@bryan_johnson: I'm starting a new longevity p...

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I'm starting a new longevity protocol: microdosing Tirzepatide, a dual GLP-1/GIP receptor agonist.

Here is the existing evidence, my protocol, measurement plan, and what I expect to achieve by this intervention.
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1/ Here’s what I’m doing and why:

What is a GLP-1RA?
A GLP-1-RA is a medication that mimics the hormone glucagon-like peptide-1, crucial for regulating blood sugar and appetite. They’re approved for managing type 2 diabetes and aiding in weight loss by reducing blood sugar levels and increasing the feeling of satiation by extending the time of digestion in the stomach.

The use of GLP-1a has surged, with a 700% increase from 2019 to 2023 among U.S. patients without diabetes but who are overweight or obese. (1)

These medications are approved for managing type 2 diabetes (e.g. Ozempic) and, in higher doses, to support weight loss in people with excessive weight (e.g. Wegovy).

Robust evidence indicates that GLP-1 agonists have a rejuvenating and anti aging effect in obese people. (2)

More recent evidence suggests a potential for GLP-1 agonists in preventing age related disease in non-obese people too, as was demonstrated that its effect in reducing Alzheimer disease risk outweighed all other diabetes medications with similar risk reduction in normal weight and obese participants (3).

There has been growing scientific data suggesting that these meds are also beneficial for longevity via several mechanisms that are independent from weight loss.

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2/ Metabolic and Longevity Benefits

Metabolic Optimization: Less glucose spikes, lower insulin levels, and thus reduced advanced glycation end-products (AGEs) (4, 5).

Anti-Inflammatory Effects: Systemic inflammation reduction by decreasing pro-inflammatory cytokines like TNF-α and IL-6, and improving gut microbiota, thereby reducing systemic immune activation (6, 7).

Mitochondrial Health: Enhanced mitochondrial biogenesis and function, prevention of mitochondrial dysfunction, reduced reactive oxygen species (ROS), and improved cellular energy metabolism (8, 9).

Caloric Restriction Mimicry: Mimics metabolic effects of caloric restriction, including reduced mTOR signaling, enhanced autophagy, and improved metabolic flexibility (10).

Multi-organ rejuvenation a new pre-print demonstrated that GLP1-RA in mice had comparable effects to mTOR inhibition by rapamycin (a well established rejuvenation intervention in mice) in reversing biological aging across multiple organs as evaluated using epigenetic biological age clocks.(11)

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3/ Possible Chronic Disease Risk Reduction

Cardiovascular Health: semaglutide a GLP-1-RA has shown promise of lifespan extension in obese individuals by reducing the risk of cardiovascular disease. (12)

Preclinical evidence also indicates improved endothelial function via increased nitric oxide production, reduced arterial stiffness, lower blood pressure, and enhanced lipid profiles with decreased LDL and triglycerides. (13)

Neuroprotection: a recent clinical study presented the first evidence in humans of GLP1-RA outperforming other treatment options in preventing the onset of Alzheimer disease in type-2 diabetes patients. This is also the first evidence of GLP1-RAs reducing the risk of an age-related disease independent of obesity and weight reduction (3).

I highlighted this exciting finding in a previous post

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Pre-clinical research on GLP1-RAs suggests potential cognitive preservation through reduced amyloid-beta accumulation, decreased neuroinflammation, enhanced synaptic plasticity, and improved mitochondrial function in neurons. (14, 15).

Cancer Risk Reduction: Lower risk of obesity-related cancers through reduced systemic inflammation and insulin levels, and suppression of pro-growth pathways like IGF-1 and mTOR (16).

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4/ My Microdosing Protocol

To evaluate the potential benefits I will start a 12 week trial of the GLP-1/GIP RA Tirzepatide (Commercial name: Munjaro for diabetes, Zepbound for weight loss).

I'll start with a weekly dose of 0.5 mg, that is 1/2 the typical microdose, and 1/5 of the typical starting does for type-2-diabetes or weight loss (17).

Why Microdosing?
As someone already metabolically healthy and in the lowest 1% of body fat content, my goal isn’t weight loss.

Microdosing allows me to harness the potential longevity benefits of GLP-1RA while minimizing side effects and avoiding unwanted weight or muscle loss.

Why Trizepatide?
Trizepatide activates both GLP-1 and GIP-1 receptors, leading to synergistic effects in lowering blood glucose, suppressing appetite, weight loss and cardiovascular protection (18, 19).

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5/ Monitoring Potential Side Effects

Even with microdosing, it’s essential to monitor for:

Gastrointestinal Issues: Nausea and vomiting are common but less likely at low doses.

Unintended Weight Loss: Increased satiety could lead to unintentional caloric restriction, I intend to stick to my 10% caloric restriction regimen. I will be watching out diligently for subcutaneous fat loss, especially in the face.

Muscle Mass Concerns: There’s potential for muscle wasting, possibly higher than expected from caloric restriction alone, typically people on GLP-1-RA tend to consume less protein due to appetite loss.

Being on the Blueprint stack I do not have to worry about this, as every calorie and macromolecule I take is calculated.

Thyroid Health: A small risk of medullary thyroid carcinoma has been noted in animal studies, though not definitively in humans

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6/ How Do we Measure Success:

I’ll perform the following tests, implement my microdosing protocol, then retest after 12 weeks to determine success of the intervention.

Metabolic Health:

+ Continuous glucose monitoring: Mean glucose, variability, peaks.

+ Insulin, HbA1c, fasting glucose, ApoB, and triglycerides.

Inflammatory Markers:
+ hs-CRP, IL-6, TNF-alpha.

Biological Age:
+ Epigenetic clocks: for speed of aging and organ biological ages.

Body Composition:
+ Whole-body MRI for visceral, subcutaneous and organ fat metrics, as well as lean (muscle) mass.

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7/ Conclusion

Microdosing GLP-1-RAs represents a promising approach to leverage their potential longevity benefits while minimizing risks. Ongoing monitoring and consultation with healthcare professionals are crucial to ensure safety and efficacy.

@bryan_johnson: I'm starting a new longevity p...

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