Hesperetin promotes longevity and delays aging via activation of Cisd2

#21

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.

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#22

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

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#23

New paper:

Hesperidin, Hesperetin, Rutinose, and Rhamnose Act as Skin Anti-Aging Agents

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):

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#24

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.

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#25

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.

#26

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-ÎČ-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

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#27

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice

Conclusions

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

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#28

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

#29

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)

#30

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.

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#31

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.

Important Distinction for Longevity Research

  • Hesperetin (The Target): This is the specific Cisd2 activator identified in recent longevity research (e.g., Shen et al.). It is the aglycone (sugar-free) form.
  • Hesperidin (The Precursor): This is the common “Citrus Bioflavonoid” found in most supplements. It is a glycoside that your gut bacteria must hydrolyze into Hesperetin. Note: Conversion rates vary significantly between individuals (bioavailability issue), which is why researchers prefer direct Hesperetin.

Top Sources for Hesperetin (Cisd2 Activator)

Below are the top sources identified, categorized by Research Grade (pure chemical, strictly for lab use) and Consumer Grade (dietary supplements, mostly precursors).

Category A: Research Grade (Pure Hesperetin, CAS: 520-33-2)

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.

Category B: Consumer Grade (Formulations & Precursors)

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.

Summary of Findings

  • Best Value for Research: Cayman Chemical provides the most aggressive pricing for high-purity Hesperetin at ~$0.20 per 100mg (buying 25g).
  • Best for Consumption: Quicksilver Scientific appears to be the only reputable consumer brand currently attempting to deliver Hesperetin (aglycone) directly, likely utilizing delivery systems to bypass the gut hydrolysis requirement.
  • The “Hesperidin” Trap: Be cautious of supplements labeled “Hesperidin Methyl Chalcone” or “Citrus Bioflavonoids” if your specific goal is Cisd2 activation via the Shen et al. protocol. While they metabolize into Hesperetin, the pharmacokinetics are different.

Next Step

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?

Skin in the Game: Citrus Flavonoid Hesperetin Reverses Skin Aging via CISD2 Activation
#32

Protocols for Hesperetin Formulation (Cisd2 Activation)

Based on the Shen et al. (2022) longevity paper and supporting pharmaceutical literature, here are the specific protocols for solubility and administration.

1. The “Shen Protocol” (Mouse Longevity Study)

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.

  • Method: Dietary Administration (Admix).
  • Vehicle: Standard mouse chow (mixed directly into the food pellets).
  • Dosage Used: 100 mg/kg/day (mouse).
  • Human Equivalent Dose (HED): The paper explicitly calculates this as ~491 mg per day for a 60kg human (approx. 8 mg/kg).
  • Why this matters: This confirms that for longevity purposes, you do not necessarily need to dissolve the compound in a harsh solvent like DMSO if you are taking it chronically. However, bioavailability remains the primary bottleneck, and simply eating the powder may result in poor absorption.

2. Solubility & Formulation Guide

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.

3. Actionable Formulation Strategies (Biohacking Context)

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.

  • Ingredients: Pure Hesperetin Powder + Sunflower Lecithin (source of PC) + Olive Oil.
  • Protocol:
  1. Mix 500mg Hesperetin with ~5g liquid Sunflower Lecithin.
  2. Add 1 tablespoon of olive oil/MCT oil.
  3. Critical Step: Use a small ultrasonic cleaner (or vigorous blending) to disperse the powder into the lipids.
  4. Result: A thick slurry where the hesperetin is encapsulated by lipids, bypassing the gut’s water barrier.

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.

  • Protocol: Take the Hesperetin (mixed in yogurt or fat) alongside 10-20mg of Piperine (Bioperine).

Option C: Dietary Admix (The Shen Method)

  • Protocol: Mix the pure powder into a high-fat carrier (yogurt, nut butter, or olive oil) and consume immediately.
  • Note: The fat is necessary to trigger bile release, which aids in the absorption of hydrophobic compounds.

Summary of Dosage for Cisd2 Activation

  • Target Daily Dose: ~500 mg (Aglycone form).
  • Timing: Split into 2 doses of 250mg (AM/PM) due to the short half-life (~2-4 hours) of flavonoids.
  • Cofactor: Always take with a fat source or Lecithin.
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Skin in the Game: Citrus Flavonoid Hesperetin Reverses Skin Aging via CISD2 Activation
#33

Hesperidin, nobiletin, and tangeretin are collectively responsible for the anti-neuroinflammatory capacity of tangerine peel (Citri reticulataepericarpium)

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#34

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.

1. What are hesperidin and diosmin?

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.

Hesperidin

  • Chemical class: Flavanone glycoside
  • Natural form found in citrus peel
  • Sugar moiety: rutinose
  • Main circulating active metabolite: hesperetin

Diosmin

  • Chemical class: Flavone glycoside
  • Semi-synthetic: usually derived from hesperidin via dehydrogenation
  • Sugar moiety: rhamnose
  • Active metabolite: diosmetin

:pushpin: Key point: Neither compound is active as-is. They must be deglycosylated by the gut microbiome before absorption.

2. Key differences (mechanistically)

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:

  • Chronic venous insufficiency (CVI)
  • Varicose veins
  • Hemorrhoids
  • Leg edema and cramps

Hesperidin is included because it:

  • Improves diosmin’s pharmacodynamics
  • Reduces capillary fragility
  • Adds anti-inflammatory and antioxidant support

This 900 mg diosmin + 100 mg hesperidin ratio matches the European prescription product (e.g., DaflonÂź 500 / 1000).

3. What is the actual bioavailability?

This is where expectations need calibration.

Raw oral bioavailability (honest numbers)

Compound Estimated Oral Bioavailability
Hesperidin <5%
Diosmin ~3–7%

Reasons:

  • Poor water solubility
  • Large molecular size
  • Dependence on gut bacterial enzymes
  • Variable microbiome conversion

:pushpin: However: Low bioavailability does not mean low effectiveness.

Why?

Because:

  • Plasma concentrations needed are very low

  • Effects are local + endothelial, not systemic

  • Metabolites accumulate in venous tissue

  • Repeated dosing improves steady-state levels

4. Does this Amazon product look legitimate?

Label analysis (your image)

  • 900 mg diosmin + 100 mg hesperidin
  • Capsule form (not micronized)
  • No bioavailability enhancers
  • No micronization claim
  • No phospholipid complex

:arrow_right: Conclusion:
This is not optimized, but it is pharmacologically meaningful.

Expected real-world absorption

  • Likely 5–10% functional uptake

  • Equivalent to roughly:

    • ~45–90 mg absorbed diosmin
    • ~5–10 mg absorbed hesperidin

That sounds small — but that’s within therapeutic range seen in trials.

5. Why do users report dramatic benefits?

This aligns well with known mechanisms:

Spider veins / varicose veins

  • ↑ Venous tone (↓ venous capacitance)
  • ↓ capillary permeability
  • ↓ inflammatory cytokines
    → Visible improvement over weeks

Leg cramps & night pain

  • Improved venous return
  • Reduced tissue hypoxia
  • Reduced nocturnal edema
    → Very common benefit

Hemorrhoids

  • This is one of the strongest evidence-backed uses

  • Diosmin reduces:

    • Bleeding
    • Pain
    • Swelling

  • Often works within 5–7 days

:pushpin: An 80% pain reduction is entirely plausible in responders.

6. What would improve bioavailability?

If you wanted to optimize further:

Best options (ranked):

  1. Micronized diosmin/hesperidin (MPFF)
    → 2–4× higher absorption

  2. Take with a fat-containing meal

  3. Pair with quercetin or rutin

  4. Healthy gut microbiome (this matters more than people realize)

Bottom line (engineering-style summary)

  • :heavy_check_mark: Hesperidin = support compound
  • :heavy_check_mark: Diosmin = primary active agent
  • :heavy_check_mark: This ratio matches proven European formulations
  • :x: Bioavailability is low but sufficient
  • :heavy_check_mark: Reported benefits are credible and expected
  • :wrench: Micronization would materially improve performance

Hesperidin = precursor (cheap, variable, gut-dependent)
Hesperetin = active form (better absorbed, more reliable)

Hesperidin is cheap and widely available. Hesperetin is not.

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#35

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.

Cellular electrophysiological effects of the citrus flavonoid hesperetin in dog and rabbit cardiac ventricular preparations | Scientific Reports.

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.

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