I asked three LLMs about its role with mitochondrial potassium channels and it does seem to have an indirect effect, but I don’t myself see it as a good intervention.
Ouabain or also known as g-strophanthin, is a plant derived toxic substance that was traditionally used as an arrow poison in eastern Africa for both hunting and warfare. Ouabain is a cardiac glycoside and, in lower doses, can be used medically to treat hypotension and some arrhythmias.
Which is the case for many things, but this seems quite sensitive. Also it is skewing the metabolism rather than fixing anything. That has its merits, but also its limitations.
Based on the study “Autonomous AI Agents Discover Aging Interventions from Millions of Molecular Profiles” (DOI: 10.1101/2023.02.28.530532), the AI-driven platform identified over 500 interventions that significantly reduce biological age.
The specific compounds and genetic intervention highlighted as examples of potential longevity-improving agents are:
NF1 knockout (Neurofibromin 1 knockout, a genetic perturbation)
The study further experimentally validated ouabain in aged mice, demonstrating reduced frailty progression, decreased neuroinflammation, and improved cardiac function.
Fenofibrate is an oral medication primarily used to treat abnormal blood lipid levels, specifically high triglycerides and low high-density lipoprotein cholesterol (HDL-C), often in conjunction with diet and exercise.
Fenofibrate: Molecular Overview and Longevity Analysis
Fenofibrate is an oral medication primarily used to treat abnormal blood lipid levels, specifically high triglycerides and low high-density lipoprotein cholesterol (HDL-C). It is typically used in conjunction with diet and exercise.
Molecule Overview
Fenofibrate belongs to the fibrate class of medications. It is a prodrug, meaning it is metabolized in the body into its active form, fenofibric acid.
Mechanism of Action: Its primary mechanism is activating the Peroxisome Proliferator-Activated Receptor alpha (PPAR-alpha). PPAR-alpha is a nuclear receptor that regulates the expression of genes involved in lipid metabolism.
Key Effects on Lipids:
Increases the breakdown of fats (lipolysis) by activating lipoprotein lipase.
Reduces the production of triglyceride-rich particles.
Increases HDL-C (the “good” cholesterol).
Decreases Triglycerides (TG), Total Cholesterol, LDL-C (the “bad” cholesterol), and Apolipoprotein B (apo B).
FDA-Approved Indications:
Severe hypertriglyceridemia (very high TG levels).
Primary hypercholesterolemia or mixed dyslipidemia (high LDL-C and TG, or low HDL-C).
Scientific and Clinical Data on Health and Longevity
Cardiovascular Risk Reduction
Overall Impact: Large-scale trials, such as the FIELD and ACCORD studies, showed that while fenofibrate therapy did not result in a statistically significant reduction in the primary composite endpoint (non-fatal heart attack and coronary heart disease death) across the entire population, it does provide evidence for reducing the risk of heart disease and death in specific contexts.
Specific Subgroups: The most prominent benefits are seen in patients with high triglycerides and low HDL-C levels, often associated with Type 2 Diabetes and Metabolic Syndrome.
Fenofibrate demonstrates clear benefits in managing microvascular complications:
Diabetic Retinopathy: Clinical data from the FIELD and ACCORD-Eye trials found that fenofibrate significantly slowed the progression of damage to the retina.
Amputation Risk: The FIELD study reported that fenofibrate therapy significantly reduced the risk of below-ankle amputations in patients with Type 2 Diabetes.
The NF1 Gene: Longevity and Stress Resistance
The Neurofibromin 1 (NF1) gene acts as a negative regulator of the pro-growth Ras pathway.
Negative Impacts of NF1 Knockout (Loss of Function)
Loss of NF1 function leads to reduced life expectancy (typically by 8 to 15 years) due to:
Increased Cancer Risk: Formation of neurofibromas and aggressive malignancies like Malignant Peripheral Nerve Sheath Tumors (MPNSTs).
Cognitive Deficits: Learning disabilities and behavioral issues affecting 50-80% of patients.
Metabolic Dysfunction: Animal models show that systemic NF1 knockout leads to acute, lethal metabolic failure.
Potential Benefits of NF1 Overexpression
Studies in model organisms (specifically Drosophila) suggest that increasing NF1 activity may offer longevity benefits:
Extended Lifespan: Overexpressing NF1 has been shown to increase lifespan in fruit flies.
Stress Resistance: Improved resistance to oxidative and heat stress, likely through better regulation of mitochondrial function and respiration.
KMO is an enzyme in the kynurenine pathway of tryptophan metabolism. It converts L-kynurenine (KYN) to 3-hydroxykynurenine (3-HK), a precursor to neurotoxic metabolites.
Mechanistic Rationale for Longevity
Reduction of Neurotoxicity: Inhibiting KMO decreases levels of 3-HK and quinolinic acid (QUIN), which are redox-active and excitotoxic.
Increased Neuroprotection: Inhibition shunts KYN toward kynurenic acid (KYNA), which is generally considered neuroprotective.
Lifespan Extension in Invertebrates: Modulating this pathway has extended lifespan in C. elegans by approximately 30%.
Fenofibrate: Excellent for metabolic health and microvascular protection in diabetics; cardiovascular benefits are subgroup-specific.
NF1 Overexpression: Promising in invertebrate models for stress resistance, but human application is currently limited to treating deficiency (Neurofibromatosis type 1).
KMO Inhibitors: A high-interest area in geroscience for reducing “inflammaging” and neurodegeneration, though still largely in the preclinical stage.
As someone with slightly elevated triglycerides, that info on fenofibrate is really interesting. Are any of you anti-aging hackers on fenofibrate? If so, how is it going?