Lifespan-Extending Endogenous Metabolites - review

#1

https://onlinelibrary.wiley.com/doi/10.1111/acel.70371

ABSTRACT
Aging is a multifactorial process influenced by genetic, environmental, and metabolic factors. Dysregulated nutrient sensing and metabolic dysfunction are hallmarks of aging, and reduction of insulin/IGF-1 signaling or metabolic interventions such as caloric restriction extend lifespan across species. Endogenous metabolites reflect and mediate these metabolic cues, linking nutrient status to epigenetic and transcriptional programs by serving as cofactors for chromatin-modifying enzymes or as allosteric modulators of transcription factors. Some metabolites have emerged as key regulators of longevity, integrating into networks to concurrently influence multiple aging-related pathways. In this review, we summarize evidence supporting the lifespan-extending effects of key endogenous metabolites across diverse model organisms and discuss their mechanisms of action. These insights underscore the potential of targeting metabolic networks as a multifaceted strategy to delay aging. Finally, we consider the translational promise of metabolite-based interventions to extend healthspan while minimizing adverse effects, and we note remaining challenges such as optimal dosing, context-specific effects, and demonstrating efficacy in humans.

#2

I think these are all pretty low-value ideas. I don’t think there is much value in small incremental increases in lifespan (typically in the 5% to 12% range in mice, as is the case here) are worth much time and energy given we have already have drug combinations like rapamycin and acarbose pushing 30% + improvements…

A brief analysis of the claims from the paper:

Part 3: Claims & Verification

Claim 1: “Endogenous metabolites like AKG and Taurine significantly extend lifespan in mammals.”

  • Verification:
    • AKG: Confirmed in C57BL/6 mice (Asadi Shahmirzadi et al., 2020) showing ~12% extension.
    • Taurine: Confirmed in mice (Singh et al., Science 2023) showing ~10-12% extension.
  • Hierarchy: Level D (Strong Animal Data) → Level C (Human Associations). Note: No Level A/B Human Lifespan data exists.
  • Safety Check: AKG is GRAS (Generally Recognized As Safe). Taurine is GRAS.
  • Translational Gap: HIGH. The “Life Extension” claim is purely murine. Human data supports healthspanmarkers (frailty, inflammation) only.

Claim 2: “Mechanism of action is primarily through epigenetic remodeling (DNA methylation).”

  • Verification: Search for “AKG TET enzyme activation.” Confirmed in vitro and in specific tissues.
  • Hierarchy: Level D (Mechanistic Speculation).
  • Uncertainty: It is unclear if oral supplementation achieves sufficient nuclear concentrations in human tissues to drive TET activity.

Claim 3: “Metabolite supplementation reverses age-related physiological decline (Frailty/Hair loss).”

  • Verification: Science 2023 (Taurine) showed reversal of specific aging phenotypes in monkeys. Rejuvant (AKG) trial showed reduction in “biological age” (DNAm).
  • Hierarchy: Level B (Small RCTs on biomarkers) / Level D (Animal Phenotypes).

Part 4: Actionable Intelligence (The Translational Protocol)

1. Alpha-Ketoglutarate (Ca-AKG)

  • Human Equivalent Dose (HED):
    • Animal Efficacy: ~2% diet or ~0.2–0.5 g/kg/day in rodents.
    • Math: 200 mg/kg (Rat) × 0.162 (Km factor) ≈ 32 mg/kg Human.
    • Result: For a 70kg human, ~2.2 grams/day.
    • Commercial Reality: Most trials (e.g., Rejuvant) use 1000 mg (1g) daily. This suggests a potential under-dosing in commercial protocols compared to animal lifespan data.
  • Pharmacokinetics: AKG has a short half-life (<30 mins). Sustained-release formulations or split dosing (3x/day) are critical.
  • Safety: NOAEL is high. Safety demonstrated up to 6g/day in humans (for osteoporosis/kidney indications).
  • Cost: High (~$50–80/month for Calcium-AKG).

2. Taurine

  • Human Equivalent Dose (HED):
    • Animal Efficacy: 1000 mg/kg/day (Singh et al.).
    • Math: 1000 × 0.08 (Mouse-to-Human) ≈ 80 mg/kg.
    • Result: For a 70kg human, ~5.6 grams/day.
    • Standard Dose: Most energy drinks/supplements have 500-1000mg. To match the Science paper lifespan data, one must consume significantly more (3–6g).
  • Safety: Very high safety profile. EFSA/FDA note safety up to 3–6g/day.
  • Cost: Very Low (Bulk powder is cheap, <$10/month).

Biomarker Verification Panel

  • Efficacy Markers:
    • AKG: Reduction in DNAm Age (GrimAge/DunedinPACE), reduced hsCRP, improved hair pigmentation(anecdotal/mouse).
    • Taurine: Serum Taurine levels (target >50 µM), reduced lipid peroxidation markers, improved exercise capacity (VO2 max).
  • Safety Monitoring:
    • Kidney Function (Cystatin C/eGFR): High protein/amino acid loads can stress compromised kidneys.
    • Calcium Levels: If using Ca-AKG, monitor for hypercalcemia.
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