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Microdosing GLP-1 for Longevity: Emerging Science
GLP-1 (Glucagon-like Peptide-1) is a hormone found in the stomach. GLP-1 has several functions regarding glucose metabolism. GLP-1 stimulates insulin release and slows down the digestion of food. Therefore, GLP-1 reduces the desire to eat because food stays in the stomach longer. GLP-1 is responsible for the sensation of satiety or feeling full.
Original purpose for developing GLP-1 medication
The original purpose for developing GLP-1 medications was to help manage blood sugar levels in patients with type 2 diabetes. The FDA approved the first GLP-1 medication for use in treating type 2 diabetes in 2005. However, it was discovered shortly thereafter that GLP-1 medications also induced significant weight loss in diabetic patients. As a result, the FDA approved GLP-1 medications for the treatment of obesity.
Purpose of GLP-1 and GIP Combination Medications
Tirzepatide is a medication that combines GLP-1 with GIP. Tirzepatide is a newer medication that has been shown to produce stronger metabolic effects and greater weight loss compared to medications that only contain GLP-1.
Reason Why Longevity Advocates Are Interested in GLP-1
Longevity advocates, such as Bryan Johnson, are interested in GLP-1 medications for reasons other than weight loss. There are several proposed mechanisms. One is related to chronic inflammation. Low-grade chronic inflammation has been demonstrated to contribute to aging, cardiovascular disease, and mortality. GLP-1 medications have shown anti-inflammatory effects in both animal and human studies. Another reason is related to caloric restriction. Caloric restriction has been demonstrated to extend life span in many types of organisms. Caloric restriction appears to work through pathways such as mTOR. mTOR is a pathway that controls cell growth and repair. Cells grow and repair based on their nutritional environment. When nutrients are abundant, mTOR promotes cell growth; when nutrients are scarce, mTOR promotes cell repair. By decreasing hunger and promoting reduced caloric intake, GLP-1 medications potentially simulate the biological signals generated by caloric restriction.
What Caloric Restriction Research Shows
Studies have shown that caloric restriction has beneficial effects on metabolic health and increases life span in animal models. Some human studies have demonstrated similar effects. A two-year trial tested a 25% reduction in calories and demonstrated improved metabolic profiles among test subjects. Blood pressure decreased, LDL cholesterol decreased, and fasting glucose decreased. Test subjects also lost weight, however, even after accounting for weight loss, some metabolic improvements persisted. These data suggest that caloric restriction itself may promote some aspects of health regardless of whether weight loss occurs.
Animal Studies Showing Effects of GLP-1 Medication
Recent studies have examined the effects of GLP-1 medication in animal models. These studies involved administering low doses of GLP-1 medication that resulted in minimal effects on food consumption and body weight. By minimizing effects on food consumption and body weight, researchers were able to examine the effects of GLP-1 medication independently of those due to weight loss. Older mice treated with low doses of GLP-1 medications for 30 weeks demonstrated improved function across multiple physiological systems. The changes demonstrated by the older mice treated with GLP-1 medications were consistent with those produced by caloric restriction and by rapamycin, a compound that inhibits mTOR activity. While these findings are encouraging, they are limited to studies in animals.
Why Microdosing Appears Appealing
Bryan Johnson took approximately 20% of a standard dose of tirzepatide. The rationale for using a low dose is to exploit any potential anti-inflammatory and/or anti-aging effects of GLP-1 drugs, without causing substantial weight loss. Theoretically, this should minimize risks associated with weight loss in individuals who are already lean. However, the appropriate dose of GLP-1 drugs needed to achieve anti-aging effects is unknown.
Significant Risks Associated with GLP-1 Medications
Loss of Muscle Mass Is the Greatest Concern
Weight loss interventions, including GLP-1 drugs, typically result in significant loss of lean body mass. Lean body mass accounts for 25 to 40% of total body weight. Unintended loss of even a small percentage of lean body mass in already lean older adults or in individuals who are otherwise healthy could increase the likelihood of becoming frail and diminish future quality of life.
Additional Known Side Effects Include:
- Nausea
- Vomiting
- Diarrhea
- Constipation
- Abdominal cramping
- Pancreatitis
- Gallstones
- Kidney damage
- Visual disturbances
- Potential Thyroid Cancer Risk
Although there have been reports of thyroid cancer risk, recent large-scale studies have not provided conclusive evidence of a direct relationship between GLP-1 drug therapy and thyroid cancer risk.
Unknowns Regarding GLP-1 Medication Use in Healthy Adults
Currently, there are no completed studies evaluating the effects of low-dose GLP-1 medications in healthy adults without obesity, diabetes, or other metabolic disorders. Therefore, it is unclear whether:
- Whether low-dose GLP-1 medications will improve longevity
- What dose of GLP-1 medication is required to prevent weight and muscle loss
- Whether side effects occur at lower doses of GLP-1 medications
- What the long-term safety profile of GLP-1 medications will be
A clinical trial is underway to address some of these unknowns. However, the results of this trial are not yet available.
What did Bryan Johnson's study really show?
Johnson ended his study after approximately 3 weeks due to an increase of about 7% in his resting heart rate. An increase in heart rate is associated with the use of tirzepatide; however, Johnson was surprised that this occurred at a relatively small dosage. Even if Johnson had not experienced any adverse reactions from using tirzepatide, a single self-study would be insufficient for providing a basis for medical recommendations. This is because individual reactions to treatments should never be considered representative of the larger population, particularly when two different treatments (in this case, tirzepatide and possibly other GLP-1 drugs) are administered simultaneously.
Practical implications
- Longevity advantages of low-dose GLP-1 drug microdosing are purely theoretical
- There is currently no data on human subjects without obesity or diabetes
- Serious muscle loss is a significant and often overlooked risk
- Side effects can occur at very low doses
- Self-studies in which individuals test their own bodies will not demonstrate whether a medication is safe or effective
Conclusion
GLP-1 medications have changed the way we treat obesity and type 2 diabetes. The potential of GLP-1 medications to improve longevity has yet to be proven. There is currently no scientific evidence supporting the use of low-dose GLP-1 medications to promote healthspan in non-obese, non-diabetic individuals. Therefore, until there is sufficient scientific research demonstrating that the use of these medications has little-to-no risk in healthy people, the risks likely far exceed the hypothetical benefits.
If you want to maximize your health span, the best ways to do so are through the use of low-cost, low-tech, and effective methods of achieving improved healthspan. These include regular physical activity, maintenance of muscle mass, control of blood pressure and lipid levels, and the maintenance of metabolic fitness. Additional related information can be found in when more health testing makes you less healthy, high-protein diets: are they good or bad, and the impact of exercise on aging and maximizing the benefits.