Aging Hearts, Aging Guts: Microbial Metabolites as Master Switches of Cardiovascular Longevity

#1

A new JCI Viewpoint paper by Ruschitzka, Vidal-Puig, and Saravi argues that gut-derived metabolites are not décor on top of classic risk factors; they are upstream drivers of vascular aging and cardiovascular disease (CVD), and thus prime gerotherapeutic targets.

The authors synthesize a decade of work showing that microbial conversion of dietary choline, carnitine, and phosphatidylcholine into trimethylamine N-oxide (TMAO) predicts long-term CVD events and mortality independently of LDL. Parallel work on aromatic amino acid metabolites — phenylacetic acid (PAA), phenylacetylglutamine (PAGln), imidazole propionate (ImP), TMAVA, and p-cresol sulfate — links Western-diet protein breakdown to endothelial senescence, thrombosis, heart failure remodeling, and impaired glucose control.

Mechanistically, these metabolites converge on senescence and inflammaging pathways: mitochondrial ROS, p53/p21–Rb DNA damage programs, p38–MAPK/NF-κB activation, SIRT1 downregulation, SASP amplification, ECM remodeling, and diastolic stiffening. Short-chain fatty acids (SCFAs) and selected indoles provide the counterpoint, supporting metabolic flexibility, restraining neutrophil extracellular traps, and dampening vascular inflammation. From a systems-aging lens, microbial metabolites are positioned upstream of mTOR/AMPK/autophagy, cGAS–STING (via DNA damage and cytosolic DNA leakage), and vascular-centric aging trajectories, even when those pathways are not always explicitly named.

The genuinely novel angle is the explicit framing of a “metabolite/senescence axis”: age-associated increases in noxious metabolites (TMAO, PAA, PAGln, ImP, TMAVA) plus loss of protective ones (SCFAs, beneficial indoles) form a modifiable cardiovascular aging program, with age-specific trade-offs (e.g., TMAO beneficial for osmoregulation in youth, toxic later). The article also highlights emerging “gut microbial age” metrics combining microbiome and metabolomics for late-life CVD risk prediction.

Therapeutically, the authors map a pipeline: diet and fiber/Mediterranean patterns; next-generation probiotics, prebiotics, and postbiotics; FMT from young donors; SCFA-releasing engineered strains (e.g., EcN-based constructs); and enzyme-level inhibitors such as the TMA-lyase blocker DMB or targeted deletion of phenylalanine-metabolizing enzymes in specific taxa. These interventions act upstream of classic gerotherapeutics (rapalogs, senolytics, NAD+ boosters) and could be layered on top as orthogonal levers on the same aging networks.

For longevity-focused readers, the key message is blunt: vascular aging is partly a microbial metabolite phenotype. If you are optimizing mTOR, AMPK, or NAD+ without tracking or modulating TMAO, PAA/PAGln, ImP, and SCFAs, you are leaving a major, and potentially earlier, lever of cardiovascular lifespan untouched.

The full paper is here: JCI 201468. The core mechanistic Nature Aging work on PAA and PAGln is here: Saeedi Saravi et al. 2025 and Yang et al. 2025.

Actionable n=1 directions for a research-literate biohacker

  • Build a “microbial cardiovascular risk panel”: plasma TMAO, PAGln, ImP, TMAVA; plus protective SCFAs or SCFA surrogates where clinically available; add hsCRP, IL-6, NT-proBNP, and arterial stiffness (PWV or augmentation index).
  • Track diet–metabolite coupling: serially measure TMAO and PAGln while cycling red meat/egg intake vs a high-fiber pescatarian/Mediterranean pattern; correlate with FMD (flow-mediated dilation) or EndoPAT-type endothelial function metrics.
  • Use SCFA-centric interventions: titrate total fiber (≥30–40 g/d), resistant starches, and targeted prebiotics; measure effects on SCFA levels (if available) and on metabolic markers (HOMA-IR, triglycerides, glycemic variability).
  • Stack classical gerotherapeutics with microbiome modulation: observe whether rapalog, SGLT2i, or senolytic cycles change metabolite levels or vascular biomarkers; explore synergistic effects on SASP markers (IL-6, TNF-α, PAI-1).
  • Explore time-restricted feeding vs constant feeding on metabolite dynamics (TMAO, ImP) and morning vs evening endothelial function; hypothesize links to circadian control of microbial metabolism and autophagy.
  • Incorporate metabolite-aware supplement decisions: reconsider high-dose L-carnitine or choline in the presence of high TMAO; prioritize interventions that increase SCFAs or protective indoles rather than adding more TMA precursors.
  • Where accessible, participate in or emulate multi-omics profiling (stool 16S/metagenomics plus plasma metabolomics) to derive an individualized “gut microbial age” trajectory anchored to vascular endpoints.
  • Use structured re-testing (e.g., every 6–12 months) to see if sustained diet and lifestyle changes compress the metabolite risk signature relative to your own baseline rather than population “normals.”

Cost-effectiveness considerations

Dietary pattern shifts toward a high-fiber Mediterranean or largely plant-forward diet are likely to be the highest-ROI lever: low marginal cost, broad cardiometabolic benefit, and consistent evidence for lowering TMAO and aromatic uremic toxins while increasing SCFAs. Commercial TMAO/metabolite panels and deep metagenomic sequencing remain relatively expensive and are not yet clearly superior to conventional risk scoring, but they may offer extra value for high-risk or highly experimental users. Engineered probiotics, enzyme inhibitors like DMB, or FMT are still experimental, with unclear long-term benefit-to-cost ratios and potential safety/regulatory constraints.

Critical limitations and knowledge gaps

The JCI article is a mechanistic and translational review, not a new trial. Much of the human data is observational metabolomics linked to outcomes; causality is inferred from animal and cell models that inevitably differ from aged human hearts, vessels, and immune systems. Clinical evidence for microbiome-targeted CVD interventions is sparse and mixed: for example, the GutHeart trial of S. boulardii in heart failure showed no functional benefit, underscoring that not all “microbiome tweaks” matter at the organ-level.

Age-dependent pleiotropy is a real concern: metabolites like TMAO may be beneficial earlier in life, so blunt suppression in young or healthy individuals might be maladaptive. Host genetics (e.g., FMO3 variants), sex, ethnicity, and broader exposome variables further complicate translation. Large, age-stratified RCTs that integrate vascular aging biomarkers, metabolomics, and microbiome profiling — and that test multi-component stacks (diet + pharmacology + microbial engineering) — are still missing.

Ten high-value questions a longevity-oriented biohacker should be asking

  1. Which of these metabolites (TMAO, PAA, PAGln, ImP, TMAVA) can I actually measure clinically today, and at what cost and reliability?
  2. How much incremental predictive value do these metabolites add on top of standard CVD risk calculators and vascular aging markers (CAC score, PWV, FMD)?
  3. What magnitude and speed of change in TMAO/PAGln/ImP can be achieved with diet alone, and how stable are these changes over years?
  4. Are there validated thresholds for these metabolites that correspond to meaningful risk differences, or is within-person change the only interpretable signal right now?
  5. How do rapalogs, SGLT2 inhibitors, GLP-1 agonists, and other gerotherapeutics affect these microbial metabolites and the senescence/SASP axis in humans?
  6. Can serial SCFA or indole measurements meaningfully track the success of fiber/prebiotic/probiotic interventions, or are simpler markers (CRP, IL-6, PWV) sufficient proxies?
  7. What is the safety profile and long-term ecological risk of chronic TMA-lyase inhibition (e.g., DMB-like molecules) or engineered SCFA-secreting strains in older adults?
  8. How should age and “microbial age” be integrated: at what chronological or biological age does aggressive suppression of TMAO, PAA, or PAGln become clearly net-beneficial?
  9. Can we design personalized stacking strategies (diet + microbiome-targeted agents + canonical geroprotectors) that measurably slow vascular aging, not just shift metabolites?
  10. Which trial-like n=1 designs (frequency of labs, imaging, functional testing) best balance cost, burden, and interpretability when experimenting with metabolite-focused interventions?

Disclaimer: All these posts are generated with the help of AI systems, and there could be mistakes. Validate with good medical sources before taking any course of action.

#2

And if you find any of the questions of interest, here are some answers:

The following addresses the nine questions provided, drawing upon the foundational paper and incorporating the most current clinical and translational research in the field of longevity and microbial metabolism.

Ten High-Value Questions for the Longevity Biohacker

1. Which of these metabolites (TMAO, PAA, PAGln, ImP, TMAVA) can I actually measure clinically today, and at what cost and reliability?

  • Routinely Measurable: Trimethylamine N-Oxide (TMAO).
    • Clinical Availability: TMAO measurement is commercially available today through major specialized and commercial laboratories (e.g., Cleveland HeartLab, Labcorp) in the US and Europe.
    • Methodology & Reliability: It is typically measured using highly sensitive and specific Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS). Reliability is high, but testing requires patient adherence to fasting (typically 8–12 hours) and often refraining from high-precursor foods (e.g., cold-water fish, red meat) for 24 hours prior to mitigate acute post-meal spikes.
    • Reference ranges are often provided (e.g., <6.2 µmol/L for low risk), though they vary by lab. Costs are not publicly listed but typically range from $150–$300 out-of-pocket or through insurance, depending on the provider and location—specialty metabolic panels can add to this.
  • Research/Specialty Measurable: PAA, PAGln, ImP, and TMAVA.
    • These metabolites are primarily research targets or included in broad, non-standardized commercial metabolomics panels (which are expensive and not covered by insurance for screening). PAGln (Phenylacetyl-L-glutamine) and TMAVA (N,N,N-trimethyl-5-aminovaleric acid) have shown strong and independent associations with MACE and heart failure, making them priority targets for future clinical assays, but they are not yet standardized markers.

2. How much incremental predictive value do these metabolites add on top of standard CVD risk calculators and vascular aging markers (CAC score, PWV, FMD)?

These metabolites provide significant incremental prognostic value (IPV):

  • These metabolites provide modest but meaningful incremental predictive value for CVD risk, often improving risk stratification by 5–15% in discrimination and reclassification metrics when added to standard tools like the Framingham Risk Score or ASCVD risk estimator. For TMAO, studies show it independently predicts incident CVD events (e.g., coronary artery disease) beyond traditional factors like age, blood pressure, cholesterol, and smoking, with hazard ratios of 1.5–2.5 for elevated levels. It correlates with PWV (r=0.2–0.4, indicating arterial stiffness) and adds prognostic value for major adverse cardiovascular events (MACE) in healthy adults.
  • Beyond Traditional Risk Calculators: TMAO is an independent predictor of all-cause mortality, major adverse cardiovascular events (MACE), and heart failure risk, even after accounting for established factors like LDL-C, hypertension, and Framingham risk scores. It improves Net Reclassification Index (NRI), demonstrating that it correctly reclassifies a notable percentage of individuals who would otherwise be deemed low or intermediate risk.
  • Beyond Vascular Aging Markers:
    • TMAO and PAGln levels correlate strongly with atherosclerotic plaque burden (e.g., high SYNTAX score) and instability.
    • TMAO is linked to increased Aortic Stiffness (measured by Pulse Wave Velocity, PWV), which is a key marker of vascular aging.
    • Their value lies in predicting the future risk of an event (MACE, thrombosis, death) driven by chronic inflammation and senescence, rather than simply measuring the static physical damage (like CAC score or PWV), offering a distinct, actionable metabolic pathway signal.

3. What magnitude and speed of change in TMAO/PAGln/ImP can be achieved with diet alone, and how stable are these changes over years?

  • Magnitude and Speed (TMAO):
    • Significant reductions are achievable quickly. Dietary restriction of TMAO precursors (choline, L-carnitine, e.g., low red meat and egg yolks) or adopting a Mediterranean/Plant-Based Diet can reduce plasma TMAO levels by 10% to over 30% within a short intervention window (e.g., 4 weeks).
  • PAGln/ImP: Data is less abundant, but their levels are also diet-sensitive, reflecting the fermentation of specific amino acids/precursors by the gut microbiome.
  • Stability over Years: This is currently a major research gap. While long-term adherence to a restrictive diet maintains lower levels, the long-term stability of the gut microbiome composition and subsequent metabolite production without continuous, strict intervention is largely unknown. However, long-term increases in TMAO levels over multiple years are strongly correlated with increased CHD risk, indicating that maintaining low levels requires consistent lifestyle choices.

4. Are there validated thresholds for these metabolites that correspond to meaningful risk differences, or is within-person change the only interpretable signal right now?

  • Validated Thresholds: No single, globally standardized or validated clinical threshold for diagnosis or treatment initiation exists for TMAO (or PAGln/ImP) due to inter-individual variability and pre-analytical issues (e.g., recent fish consumption).
  • Interpretable Signal: The most reliable and powerful signal is the within-person change. A patient who shows a significant, sustained increase in TMAO over time, or whose level is consistently in the highest quartile across multiple measurements, is recognized as being at substantially higher long-term risk for MACE and mortality. In the absence of a hard threshold, tracking a personalized baseline and monitoring upward trends is the most interpretable approach for a biohacker.

5. How do rapalogs, SGLT2 inhibitors, GLP-1 agonists, and other gerotherapeutics affect these microbial metabolites and the senescence/SASP axis in humans?

These agents primarily target the metabolic and inflammatory drivers of aging, which often interact with microbial metabolites:

Gerotherapeutic Class Effect on Metabolites (TMAO/PAGln) Effect on Senescence/SASP Axis
GLP-1 Agonists (e.g., Semaglutide, Liraglutide) Reduces TMAO (Demonstrated in preclinical models of heart failure; likely via systemic metabolic improvement and altered gut motility/microbiome environment). Reduce systemic inflammation, improve endothelial function, and likely mitigate the SASP (Senescence-Associated Secretory Phenotype) due to their broad metabolic and cardiovascular benefits.
SGLT2 Inhibitors (e.g., Dapagliflozin, Empagliflozin) Effect on TMAO is less clear in human data, but they target pathways linked to its effects. Induce a state of pseudo-energy deprivation (via glucose loss), which activates AMPK. This leads to indirect senolytic activity, reducing the SASP and promoting clearance of senescent cells. They synergize with mTOR inhibition.
Rapalogs (mTOR inhibitors, e.g., Sirolimus) Not directly studied in large human cohorts for TMAO, but may modulate the pathways. Canonical geroprotectors that inhibit the mTORC1 pathway, a key regulator of aging, cellular senescence, and inflammation. Their primary role is in regulating cell growth and nutrient sensing, which underlies SASP reduction.

6. Can serial SCFA or indole measurements meaningfully track the success of fiber/prebiotic/probiotic interventions, or are simpler markers (CRP, IL-6, PWV) sufficient proxies?

Serial SCFA (Short-Chain Fatty Acid, e.g., butyrate) or indole measurements are useful for mechanistic insight, but are often not sufficient or reliable for tracking success alone:

  • Challenges: SCFA levels (in blood or stool) exhibit high inter-individual variability and significant postprandial fluctuation, making serial tracking challenging outside of a controlled trial.
  • Tracking Success: The goal of the intervention is to improve functional outcomes and reduce inflammaging. Therefore, tracking success should focus on:
    1. Downstream Functional Markers: CRP (C-Reactive Protein) and IL-6 (Interleukin-6) track the reduction in inflammation (SASP) driven by metabolite changes.
    2. Vascular Aging Markers: PWV (Pulse Wave Velocity) measures the functional slowing of vascular aging.

Conclusion: A stacking strategy is recommended: use SCFA/Indole measurements once or twice (pre/post intervention) to confirm microbial activity shift, but rely on CRP, IL-6, and PWV as the primary, more stable, and clinically recognized proxies for long-term health benefits.

7. What is the safety profile and long-term ecological risk of chronic TMA-lyase inhibition (e.g., DMB-like molecules) or engineered SCFA-secreting strains in older adults?

  • TMA-lyase Inhibitors (e.g., DMB):
    • Safety Profile: In preclinical models (mice), DMB is non-lethal to the gut bacteria and effectively lowers TMAO, attenuating atherosclerosis and thrombosis risk. However, the long-term safety profile and large-scale efficacy in non-diseased older human populations are currently unknown. These molecules are in development but lack Phase 3 long-term human data.
    • Ecological Risk: The primary risk is the long-term ecological perturbation. Inhibiting a central microbial metabolic pathway like TMA formation (which utilizes essential dietary nutrients like choline) could have unknown downstream consequences on other vital microbial functions, competition, or host nutrient absorption.
  • Engineered SCFA-Secreting Strains: The safety profile is generally promising, often relying on established probiotic species. However, long-term ecological risk involves ensuring the engineered strain maintains stability, does not competitively displace essential keystone species, and does not carry transferable resistance genes. This field is rapidly advancing but requires extended follow-up trials.

8. How should age and “microbial age” be integrated: at what chronological or biological age does aggressive suppression of TMAO, PAA, or PAGln become clearly net-beneficial?

  • Integration: TMAO levels generally increase with chronological age. Research using Microbiome Clocks and Biological Age (BA) algorithms (like PhenoAge) demonstrates that an elevated TMAO level is most concerning when it contributes to a Biological Age that significantly exceeds the Chronological Age.
  • Net-Beneficial Aggression: Aggressive suppression (e.g., using TMA-lyase inhibitors, if approved) becomes clearly net-beneficial when:
    1. Vascular Pathology is Established: In individuals with established ASCVD (Atherosclerotic Cardiovascular Disease), Heart Failure (HF), or severely high PWV, regardless of chronological age. The association between TMAO and vascular damage is particularly strong in the elderly (>65 years).
    2. Biological Age Acceleration: When a biological age test (incorporating markers like CRP, creatinine, and potentially TMAO itself) indicates accelerated aging (high $\Delta$Age), suggesting the individual is biologically vulnerable to the chronic inflammation driven by these metabolites.

9. Can we design personalized stacking strategies (diet + microbiome-targeted agents + canonical geroprotectors) that measurably slow vascular aging, not just shift metabolites?

Yes, this is the current objective of Precision Geromedicine.

Personalized stacking strategies are designed to address the interconnected hallmarks of aging (inflammation, senescence, metabolic dysfunction) using multiple targeted interventions.

  • Strategy Components:
    • Metabolite Shifting (Microbiome Target): Strict, personalized dietary control (based on genetic and microbiome profiles) + specific fiber/prebiotic/probiotic strains (e.g., Akkermansia, Bifidobacterium supplementation) to reduce TMAO/PAGln.
    • Senescence & Metabolism (Canonical Geroprotectors): Adding SGLT2 inhibitors (to reduce SASP/activate AMPK) and/or Rapalogs (to modulate mTORC1) to target the cellular consequences of microbial metabolites.
  • Measurable Outcomes: The success of this stacking approach should not rely on metabolite levels alone, but on measurable slowing of vascular aging, tracked by:
    • Improved Endothelial Function (FMD)
    • Reduced Arterial Stiffness (PWV)
    • Reduction in chronic, low-grade inflammation (CRP/IL-6)
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#3

TMAO is likely bad, but it seems TMA might have positive uses by the body, as well:

Using mice, human cell models, and molecular target-screening, the scientists found that when the nutrient choline hits the gut, microbes convert it into a metabolite called trimethylamine (TMA). TMA, in turn, binds to IRAK4, blocks its activity, reduces inflammation, and restores insulin sensitivity.

Maybe there’s a threshold effect, whereby if you are below the threshold, then TAM helps you; but then if you are above it, you get excess TMAO and that increases CVD.

#4

“Common nutrient turns our guts into diabetes-fighting chemical factories”.

Summary: ChatGP 5 (Paid)

When you consume choline (from supplements or foods such as eggs, meat, lecithin), it enters the gut, where certain bacteria metabolize it into trimethylamine (TMA).

Traditionally, TMA is known as the precursor of TMAO (trimethylamine-N-oxide), which has been controversially linked to cardiovascular risk.

But this study introduces a new, different mechanism:

Gut microbes convert choline → TMA.

TMA binds directly to IRAK4, a key kinase in the inflammatory signaling pathway (MyD88 → IRAK4 → NF-κB).

When TMA blocks IRAK4, the inflammatory cascade is reduced.

Less inflammation improves insulin sensitivity, at least in mice and human cell models.

In short:

Choline → TMA → inhibits IRAK4 → lowers inflammation → improves insulin signaling.

This is essentially an anti-inflammatory mechanism opposite of what earlier TMA/TMAO theories suggested.

About IRAK4 (why blocking it matters)

IRAK4 (Interleukin-1 Receptor–Associated Kinase 4) is a central switch in innate immunity and chronic inflammation:

When Toll-like receptors (TLRs) detect stress or pathogens, IRAK4 activates NF-κB, producing cytokines like IL-1β and TNF-α.

Chronic overactivation of IRAK4 contributes to:

  • metabolic inflammation
  • insulin resistance
  • obesity-associated metabolic dysfunction
  • autoimmune disorders

Pharmaceutical companies already develop IRAK4 inhibitors for metabolic and inflammatory diseases.

This research suggests that TMA acts as a natural IRAK4 inhibitor.

Key implications of the study

:heavy_check_mark: 1. It challenges the idea that all TMA/TMAO is harmful

The cardiovascular-risk narrative around TMAO has been controversial.

This study underscores that TMA may have therapeutic anti-inflammatory effects, at least in metabolic pathways.

:heavy_check_mark: 2. It reframes choline as potentially metabolically beneficial

Choline intake may:

  • reduce low-grade systemic inflammation
  • improve insulin signaling
  • support hepatic fat metabolism (choline deficiency causes fatty liver)
  • This aligns with rodent research showing choline supplementation prevents diet-induced metabolic dysfunction.

:heavy_check_mark: 3. It highlights the importance of which gut microbes process choline

Not all microbiomes will generate the same TMA profile.

This could explain:

  • why choline affects individuals differently
  • why some people produce high TMAO while others do not
  • why metabolic responses vary dramatically between subjects

Future therapeutic directions may include:

  • microbiome engineering
  • probiotics that produce favorable TMA levels
  • or modulating TMA conversion without increasing TMAO.

Caveats

Before interpreting this as proof that choline improves insulin resistance in humans:

The study is preclinical (mice + human cells).

TMA was shown to inhibit IRAK4, but TMAO may behave differently.

Human metabolic outcomes depend heavily on:

  • liver conversion of TMA → TMAO
  • kidney clearance
  • microbiome composition
  • diet interactions

Nonetheless, the mechanism is compelling.

Bottom Line

This research supports the idea that choline may have anti-inflammatory and pro-metabolic effects, mediated indirectly through microbial production of TMA, which acts as a natural IRAK4 inhibitor.
TMA Production Ranking (Highest → Lowest) Choline salts (bitartrate, chloride, citrate)

Added question response:
FWIW: ChatGPT 5 response:

Best Dose Range for High TMA but Low TMAO

→ 250–350 mg of choline bitartrate once daily

"This range reliably increases gut TMA production, but only mildly increases TMAO in most adults. This is the “sweet spot” "

Recommended Plan:

→ 300 mg choline bitartrate with food once daily

Why with food?

  • Slows absorption
  • Reduces the sharp TMAO conversion spike
  • Increases microbial access to choline (more TMA)
  • Produces a smoother, lower TMAO curve

Why not on an empty stomach?

Faster absorption → more choline bypasses the colon → less TMA but more TMAO.

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