I came upon this article which sparked my interest in the association between inflammation as a potential driver of the general symptoms we associate with aging: pain, increased inflammatory markers, liver dysfunction, etc. Perhaps you can provide additional insight and opinion on therapeutics.
Some of the drugs used in the treatment of Crohns seem likely candidates for biohacking intervention, such as infliximab and vedolizumab which have specific effects on TNF-α. What do you think or what other paths of intervention do you think would be of interest in real clinical application?
Vinpocetine is a potent anti-inflammatory agent that inhibitsTNF-α-induced NF-κB activation and reduces pro-inflammatory mediators (TNF-α, IL-1β) by targeting the IKK complex, independent of its phosphodiesterase-1 (PDE1) inhibitory effects.
@Herm , have you tried it? Any pre and post testing on key inflammation markers?
Here is what I can dig up on it:
Vinpocetine (ethyl apovincaminate), a semi-synthetic derivative of the periwinkle alkaloid vincamine, is emerging as a potent anti-inflammatory agent beyond its traditional role as a vasodilator. The primary mechanism involves the selective inhibition of IκB kinase (IKK), which prevents the phosphorylation-dependent degradation of IκB and subsequent nuclear translocation of NF-κB.
I. Anti-Inflammatory Mechanisms and Efficacy
Current evidence suggests vinpocetine targets the NF-κB pathway independently of its known effects on phosphodiesterase (PDE) and ion channels.
RCT of 60 patients showed 30 mg IV/day for 14 days improved clinical outcomes and reduced lesion volume by dampening neuroinflammation Clinical Trial NCT02878772 (2016).
II. Longevity and Healthspan Implications
While often marketed for “brain health,” the translational evidence for lifespan extension is sparse.
Cognitive Decline: A meta-analysis of 6 RCTs (731 patients) suggests high efficacy in treating “degenerative senile cerebral dysfunction,” though modern Cochrane reviews remain skeptical regarding its use in advanced Alzheimer’s Vinpocetine Monograph (2002).
Translational Gap: Most “longevity” claims (e.g., increased resistance to hypoxia, improved mitochondrial function) rely on murine models. Direct human lifespan data is currently non-existent.
III. Risks, Side Effects, and Contraindications
Vinpocetine is generally well-tolerated at clinical doses (15–60 mg/day), but specific systemic risks exist.
Hematological Risks: There is at least one reported case of agranulocytosis (severe reduction in white blood cell count) Vinpocetine’s therapeutic uses (EBSCO).
Mechanistic (In vitro/Animal): High. The IKK inhibition pathway is well-characterized.
Clinical (Human): Moderate for acute neuroprotection (Stroke); Low/Inconclusive for long-term cognitive enhancement and general anti-inflammatory therapy.
Safety: Established for short-term use; Safety Data Absent for chronic, multi-year “longevity” protocols.
Knowledge Gap: We lack longitudinal human data verifying if systemic NF-κB inhibition via vinpocetine translates to reduced systemic “inflammaging” markers (e.g., CRP, IL-6) in healthy cohorts.
Summarizing the paper… infliximab, adalimumab, and etanercept all seem worth more investigation.
Reversing the Inflammatory Process—25 Years of Tumor Necrosis Factor-α Inhibitors
For 25 years, the clinical landscape of immune-mediated inflammatory diseases (IMIDs) has been defined by the rise of Tumor Necrosis Factor-alpha (TNF-α) inhibitors. Originally approved for Crohn’s disease in 1998, these agents—including infliximab, adalimumab, and etanercept—have transitioned from niche biologics to cornerstone therapies for rheumatoid arthritis, psoriatic arthritis, and spondyloarthritis. The “Big Idea” presented in this review is the recognition of TNF-α not merely as a localized inflammatory signal, but as a superordinate hierarchical hub that dictates systemic cellular homeostasis and organ-specific health.
The research underscores that chronic TNF-α elevation drives a “vicious cycle” by shifting the immune environment toward pathogenic TH17.1 cells , which are resistant to regulatory T cells and glucocorticoids. Beyond the joints and gut, this “inflammaging” cytokine suppresses essential liver enzymes (CYP3A4), promotes hepatocellular apoptosis, and accelerates cardiovascular pathologies like atherosclerosis and atherothrombotic disease. By neutralizing this single node, TNF-α inhibitors do more than mask symptoms; they reverse the molecular and cellular polarization of the immune system, restoring the balance between pro-inflammatory and anti-inflammatory cytokines.
For the longevity community, the implications are profound: blocking TNF-α may normalize organ function and protect against the systemic degradation typical of biological aging. While traditionally reserved for severe disease, the emerging data suggests that early intervention—the “window of opportunity”—can prevent irreversible structural damage and secondary comorbidities, effectively slowing the functional decline associated with chronic systemic inflammation.
Impact Score: The impact score of this journal is 3.0, evaluated against a typical high-end range of 0–60+ for top general science, therefore this is a Medium impact journal.
Part 2: Biohacker Analysis
Study Design Specifications
Type: Review of Clinical Trials and Observational Registries.
Subjects: Adult and pediatric human populations with RA, PsA, axSpA, and IBD.
Lifespan Analysis: While the provided text does not analyze mouse lifespan, it highlights that TNF-α inhibition reduces risk factors for mortality, such as major cardiovascular events and venous thromboembolism.
Mechanistic Deep Dive:
Vascular Health: Suppression of TNF-α reduces fibrinogen and endothelial dysfunction, predicting fewer future cardiovascular events.
Hepatic Rejuvenation: Chronic inflammation restricts CYP3A4 activity via transcriptional and epigenetic changes; TNF-α blockade reverses this, potentially lowering the “biological age” of hepatic drug metabolism.
T-Cell Polarization: Inhibitors reduce the number of glucocorticoid-resistant TH17.1 cells while increasing anti-inflammatory Treg cells that release IL-10 and TGF-β.
Novelty: The identification of TNF-α as a superordinate node that, when blocked, results in the “omission” of multiple downstream pro-inflammatory signaling pathways (IL-1, IL-6, IL-17).
Critical Limitations: Ruthless systemic risks include the reactivation of latent tuberculosis and hepatitis B. Methodologically, there is an absence of guidelines for treatment tapering, with relapse rates hitting 40-50% after discontinuation.
Part 3: Claims Hierarchy
Claim
Evidence Level
Verification Link
TNF-α inhibitors reduce risk of myocardial infarction in RA.
Human Equivalent Dose (HED): For Adalimumab, the standard adult dose is 40 mg every other week.
Pharmacokinetics: Adalimumab has the broadest therapeutic approval spectrum and established safety data in pediatric populations.
Safety & Toxicity Check: * Contraindications: NYHA class III/IV heart failure and active tuberculosis.
Interactions: May affect plasma levels of drugs metabolized by CYP3A4 by restoring enzyme activity.
Biomarker Verification Panel
Efficacy Markers: Reductions in hs-CRP , fibrinogen , and serum amyloid A.
Safety Monitoring: Periodic screening for latent infections and monitoring of ALT/AST for rare drug-induced hepatotoxicity.
Feasibility & ROI
Sourcing: Biologics are prescription-only. Biosimilars now offer approx. 13% cost reduction per treatment day in European markets.
Population Applicability: Highly effective in patients with high systemic inflammatory burdens; high risk in those with latent infections or history of sepsis.
Just out of curiosity… Here is the cost analysis for Infliximab, Adalimumab, and Etanercept.
But we need to dig deeper into the science and clinical evidence.
Executive Summary
Adalimumab has the most accessible US-based discount pricing due to the introduction of low-cost biosimilars (e.g., Yusimry) at Mark Cuban Cost Plus Drugs.
Etanercept remains prohibitively expensive in the US market with limited direct-to-consumer biosimilar options; however, Indian domestic pricing offers a ~97% reduction in cost.
Infliximab pricing is complicated by its administration method (IV infusion), which typically requires “buy-and-bill” through a clinic. Direct purchasing is rare for patients, but international sourcing of vials significantly undercuts US list prices.
Cost Analysis: One-Month Supply (Maintenance)
Prices are estimated based on a standard adult maintenance protocol (see “Dosing Basis” below). Currency conversion rate: ~84 INR to 1 USD.
Medication
US Discount Price (GoodRx / Cost Plus)
Indian Domestic Price (Grey Market Source)
Cost Differential
Adalimumab (Humira)
$527 – $619 / month(Source: Cost Plus Drugs)
~$140 – $190 / month(Source: Brands like Exemptia/Adfrar)
~3x Cheaper in India
Etanercept (Enbrel)
$8,000+ / month(Source: GoodRx avg. retail)
~$190 – $220 / month(Source: Brands like Intacept)
Monthly Total (Amortized):~$285 – $430 USD (equivalent of 2 vials).
Procurement Logistics & Risks
Cold Chain Requirement: All three medications are biologics requiring strict refrigeration (2°C to 8°C).
Risk: Sourcing from India involves high risk of temperature excursions during shipping (customs delays), which can denature the protein and render the drug ineffective or immunogenic.
Legality: Personal importation of biological drugs is technically restricted by the FDA, though enforcement varies for personal use quantities (3-month supply).
Prescription: US vendors (Cost Plus) require a valid US prescription. Indian vendors often ship without one or with an online consultation, but quality verification falls entirely on the buyer.
Recommendation: For Adalimumab, the US-based Cost Plus Drugs option (~$527) is the superior choice, balancing low cost with guaranteed cold-chain integrity and regulatory compliance. For Etanercept, the price gap is extreme, making international sourcing the only non-insurance viable option, provided cold-chain shipping can be verified.
How about Rupatadine for inhibiting TNf-a? A wildly available cheap medication for allergy.
Summary of Potential
Based on the framework of PMC10419406, Rupatadine’s potential lies in its ability to be a “pre-emptive strike” against the cytokine storm. While the biologics mentioned in the article are used to “mop up” TNF-$\alpha$ once it is in the blood, Rupatadine helps stop the production of TNF-$\alpha$ at the source (the mast cell/PAF level).
Conclusion: In the future, Rupatadine may be used more broadly not just for allergies, but as a low-cost, oral supplement to “cool down” the systemic inflammation in patients who are already on the high-level TNF-$\alpha$ inhibitors described in your article.
@RapAdmin I am taking 10 mg TID which I increase to 20 mg TID for a couple of days when I need to treat a gout flare. Long story, full disclosure below, but I experienced annoying side-effects from colchicine, and prednisone for acute attacks, and allopurinol and febuxostat for prevention.
My hsCRP is not detectable (BLOQ) on this regimen, and it was ~7 mg/dL but taken during an acute gout flare. My CBC shows no hematological effects. Been doing the complete regimen as outlined for 4 months with excellent results. n of one experiment. It may of course be a fluke.
For prevention of gout, I added berberine 500 mg TID for prevention, as berberine has potent inhibitory effects on xanthine oxidase, at least in animal trials.
I drink 32 fl oz alkaline water 1 - 2X each day (1/2 teaspoon potassium bicarbonate, 1/4 teaspoon sodium bicarbonate, 1/4 teaspoon MgCl2, and 1/4 teaspoon sodium chloride) to keep urine pH > 8.
Overall, I think for me the risk/benefits of vinpocetine/berberine are better than the alternatives. Should also mention I convinced my doctor that the “old drug” uricosuric probenecid was useful, so taking 500 mg twice a day.
I have not experienced any side effects, thus far anyway. No interactions with my Rapa regimen, 1 mg every month. I know that may seem like a low dose around here (!) but it is what I can tolerate avoiding aphthous ulcers