AGE/DOSE
Brain & Neurons

Buck Institute Study Shows Anti-Aging Supplement Urolithin A Extends Lifespan and Counters Alzheimer’s

Urolithin A moderately extends the lifespan of normal mice and reduces Alzheimer’s mouse model pathology.

By Daniel R. Miranda, Ph.D.

Key Points:

  • Urolithin A (UA) extends the lifespan of naturally aged mice by about 19%. 
  • Learning and memory are improved by UA in Alzheimer’s model. 
  • UA reduces Alzheimer’s-related amyloid-beta protein in Alzheimer’s model. 

UA is produced by our gut bacteria after we eat ellagitannin-containing plant foods like pomegranates, strawberries, and walnuts. Large doses of UA have been shown to improve muscle health in older individuals and physical performance in overweight adults. Now, a new study suggests that UA could alleviate Alzheimer’s dementia (AD) and promote longevity. 

Researchers from the Buck Institute for Research on Aging report in GeroScience that UA improves cognitive deficits in a mouse model for AD.  Ballesteros-Alvarez and colleagues also show that UA reduces amyloid-beta plaques, a hallmark feature of AD. Furthermore, UA is shown to extend the lifespan of normal mice, suggesting anti-aging effects that go beyond the brain.  

UA Increases Mouse Lifespan 

The health of our mitochondria is critically important for the health and survival of our cells. Mitophagy is the process of clearing out defective mitochondria to maintain mitochondrial health. Mitophagy, and autophagy — the more general clearance of cellular waste — are implicated in aging and lifespan. Furthermore, UA is known to induce mitophagy. Thus, Ballesteros-Alvarez and colleagues placed 25 mg/kg/day of UA into the food of mice on alternate weeks (1 week on, 1 week off) and compared their survival to mice on a normal diet. They found that UA extended the median lifespan of the mice by 18.75%.  

(Ballesteros-Alvarez et al., 2022 | GeroScience) Urolithin A (UA) Extends Lifespan. Compared to mice on a normal diet (red), mice fed a diet containing UA starting at 3-months-of-age lived about 19% longer, as measured by percent survival.

UA has previously been shown to rescue cognitive deficits in the APP/PS1 mouse model for AD. Ballesteros-Alvarez and colleagues assessed the spatial memory of another mouse model for AD called 3xTg. They used the Morris water maze test, which involves the mice learning to find a platform in a pool of water to escape from drowning. According to the test, 3xTg mice fed a normal diet had impairments in learning and memory. However, feeding the 3xTg mice UA countered these cognitive impairments. 

(Ballesteros-Alvarez et al., 2022 | GeroScience) Urolithin A (UA) Improves Learning and Memory. On days 3 and 4 of training/learning, Alzheimer’s model mice fed a normal diet (red) took longer to escape (Escape latency) from the Morris water maze (MWM) relative to normal mice (blue and gray), signified by *. However, Alzheimer’s mice fed UA (pink) took less time to escape compared to Alzheimer’s mice on a normal diet, signified by #.

The hippocampus is the region of the brain responsible for consolidating memories. The buildup of amyloid-beta protein in the hippocampus is associated with memory loss in AD patients. Ballesteros-Alvarez and colleagues assessed hippocampus amyloid-beta levels in 3xTg mice using an antibody that fluoresces green. They found that amyloid-beta plaques were increased in 3xTg brains from mice fed a normal diet, but nearly absent in 3xTg mice fed UA. These findings demonstrate that UA reduces Alzheimer’s plaques in the 3xTg AD model. 

(Ballesteros-Alvarez et al., 2022 | GeroScience) Urolithin A (UA) Reduces Alzheimer’s Plaques. Alzheimer’s plaques (Aβ) were stained with an antibody to fluoresce green (MOAB-2 immunostaining) in the brain (hippocampus) of Alzheimer’s model mice (3xTg). Left: Representative images from mice fed normal (CTRL) and UA diet. Right: Average values showing that that 3xTg mice fed UA (pink) have less plaques than 3xTg mice fed a normal diet (red).

Is Urolithin a Better Solution to Alzheimer’s?

Upon further analysis, Ballesteros-Alvarez and colleagues found that increased amyloid-beta plaques correlated with better cognition in the AD mouse model fed a normal diet, suggesting that these Alzheimer’s plagues are protective. 

“Our results may speak to the ongoing and highly publicized controversies surrounding AD clinical trials, where therapeutics designed to expressly prevent plaque formation, while often efficacious in lessening plaque load, are routinely and notoriously ineffective at meeting their primary endpoint, namely preventing of slowing cognitive decline,” state the authors.

UA seems to target one of the underlying features of Alzheimer’s cellular pathology by promoting autophagy rather than directly targeting Alzheimer’s plaques, which are likely a consequence of the underlying pathology. Therefore, UA could potentially provide more therapeutic value than current FDA-approved drugs that target Alzheimer’s plaques directly.

Model & Dosage

Model: 3-month-old male C57BL/6NJ

Dosage: Estimated 5 mg/kg/day (from 25 mg/kg/day in food) of urolithin A on alternate weeks (1 week on, 1 week off)

Source

Ballesteros-Álvarez, J., Nguyen, W., Sivapatham, R. et al. Urolithin A reduces amyloid-beta load and improves cognitive deficits uncorrelated with plaque burden in a mouse model of Alzheimer’s disease. GeroScience 45, 1095–1113 (2023). https://doi.org/10.1007/s11357-022-00708-y

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