Autonomous AI Agents Discover Aging Interventions from Millions of Molecular Profiles (Preprint 22 Nov)

#1

https://www.biorxiv.org/content/10.1101/2023.02.28.530532v4.full

Seemed interesting and I would like to have seen their full list of interventions. They picked one “ouabain” and I asked chatGPT about it.

Toxicity

  • At higher doses it is quite toxic:
  • Can cause arrhythmias, nausea, neurological symptoms, and potentially cardiac arrest.
  • It’s one of the classic “digitalis-like” poisons affecting heart rhythm.
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#2

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.

#3

Literally, dose makes the poison…

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.

#4

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.

#5

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:

  • Ouabain
  • KMO inhibitor (Kynurenine 3-monooxygenase inhibitor)
  • Fenofibrate
  • 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.

#6

Details on these potential interventions:

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.

:pill: Molecule Overview: Fenofibrate

Fenofibrate belongs to the fibrate class of medications. It is actually a prodrug, meaning it’s metabolized in the body into its active form, fenofibric acid.

  • Mechanism of Action: Its primary mechanism is activating the Peroxisome Proliferator-Activated Receptor alpha ($\text{PPAR}\alpha$) . $\text{PPAR}\alpha$ is a nuclear receptor that regulates the expression of genes involved in lipid metabolism.
  • Key Effects on Lipids:
    • Increases the breakdown of fats ($\text{lipolysis}$) by activating lipoprotein lipase.
    • Reduces the production of triglyceride-rich particles.
    • Increases $\text{HDL-C}$ (the “good” cholesterol).
    • Decreases $\text{Triglycerides}$ ($\text{TG}$), $\text{Total Cholesterol}$, $\text{LDL-C}$ (the “bad” cholesterol), and $\text{Apolipoprotein B}$ ($\text{apo B}$).

Fenofibrate is FDA-approved for the management of:

  • Severe hypertriglyceridemia (very high $\text{TG}$ levels).
  • Primary hypercholesterolemia or mixed dyslipidemia (high $\text{LDL-C}$ and $\text{TG}$, or low $\text{HDL-C}$).

:microscope: Scientific and Clinical Data on Health & Longevity Benefits

While fenofibrate is highly effective at improving a patient’s lipid profile, the evidence regarding its direct impact on overall longevity and major cardiovascular events is more nuanced, though significant benefits exist for specific patient populations.

Cardiovascular Risk Reduction

  • Overall Impact: Large-scale trials, such as the FIELD and ACCORD studies, have shown that while fenofibrate therapy did not result in a statistically significant reduction in the primary composite endpoint (like non-fatal heart attack and coronary heart disease death) across the entire population studied, it does provide evidence for reducing the risk of heart disease and death.
  • Specific Subgroups: The most prominent benefits for cardiovascular risk reduction are seen in patients with a specific type of dyslipidemia, often associated with Type 2 Diabetes and Metabolic Syndrome:
    • Patients with high triglycerides and low $\text{HDL-C}$ levels have shown a significant reduction in cardiovascular events when treated with fenofibrate, especially when added to statin therapy (ACCORD Lipid Trial subgroup analysis).

Diabetic Complications

Fenofibrate has demonstrated clear benefits in managing microvascular complications of Type 2 Diabetes:

  • Diabetic Retinopathy: Clinical data from the FIELD and ACCORD-Eye trials found that fenofibrate significantly slowed the progression of diabetic retinopathy (damage to the retina) and reduced the need for laser treatment.
  • Amputation Risk: The FIELD study reported that fenofibrate therapy significantly reduced the risk of below-ankle amputations in patients with Type 2 Diabetes, independent of its lipid-lowering effects.

Non-Lipid-Related Potential Benefits

Research suggests fenofibrate’s action via $\text{PPAR}\alpha$ provides other protective effects:

  • Anti-inflammatory Effects: Fenofibrate exhibits a robust anti-inflammatory effect by activating $\text{PPAR}\alpha$, which helps suppress inflammatory pathways. This has been noted to reduce markers of inflammation, such as $\text{C-reactive protein}$ ($\text{CRP}$), particularly in high-risk patients.
  • Non-Alcoholic Fatty Liver Disease (NAFLD): Fenofibrate is one of the most effective medicines in reducing serum triglyceride levels in people with $\text{NAFLD}$ (now often called $\text{MASLD}$). Experimental evidence and small clinical studies suggest a protective role against liver steatosis (fatty liver) due to its lipid-lowering, anti-inflammatory, and anti-oxidant actions in the liver.
  • Gout: Fenofibrate has an off-label use as an added therapy for high blood uric acid levels in people with gout, as it can enhance uric acid excretion.

In summary, fenofibrate’s primary role is in lipid management, but clinical trials support its use for reducing the risk of specific diabetic complications (retinopathy, amputation) and providing cardiovascular benefits in patients with combined high $\text{TG}$ and low $\text{HDL-C}$.

The NF1 knockout

Scientific and Clinical Data on Health and Longevity

The NF1 knockout, or loss of neurofibromin function, is strongly associated with significant negative impacts on health and longevity, rather than benefits.

:chart_with_downwards_trend: Negative Health and Longevity Impacts

NF1 patients exhibit a reduced life expectancy, typically by 8 to 15 years, compared to the general population. The primary causes of this reduction and associated morbidity are:

  • Increased Cancer Risk: NF1 is a tumor predisposition syndrome. Loss of NF1 function is the direct cause of:
    • Benign Tumors: Formation of multiple cutaneous neurofibromas (cNF) and plexiform neurofibromas (pNF), which can cause disfigurement, pain, and loss of function.
    • Malignancies: Increased risk for aggressive cancers, notably Malignant Peripheral Nerve Sheath Tumors (MPNSTs) and various gliomas (brain tumors). Malignancy is a leading cause of mortality in NF1 patients.
  • Cognitive and Neurological Deficits: Approximately 50-80% of individuals with NF1 experience cognitive impairments, learning disabilities, and behavioral issues (e.g., ADHD, autism spectrum disorder symptoms). Neurofibromin is highly expressed in the nervous system and its loss of function impacts neuronal signaling, dopamine levels, and circadian rhythms, leading to:
    • Impaired learning and memory.
    • Sleep fragmentation and disruption of deep sleep.
  • Cardiovascular Issues: There is an increased prevalence of vascular problems, including hypertension, arterial stenosis, and aneurysms, particularly in younger NF1 patients.
  • Metabolic Dysfunction (Animal Data): In adult mouse models, systemic NF1 knockout (complete loss in all cells) leads to an acute, lethal phenotype characterized by severe metabolic dysfunction and significantly decreased survival (days). This suggests NF1 is essential for adult metabolic function. Drosophila models also show a shortened lifespan and altered metabolic rate due to Nf1 loss.

The research exploring the over-expression of the Neurofibromin 1 (NF1) gene is primarily focused on animal modelsand suggests potential benefits related to longevity and stress resistance, which aligns with its normal function as a negative regulator of the pro-growth Ras pathway.

Here is a summary of the scientific data:

:microscope: Longevity and Stress Resistance in Model Organisms

The most compelling data for a direct longevity benefit comes from studies in the fruit fly, Drosophila melanogaster:

  • Extended Lifespan: In Drosophila models, overexpressing the NF1 gene has been shown to increase the organism’s lifespan compared to wild-type flies.
  • Increased Stress Resistance: Flies with NF1 overexpression also exhibited improved resistance to environmental stressors, specifically:
    • Oxidative Stress: They showed a significant reduction in reactive oxygen species (ROS) production and increased resistance to oxidative stress.
    • Heat Stress: They displayed enhanced resistance to heat stress.
  • Mechanism: These longevity and stress-resistance effects are associated with the proposed role of neurofibromin in regulating mitochondrial function and respiration , which are key factors in aging and cellular health.Neurofibromin regulates mitochondrial respiration and subsequent ROS production via the cAMP pathway.

:brain: Potential Cognitive/Neurological Benefits

Neurofibromin’s function as a Ras-GTPase-activating protein (GAP) is critical for properly regulating the Ras/MAPK pathway in the central nervous system, which is essential for learning and memory.

  • Normalizing Ras Activity: Overexpressing the NF1 gene’s functional domain (GTPase-activating protein-related domain, GRD ) is sufficient to normalize hyperactive Ras levels in NF1-deficient cells.
  • Implication for Cognition: Since the learning and memory deficits seen in NF1 heterozygous mouse models are caused by this Ras hyperactivation, restoring or increasing neurofibromin function could theoretically boost synaptic plasticity and cognitive function by tightly controlling the duration and amplitude of Ras signaling. This is the rationale behind current NF1 therapies.

:warning: Caveats and Clinical Reality

It is crucial to note that while the Drosophila data is promising, there are currently no clinical trials or mainstream therapies investigating the targeted over-expression of the NF1 gene in healthy humans for the sole purpose of longevity.

  • Clinical Focus: Current human genetic and clinical research on NF1 is solely focused on gene replacement/restoration therapy to treat the Neurofibromatosis type 1 disease, not to enhance healthy longevity.
  • Complex Regulation: The Ras pathway is fundamental to all cellular processes, including cell growth, differentiation, and apoptosis. While moderate and transient activation is essential, persistent hyperactivation(as seen in NF1 loss) causes cancer. Conversely, excessive suppression due to massive overexpression could potentially lead to unforeseen negative side effects, though this has not been widely reported or studied in healthy mammalian models in a longevity context.

In conclusion, the most direct evidence comes from invertebrate models where NF1 overexpression extends lifespan by improving mitochondrial function and stress resistance. In the context of the Ras pathway, increasing NF1 serves as a potent negative regulator , which is viewed as a health benefit, particularly for preventing tumor formation and cognitive deficits linked to Ras hyperactivation.

Kynurenine 3-monooxygenase inhibitor

1. What KMO is, and what KMO inhibitors do

Kynurenine 3-monooxygenase (KMO) is a FAD-dependent enzyme in the kynurenine pathway of tryptophan metabolism. It sits at a key branchpoint, converting L-kynurenine (KYN) to 3-hydroxykynurenine (3-HK). 3-HK is further metabolized to 3-hydroxyanthranilic acid (3-HAA) and quinolinic acid (QUIN), which are redox-active and excitotoxic metabolites, respectively. In contrast, when KMO is inhibited, KYN is shunted toward kynurenic acid (KYNA), a neuroactive metabolite that is an antagonist at NMDA and α7-nicotinic receptors and generally considered neuroprotective but potentially cognitively blunting at higher levels. oai_citation:0‡PMC

Key points mechanistically:

  • Under inflammation/aging, KMO expression and activity increase in microglia and macrophages, driving higher 3-HK/QUIN and oxidative stress, mitochondrial damage, and excitotoxicity. oai_citation:1‡PMC
  • KMO inhibition decreases 3-HK/QUIN, increases KYNA, and can alter NAD⁺ biosynthesis because QUIN is a precursor for de novo NAD⁺ production. oai_citation:2‡PMC

Representative small-molecule KMO inhibitors:

  • Ro 61-8048 – classic, brain-penetrant KMO inhibitor used widely in preclinical models. oai_citation:3‡tocris.com
  • JM6 – an orally active prodrug that inhibits peripheral KMO and indirectly raises brain KYNA. oai_citation:4‡PMC
  • Newer, more drug-like scaffolds and brain-penetrant inhibitors are being developed (e.g., the Kynos Therapeutics program KNS366). oai_citation:5‡Cell

No KMO inhibitor is currently an approved drug; the field is preclinical to very early clinical.

2. Mechanistic rationale for health and longevity

The KMO branch of the kynurenine pathway is attractive for longevity for several interconnected reasons:

  1. Neurotoxicity and neurodegeneration
    3-HK and QUIN generate reactive oxygen species and promote excitotoxic neuronal death; KYNA is neuroprotective in many models. In aging and neurodegenerative disease, the balance shifts toward 3-HK/QUIN. oai_citation:6‡PMC

  2. Inflammation and organ injury
    KMO is upregulated by inflammatory cytokines (e.g., IFN-γ) and is implicated in acute pancreatitis, sepsis, and multiple organ dysfunction, where higher 3-HK relates to worse outcomes. oai_citation:7‡MDPI

  3. Aging biology / frailty
    Multiple human cohorts link high KYN, high KYN/TRP ratio, and high downstream metabolites (including 3-HK) with frailty, disability, and mortality in older adults. oai_citation:8‡ScienceDirect

  4. Geroscience angle: modulating the kynurenine pathway extends lifespan in invertebrates
    Reducing flux through various KP enzymes (TDO, KYNU, HAAO) extends lifespan and delays functional decline in C. elegans, with ~30% lifespan extension reported for haao-1 knockdown and similar effects for tdo-2 / kynu-1 downregulation. oai_citation:9‡Nature
    This demonstrates that some dampening of KP activity can be pro-longevity, even though KMO itself has not yet been directly tied to lifespan extension in wild-type mammals.

The logical but unproven longevity hypothesis is that partial, well-timed KMO inhibition might:

  • Reduce chronic neuroinflammation and excitotoxicity
  • Mitigate inflammaging-driven organ damage
  • Possibly improve neuromuscular aging by lowering toxic KP metabolites

All of that is still speculative at the human lifespan level.

Full analysis here: ChatGPT - KMO inhibitor overview