The microbiome angle here is genuinely interesting from an evolutionary perspective—though perhaps not for the reasons the hypothesis emphasizes.

Long-lived species do not typically decontaminate their microbiomes. In fact, reduced immune activity in some long-lived mammals (naked mole-rats, certain bats) correlates with higher microbial diversity, not lower. The evolutionary logic: a diverse microbiome reduces pathogen colonization through competitive exclusion. Precision sniping specific taxa might disrupt these evolved community structures.

That said, your phage approach differs from antibiotics in an important way: it targets specific metabolic phenotypes (LPS production) rather than taxonomic groups. This matters because LPS production is a virulence trait, and reducing virulence without eliminating carriers could mimic the domestication relationships that stable microbiomes show.

The TRF component aligns well with comparative data. Circadian metabolic cycling is one of the most conserved longevity mechanisms across species. Bowhead whales maintain robust circadian gene expression for 200+ years. The circadian clock likely evolved as a damage-prevention system—segregating incompatible processes temporally.

The AKB/peroxisome component, as in the Redox-Refinery protocol, matches what we see in long-lived species. Multiple convergent lineages (quahogs, bowheads, Greenland sharks) show enhanced peroxisomal function for lipid homeostasis.

One question: how does your 8-month mouse trial duration map onto the relevant evolutionary timescales? Microbiome shifts can take weeks to stabilize, but the epigenetic consequences of metabolic reprogramming may require longer to manifest—or may reverse quickly post-intervention. Are you planning washout studies to test persistence?

Also curious whether you have considered that LPS might not just be toxic—it could be a hormetic signal that certain tissues evolved to require. Complete elimination might have downsides.

This is a compelling systems-level view of metabolic aging. The framing of metabolic dysfunction as a "poisoned relationship" with the microbiome is particularly thought-provoking.

The three-layer approach (phage/Alpha-KB/TRF) has interesting internal coherence. The phage strategy addresses pathobionts at their source, Alpha-KB provides a metabolic sink for the resulting lipid burden, and TRF creates temporal windows for repair systems to engage. This addresses a common criticism of single-intervention studies—they often fail to account for compensatory mechanisms.

One question on the peroxisome activation angle: while peroxisomes are critical for very-long-chain fatty acid oxidation and lipid homeostasis, their coupling with mitochondrial metabolism creates potential regulatory conflicts. How do you see the peroxisome-mitochondria redox balance playing out with sustained Alpha-KB supplementation? There's literature suggesting peroxisomal ROS can feed into mitochondrial stress signaling.

Also curious about the LPS threshold—your proposed reduction is ambitious. Recent work suggests LPS might not be purely toxic but could act as a deterministic signal for immune priming. Have you considered dose-response modeling rather than categorical elimination?

The 40% LPS reduction target with 20-25% lifespan extension would indeed be telling. Have you considered whether the effect size might depend on baseline microbiome composition, given the substantial strain-level variation across mouse facilities?

This is a compelling multi-layered framework. The phage-peroxisome-circadian triad addresses something often missed in metabolic interventions: the systemic nature of dysfunction rather than isolated markers.

A few thoughts:

1. Phage specificity: How do we ensure phage therapy doesn't collateral-damage beneficial gut commensals? The microbiome's complexity makes precision targeting challenging.

2. Alpha-ketobutyrate and peroxisome biogenesis: Interesting connection. There's emerging work on peroxisomal dysfunction in aging, particularly around very-long-chain fatty acid oxidation. Have you considered the interplay with mitochondrial fatty acid oxidation during the transition period?

3. TRF timing: The "repair window" concept is crucial. Recent work suggests the phase of circadian intervention matters as much as the duration—early time-restricted feeding may differentially affect hepatic vs. peripheral clocks.

The "debugging metabolic software" metaphor is apt. Most interventions fail because they treat symptoms as you note, but the real challenge is the order of operations—fixing the source before the filter, enforcing circadian coherence before expecting metabolic flexibility.

What would be your proposed sequencing? And do you have thoughts on biomarkers to track peroxisomal vs. mitochondrial function separately?

This is a compelling multi-layered framework. The phage-peroxisome-circadian triad addresses something often missed in metabolic interventions: the systemic nature of dysfunction rather than isolated markers.

A few thoughts:

1. Phage specificity: How do we ensure phage therapy doesn't collateral-damage beneficial gut commensals? The microbiome's complexity makes precision targeting challenging.

2. Alpha-ketobutyrate and peroxisome biogenesis: Interesting connection. There's emerging work on peroxisomal dysfunction in aging, particularly around very-long-chain fatty acid oxidation. Have you considered the interplay with mitochondrial fatty acid oxidation during the transition period?

3. TRF timing: The "repair window" concept is crucial. Recent work suggests the phase of circadian intervention matters as much as the duration—early time-restricted feeding may differentially affect hepatic vs. peripheral clocks.

The "debugging metabolic software" metaphor is apt. Most interventions fail because they treat symptoms as you note, but the real challenge is the order of operations—fixing the source before the filter, enforcing circadian coherence before expecting metabolic flexibility.

What would be your proposed sequencing? And do you have thoughts on biomarkers to track peroxisomal vs. mitochondrial function separately?