January 31, 2007
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?

Share |      Randall Parker, 2007 January 31 10:34 PM  Brain Aging


Comments
Jim said at February 1, 2007 6:10 AM:

i would suspect that drinking inadequate amounts of water could cause greater uric acid levels and therefore the associated illnesses and entropy. have desert-dwelling people evolved better mechanisms to deal with less available water?

rsilvetz said at February 1, 2007 9:17 AM:

Actually, the relationship of kidney function to survival is very stark and very clear. Not online anywhere so don't bother Googling. Saw it in a great presentation from John Sperling's shop.... (you might remember Sperling --- he was responsible for CC -- the cloned cat).

EStein said at February 1, 2007 9:42 AM:

Is Uric Acid the same as BUN?

Brian T said at February 2, 2007 5:16 AM:

High Uric Acid levels forming crystals in joints is commonly known as Gout, considered a form of arthritis. In Gout diagnosis it is usually attributed to either overproduction in the kidneys or lack of removal in the urinary system with a different medicine for each. I was so diagnosed 7 years ago with a overproduction Uric Acid level over 9 mg/dL; medication now has that under 5. Although my major problem was in my knee, foot and hand joints, I could see that if UA crystals are forming in the brain tissue that would have impacts. It's been several years since my levels were overly high but my memories of that time do include times where my thought processes could be considered impacted.

BBM said at February 2, 2007 6:54 AM:

It is unclear if this is simply an association, or a cause and effect relationship.

No, BUN is not the same as Uric acid.

There are several anti-gout meds that increase excretion like Probenacid IIRC (I'm a surgeon and don't deal with gout routinely). If there is a causal relationship, you'd tink that people on probenacid might score better on mental acuity tests etc than controlls.

Simo said at February 2, 2007 7:18 AM:

Uric acid is linked to higher achievement (at younger age). There was discussion about uric acid in Gene Expression last August.

Below is the summary from Gene Expression. In addition, the structure of uric acid is highly similar to caffeine.

  • Groups with above-average IQ (Ph.D. students, med students, business executives) show higher levels of blood serum uric acid (SUA). The overall correlation between SUA and IQ is rather small, however, averaging about 0.085 over several studies with a combined N in the thousands.
  • It appears that the SUA exerts its chief causal influences on achievement per se rather than sheer ability, as if SUA acted as a drive-inducing cortical stimulant. In a study of 149 male high school students, SUA level was most notably correlated with the residual of the regression of GPA on IQ. SUA level was also correlated with number of extracurricular activities. In another study SUA showed a significant point-biserial correlation with "school dropout/persistance in school" as well as correlations with "need for achievement."
  • When 144 university professors were rated on overall level of achievement, the ratings were correlated 0.50 with SUA level. Among nontenured faculty, number of publications was correlated 0.37 with SUA level.
  • Several studies have found that SUA level is correlated with upward social mobility, although apparently one large study is contra.
  • One large study (N = 1500) found higher SUA levels in professionals and executives than in farmers and unskilled workers.
John Faughnan said at February 2, 2007 2:25 PM:

Can you PLEASE study the difference between correlation and causation? Please?! I enjoy your blog, but you are constantly doing this.

Mensarefugee said at February 3, 2007 2:03 PM:

i would suspect that drinking inadequate amounts of water could cause greater uric acid levels and therefore the associated illnesses and entropy. have desert-dwelling people evolved better mechanisms to deal with less available water?

Read "Your Body's many cries for Water" by Dr. Fereyedoon Batmanghelidj

Doug said at February 5, 2007 4:28 PM:

I searched Google for

"uric acid" ("vitamin d3" OR "cholecalciferol")

and found the abstract below at PubMed. I'm sorry (not really!) to be such a one-trick pony, but the ongoing positive reinforcement is having its effect: I see a chronic illness and look for the connection to low vitamin D3 or a problem of vitamin D3 metabolism. (I wonder if other people's lack of a similar, acquired tendency is a sign of vitamin-D3 insufficiency. No, really.)

1: Metabolism. 1998 Mar;47(3):336-8. Links
Decreased serum concentrations of 1,25(OH)2-vitamin D3 in patients with gout.Takahashi S, Yamamoto T, Moriwaki Y, Tsutsumi Z, Yamakita J, Higashino K.
Third Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.

We measured serum concentrations of 1,25(OH)2-vitamin D3, 25(OH)-vitamin D3, parathyroid hormone (PTH), and uric acid in 114 male patients with primary gout and 51 normal male control subjects. Serum 1,25(OH)2-vitamin D3 was significantly lower in patients with gout compared with control subjects (38.4 +/- 11.9 v 44.4 +/- 11.0 pg/mL, P I searched Google for

"uric acid" ("vitamin d3" OR "cholecalciferol")

and found the abstract below at PubMed. I'm sorry (not really!) to be such a one-trick pony, but the ongoing positive reinforcement is having its effect: I see a chronic illness and look for the connection to low vitamin D3 or a problem of vitamin D3 metabolism. (I wonder if other people's lack of a similar, acquired tendency is a sign of vitamin-D3 insufficiency. No, really.)

1: Metabolism. 1998 Mar;47(3):336-8. Links
Decreased serum concentrations of 1,25(OH)2-vitamin D3 in patients with gout.Takahashi S, Yamamoto T, Moriwaki Y, Tsutsumi Z, Yamakita J, Higashino K.
Third Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.

We measured serum concentrations of 1,25(OH)2-vitamin D3, 25(OH)-vitamin D3, parathyroid hormone (PTH), and uric acid in 114 male patients with primary gout and 51 normal male control subjects. Serum 1,25(OH)2-vitamin D3 was significantly lower in patients with gout compared with control subjects (38.4 +/- 11.9 v 44.4 +/- 11.0 pg/mL, P

PMID: 9500573 [PubMed - indexed for MEDLINE]

Doug said at February 5, 2007 4:30 PM:

Sorry for the garbled post! Fortunately, I think it's clear enough despite the mess!

Alan said at February 15, 2007 2:03 AM:

Interesting, thanks.

There's a bunch of old literature on uric acid vis a vis I.Q. and
"achievement motivation", showing generally a correlation
(higher of one, higher of the other).

Below are some abstracts and citations, FYI.


PMID: 1156740 at http://www.ncbi.nlm.nih.gov/PubMed/

Br J Psychol. 1975 May;66(2):175-80

Uric acid and divergent thinking: a possible relationship.

Kennett KF, Cropley AJ.

An exploratory investigation of the relationship between serum
uric acid levels in male university students and their scores on
tests of convergent and divergent thinking was carried out. The
data suggested that uric acid levels are lower in highly divergent
thinkers than in less divergent. This led to the speculation that
uric acid may be an important biochemical precursor of
intellectual functioning. If it does affect intellectual
functioning, this may result from the action of uric acid as an
endogenous cortical stimulant, or possibly from its action as a
facilitator of learning.

------------------------------------------------------------------

PMID: 6540956 at http://www.ncbi.nlm.nih.gov/PubMed/

Acta Genet Med Gemellol (Roma). 1984;33(2):237-42

Blood uric acid level and IQ: a study in twin families.

Inouye E, Park KS, Asaka A.

Applying newly devised model, heritability (VA/VP) of plasma uric
acid level, corrected for age and sex and standardized, was
estimated at 0.8 in families consisting of twin parents, spouses
and children. Correlation between spouses due to common genotype
(rho) was approximately 0.1, and variance due to common familial
environment (VEC/VP) was -0.3. Analysis of families of selected
twin children and their parents resulted in two estimates of
heritability: approximately 0.7 and 0.3, rho being 0.34 and 0.04,
and VEC/VP being 0.04 and 0.34, respectively. Regression of IQ (y)
on corrected and standardized plasma uric acid level (x) in the
twin children was y = 5.56x + 123, correlation being 0.334 (p less
than 0.025). The result indicates a genetic basis of blood uric
acid level, which may have resulted from polymorphisms in purine
metabolism pathway, end product of which is uric acid in man. The
significant correlation between plasma uric acid level and IQ
suggests a contribution of partly common gene loci to the two
quantitative traits.

------------------------------------------------------------------

NO ABSTRACTS ONLINE:
(the paper by Kasl et al, JAMA 1970, is the best of the bunch)

Cervini C, Burroni M, Zampa AM. Genes for super-intelligence? J
Med Genet. 1982 Oct;19(5):392. No abstract available. PMID:
7143398

Park KS, Inouye E, Asaka A. Plasma and urine uric acid levels:
heritability estimates and correlation with IQ. Jinrui Idengaku
Zasshi. 1980 Sep;25(3):193-202. No abstract available. PMID:
7194385

Stevens HA, Cropley AJ, Blattler DP. Intellect and serum uric
acid: an optimal concentration of serum urate for human learning?
Soc Biol. 1975 Fall;22(3):229-34. No abstract available. PMID:
1216005

Klebba JT, Gershbein LL, Marks R. Correlation of bio-clinical
parameters and intelligence in subjects with Down's syndrome and
other retardates. Res Commun Chem Pathol Pharmacol. 1974
May;8(1):159-80. No abstract available. PMID: 4277109

Mertz DP [Gout hazard as the price for development of
intelligence?] Dtsch Med Wochenschr. 1974 Jan 4;99(1):24-6.
German. No abstract available. PMID: 4809232

Montoye HJ, Mikkelsen WM. Serum uric acid and achievement in high
school. Arthritis Rheum. 1973 May-Jun;16(3):359-62. No abstract
available. PMID: 4708014

Kasl SV, Brooks GW, Rodgers WL. Serum uric acid and cholesterol in
achievement behavior and motivation. II. The relationship to
college attendance, extracurricular and social activities, and
vocational aspirations. JAMA. 1970 Aug 24;213(8):1291-9. No
abstract available. PMID: 5468326

Paulson GW, Son CD, Nance WE. Neurologic aspects of typical and
atypical Down's syndrome. Dis Nerv Syst. 1969 Sep;30(9):632-6. No
abstract available. PMID: 4242004

Bland JH, Jarrett FA, Plunkett GE, Ravaris CL, Sylwester D. Survey
of serum uric acid concentration in an institutionalized mentally
retarded population. Fed Proc. 1968 Jul-Aug;27(4):1087-90. No
abstract available. PMID: 5658476

RICHARD NKOMO said at November 4, 2009 4:00 AM:

EVERYTIME MY URIC ACID IS HIGH MY BRAIN FUNCTION IS RETARDED, i REALY STRUGLLE TO CONSTRUCT A GOOD SENTENCE . i AM PREPARED TO PROVIDE MORE INFORMATION TO ANY RESAERCHER WHO IS FOLLOWING UP THIS SUBJECT, THE FINDINGS FROM RANDAL PARKER MAKES SENSE TO ME. sO LETS FOLLOW IT UP AND SEE WHERE IT GOES.

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