Uric Acid Correlates With Brain Aging

Rising uric acid probably makes our minds slow down as we age.

WASHINGTON Researchers at the Johns Hopkins and Yale university medical schools have found that a simple blood test to measure uric acid, a measure of kidney function, might reveal a risk factor for cognitive problems in old age. Of 96 community-dwelling adults aged 60 to 92 years, those with uric-acid levels at the high end of the normal range had the lowest scores on tests of mental processing speed, verbal memory and working memory. The findings appear in the January issue of Neuropsychology, which is published by the American Psychological Association (APA). High-normal uric acid levels, defined in this study as 5.8 to 7.6 mg/dL for men and 4.8 to 7.1 mg/dL for women, were more likely to be associated with cognitive problems even when the researchers controlled for age, sex, weight, race, education, diabetes, hypertension, smoking and alcohol abuse. These findings suggest that older people with serum (blood) uric-acid levels in the high end of the normal range are more likely to process information slowly and experience failures of verbal and working memory, as measured by the Wechsler Adult Intelligence Scale and other well-established neuropsychological tests. It might be useful for primary-care physicians to ask elderly adults with high normal serum uric acid about any problems they might be having with their thinking, and perhaps refer those who express concern, or whose family members express concern, for neuropsychological screening, says lead author David Schretlen, PhD. The link between high-normal uric acid and cognitive problems is also sufficiently intriguing for the authors to propose clinical studies of whether medicines that reduce uric acid, such as allopurinol, can help older people with high-normal uric acid avoid developing the mild cognitive deficits that often precede dementia.

Would the growth of younger replacement kidneys prevent the rise of uric acid with age? Or could stem cell therapies or gene therapies do the trick?

For reasons that are not entirely clear, uric acid levels increase with age, says Dr. Schretlen. Higher levels of uric acid are linked with known risk factors for dementia, including high blood pressure, atherosclerosis, Type 2 diabetes and the metabolic syndrome of abdominal obesity and insulin resistance. Dr. Schretlen also says there is mounting evidence that end-stage renal (kidney) disease increases the risk of cognitive dysfunction and dementia in elderly adults. Given this web of connections, uric acid could potentially become a valuable biological marker for very early cognitive problems in old age.

If our uric acid levels are rising as a side effect of kidney aging and if the higher uric acid levels deliver no real benefit then efforts to keep uric acid down would slow brain aging. The brain is the toughest rejuvenation challenge. Anything we can to do delay brain aging will give us more time to find ways to make 100 billion neurons in our brains young again.

Update: As some commenters have pointed out, this study does not prove the direction of causation runs from higher uric acid to faster brain aging. Another possible direction of causality runs from high oxidative stress to both higher uric acid and faster brain aging. The higher oxidative stress could impair kidney function and brain function and cause higher uric acid to correlate with faster brain aging. Or the body could make more uric acid as a protectant against certain kinds of radicals. For example, uric acid appears to protect against peroxynitrite. So the higher uric acid might be an indicator of some other problem that is causing the accelerated brain aging.

Early diabetes suppresses uric acid. Yet diabetes increases oxidative stress and accelerates aging. Could it be that effects of diabetes are worsened by the lower uric acid? Also, insulin prevents oxidative stress-caused decreases in intracellular uric acid and in intracellular antioxidant glutathione. Perhaps rather than take drugs to lower uric acid a person with high uric acid should first try a variety of antioxidants and other brain protecting compounds.

Update II: Bonnie Firestein's research team at Rutgers University have found that uric acid stimulates brain astroglial cells to make transporter proteins that haul away compounds that do damage to nerves and uric acid may therefore be neuroprotective.

Uric acid's effects on the health of neurons had been observed by other researchers, but the mechanics of how it confers protection has remained a mystery. "It is interesting to note that people with gout never seem to develop multiple sclerosis," Firestein said. "In animal models of multiple sclerosis, the addition of uric acid reduces symptoms and improves prognosis. The same is true for one type of Parkinson's disease tested." The Firestein team's breakthrough studies revealed that uric acid can stimulate astroglial cells to produce transporter proteins that carry harmful compounds away from neurons in jeopardy of chemical damage. This opens the door to identifying a unique drug target for new therapies. Glutamate is a compound that under normal circumstances aids neurons in transmitting signals for cognitive functions in the brain, such as learning and memory. In the case of spinal cord injury or stroke where there is physical cell damage, however, an excess of glutamate is released and it accumulates around the remaining intact neurons, eventually choking them to death. When Firestein's group added uric acid to a mixed culture of rat spinal cord neurons and astroglial cells, the production of the glutamate transporter EAAT-1 increased markedly. The challenge now is find the most effective strategy for increasing the production of the transporter, using drug therapies or other means.

So then does the higher blood uric acid increase brain aging or decrease it?