl-L-carnitine
Acetyl-L-carnitine (ALCAR) is a form of carnitine that crosses the blood-brain barrier (the biological boundary protecting the brain) and shows neuroprotective effects in animal models. Meta-analyses of human clinical trials show heterogeneous results. A Cochrane review published in 2003 concluded that a possible benefit on cognition in patients with mild cognitive impairment was present, but highlighted the poor methodological quality of available studies (PubMed).
In healthy subjects without documented cognitive impairment, the evidence is insufficient. A signal exists in certain pathological populations. It does not justify a general-public formulation.
Coenzyme Q10 (ubiquinone and ubiquinol)
Coenzyme Q10 is a cofactor of the mitochondrial respiratory chain (the cellular system that converts nutrients into energy as ATP). It exists in two interconvertible forms: ubiquinone (oxidized) and ubiquinol (reduced, biologically active). Endogenous production declines from around age twenty, an argument routinely used by the industry to justify supplementation.
The most robust clinical trial is Q-SYMBIO: 420 patients with severe heart failure, 300 mg/day for two years, significant reduction in cardiovascular mortality (PubMed). A solid result. But this is a treatment trial for advanced cardiovascular disease, not a demonstration of longevity benefit.
The KiSel-10 study, frequently cited in the anti-aging context, combined CoQ10 (200 mg) and selenium (200 µg) in elderly Swedish subjects. Cardiovascular mortality was halved after twelve years of follow-up (PubMed). However, the study population lived in a region with selenium-poor soils, and selenium deficiency itself is associated with cardiovascular mortality. The effect of selenium alone cannot be separated from that of CoQ10. This confounder is systematically omitted by supplementation advocates.
In healthy adults, no randomized trial has measured a longevity benefit. Systematic reviews conclude that there is insufficient evidence to recommend CoQ10 as an anti-aging therapy (PubMed). A paradox from animal models further complicates the picture: organisms carrying partial CoQ10 biosynthesis deficiencies live longer, likely through mitohormesis (moderate mitochondrial stress triggering protective adaptive responses). If partial deficiency extends lifespan, the rationale for systematic supplementation becomes hard to defend.
One final note: the marketing distinction between ubiquinol ("the active form") and ubiquinone is fragile. The body converts both forms in both directions. Galenic formulation quality influences bioavailability more than the choice of chemical form (PubMed).
Spermidine
Spermidine is an endogenous polyamine (naturally produced by the body and the gut microbiome) involved in inducing autophagy (the cellular recycling program). Its preclinical record is among the strongest in the field of nutritional longevity. Adding spermidine to the drinking water of mice extended their lifespan and reduced age-related cardiovascular decline (PubMed). In 2024, a study published in Nature Cell Biology showed that spermidine is essential to the mechanism by which fasting triggers autophagy, via hypusination of the eIF5A protein (a post-translational modification conserved from yeast to humans) (PubMed). The Bruneck cohort (829 participants, 20-year follow-up) associates high dietary spermidine intake with a mortality reduction equivalent to 5.7 years of age (PubMed).
Despite these converging signals, human intervention trials do not follow. The SmartAge Phase IIb trial (100 participants, wheat germ extract, 12 months) did not meet its primary endpoint on memory (PubMed). Of the three published randomized trials, two show a positive signal in small samples and the third (the largest and longest) finds no significant effect.
The underlying problem is pharmacokinetic. A randomized controlled study showed that 15 mg/day of spermidine for five days does not raise plasma spermidine levels (PubMed). The molecule is converted to spermine in the gut before reaching systemic circulation. At 40 mg/day for 28 days, circulating polyamine levels barely change. The human body regulates polyamines homeostatically, rendering oral supplementation largely ineffective at tissue-level concentrations.
A recent signal warrants additional caution. A study from Tokyo University of Science published in the Journal of Biological Chemistry in 2025 showed that polyamines activate two distinct pathways depending on cellular context: in healthy cells, they stimulate eIF5A1, which promotes autophagy; in cancer cells, they increase production of eIF5A2, a related protein that facilitates tumor growth (PubMed). This does not prove that spermidine causes cancer in healthy subjects. It establishes that in a pre-existing tumoral context (including undiagnosed tumors), polyamines could fuel progression.
The POLYCAD trial (Aarhus, Denmark), testing 24 mg/day for 48 weeks in 187 coronary patients, is expected to deliver results in 2026. It is the first long-duration, high-dose trial. Its conclusions could alter this assessment.
Unfavorable benefit/risk ratio: the third filter
Beta-carotene
Beta-carotene is a precursor of vitamin A found in carrots, spinach, and many multivitamin supplements. Its reputation as a protective antioxidant seemed solid until the publication of two major clinical trials.
The ATBC trial (Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study), conducted in 29,000 Finnish smokers, showed an 18% increase in lung cancer incidence in the group supplemented with 20 mg/day of beta-carotene (PubMed). The CARET trial (Beta-Carotene and Retinol Efficacy Trial), conducted in 18,000 smokers and asbestos-exposed workers, confirmed this signal with a 28% increase in lung cancer risk, leading to early termination of the trial (PubMed).
High-dose vitamin A (retinol)
Vitamin A is essential. It is also one of the most hepatotoxic (liver-toxic) vitamins at excessive doses. The review by Penniston and Tanumihardjo published in the American Journal of Clinical Nutrition documents a narrow therapeutic window: intakes exceeding 10,000 IU/day of preformed retinol over the long term carry documented dose-dependent hepatotoxicity and teratogenic risk (toxic to fetal development) (PubMed).
Provitamin A (dietary beta-carotene) does not carry the same risk because conversion to active retinol is regulated by the body. Preformed retinol supplementation at common marketing doses, however, regularly exceeds this safety threshold.
High-dose vitamin E (alpha-tocopherol)
Vitamin E in its alpha-tocopherol form (the most common in supplements) long benefited from an assumed protective status. The meta-analysis by Miller et al., published in the Annals of Internal Medicine in 2005, ended this assumption. Drawing on 135,967 participants from 19 randomized clinical trials, it showed that doses of 400 IU/day or more of alpha-tocopherol were associated with a statistically significant increase in all-cause mortality (PubMed).
The suspected mechanism involves high-dose alpha-tocopherol interfering with other vitamin E isomers (notably gamma-tocopherol), reducing their plasma availability. This is an example of the complexity of interactions between forms of the same nutrient that simplified supplementation protocols overlook.
Alpha-lipoic acid
Alpha-lipoic acid (ALA) is an endogenous liposoluble (fat-soluble) antioxidant involved in mitochondrial metabolism. Its clinical profile is limited by multiple drug interactions: it potentiates the hypoglycemic effect of insulin and oral antidiabetic drugs, and can interfere with levothyroxine (a thyroid hormone treatment).
Cases of autoimmune insulin syndrome (a rare form of hypoglycemia linked to anti-insulin antibodies) have been reported in connection with ALA supplementation, primarily in Asian populations (PubMed). This signal, rare but severe, combined with the heterogeneity of clinical trial results on primary outcomes of interest, leads to its exclusion from a formula intended for an unselected audience.
Ashwagandha (Withania somnifera)
Ashwagandha is the best-selling adaptogen in the world. Randomized clinical trials confirm a significant reduction in serum cortisol and measurable decreases in anxiety scores (PubMed). Short-term anxiolytic efficacy is documented.
The problem lies elsewhere. Ashwagandha acts simultaneously on three neuroendocrine systems: it suppresses the hypothalamic-pituitary-adrenal (HPA) axis (the central stress response system), directly activates GABA-A receptors (the same receptors targeted by benzodiazepines) (PubMed), and modulates serotonergic 5-HT1A receptors through a mechanism shared with SSRI antidepressants.
This triple mechanism produces, in a subset of users on continuous intake, emotional blunting. Not merely a reduction in anxiety: a dampening of the entire emotional spectrum, including positive emotions. Published cases document measurable adrenal hypofunction after 10 weeks of supplementation, reversible upon discontinuation. Clinical trials reveal a telling finding: cortisol decreases significantly and reproducibly, but perceived stress reduction does not always follow (PubMed). The body produces less cortisol. The subject does not necessarily feel better.
No clinical trial has measured emotional blunting using validated instruments. The absence of measurement is not the absence of effect. For a precision formula intended for continuous daily use, the risk of chronic endocrine suppression is a signal we cannot ignore.
Rhodiola rosea
Rhodiola rosea is a Scandinavian and Siberian adaptogen with solid short-term clinical data. Randomized trials show sustained anti-fatigue effects over periods of 4 to 12 weeks (PubMed).
Two problems prevent its inclusion in a precision formula.
The first is the complete absence of data beyond 12 weeks. No study has measured the safety or efficacy of continuous long-term use. Traditional Siberian and Scandinavian usage was seasonal and situational, never daily year-round. Modern practitioners recommend cycling (typically 12 weeks on, 1 to 2 weeks off) (PubMed). This mode of administration is incompatible with a formula designed for regular daily intake.
The second is pharmacological. Rhodiola significantly inhibits monoamine oxidases A and B (MAO, the enzymes that degrade serotonin, dopamine, and norepinephrine) in vitro. This inhibition creates a potential for interactions with serotonergic antidepressants, opioids, and sympathomimetics. The lack of thorough human pharmacokinetic data makes it impossible to reliably model these interactions, even within an individualized health profile.
What science will illuminate next
Several molecules absent today are the subject of ongoing clinical trials. Fisetin is being studied in a randomized trial funded by the National Institute on Aging (NIA) on markers of cellular senescence in older adults. Ergothioneine is entering pilot intervention protocols. Apigenin is being tested in sleep trials.
If these trials produce data that meet the three selection criteria, the conclusions will evolve. The selection process is not a fixed list. It is a method of continuous evaluation.
The principle governing this inventory of exclusions is straightforward: a rigorous formula in which every bioactive has passed all three filters is preferable to an extended list of molecules half of which rest on a preclinical promise. The value of a formula is not measured by the length of its ingredient list. It is measured by the solidity of each of its choices, including its choices of exclusion.
Frequently asked questions
References
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