Looks like they are a neutraceuticals based company pushing a niche angle.
This review paper sponsored by Bioactor bv mentions both compounds:
I found no USPTO patent application to the 2011 reference, only a recent application about some type of analog molecule, perhaps bioavailability.
In their products they only talk about Hesperidin, in this product 65% (never mentioning Hesperetin levels or percentages):
“I’m waiting for the bioavailability issue to be addressed. As @Mac says, to duplicate the mouse doses with lifespan benefit (study) you’d have to take something on the order of 30g per day, so it seems unreasonable right now.”
I think @Mac was referring to the study on reversing arterial stiffness. However, even if the average weight of the mouse strain and grams of daily food intake that he gave are reasonable estimates (3 grams of food/day and 30 gram mouse), his calculation is way off because you have to apply an interspecies dosage scaling factor. So he arrived at a daily human dose of 35 grams for a 70 kg human. And in actuality, you’d want to take 35 and divide by 12.3. So 35÷12.3 = 2.85 grams. (There are different formulas, but 12.3 is a typical factor for mouse to human scaling). Also, in the arterial stiffness study it doesn’t look like they tried a lower dosage, so it’s unclear how much lower the dosage can go while still getting this benefit.
In the lifespan study, they adminstered hesperetin at 100 mg/kg. So if you take this, divide by 12.3, and multiply by 70 for a 70 kg person, you get about 569 milligrams per day for a 70 kg person. Now, as far as what the equivalent is with “hesperidin”, I don’t know yet. In other words, if one group of people took 500 mg of hesperitin with a meal, and a second group ate the same meal with 500 mg of hesperidin, how serum levels of hesperetin compare after digestion? Maybe the answer is in the literature.
In the study below, 8 weeks of hesperidin at 500 mg/day improved muscle mass and reduced fat in cyclists when compared to placebo. Some supplement labels suggest 500 mg one or twice daily. I may try 500 mg with food every 12 hours (plus a good probiotic to improve bioavailability as suggested by researchers). But I’m still reading and researching.
There are also a few studies with cyclists taking 500mg/day, the results seem quite impressive but I cannot find 500mg pills only 150mg combined with other substances
More info (and Examine.com has a lot of good detailed information on this topics) - it seems Hesperidin / hesperetin could possibly interact with rapamycin doses / bioavailability - something to dig deeper into if considering it:
That being said, in animal studies oral intake of hesperidin at a dose similar to that used in humans seems to be a very potent cardioprotection agent and is quite protective of the brain in response to various stressors; the protection is antioxidative in nature, but it seems to work through a currently not identified antioxidant responses from the genome. Aside from the protective effects (most notable in the heart and brain, but extend to every organ), hesperidin may be able to reduce a lack of appetite and have minor anti-allergic properties.
Orange peels can actually be used to get the supplemental dosage of hesperidin seen in the human studies, and hesperidin is known to interact with a variety of drug metabolizing enzymes so it should be approached cautiously if also using pharmaceuticals.
Another interesting flavanone, 7,8-Dihydroxyflavone has properties other than what I consider the main benefit which is increasing neurogenesis. They include estrogen suppression, endothelial cell protection, neuroprotection, and squamous cell cancer protection.
“Here we demonstrate that 7,8-DHF administered in drinking water significantly decreases the severity of pathologies in Mecp2 mutant mice, including improvements in life span, body mass, voluntary running wheel distance, hippocampal neuronal nuclei size, and breathing abnormalities”
Suggesting 7,8-dihydroxyflavone as a promising nutraceutical against CNS disorders.
Treatment with the flavonoid 7,8-Dihydroxyflavone: a promising strategy for a constellation of body and brain disorders
New paper:
Aging is a complex physiological process that can be accelerated by chemical (high blood glucose levels) or physical (solar exposure) factors. It is accompanied by the accumulation of altered molecules in the human body. The accumulation of oxidatively modified and glycated proteins is associated with inflammation and the progression of chronic diseases (aging). The use of antiglycating agents is one of the recent approaches in the preventive strategy of aging and natural compounds seem to be promising candidates. Our study focused on the anti-aging effect of the flavonoid hesperetin, its glycoside hesperidin and its carbohydrate moieties rutinose and rhamnose on young and physiologically aged normal human dermal fibroblasts (NHDFs). The anti-aging activity of the test compounds was evaluated by measuring matrix metalloproteinases (MMPs) and inflammatory interleukins by ELISA. The modulation of elastase, hyaluronidase, and collagenase activity by the tested substances was evaluated spectrophotometrically by tube tests. Rutinose and rhamnose inhibited the activity of pure elastase, hyaluronidase, and collagenase. Hesperidin and hesperetin inhibited elastase and hyaluronidase activity. In skin aging models, MMP-1 and MMP-2 levels were reduced after application of all tested substances. Collagen I production was increased after the application of rhamnose and rutinose.
Full paper (Open access):
Many years ago I used a bitter orange supplement to help with weight loss. Bitter orange was once a rage in the weight loss community. I don’t recall it actually being very effective for that. If it was, it would still be a big deal.
FWIW:
A quick look at the supplements available at Amazon shows two major forms of hesperidin supplements: methyl chalcone is a modified form of hesperidin that is often used in dietary supplements due to its enhanced bioavailability and Citrus aurantium, also known as bitter orange, which is believed to have potential weight loss and thermogenic effects.
So, if I decide to try it I will probably go for the methyl chalcone form because of its better bioavailability and I don’t need any weight loss or thermogenic effects. I am mainly interested in its possible anti-aging effects.
Renue By Science is planning to release a LIPO version of Hesperidin by Aug or Sep '23 : They already have LIPO Hesperidin in a mixed LIPO product with 150mg Hesperidin + 100mg CoQ10 + 65mg Tr-Resveratrol + 35mg Green Tea Extract. Based on past history their pure LIP0 Hesperidin will have roughly twice the dosage of the combo product (as is the case with their current 200mg CoQ10 or 125mg Resveratrol or 75 mg Green Tea Extra single item LIPO versions), but if you like those additional items as well the 4-in-1 combo is 50% cheaper than buying them individually.
Hesperidin is converted by the gut microflora into hesperetin.
After oral intake of hesperidin, it is able to be hydrolyzed and de-glycosylated by the gut microflora into its aglycone form hesperetin; this mainly occurs in the colon. Once this has occurred, the hesperetin is absorbed into systematic circulation by colonocytes via proton-coupled active transport and transcellular passive diffusion [77]. In addition, plasma hesperetin is further metabolized into other metabolites, including hesperetin glucuronide (H7G, hesperetin-7-O-β-D-glucuronide) and hesperetin sulfate (H7S, hesperetin-7-O-sulfate) in the liver (Figure 2G,H). Our recent studies showed that hesperetin and its metabolite H7S are both able to enhance CISD2 expression [75].
what is the best probiotics or enzyme?
https://www.sciencedirect.com/science/article/pii/S0022316622080713
Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperetin could act as a functional food or as a skincare product for fighting skin aging.
full paper
Thank you so very much. Searching on that I found it. I was adding three variaties (from peel, micronized, citrus bioflavanoids). Now found 100gram powder on amazon:
Akersunder VP/Vitamin P/Hesperidin Methyl chalcone Food Grade 100 Grams., 100.07 g (Pack of 1) : Amazon.co.uk: Health & Personal Care
Excellent article listing ways to activate CISD2 (e.g… weight loss surgery, exercise etc. and the effect of CISD2)
IJMS | Free Full-Text | Rejuvenation: Turning Back Time by Enhancing CISD2 (mdpi.com)
Thanks for the link.
4.3. Natural Compounds That Can Upregulate CISD2 Expression
Several naturally derived compounds have been identified to increase CISD2 gene expression, including hesperetin, curcumin, wild bitter melon (WBM) extract, α-eleostearic acid, egg shell membrane (ESM) powder, and hydrated ESM (Table 1 (B)). In addition to hesperetin, which will be discussed in Section 5, the other compounds mentioned above are briefly described below.
I’ll remember that next time I cook hard-boiled eggs. They can also be bought in capsule form.
an update on availability of this compound:
Yes, it is possible to purchase Hesperetin (the aglycone form) directly, though it is primarily sold as a research chemical rather than a consumer supplement.
Below are the top sources identified, categorized by Research Grade (pure chemical, strictly for lab use) and Consumer Grade (dietary supplements, mostly precursors).
These sources sell the pure aglycone powder. Warning: sold for “Research Use Only” (RUO)—not certified for human consumption (often lack food-grade heavy metal/solvent testing).
| Rank | Source | Product Format | Price (Approx.) | Price per 100mg |
|---|---|---|---|---|
| 1 | Cayman Chemical | Bulk Powder (≥98%) | $50.00 / 25g | $0.20 |
| 2 | Chem-Impex | Bulk Powder | $18.50 / 5g | $0.37 |
| 3 | Ambeed | Bulk Powder | $6.00 / 1g | $0.60 |
| 4 | TCI America | Crystal Powder (>97%) | $31.25 / 5g | $0.63 |
| 5 | Sigma-Aldrich | Analytical Standard | ~$78.00 / 5g | $1.56 |
| 6 | LKT Labs | Crystalline Powder | $37.80 / 1g | $3.78 |
| 7 | MedChemExpress | Reagent Grade | $66.00 / 10mg | $660.00* |
*Note: MedChemExpress and similar “MedChem” suppliers price for high-throughput screening libraries, hence the astronomical per-mg cost compared to bulk chemical suppliers.
These are food-grade and safe for consumption but are usually the precursor (Hesperidin) or a complex.
| Rank | Source | Product | Price (Approx.) | Price per 100mg |
|---|---|---|---|---|
| 8 | Quicksilver Scientific | “Immune Charge” (Zinc + Hesperetin) | $57.00 / 60 caps | N/A (Blend)* |
| 9 | Swanson | Hesperidin (Precursor) 500mg | $18.00 / 60 caps | $0.06 |
| 10 | Life Extension | “News Hesperidin” (Precursor) | $24.00 / 60 caps | $0.08 |
*Quicksilver is one of the few brands explicitly listing Hesperetin (aglycone) in a liposomal/complexed form, but it is part of a proprietary blend, making exact “per mg” pricing impossible to calculate.
Would you like me to find the specific solubility protocols (e.g., DMSO vs. Ethanol/Oil) used in the Cisd2 longevity papers to help you evaluate the formulation requirements for the pure compound?
Based on the Shen et al. (2022) longevity paper and supporting pharmaceutical literature, here are the specific protocols for solubility and administration.
The specific protocol used to achieve the life-extension results in the Shen et al. paper was surprisingly simple. They did not use a liquid solvent for the chronic administration; they used a dietary admixture.
If you purchase the pure powder (CAS: 520-33-2), you will find it is a hydrophobic white powder that clumps in water. Below are the solubility limits and practical formulation methods.
| Solvent/Vehicle | Solubility | Notes |
|---|---|---|
| Water | Insoluble | < 0.1 mg/mL. Do not attempt to mix with water/juice; it will float or settle. |
| DMSO | High (~30 mg/mL) | Lab Only. Used for cell cultures (in vitro). Toxic for chronic human consumption. |
| Ethanol (100%) | Low (~1 mg/mL) | Poor solubility. You would need excessive alcohol to dissolve a daily dose (490mg). |
| Fats/Oils | Moderate | Lipophilic, but requires an emulsifier (like Lecithin) to stay in solution. |
Since you cannot use DMSO (toxic) and Ethanol is inefficient, here are the three practical methods to mimic the bioavailability seen in advanced pharmaceutical studies.
Option A: The “Liposomal-Like” Emulsion (Best for Absorption)
Research shows that co-formulating Hesperetin with Phosphatidylcholine (PC) or TPGS increases bioavailability by 16–20 fold.
Option B: The “Piperine Boost”
Studies indicate that co-administering with Piperine (Black Pepper Extract) significantly inhibits the glucuronidation of Hesperetin, keeping it in the active aglycone form longer.
Option C: Dietary Admix (The Shen Method)
Hesperidin, nobiletin, and tangeretin are collectively responsible for the anti-neuroinflammatory capacity of tangerine peel (Citri reticulataepericarpium)
I was not sure what the difference was between hesperidin and diosmin. Most of the supplements on Amazon contain both. I asked ChatGPT 5 to evaluate a typical Amazon supplement containing both:
Query: What is the difference between hesperidin and diosmin? This is the label from a supplement from Amazon. What do you think the actual bioavailability is?
Hesperidin and diosmin are citrus-derived flavonoids widely used as venotonics, particularly in Europe, for the management of chronic venous insufficiency (CVI), varicose veins, spider veins, leg edema, cramps, and hemorrhoids. Hesperidin is a naturally occurring flavanone glycoside found in citrus peels and serves primarily as a supportive compound. Diosmin is a semi-synthetic flavone derived from hesperidin and is the principal active agent responsible for most clinical benefits.
The supplement shown (900 mg diosmin + 100 mg hesperidin) closely mirrors well-studied European formulations such as Daflon/MPFF, though it is not micronized and therefore not optimized for absorption. Nevertheless, reported user benefits—including reduced leg pain, improved circulation, fewer cramps, and hemorrhoid relief—are credible and consistent with established pharmacology. Micronized formulations or administration with food may further enhance effectiveness, but the product as labeled is pharmacologically reasonable and likely beneficial for venous symptoms.
Both are citrus flavonoids, primarily from orange peels (Citrus aurantium), and both are glycosylated flavones, meaning they are poorly absorbed until metabolized by gut bacteria.
Key point: Neither compound is active as-is. They must be deglycosylated by the gut microbiome before absorption.
| Feature | Hesperidin | Diosmin |
|---|---|---|
| Origin | Naturally abundant | Semi-synthetic derivative |
| Potency | Moderate | Higher |
| Vein tone effects | Mild–moderate | Strong |
| Lymphatic drainage | Mild | Strong |
| Anti-edema | Mild | Strong |
| Evidence base | Good | Excellent |
| Typical dose | 100–500 mg | 500–1,000 mg |
Diosmin is the workhorse for:
Hesperidin is included because it:
This 900 mg diosmin + 100 mg hesperidin ratio matches the European prescription product (e.g., Daflon® 500 / 1000).
This is where expectations need calibration.
| Compound | Estimated Oral Bioavailability |
|---|---|
| Hesperidin | <5% |
| Diosmin | ~3–7% |
Reasons:
However: Low bioavailability does not mean low effectiveness.
Because:
Plasma concentrations needed are very low
Effects are local + endothelial, not systemic
Metabolites accumulate in venous tissue
Repeated dosing improves steady-state levels
Conclusion:
This is not optimized, but it is pharmacologically meaningful.
Likely 5–10% functional uptake
Equivalent to roughly:
That sounds small — but that’s within therapeutic range seen in trials.
This aligns well with known mechanisms:
This is one of the strongest evidence-backed uses
Diosmin reduces:
Often works within 5–7 days
An 80% pain reduction is entirely plausible in responders.
If you wanted to optimize further:
Best options (ranked):
Micronized diosmin/hesperidin (MPFF)
→ 2–4× higher absorption
Take with a fat-containing meal
Pair with quercetin or rutin
Healthy gut microbiome (this matters more than people realize)
Hesperidin = support compound Diosmin = primary active agent This ratio matches proven European formulations
Bioavailability is low but sufficient
Reported benefits are credible and expected
Micronization would materially improve performanceHesperidin = precursor (cheap, variable, gut-dependent)
Hesperetin = active form (better absorbed, more reliable)
Hesperidin is cheap and widely available. Hesperetin is not.
There was an earlier thread here about hesperidin (which the gut converts to hesperitin). I started eating citrus peels, which are good sources of hesperidin. I was also chasing the effect of decreasing systolic BP.
Not for me. The citrus peels gave me morse code heart beats. Poking around shows that hesperidin can affect heart rhythm. Most of it is beneficial, but there is some negative (my experience) effect on heart rhythm.
These results suggest that hesperetin at close to relevant concentrations inhibits the IKs outward potassium current and thereby reduces repolarization reserve. This effect in certain specific situations may prolong the QT interval and consequently may enhance proarrhythmic risk.
This is a narrative review, not an experiment. It compiles roughly 193 references to argue that hesperidin — a flavonoid concentrated in citrus peels — is a promising multi-system nutraceutical with anti-inflammatory, antioxidant, cardiovascular, metabolic, and neuroprotective effects, largely mediated through Nrf2 activation, NF-κB suppression, AMPK/PPAR-γ signaling, and gut-microbiome interactions. The authors’ own central admission undercuts the enthusiasm: hesperidin’s oral bioavailability is dismal (quoted variously at ~20%, under 10%, and under 5%), and the human evidence is thin, short, and small. The paper reads as an optimistic catalog of mechanisms rather than a critical weighing of clinical value.
Eat the peel, not the juice. That is the practical thrust buried inside this sprawling review of hesperidin, the flavonoid that gives oranges, lemons, and bergamot much of their biochemical interest. The authors survey fifteen years of literature to make the case that this cheap, food-derived compound could sit at the intersection of cardiovascular, metabolic, and brain health — the trifecta longevity-minded readers care about.
The proposed biology is coherent and familiar. Hesperidin (and its more absorbable aglycone, hesperetin) appears to switch on the Nrf2 antioxidant program, dampen the NF-κB and NLRP3 inflammatory machinery, nudge AMPK and PPAR-γ toward better glucose handling, and feed gut bacteria that produce short-chain fatty acids. Gut microbes are central to the story twice over: they cleave hesperidin’s sugar groups to release the active form, and their metabolites (like 3-HPPA and hippuric acid) may carry the signal onward through a proposed gut-brain axis. The review leans heavily on this axis as a unifying theme linking metabolism, mood, neurodegeneration, and even cancer surveillance.
But the review keeps tripping over its own headline problem: almost none of this compound reaches your bloodstream intact. The authors concede bioavailability figures as low as 5 percent, blamed on poor water solubility and aggressive first-pass metabolism in the gut and liver. Their proposed fixes — nanoencapsulation, phytosomes, cyclodextrin complexes — are real research directions, but the authors themselves note these are costly and clinically unproven at scale.
The human evidence is where enthusiasm should cool. The clinical signal that survives scrutiny is modest: around 500 mg/day for six-plus weeks associates with improved vascular function and small blood-pressure reductions in hypertensive or diabetic patients. Several of the cited meta-analyses actually report null effects on blood glucose and lipids. The review does not resolve these contradictions; it presents supporting and null studies side by side without adjudicating.
The honest takeaway: hesperidin is a plausible, low-risk dietary flavonoid with a genuine but small cardiovascular signal, wrapped in a great deal of mechanistic speculation that human trials have not yet earned. [Confidence: High that the review is optimistic; Medium on the underlying cardiovascular signal]
The defensible, food-first takeaways are narrow. Whole citrus and zest deliver more hesperidin than processed juice, because much of the compound sits in the peel and membranes — a free dietary tweak with no downside.
The best-supported supplemental signal: roughly 500 mg/day for at least six weeks is associated with improved vascular function in hypertensive/diabetic patients, and the review cites systolic/diastolic BP reductions of about 5–10%. To size that: a 5–10% drop from a systolic of 140 mmHg is roughly 7–14 mmHg. If real, that magnitude is clinically meaningful (comparable to a low-dose antihypertensive), but the review’s own cited meta-analyses disagree on whether the effect is robust. [Confidence: Low-to-Medium]
For glucose and lipids, be skeptical: at least two cited meta-analyses (refs 149, 192) report no significant effect on blood glucose, lipid profile, or BP — directly contradicting the review’s metabolic enthusiasm. Treat metabolic claims as unproven. [Confidence: Medium]
Absorption practicalities the review supports: take with a fat-containing meal, and note that hesperetin (aglycone) forms reach peak plasma far faster (tmax ~0.6 h vs 7 h) and higher than hesperidin. If supplementing, hesperetin or enzymatically-modified forms are pharmacokinetically superior. Standard doses run 250–1,000 mg/day; GI upset (bloating, mild diarrhea) is the main reported effect above 1,000 mg/day. [Confidence: Medium]