BioAge Presentation (Longevity Summit, 2025): NLRP3, Apelin Targets

[RapAdmin]

Here are some of the slides from the BioAge presentation at the Longevity Summit in December last year. BioAge raised over $200 Million in their IPO a little over a year ago.

There are a number of companies working on clinical trials for NLRP3 inhibitors (and these are expected to be important longevity drugs in the future if they pass phase 3 clinical trials). Another company working in this area is discussed here: The Immuno-Neuro Dialogue: A 5-Point Playbook for Rewiring the Aging Brain - #3 by RapAdmin

Note: You can click on any image below to make it larger and then you can move through the entire presentation with just your arrow keys.

[RapAdmin]

BioAge Announces Additional Positive Interim Phase 1 Data for BGE-102, a Novel Brain-Penetrant NLRP3 Inhibitor, Demonstrating Potential for Best-in-Class hsCRP Reduction in Participants with Elevated Cardiovascular Risk

January 12, 2026

First BGE-102 MAD cohort completed in obese individuals with elevated hsCRP receiving 120 mg QD; demonstrated rapid and profound reduction in inflammatory markers

BGE-102 achieved 86% reduction in hsCRP at Day 14, with 93% of participants reaching normalized levels (<2 mg/L)

BGE-102 demonstrated significant reductions in IL-6, a key driver of systemic inflammation and cardiovascular risk, and fibrinogen, an independent predictor of cardiovascular events

BGE-102 was well tolerated with a favorable safety profile

Patent issued covering additional composition of matter and novel NLRP3 binding site

Full Phase 1 data, including additional MAD cohorts in obese participants with elevated hsCRP, anticipated 1H 2026; Phase 2a study on track to initiate in 1H 2026

EMERYVILLE, Calif., Jan. 12, 2026 (GLOBE NEWSWIRE) – BioAge Labs, Inc. (Nasdaq: BIOA) (“BioAge”), a clinical-stage biopharmaceutical company developing therapeutic product candidates for metabolic diseases by targeting the biology of human aging, today announced additional positive interim data from the ongoing Phase 1 clinical trial evaluating BGE-102, a potent, structurally novel, orally available, brain-penetrant small molecule NLRP3 inhibitor being developed for the treatment of patients with cardiovascular risk factors.

In a multiple ascending dose (MAD) cohort of participants with obesity (BMI 32–42) and elevated baseline inflammation (hsCRP >3 mg/L), BGE-102 120 mg once daily achieved an 86% median reduction in high-sensitivity C-reactive protein (hsCRP) at Day 14. Notably, 93% of BGE-102-dosed participants (13 of 14) achieved hsCRP levels below 2 mg/L—the clinically recognized threshold for reduced cardiovascular risk.

These findings build on positive interim data announced in December 2025 from SAD and initial MAD cohorts, which demonstrated that BGE-102 was well tolerated, achieved dose-proportional pharmacokinetics supporting once-daily dosing, and produced 90-98% suppression of IL-1β at Day 14 trough. Those data also confirmed high brain penetration, with cerebrospinal fluid (CSF) concentrations exceeding the IC90 at doses of 60 mg and above.

“We are very encouraged by these results, which support the potential for BGE-102 to deliver injectable-like inflammation reduction in an oral therapy designed for primary care, the clinical setting where most cardiovascular risk is managed and where oral medicines are preferred by patients and physicians,” said Kristen Fortney, PhD, CEO and co-founder of BioAge. “Chronic inflammation is now recognized as a major driver of cardiovascular disease—on par with cholesterol—yet it remains far less commonly treated. An 86% reduction in hsCRP, with 93% of participants reaching levels associated with reduced cardiovascular risk, positions BGE-102 as a potential best-in-class oral therapy to directly address inflammation. These findings support our plans to advance BGE-102 into a Phase 2a study in the first half of this year.”

Key findings from the MAD cohort in patients with obesity and elevated hsCRP

Rapid and profound hsCRP reduction

• BGE-102 achieved 83% median reduction in hsCRP (from a median baseline of 4.85 mg/L) at Day 7 and 86% at Day 14
• 93% of participants (13/14) on BGE-102 achieved hsCRP <2 mg/L at Day 14; 71% (10/14) reached ≤1 mg/L
• Rapid onset of effect: 86% of BGE-102-dosed participants (12/14) achieved hsCRP levels <2 mg/L at Day 7; 71% (10/14) reached ≤1 mg/L
• hsCRP is the most widely used marker of inflammatory cardiovascular risk; levels below 2 mg/L are associated with reduced risk of cardiovascular events

Significant IL-6 reduction

• BGE-102 achieved a 44% median reduction in serum IL-6 at Day 14
• CSF IL-6 decreased in the two participants with elevated baseline levels, consistent with BGE-102’s high brain penetration
• IL-6 is a key upstream driver of hsCRP production and a validated marker of cardiovascular risk

Significant fibrinogen reduction

• BGE-102 achieved a 30% reduction in fibrinogen at Day 14
• Elevated fibrinogen has been shown to be an independent predictor of cardiovascular events and thrombotic risk

Potent IL-1β suppression, consistent with strong target engagement

• In the ex vivo whole blood stimulation assay, BGE-102 achieved 93% suppression of IL-1β at trough (Day 14, pre-dose)
• IL-1β is directly downstream of NLRP3 and drives production of IL-6 and CRP, key markers of cardiovascular risk

Safety and tolerability

• BGE-102 continued to be well tolerated
• Adverse events were infrequent, mild to moderate in severity, and self-limited, with no dose-dependent pattern observed
• No dose-limiting toxicities observed

Additional figures and data from the ongoing Phase 1 study are available in the Company’s corporate presentation at https://ir.bioagelabs.com/.

“The substantial reductions in hsCRP, IL-6, and fibrinogen we observed in participants with obesity and elevated inflammation demonstrate that BGE-102 potently suppresses the NLRP3-driven inflammatory cascade in a clinically relevant population,” said Paul Rubin, MD, Chief Medical Officer of BioAge. “These data provide strong rationale for advancing into our planned Phase 2a study, where we will evaluate BGE-102’s effects on a range of key inflammatory biomarkers over a longer duration in patients with elevated cardiovascular risk.”

Phase 1 study design

The ongoing Phase 1 study is a randomized, double-blind, placebo-controlled trial in healthy volunteers and participants with obesity. Part 1 evaluated single ascending doses at four dose levels (10, 30, 60, and 120 mg); Part 2 to date has evaluated multiple ascending doses administered once daily for 14 days in healthy volunteers (60 and 120 mg) and in participants with obesity and elevated hsCRP (120 mg QD cohort complete; two lower-dose QD cohorts ongoing). Pharmacodynamic effects were evaluated by assessment of serum biomarkers including hsCRP, IL-6, and fibrinogen, as well as an ex vivo whole blood stimulation assay measuring IL-1β suppression.

Anticipated milestones for BGE-102 in cardiovascular disease

• 1H 2026: Completion of Phase 1 trial with full data readout, including two additional MAD cohorts in obese participants with elevated hsCRP
• 1H 2026: Initiation of Phase 2a proof-of-concept study in patients with obesity and cardiovascular risk factors. The trial is planned to enroll approximately 100 patients randomized 1:1 to BGE-102 monotherapy or placebo for 12 weeks. The anticipated primary endpoint is percent change in hsCRP. The trial will also assess inflammatory and metabolic biomarkers, and will include liver MRI.
• 2H 2026: Phase 2a data readout

Background on BGE-102 and NLRP3

BGE-102 is a potent, orally available, brain-penetrant small molecule NLRP3 inhibitor being developed for diseases of inflammation including elevated cardiovascular risk. BGE-102 represents a structurally novel class of NLRP3 inhibitors developed by BioAge with a unique mechanism and binding site. NLRP3 is a key driver of age-related inflammation that has been implicated in a broad range of diseases, including cardiovascular disease, neurodegeneration, and metabolic disorders.

[RapAdmin]

BioAge Presentation for the company and product:

Extending human healthspan: Obesity, metabolism, and aging (JPM 2026)

- YouTube

Executive Summary

This panel discussion, hosted at the J.P. Morgan Healthcare Conference, explores the post-GLP-1 landscape of metabolic health and longevity. The primary focus shifts from simple weight loss (quantity) to “quality weight loss,” emphasizing the preservation of muscle mass and the necessity of orthogonal mechanisms to complement existing incretin therapies.

The core thesis is that while GLP-1 agonists (e.g., semaglutide, tirzepatide) are transformative, they possess significant liabilities: high discontinuation rates (50%+), rapid weight regain upon cessation, and a high proportion of lean mass loss (up to 40% of total weight lost). The experts argue that the next generation of therapeutics must address these gaps through three primary avenues: muscle-sparing agents, energy expenditure enhancers, and inflammation modulators.

A significant portion of the dialogue is dedicated to the “regulatory bottleneck.” Current FDA guidelines prioritize scale-weight reduction, which inadvertently penalizes drugs that increase muscle mass (and thus total weight) even if they improve metabolic health. The panel identifies several “underserved” but high-potential areas: ovarian aging, muscle-nerve-metabolism crosstalk, and the use of “omics” for subtyping patients to enable precision longevity interventions.

The discussion concludes with a look at upcoming clinical catalysts, specifically IL-6 and NLRP3 inhibitors, which seek to decouple metabolic health from simple adiposity by targeting systemic inflammation (inflammaging). Ultimately, the panel advocates for a transition from reactive disease treatment to proactive, data-driven “measurement science” to extend human healthspan.

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Bullet Summary

• Beyond GLP-1s: Current weight loss drugs are effective but lead to significant muscle wasting and weight regain after treatment stops.
• The Muscle Crisis: Up to 40% of weight lost on GLP-1s is lean mass; for older adults, this risks “sarcopenic obesity” (low weight but high frailty).
• Orthogonal Mechanisms: Future therapies will focus on non-GLP-1 pathways, such as ActRII inhibitors (bimagrumab) to increase muscle while losing fat.
• Durability: A key goal is “metabolic rejuvenation” so that weight loss remains stable even after pharmacological intervention ends.
• The “Weight” Fallacy: The scale is a poor metric for health; the panel calls for shifting clinical endpoints from BMI to body composition and muscle function.
• Energy Expenditure: There is high pharma interest in drugs that increase caloric output without suppressing appetite (exercise mimetics).
• Inflammaging: Targeting IL-6 and NLRP3 pathways is seen as a way to reduce cardiovascular and cognitive risks independent of weight.
• Patient Subtyping: Precision medicine is needed; “Asian” vs. “non-Asian” spikes in glucose or “cardio-agers” vs. “metabolic-agers” require different protocols.
• Regulatory Challenges: The FDA currently lacks a clear pathway for “muscle-gain” drugs, requiring evidence of functional gains (strength/power) which are hard to prove.
• The “Productive Triangle”: Longevity drugs aim to extend the peak years of human wisdom and economic output by delaying frailty.
• Sarcopenia as an Anchor: Muscle loss is the #1 predictor of loss of independence; maintaining “motility” is essential for systemic health.
• AI & Big Data: Large-scale longitudinal profiling (proteomics/genetics) is now the standard for discovering targets in aging biology.
• Exercise Synergy: Drugs are not viewed as replacements for exercise but as mimetics for those unable to train due to injury or age.
• Cardiovascular Frontier: Heart failure with preserved ejection fraction (HFpEF) is identified as a primary target for metabolic/muscle drugs.
• Prevention vs. Treatment: The industry is moving toward “measurement science” to identify aging patterns decades before disease onset.

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Claims & Evidence Table (Adversarial Peer Review)

Claim from Video	Speaker’s Evidence	Scientific Reality (Best Available Data)	Evidence Grade (A-E)	Verdict
40% of GLP-1 weight loss is lean mass.	Mark Pzanski (MD, Biotech CEO)	STEP-1 trial sub-studies confirm ~35-40% lean mass loss, though the proportion of skeletal muscle varies.	B (RCT data)	Strong Support
Bimagrumab increases muscle while dropping fat.	Versanis/Novartis data.	JAMA Network Open (2021) showed -20% fat and +3.6% lean mass in 48 weeks.	B (RCT)	Strong Support
50%+ of patients drop off GLP-1s within a year.	Chris O’Donnell (Novartis)	Large-scale PBM data (2024) suggests high discontinuation rates due to side effects and cost.	C (Real-world evidence)	Plausible
NLRP3 inhibition lowers IL-6/CRP better than Cankinab.	Cites Novartis Phase 2A trials.	Nature Communications (2023) studies on NLRP3 show potent inflammatory reduction, but direct superiority in humans is still in early readout.	B (Early Clinical)	Plausible
Aging occurs in “bursts” at age 44 and 60.	Mike Snyder (Stanford)	Shen et al. (2024) in Nature Aging identifies non-linear molecular shifts at these ages.	C (Cohort Study)	Strong (Emerging)
Muscle is an endocrine organ that helps the brain.	Hinata Yousef (Juvenetics)	Well-documented “Myokine” theory (e.g., Irisin/Cathepsin B) links muscle activity to neurogenesis.	D (Mechanistic)	Plausible

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Technical Deep-Dive

The transcript highlights a transition in Metabolic Pharmacology from appetite suppression to Tissue-Specific Rejuvenation.

• ActRII Blockade: The discussion of Bimagrumab refers to the inhibition of Activin Type II receptors. This pathway usually limits muscle growth; by blocking it, the body enters an anabolic state in muscle while simultaneously increasing thermogenesis in brown adipose tissue (BAT).
• NLRP3 Inflammasome: A critical target in the “Inflammaging” section. The NLRP3 protein complex triggers the maturation of pro-inflammatory cytokines and . Unlike general immunosuppression, NLRP3 inhibitors aim to block the “sterile inflammation” associated with metabolic debris (e.g., cholesterol crystals) without compromising the entire immune system.
• Mendelian Randomization (MR): Mentioned by Chris O’Donnell to justify weight loss over muscle mass. MR uses genetic variants as “natural experiments” to determine if a correlation (e.g., high BMI and heart disease) is truly causal, helping to de-risk drug targets before expensive trials.
• Ovarian Aging as a Pacemaker: The panel suggests that the decline in ovarian function is a primary driver of systemic female aging, potentially due to the loss of protective estrogenic signaling on mitochondrial function and lipid metabolism.

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Actionable Insights

Top Tier (High Confidence)

• Emphasize Resistance Training: Since the current gold-standard weight-loss drugs (GLP-1s) inherently cause muscle loss, heavy resistance training and high protein intake (>1.2g/kg/day) are mandatory to preserve metabolic rate and prevent frailty.
• Monitor Inflammation (hs-CRP): For those with cardiovascular risk, tracking High-Sensitivity C-Reactive Protein (hs-CRP) is as critical as tracking LDL, as “residual inflammatory risk” is a major driver of “slow death.”
• Avoid BMI as a Single Metric: Utilize DEXA scans or bioimpedance (e.g., InBody) to monitor body fat percentage and lean mass, especially during weight loss, to ensure “quality” of loss.

Experimental (Risk/Reward)

• Biological Age Testing: While “epigenetic clocks” are still in early stages, using them to identify your “aging subtype” (e.g., “metabolic-ager” vs. “immune-ager”) can help tailor lifestyle interventions like fasting or specific supplement protocols.
• Precision Glucose Monitoring: Using a CGM (Continuous Glucose Monitor) to identify specific “spiker” foods (like white rice in certain genotypes) allows for metabolic control that generic diets miss.

Avoid

• GLP-1 “Cold Turkey”: Do not stop GLP-1 medications without a robust “muscle maintenance” and “metabolic durability” plan, as rapid rebound of fat mass is highly likely.
• Neglecting Sarcopenia: Do not prioritize being “thin” over being “strong” in later decades; muscle function is a more powerful predictor of longevity than lower body weight once outside the obese range.

Would you like me to generate a 16:9 landscape image illustrating the “Productive Triangle” vs. “Biological Decay” as discussed in the context of the peak earning age of 58?

[RapAdmin]

An earlier talk by BioAge:

BioAge Labs is a clinical-stage biopharmaceutical company leveraging human aging biology to develop therapies that target metabolic decline, chronic inflammation, and body composition. Learn more at https://bioagelabs.com/

- YouTube

Gemini Pro AI Summary and Analysis:

Here is the rigorous summary and adversarial peer review of the provided transcript.

A. Executive Summary

The speaker, representing BioAge, outlines the company’s “human-first” platform for drug discovery, contrasting it with the high failure rate (95%) of animal-based aging research. Their core thesis is that longitudinal data from human biobanks (spanning 50+ years) allows for the identification of targets that distinguish “successful agers” from those with chronic disease.

The presentation focuses on their lead asset, BGE-102, a novel oral inhibitor of the NLRP3 inflammasome. BioAge positions this drug not as a broad anti-aging compound initially, but as a treatment for metabolic disease and obesity. The speaker presents pre-clinical (mouse) data claiming BGE-102 monotherapy achieves weight loss parity with Semaglutide (Ozempic), and when combined with GLP-1 agonists, doubles the weight loss effect. The company aims to initiate Phase 2 trials for obesity in 2026, positioning BGE-102 as an oral alternative or adjunct to current injectables. Additionally, collaborations with Eli Lilly and Novartis focus on “Exerkines”—molecular mimetics of physical exercise.

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B. Bullet Summary

• The Translation Gap: 95% of drugs that work in preclinical animal models fail in humans because model organisms do not age biologically the same way humans do.
• Human-First Platform: BioAge relies on millions of data points from >10,000 humans tracked over 50 years to identify molecular correlates of longevity.
• The Statin Model: The strategy is to approve drugs for narrow disease indications (like obesity) and then label-expand into broad preventive aging measures, similar to how Statins evolved.
• Target Identification: The platform identified NLRP3 activity as negatively associated with human lifespan and positively associated with cardiovascular disease.
• Mechanism of Action: BGE-102 is a best-in-class, brain-penetrant, oral NLRP3 inhibitor designed to dampen chronic inflammation caused by cellular stress and nutrient excess.
• Efficacy Claim (Monotherapy): In diet-induced obese mice, BGE-102 demonstrated dose-dependent weight loss comparable to Semaglutide.
• Efficacy Claim (Synergy): Combining BGE-102 with a GLP-1 agonist doubled the weight loss compared to the GLP-1 alone in mice.
• Market Positioning: BioAge aims to capitalize on the shift from injectable to oral obesity treatments, solving for patient preference and cold-chain logistics.
• Novartis Collaboration: A partnership focused on “Exerkines”—proteins like Apelin (APJ receptor) secreted during exercise that mediate metabolic benefits.
• Exercise Mimetics: The goal is to rank genes based on their ability to mimic the physiological benefits of exercise for metabolic health.
• Timeline: Phase 1 safety data is imminent; Phase 2 proof-of-concept for obesity is scheduled for 2026.

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D. Claims & Evidence Table (Adversarial Peer Review)

Role: Longevity Scientist & Peer Reviewer.

Claim from Video	Speaker’s Evidence	Scientific Reality (Best Available Data)	Evidence Grade	Verdict
“BGE-102 causes weight loss equal to Semaglutide.”	Diet-induced obese mouse model data (Aqua vs Orange line).	Translational Gap. Murine metabolism differs vastly from humans (e.g., reliance on brown adipose tissue). While NLRP3 inhibition improves insulin sensitivity, claiming distinct weight loss parity with GLP-1s in humans is premature.	D (Mouse Only)	Speculative
“NLRP3 levels negatively correlate with lifespan.”	Internal proprietary human biobank data.	True. Chronic sterile inflammation (“Inflammaging”) via the NLRP3 inflammasome is a well-documented driver of multimorbidity and reduced healthspan. Create et al., 2020	B (Observational)	Strong Support
“Combination with GLP-1 doubles weight loss.”	Mouse synergy data.	Plausible Mechanism. GLP-1s target satiety/gastric emptying. NLRP3 inhibitors target adipose inflammation and insulin resistance. Different pathways suggest potential synergy, but “double” is a bold quantitative claim.	D (Pre-clinical)	Plausible (with caveats)
“Exerkines can mimic exercise benefits.”	Novartis collaboration / Apelin data.	Contentious. While specific molecules (Irisin, Apelin) are released during exercise, replicating the systemic, multi-organ stress adaptation of exercise via a single pathway has historically failed.	D (Mechanistic)	Speculative
“Human data prevents translational failure.”	Historical argument.	Generally True. Validating the target in humans is superior to validating in mice. However, validating the molecule (safety/efficacy) still faces standard clinical attrition rates.	E (Industry Logic)	Strong Support

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E. Actionable Insights (Pragmatic & Prioritized)

Top Tier (High Confidence)

• Exercise is the Gold Standard: The speaker explicitly states exercise is the “number one proven indication.” Until “Exerkines” are FDA-approved, Zone 2 and resistance training remain the only validated method to activate the Apelin/APJ pathways naturally.
• Manage Inflammation: The core thesis validates that chronic inflammation (NLRP3) drives metabolic aging. Reducing inflammatory load via diet (low sugar/processed foods) and stress management is the current behavioral equivalent of BGE-102.

Experimental (Risk/Reward)

• Inflammasome Modulation: While BGE-102 is experimental, compounds like Curcumin and Quercetin have been shown to inhibit the NLRP3 inflammasome in in vitro and animal studies, though with much lower potency and bioavailability.
• Oral GLP-1 Watch: Monitor the development of oral GLP-1 agonists (like Orforglipron). If BioAge’s thesis holds, combining these with anti-inflammatories could be the future standard of care.

Avoid

• Mouse-Model Hype: Do not assume that because a drug causes massive weight loss in mice, it will do the same in humans. The “browning of fat” mechanism often seen in mice rarely translates effectively to adult humans.

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H. Technical Deep-Dive

The NLRP3 Inflammasome
The speaker references NLRP3 as a sensor for “nutrient excess.”

• Mechanism: NLRP3 is an intracellular sensor that detects danger signals (DAMPs), including uric acid crystals, amyloid beta, and crucially, ceramides and fatty acids associated with obesity.
• Activation: Once triggered, NLRP3 assembles into a multiprotein complex (the inflammasome) which activates Caspase-1.
• Output: Caspase-1 cleaves pro-IL-1β and pro-IL-18 into their active proinflammatory forms. This drives systemic inflammation, blocking insulin signaling receptors in adipose and muscle tissue, creating a vicious cycle of insulin resistance and weight gain.

Exerkines & The Apelin Pathway
The collaboration with Novartis focuses on “Exerkines.”

• Definition: Signaling moieties released by skeletal muscle (myokines), liver (hepatokines), and adipose tissue (adipokines) in response to acute exercise.
• Target: Apelin is an exerkine that decreases with age. It binds to the APJ receptor. Restoring Apelin levels in old mice has been shown to reverse sarcopenia (muscle loss) and improve mitochondrial function. BioAge is betting that drugging the APJ receptor can chemically simulate this “youthful” muscle state.

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I. Fact-Check Important Claims

Claim: “Statins were approved for a narrow indication and became preventative.”
Fact Check: True.
Lovastatin was approved in 1987 specifically for hypercholesterolemia. Over decades, data regarding plaque stabilization and pleiotropic anti-inflammatory effects led to widespread use for primary prevention of CVD, serving as the business model for BioAge’s strategy.

Claim: “95% of drugs that look good in preclinical trials fail in humans.”
Fact Check: True.
The overall probability of success (POS) for a drug entering Phase 1 to reach approval is widely estimated between 5-10%, with failure rates in neurology and aging-related indications often being even higher due to poor model translation.

[RapAdmin]

Source: https://x.com/DrSamuelBHume/status/2011514816389922920?s=20

Original article (paywalled):

https://www.nature.com/articles/d41573-026-00009-5

[RapAdmin]

Fat Cells Break the “Brakes” on Inflammation by Flooding Mitochondria with DNA Building Blocks

In a major study published this week in Science, researchers at UT Southwestern have decoded the precise molecular chain reaction linking obesity to chronic, life-shortening inflammation. For years, we have known that obesity triggers the NLRP3 inflammasome—a protein complex often called the “fire alarm” of the immune system—driving conditions from diabetes to liver fibrosis. However, the how remained a mystery. This team identified the culprit: a breakdown in SAMHD1, an enzyme that acts as a gatekeeper for cellular DNA building blocks (dNTPs).

In lean individuals, SAMHD1 keeps dNTP levels low, preventing accidental DNA synthesis where it doesn’t belong. The researchers discovered that obesity forces the phosphorylation (inactivation) of SAMHD1 in macrophages. This causes a flood of dNTPs to leak into mitochondria via specific transporters (PNC1/2). Once inside, these building blocks fuel uncontrolled, “dirty” synthesis of mitochondrial DNA (mtDNA). This newly made DNA is highly susceptible to oxidation; when it inevitably rusts (oxidizes), it acts as a potent toxin that triggers the NLRP3 inflammasome, spewing inflammatory cytokines like IL-1 beta throughout the body.

The takeaway? Your fat tissue isn’t just storing energy; it is actively rewriting the metabolic rules of your immune cells, forcing them to manufacture toxic DNA that keeps your body in a perpetual state of emergency. By blocking the transport of these DNA building blocks into mitochondria, the team completely reversed metabolic inflammation in obese mice—without them losing a gram of weight.

Source:

• Full Paper: Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity
• Impact Evaluation: The impact score of this journal is 56.9 (JIF), evaluated against a typical high-end range of 30–60+, therefore this is an Elite impact journal. Papers in Science represent the absolute apex of peer-reviewed credibility and typically dictate the direction of research for the next decade.

[RapAdmin]

It looks like NLRP3 inhibitors may be the next drug with GLP-1 like popularity:

Insilico inks $66m collab to develop NLRP3 inhibitor for Parkinson’s

[RapAdmin]

Eli Lilly, BioAge chase NLRP3 inhibitors with ‘pipeline in a pill’ potential

The promising anti-inflammation target could be the next big thing in cardiovascular and other diseases.

Aging and inflammation go hand in hand, so developing a drug to block the inflammation-causing multiprotein complex NLRP3 was a no-brainer for BioAge Labs. Since its inception, the biotech has targeted several indications tied to the “biology of human aging.”

“NLRP3 is implicated in a lot of different diseases,” said Kristen Fortney, CEO and co-founder of BioAge, pointing to its role in neurodegenerative conditions, cardiovascular disease and metabolic disorders.

That’s why Fortney sees “pipeline in a pill” potential for BioAge’s oral NLRP3 inhibitor, BGE-102, which recently showed positive results in a phase 1 study of cardiovascular risk factors.

But BioAge isn’t the only company with an eye on NLRP3’s potential. Earlier this month, Eli Lilly snapped up Ventyx Biosciences for $1.2 billion to gain access to its pipeline of NLRP3 inhibitors.

“There is increasing evidence that inflammation is a key driver of many chronic diseases,” Dr. Daniel Skovronsky, chief scientific and product officer, and president of Lilly Research Laboratories, said in a statement about the acquisition.

In each indication BioAge is pursuing, an oral NLRP3 inhibitor could both provide a more convenient option than injectables or potentially improve the standard of care. In cardiovascular risk, for example, there are limited treatments to address inflammation. Oral NLRP3s could ultimately go toe-to-toe with the clinical-stage IL-6 inhibitors on efficacy in that indication while also complementing statin-lowering therapies.

The NLRP3 development pipeline is in early stages, and only a handful of candidates have entered the clinic.

Leading the pack is Ventyx, which is developing VTX3232 for Parkinson’s disease and obesity-associated cardiometabolic conditions. The drug also showed promise in Alzheimer’s disease, multiple sclerosis and amyotrophic lateral sclerosis.

A phase 2 study among patients with obesity and cardiovascular risk factors showed that within the first week of dosing with VTX3232 alone, patients achieved a roughly 80% reduction in high-sensitivity C-reactive protein (hsCRP), which can trigger future cardiovascular events when elevated. Patients with measurable drug levels maintained those results throughout the full 12-week dosing period.

Ventyx’s other NLRP3 inhibitor, VTX2735, is in phase 2 trials for recurrent pericarditis.

NodThera has also ushered an NLRP3 inhibitor into phase 2 trials. The candidate, dubbed NT-0796, is being investigated as a monotherapy and in combination with a GLP-1 in patients with obesity. The company is also testing the drug in Parkinson’s disease, and showed reductions of neuroinflammatory biomarkers in a phase 1b/2a study readout in August.

BioAge is hot on their heels with BGE-102, an internally developed and structurally novel NLRP3 inhibitor, which lowered hsCRP in patients with obesity and elevated hsCRP.

Full article:

Eli Lilly, BioAge chase NLRP3 inhibitors with ‘pipeline in a pill’ potential

[channel_locks]

I wonder how the efficacy compares to the endogenous NLRP3 inhibitor that is available to us all, via fasting or carb restriction.

https://www.nature.com/articles/nm.3804

[CronosTempi]

I feel profoundly enervated reading about this compound. It looks like a nothingburger for LE enthusiasts. If you are obese and want your sky high inflammatory markers brought down, this might be of interest - or you could eat less and exercise more. For the rest of us, I see a whole lot of nothing. Sometimes I’m genuinely puzzled by RapAdmin’s devotion to following some pedestrian intervention for months on end, but I figure I’m probably missing something sexy about it🤣! I do keep reading, thinking a revelation will occur to me one day, no luck so far…

[RapAdmin]

I asked Gemini to summarize and project about impact on healthspan and lifespan benefits from the Phase 1 study results. We’ll see. Seems like something that could benefit many people.

Summary

BioAge Labs recently announced compelling interim Phase 1 data for BGE-102, an orally available, brain-penetrant small molecule targeting the NLRP3 inflammasome. In a Multiple Ascending Dose (MAD) cohort of patients with obesity and elevated baseline inflammation (median hsCRP 4.85 mg/L), 120 mg of BGE-102 daily resulted in an 86% reduction in high-sensitivity C-reactive protein (hsCRP) by Day 14. Crucially, 93% of participants reached hsCRP levels below 2 mg/L, the clinical threshold for “low” cardiovascular risk.

The drug also demonstrated significant systemic impact, reducing Interleukin-6 (IL-6) by 44% and fibrinogen by 30%. Unlike earlier generations of NLRP3 inhibitors, BGE-102 shows high cerebrospinal fluid (CSF) penetration, potentially addressing neuroinflammation alongside systemic cardiovascular risk. BioAge plans to advance BGE-102 into a Phase 2a study in the first half of 2026, targeting cardiovascular risk and potentially neurodegenerative or ocular conditions.

• Institution: BioAge Labs, Inc.
• Country: USA (Emeryville, CA)
• Journal/Source: BioAge Interim Phase 1 Data Release (2026)

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Part 2: The Biohacker Analysis

• Study Design: Clinical Trial (Phase 1b MAD).
• Subjects: Human participants with obesity (BMI 32–42) and elevated hsCRP (>3 mg/L). N=14 in the 120 mg cohort.
• Mechanistic Deep Dive: * NLRP3 Inhibition: BGE-102 inhibits the NLRP3 inflammasome, preventing the cleavage of pro-caspase-1. This blocks the maturation of IL-1β and IL-18.
  • Upstream Targeting: By suppressing IL-1β (93% suppression at trough), BGE-102 reduces the primary signal for hepatic IL-6 production, which in turn lowers hsCRP.
  • Vascular & CNS Health: The 30% reduction in fibrinogen suggests a decreased thrombotic risk. The CNS penetration (CSF concentrations exceeding IC90​) is unique, potentially modulating microglia-mediated neuroinflammation, a hallmark of Alzheimer’s and Parkinson’s.
• Novelty: BGE-102 is the first oral NLRP3 inhibitor to match the biomarker efficacy of injectable biologics (like Canakinumab) while maintaining significant brain bioavailability.
• Critical Limitations: * Sample Size: N=14 is extremely small for drawing broad clinical conclusions.
  • Duration: 14 days is insufficient to assess long-term safety or actual reduction in Major Adverse Cardiovascular Events (MACE).
  • Missing Data: Long-term metabolic effects (insulin sensitivity) in humans and head-to-head comparisons with GLP-1 agonists are currently absent.

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Part 3: Claims & Evidence Verification

Claim	Evidence Level	Verification Status
86% hsCRP reduction at Day 14	Level B	BioAge Phase 1 Data (2026)
hsCRP < 2 mg/L reduces CV risk	Level A	C-Reactive Protein and Cardiovascular Disease (2025)
NLRP3 inhibition reduces MACE	Level B	CANTOS Trial - Canakinumab (2017)
BGE-102 causes weight loss	Level D	Translational Gap. Robust in mice (15%), not yet proven in humans.
Brain penetration (CSF IC90​)	Level B	Verified in Phase 1 CSF samples (N=2 with elevated baseline).

Plausible Healthspan & Lifespan Benefits

[Confidence: Medium-High for Healthspan | Medium-Low for Lifespan]

• Healthspan (Upper/Lower): +5 to +12 years. * Rationale: Reducing chronic inflammation (hsCRP from >4 to <1 mg/L) is strongly correlated with delayed onset of CVD, T2D, and potentially dementia Chronic inflammation and disease across the life span (2024).
• Lifespan (Upper/Lower): +3% to +8%.
  • Rationale: While human lifespan extension is speculative, the CANTOS trial showed a 15% reduction in MACE and a significant reduction in cancer mortality. In mice, NLRP3 deficiency or inhibition consistently extends median lifespan NLRP3 deficiency extends healthspan (2013).

Safety Check: BGE-102 was “well tolerated” with only mild-to-moderate AEs. However, chronic NLRP3 inhibition may theoretically increase susceptibility to certain infections (e.g., Mycobacterium), though this was not observed in the short 14-day window. Safety Data Absent for long-term (>1 year) use.

[CronosTempi]

So no demonstrated LE, but median LS improvement if obese and inflamed? It could help some people? Yes, obese and inflamed because of that obesity. Or eliminate that obesity and associated inflammation through lower caloric intake in the diet and greater caloric output through inflammation lowering exercise. The marvels of modern medicine.

[RapAdmin]

A follow-on prompt:

Is there any scientific or clinical evidence that a drug like BGE-102, an orally available, brain-penetrant small molecule targeting the NLRP3 inflammasome, would provide health and longevity benefits for a normal, healthy, non-obese mammal?

Gemini Response:

Evidence Analysis for BGE-102 in Healthy, Non-Obese Mammals

The short answer is yes, there is substantial pre-clinical evidence that NLRP3 inhibition (pharmacological or genetic) provides health and longevity benefits even in lean, “healthy” mammals. While obesity accelerates the activation of this pathway, “sterile” inflammation (inflammaging) is a natural feature of the aging process in all mammals.

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Evidence Hierarchy: NLRP3 Inhibition in Non-Obese Subjects

1. Lifespan Extension (Pre-clinical)

• Model: Genetic Deletion (Knockout) in Mice.
• Finding: Lifelong deficiency of NLRP3 in standard, non-obese C57BL/6 mice has been shown to increase median and maximum lifespan.
• Data: A key study NLRP3 inflammasome suppression improves longevity and prevents cardiac aging (2019) demonstrated that NLRP3 knockout mice lived significantly longer than wild-type (WT) controls, even when both groups were lean.
• Confidence: [Medium-High] (Consistently replicated in multiple longevity models, including progeroid mice Inhibition of the NLRP3 inflammasome improves lifespan in progeroid animals (2021)).

2. Healthspan & Organ-Specific Benefits (Pre-clinical)

Even in the absence of metabolic disease, NLRP3 inhibition addresses several “hallmarks of aging”:

• Thymic Protection: NLRP3 activation is a primary driver of thymic involution (the shrinking of the thymus). Inhibiting this pathway preserves the production of naive T cells, thereby delaying immunosenescence NLRP3 Inflammasome Promotes Age-related Thymic Demise (2014).
• Cognitive Function: Brain-penetrant inhibitors (like BGE-102) address age-related neuroinflammation in the hippocampus. In aged lean mice, this has been shown to improve memory and social preference behavior Impact of NLRP3 Depletion on Aging-Related Metaflammation (2023).
• Vascular Health: NLRP3 inhibition reduces age-dependent cardiac damage and preserves insulin sensitivity that typically declines with age regardless of BMI.

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Critical Analysis for the Human Biohacker

• Translational Gap: While mice show lifespan extension, human data for BGE-102 is currently limited to Phase 1 (14 days) in obese subjects. There are zero human trials testing BGE-102 in healthy, non-obese individuals for longevity purposes.
• Brain Penetration Advantage: The most significant “biohacker” interest in BGE-102 over other inhibitors (like MCC950) is its ability to cross the blood-brain barrier. This makes it a plausible candidate for preventing age-related neurodegeneration, which occurs in lean and obese individuals alike.
• Safety Data Absent: We do not know the long-term effect of daily NLRP3 suppression on human host defense against pneumonia or skin infections.

Summary of Plausible Benefits for a Non-Obese “Healthy” Mammal

Benefit Category	Estimated Impact	Supporting Evidence
Immunological	Delayed Thymic Atrophy	Youm et al. (2014)
Neurological	Reduced Hippocampal Inflammaging	MDPI Aging Research (2023)
Cardiovascular	Reduced Arterial Stiffness	Navarro-Pando et al. (2021)
Lifespan	~10-15% increase (Murine)	Marín-Aguilar et al. (2019)