Exercise in a Pill? Ketone Body β-Hydroxybutyrate "De-Ages" the Liver via cGAS-STING Inhibition

#1

In a compelling new study from the Shanghai University of Sport (China), researchers have potentially cracked the code on how aerobic exercise protects the liver from aging—and how a simple metabolite might mimic this effect without a single step on the treadmill. Published in Aging Cell, the study identifies β-Hydroxybutyrate (BHB)—the body’s primary ketone produced during fasting or intense exercise—as a potent “exercise mimetic.”

The “Big Idea” here moves beyond the traditional view of ketones as merely alternative fuel. The researchers discovered that aging livers suffer from mitochondrial dysfunction, which causes them to leak mitochondrial DNA (mtDNA) into the cytosol. This leakage triggers the cGAS-STING pathway, an innate immune alarm system that mistakes the stray DNA for a virus, driving chronic inflammation (inflammaging) and liver degeneration.

Crucially, the study demonstrates that BHB directly inhibits this cGAS-STING activation. By administering exogenous BHB to naturally aged mice, the researchers were able to “de-age” the liver, restoring mitochondrial homeostasis, shifting macrophages from a pro-inflammatory (M1) to a restorative (M2) state, and reducing cell death (PANoptosis). The implication is profound: BHB supplements could theoretically offer a “biochemical bypass” to obtain specific anti-inflammatory benefits of exercise, particularly for populations unable to perform rigorous physical activity.

Open Access Research Paper: β-Hydroxybutyrate Acts as an Exercise Mimetic to Protect the Aging Liver

  • Institution: Shanghai University of Sport, China.
  • Journal: Aging Cell (Wiley).
  • Impact Evaluation: The impact score of this journal is ~8.0 (2023 JIF), evaluated against a typical high-end range of 0–60+ for top general science (e.g., Nature is ~64). Therefore, this is a High impact journal, ranking in Q1 for Cell Biology and Geriatrics.

Study Design Specifications

  • Type: In vivo (Murine) and In vitro (Cellular Senescence models).
  • Subjects:
    • Species: Mice (Mus musculus).
    • Strain: C57BL/6 (Standard model for aging).
    • Group: Naturally aged mice (likely 18-24 months) vs. Young controls.
    • Intervention: Intraperitoneal (IP) injection of β-Hydroxybutyrate (200 mg/kg) vs. Saline control.
  • Lifespan Data:
    • Global Lifespan: Not Measured in this specific study (endpoint was liver pathology).
    • Context: Previous studies (e.g., Roberts et al., 2017) have shown BHB/Ketogenic diets can extend median lifespan in mice by ~13%, but this paper focuses strictly on liver healthspan and organ-specific pathology.

Mechanistic Deep Dive

The authors map a precise longevity pathway that validates the “Mitochondrial-Inflammation” theory of aging:

  1. The Trigger: Aging leads to mitochondrial membrane permeability.
  2. The Signal: Mitochondrial DNA (mtDNA) leaks into the cytosol.
  3. The Alarm: cGAS-STING (Cyclic GMP-AMP Synthase - Stimulator of Interferon Genes) detects this DNA.
  4. The Damage: This activates NF-κB and IRF3, polarizing Macrophages to the M1 (inflammatory) phenotype, causing liver steatosis (fatty liver) and fibrosis.
  5. The Fix (BHB): BHB blocks this cascade upstream by stabilizing mitochondrial quality control and directly inhibiting STING activation.
  • Organ Priority: Liver (Hepatic aging is a central driver of systemic metabolic dysfunction).

Novelty

We knew BHB was anti-inflammatory (via NLRP3 inflammasome inhibition), but this paper links it specifically to the cGAS-STING pathway in the context of mitochondrial DNA leakage. This provides a new, specific molecular target for why ketones reduce “sterile inflammation” in aging tissues.

Critical Limitations

  • Route of Administration: The study used Intraperitoneal (IP) injections, which bypass digestion. Oral bioavailability of ketone salts/esters is good but not identical to IP.
  • No Survival Curve: We do not know if this liver rescue translates to longer overall life for these specific mice.
  • Mitochondrial Specificity: It is unclear if BHB repaired the mitochondria or just masked the signal of their failure (blocking the smoke alarm rather than putting out the fire), though data suggests some restoration of homeostasis.
  • Sex Bias: Many murine longevity studies show sex-dimorphic effects (e.g., 17α-estradiol works only in males). The summary does not explicitly confirm if both sexes were equally responsive.

Part 3: Actionable Intelligence

The Translational Protocol (Rigorous Extrapolation)

1. Human Equivalent Dose (HED)

The study used 200 mg/kg via IP injection in mice.

  • Calculation: Mouse Dose (200 mg/kg) × (Mouse Km [3] / Human Km [37]) = 16.2 mg/kg.
  • For a 75 kg Human: 16.2×75=1,215 mg (approx. 1.2 grams/day).
  • Correction Factor: Since the study used IP (100% absorption) and oral bioavailability of BHB salts is high but slower, a safety buffer of 2x is reasonable for oral supplementation.
  • Target Oral Dose: 2.5 – 3.0 grams of BHB per day.
    • Note: This is significantly lower than the 10–30g doses often used for “nutritional ketosis” or weight loss, suggesting a signaling effect rather than a metabolic fuel effect.

2. Pharmacokinetics (PK/PD)

  • Half-Life: Endogenous BHB has a short half-life (min to hours). Exogenous ketone salts/esters peak in blood within 30–60 minutes and return to baseline within 3–4 hours.
  • Dosing Strategy: To mimic the “exercise” pulse seen in the study, a single bolus dose before a fasted period or prior to light activity may be optimal, rather than trickling it in throughout the day.

3. Safety & Toxicity Check

  • NOAEL: BHB is a breakdown product of fat; the body handles it naturally. NOAEL for ketone esters is high (>5g/kg in rats).
  • Safety Signals:
    • Kidney Load: High doses of ketone salts (e.g., Na-BHB, Ca-BHB) deliver massive mineral loads. Avoid sodium-based salts if hypertensive. Use Magnesium/Potassium salts or Ketone Esters.
    • Ketoacidosis: Virtually impossible in non-diabetics with supplements alone (levels reach ~1-3 mM; ketoacidosis is >15-20 mM).
    • Data Absent: Long-term impact of constant mTOR suppression via cGAS-STING modulation is unknown.

Biomarker Verification Panel

  • Efficacy:
    • hs-CRP: Should decrease if systemic inflammation is blunted.
    • ALT/AST & GGT: Liver enzymes should improve (lower) if the “aging liver” protection is working.
    • Circulating mtDNA: (Advanced) Specialized labs can measure cell-free mitochondrial DNA; this should decrease.
  • Safety Monitoring:
    • Electrolytes: If using salts, monitor Sodium and Potassium.
    • eGFR: Monitor kidney function due to salt load.

Feasibility & ROI

  • Sourcing: Commercially available as Ketone Salts (cheaper, salty) or Ketone Esters (expensive, bad taste, potent).
    • Recommendation: Ketone Esters (e.g., R-1,3-butanediol monoester) are chemically closer to the bioactive form without the salt load.
  • Cost: ~$3–$5 per serving.
    • Monthly Cost: ~$100–$150.
  • ROI: High for those with NAFLD (fatty liver) or high inflammatory markers. Medium for healthy optimizers (exercise is free and does more).

Population Applicability

  • Contraindications:
    • SGLT2 Inhibitors (Jardiance, etc.): HIGH RISK. Combining SGLT2i + Ketones increases risk of euglycemic diabetic ketoacidosis.
    • Severe Renal Impairment: Avoid salt-based ketones.
  • Target Audience: Aging individuals with elevated liver enzymes, metabolic syndrome, or inability to exercise (sarcopenia/injury).

Part 4: The Strategic FAQ

Q1: Can I just eat a Ketogenic Diet (Keto) instead of taking supplements? Answer: Yes, but with caveats. A strict keto diet elevates endogenous BHB to 0.5–3.0 mM, matching the study’s effective range. However, the study used a pulseof BHB (mimicking exercise). Constant ketosis has different long-term effects (e.g., potential lipid issues) than the pulsatile signaling provided by supplements or exercise.

Q2: Does this replace the need for Zone 2 cardio? Answer: No. [Confidence: High]. While BHB mimics one pathway (cGAS-STING inhibition) of exercise, it does not replicate hemodynamic flow, VO2 max improvement, muscle mechanotransduction, or neurotrophic factor release (BDNF) driven by physical movement.

Q3: Is there a conflict with Rapamycin? Answer: Likely Synergistic. Rapamycin inhibits mTORC1; BHB inhibits cGAS-STING and NLRP3. These are complementary anti-aging pathways. No direct negative interaction is known.

Q4: I take Metformin. Is this safe? Answer: Generally Yes. Metformin shifts fuel use toward glycolysis/fat oxidation. Adding ketones provides an alternative fuel source. However, monitor for GI distress, as both can upset the stomach.

Q5: What is the best time of day to take this? Answer: Morning Fasted State. To mimic the “exercise” effect and maximize mitochondrial biogenesis signaling, take it when insulin is low. Insulin spikes inhibit endogenous ketone production.

Q6: Why did they use injections (IP) instead of oral dosing? Answer: Precision. In mouse studies, IP injection ensures 100% of the dose enters circulation immediately, bypassing variations in absorption or gut microbiome degradation. Oral dosing in humans requires higher doses to achieve similar blood peaks.

Q7: Will this work for alcohol-induced liver damage? Answer: Speculative but Plausible. [Confidence: Medium]. The mechanism (blocking inflammation from damaged mitochondria) overlaps with alcohol pathology. However, BHB does not remove the toxic acetaldehyde produced by alcohol.

Q8: Does BHB affect sleep? Answer: Variable. Some users report increased alertness (norepinephrine release), while others find the GABAergic effects (BHB can convert to GABA precursors) sedating. Avoid taking it immediately before bed initially.

Q9: Can I use “Raspberry Ketones”? Answer: NO. [Confidence: High]. “Raspberry Ketones” are a marketing scam; they are structurally unrelated to physiological BHB and have no effect on cGAS-STING or ketosis. You must use Beta-Hydroxybutyrate salts or esters.

Q10: What is the “Panoptosis” mentioned in the study? Answer: Cell Death Trifecta. PANoptosis is a newly defined, regulated cell death pathway that integrates components of Pyroptosis (inflammatory), Apoptosis (suicide), and Necroptosis (uncontrolled). BHB stopping this suggests it preserves liver mass profoundly, not just by stopping one type of death, but by stabilizing the master switch.

Related Reading:

1 Like
#2

This is a really solid paper, and I think it adds important clarity to why sterile inflammation ramps with age, especially in metabolically dense organs like the liver. What stood out to me is that the pathology here isn’t “STING being bad,” it’s “mitochondria behaving badly” and repeatedly tripping an otherwise appropriate innate immune alarm.

BHB’s ability to dampen cGAS–STING signaling is compelling, particularly as a short-term or situational intervention (fasting, exercise states, metabolic stress). That said, I see BHB more as a signal modulator than a full architectural fix.

Rapamycin, by contrast, seems to operate one layer upstream:
– improving mitophagy
– reducing the persistence of dysfunctional mitochondria
– lowering mtDNA leakage in the first place
– and thereby functionally quieting chronic cGAS–STING activation without disabling the pathway itself.

In other words, BHB appears to mute the alarm, while rapamycin reduces the number of false alarms being generated.

For aging biology, where immune competence still matters, that distinction feels important. Chronic STING suppression could create blind spots over time, whereas restoring mitochondrial quality control reduces the need for suppression altogether.

I actually see these as complementary rather than competing: BHB as an acute metabolic/anti-inflammatory signal, rapamycin as a long-term systems stabilizer.

If the goal is durable healthspan rather than organ-specific rescue, fixing mitochondrial turnover upstream seems like the strategy with better compounding potential.

3 Likes
#3

If you take retatrutide, you’re already producing elevated levels of bhb, after 24 weeks of treatment.

IMG_6118
IMG_61181206×696 434 KB

Basically, you are in mild ketosis, even if not adhering to a ketogenic diet, without the drawbacks of such diet, like diet adherence and possible lipid issues.

Full Presentation here Media Centre | EASD

I have not seen similar data for dual GCGR agonists like mazdutide and survodutide, but I would speculate a similar rise in endogenous bhb production.

2 Likes
#4

Wow, the more I read about Reta the more it sounds like a miracle drug. Stopping Tirze and starting Reta this week. I have a question though: I have been on Tirze for over 8 months and have lost some decent weight (most in the first 4 months), still need to lose another 10-15Lbs. I have been on 8-9mg Tirze for last 2 months or so and have stalled. Here is my question:

If I stop Tirze, should I start Reta at the minimum suggested dose (2.5mg) or is that too low since I’ve been on Tirze doing somewhat of a high dose? In other words, if I were to do equivalent of my Tirze dose on Reta I would have to start at 6-7mg, or should I just ignore the equivalent of Tirze and just start fresh with RETA?

#5

I would really like to take BHB every morning. In the past, I tried a couple of different brands but I could not stomach taking BHB every morning.
The stuff tastes awful and ruins the taste of whatever you put it in. Usually, I can put some nasty stuff in my coffee because I usually drink it black, and it masks the bad flavor somewhat.

If anyone has found a good way to take BHB, please share.

#6

Interesting.

In a recent interview on the Drive Podcast, Dom D’agastino says he prefers salts over esters because the latter may spike ketone levels quickly: https://youtu.be/jW0cVEgW9YY?si=iK6h-Hirz7q7DNdq&t=5659

So maybe the pasted recommendation about being careful about dosage, by for example, using it before activities may be better.

#7

I would start fresh to gauge your tolerance of side effects. You could do 2mg on week 1, then increase your dose by 1 or 2mg the next week. I don’t have a good suggestion of a good dose to get to, but the 4mg seems to be a good first therapeutic dose, and the 6-8mg dose seems to be a sweet spot for many.

No need to gradually titrate down on tirzepatide. Coming from tirzepatide, you might notice less appetite suppression, that’s normal. Appetite suppression is not an indication of more weight loss anyway

BTW, the dosing schedule is 2,4,6,9,12.

1 Like
#8

More good news on BHB, an October’25 paper, but its more complex than just “drink your ketones”:

Exercise Mimetics: The “Ketone Signal” That Reverses Brain Aging

The Big Idea: We’ve known that aerobic exercise fights brain aging, but the molecular “messenger” has been elusive. This study identifies β-hydroxybutyrate (β-HB)—the primary ketone body produced during fasting or exercise—as that critical messenger. However, it’s not just fuel; it’s a signal. The researchers demonstrate that β-HB activates a specific receptor (GPR109A) on neurons, triggering a nuclear chain reaction (via PPAR$\gamma$) that slashes neuroinflammation and boosts BDNF (Brain-Derived Neurotrophic Factor).

The Twist: They didn’t just watch it happen; they broke it to prove it works. Using genetically modified mice missing the ketogenic enzyme BDH1, they showed that without the ability to naturally produce and process ketones, exercise fails to improve cognition. Crucially, simply injecting ketones into these “broken” mice didn’t work either—suggesting that your body’s metabolic machinery must be intact to benefit from exogenous ketone supplements. This challenges the popular “drink your ketones” biohack for those with underlying metabolic dysfunction.

Open Access Research Paper: Exercise-induced β-hydroxybutyrate contributes to cognitive improvement in aging mice
Impact Evaluation: The impact score of this journal is ~10.3 (CiteScore ~10.8), evaluated against a typical high-end range of 0–60+ for top general science. Therefore, this is a High impact journal (Q1 in Sport Sciences).

Novelty & Critical Insight

  • The “Metabolic Competence” Requirement: This is the most critical finding for biohackers. In BDH1 KO mice, the GPR109A receptor was downregulated. Consequently, exogenous ketones failed to improve cognition and actually exacerbated inflammation in these compromised animals.
  • Implication: You cannot simply “bypass” a broken metabolism with supplements. If your endogenous ketogenic machinery (BDH1 expression) is compromised (potentially by severe metabolic dysfunction or liver disease), your cells may lack the receptor density (GPR109A) to “hear” the signal from the exogenous ketones.

The Strategic FAQ

Q1: This study identified GPR109A as the receptor. Isn’t that the “Niacin Receptor”? A: Yes. Niacin (Nicotinic Acid) is a potent GPR109A agonist. Theoretically, low-dose Niacin (enough to cause a mild flush) activates the same pathway. However, β-HB activates it without the intense prostaglandin-mediated flushing that limits Niacin compliance.

Q2: Should I stack this with Rapamycin? A: Likely Yes. Rapamycin inhibits mTOR; Ketogenic diets/signaling typically inhibit mTOR in the brain while preserving mitochondrial function. There is no direct mechanistic conflict; in fact, they may be synergistic in suppressing senescent cell phenotypes (SASP).

Q3: Can I verify BDH1 status in humans? A: Not easily outside of a liver biopsy. However, Metabolic Flexibility is a proxy. If you cannot easily switch to fat burning (e.g., you get “hangry” or hypoglycemic easily during short fasts), your BDH1/Ketolysis machinery may be sluggish.

Q4: Does this mean I don’t need to exercise if I take Ketones? A: No. The study showed Exogenous β-HB mimickedthe cognitive gains, but exercise activates dozens of other pathways (myokines, vascular shear stress) that ketones alone do not. Use ketones to augment or as a bridge on non-training days.

Q5: The HED is only ~1.2g. Commercial supplements recommend 10g+. Why the discrepancy? A: Commercial doses aim for metabolic fuel (ATP generation) or appetite suppression. This study identifies a signaling effect (hormetic trigger). Biology often uses low doses for signaling and high doses for fuel. The signaling benefit likely saturates early.

Q6: Is there a risk of “Euglycemic Diabetic Ketoacidosis” if I take this with Metformin? A: Low Risk. Metformin + Low Dose Exogenous Ketones is generally safe. The dangerous trio is SGLT2 Inhibitors + Ketones + Low Insulin. If you are on an SGLT2 inhibitor (Jardiance, Farxiga), consult a physician before adding ketones.

Q7: Will this work if I eat a high-carb diet? A: Uncertain. High insulin suppresses endogenous ketogenesis and can downregulate PPAR gamma. The “signal” (ketone) might fight an uphill battle against the “noise” (insulin/inflammation) of a high-carb diet.

Q8: Why did the BDH1 Knockout mice get worse with ketones? A: Without BDH1, the liver couldn’t clear the injected ketones, leading to unnaturally prolonged elevation. This metabolic “backlog” likely caused oxidative stress or inflammatory feedback loops. It highlights that clearance is as important as production.

Q9: What is the best time to dose? A: Based on the study’s “post-exercise” data: Immediately post-workout (to amplify the natural spike) or Morning fasted (to mimic the overnight fasting state).

Q10: Salts vs. Esters? A: The study used Salts (Sodium β-HB). Esters are more potent but taste horrible and are costly. Given the low dose required for the signaling effect, Salts are the logical, practical choice.

#9

Soda stream is the answer. I used to put a scoop each of mg,Na, and K BHB in with a mix that is artificially sweetened and flavored like bomb pops. Tiny amount of the mix, less than half a scoop. So that lasts more than a month. A couple weeks ago the bomb pop mix ran out and I thought it would be a disaster, which it was plain, but if you carbonate it tastes great. So don’t really need the mix, but it’s better. Really a treat actually I’m not suffering at all. Use cold water from the fridge, it carbonates better.

1 Like