Noob Urolithin-A benefits question

General
1

Hi. I recently ordered the Healthspan Urolitihin-A. It’s only been a few weeks. I know the research indicates changes after one to two months. Just curious if anyone has been taking it for longer and what effects do you experience?
I also see that most of the research has higher daily dosages (eg., 1 gm/day) than the prescription.

2

i just started Urolithin A from Timeline and no noticeable changes so far

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I curious what research have you found on it? What daily dosage was in the research?

4

Hello! This is Brandon from the Healthspan Clinical Team. Below is some of the foundational research we aggregated upon launching our Urolithin A protocol. Most research ranges in dosing from 500-1,000mg/day, depending on the population/activity level of folks.

Preclinical Animal Studies:

  1. Duchenne Muscular Dystrophy (DMD) Study by Luan et al. (2021):
    • Objective: Investigated whether UA could stimulate mitophagy in DMD, a genetic disorder that causes muscle degeneration due to defective mitochondrial function.
    • Key Findings:
      • In mouse models and human muscle cells, UA improved mitochondrial cleaning and enhanced oxygen utilization in muscle cells.
      • These improvements suggest UA could reduce DMD symptoms by promoting the removal of dysfunctional mitochondria, thus supporting healthier muscle cells.
  2. Metabolic Cardiomyopathy (MC) Study by Huang et al. (2023):
    • Objective: Examined whether UA could restore mitophagy and improve mitochondrial function in obese mice with MC, a condition caused by fat accumulation in heart cells.
    • Key Findings:
      • UA improved mitophagy, reducing fat buildup in heart cells and improving heart function.
      • When mitophagy was blocked in experiments, the protective effects of UA were diminished, confirming that UA’s benefits are largely due to enhanced mitochondrial recycling.

Human Studies:

  1. Singh et al. (2022):
    • Objective: Studied the effect of UA (sold as Mitopure) on mitophagy and muscle function in middle-aged adults over four months.
    • Key Findings:
      • Participants taking UA showed improved mitophagy, muscle strength (12% increase), and aerobic endurance (measured through VO₂ max and the 6-minute walk test).
      • Lower levels of plasma acylcarnitines (fat transport molecules) and C-reactive proteins (inflammation markers) were observed, indicating improved mitochondrial function and reduced inflammation.
  2. D’Amico et al. (2022):
    • Objective: Explored whether UA could help treat osteoarthritis (OA) by enhancing mitochondrial function in joint tissues.
    • Key Findings:
      • UA improved mitochondrial respiration in human knee joint cells and reduced cartilage degradation, inflammation, and pain in mouse models of OA.

Comparative Analysis of UA vs. Other Mitophagy Inducers:

  • Rapamycin:
    • Rapamycin is a well-known mitophagy inducer that strongly inhibits mTOR, leading to autophagy. However, this strong mTOR inhibition can affect many other cellular processes, potentially leading to side effects.
    • UA’s Advantage: UA activates mitophagy without strongly inhibiting mTOR, making it a more targeted approach with fewer risks of side effects related to mTOR suppression.
  • Nicotinamide Riboside (NR) and Nicotinamide Mononucleotide (NMN):
    • Both NR and NMN work by increasing NAD+ levels, which are important for mitochondrial energy production. These compounds activate sirtuins, proteins that regulate mitochondrial health.
    • UA’s Unique Action: Unlike NR and NMN, UA does not rely on NAD+ to promote mitophagy but directly activates it via AMPK and other pathways.
  • Resveratrol: Activates sirtuin 1 (SIRT1), which supports mitochondrial biogenesis (the creation of new mitochondria). However, resveratrol’s role in mitophagy is less understood compared to UA, which more specifically targets mitochondrial recycling.
  • Spermidine: Induces autophagy in a broader sense but is less targeted toward mitophagy compared to UA.

Future Directions and Research:

  • Longitudinal Studies: More research is needed to evaluate the long-term effects of UA in humans, especially at higher doses.
  • Gut Microbiota Variability: Research on how variations in gut microbiota influence UA’s effectiveness is crucial for personalized dosing and effectiveness.
  • Mitophagy Assessment Tools: New techniques like MitoQC, which can visually track mitophagy in real-time, are needed to better understand how UA promotes mitophagy in humans.
  • New Applications: UA’s potential in cancer treatment, athletic recovery, and personalized medicine is worth exploring, particularly in combination with other compounds like rapamycin or NAD+ boosters.

Mechanism of Mitophagy:

  • PINK1/Parkin Pathway:
    • PINK1 (PTEN-induced kinase 1): This is a protein that acts as a sensor for mitochondrial health. In healthy mitochondria, PINK1 is imported into the mitochondria and quickly degraded. But when mitochondria become damaged (for example, due to stress or ROS buildup), PINK1 accumulates on the outer membrane of the mitochondria.
      • Why does this happen? Damaged mitochondria lose their membrane potential (the difference in charge across the mitochondrial membrane). This loss of membrane potential prevents PINK1 from being imported and degraded inside the mitochondria, causing it to accumulate on the surface as a signal for damage.
    • Parkin: Once PINK1 accumulates, it recruits another protein called Parkin. Parkin is a type of enzyme (called a ubiquitin ligase) that “tags” the damaged mitochondria with small proteins called ubiquitins. This tagging process (called ubiquitination) marks the mitochondria for degradation.
      • What is ubiquitination? Ubiquitination is the process by which the cell attaches ubiquitin molecules to proteins or organelles that are destined for destruction. Think of it like putting a “trash tag” on something so the cell knows to dispose of it.
    • Autophagosome Formation: Once tagged, the damaged mitochondria are engulfed by structures called autophagosomes. These are double-membraned vesicles (like bubbles) that wrap around the mitochondria, eventually fusing with lysosomes (organelles containing digestive enzymes) to break down and recycle the mitochondria.
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Hi Moos. This is totally anecdotal, but I started taking Urolithin A (1000mg/d) 1 year ago after listening to a Peter Attia podcast that had a guest that was convinced it is the best thing since sliced bread ; ). I am an athlete and I do feel like my general endurance has been positively impacted by the addition of urolithin A. I seem to survive longer in hard, 3-hour race efforts without cramping or bonking. Again, this is highly subjective and and a N=1, so take it with a grain of salt.

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