February 06, 2007
AMPK Enzyme Declines In Aging Muscles

As we age a key enzyme in our muscle declines and exercise does less to raise its level.

The researchers found that so-called AMP-activated protein kinase (AMPK) slows down in the skeletal muscle of 2-year-old rats relative to 3-month-old rats. A chief regulator of whole-body energy balance, AMPK in skeletal muscle stimulates the oxidation of fatty acids and the production, or biogenesis, of power-producing mitochondria that burn fat and fuel cells,according to the researchers.

The new findings might help to explain "what happens as we age," said Gerald I. Shulman, a Howard Hughes Medical Institute investigator at Yale University School of Medicine.

Why does AMPK decline as we age? Is the decline an adaptation because the muscle's mitochondria become too damaged?

In response to exercise and other stimuli older rats produced far less AMPK.

In the current study, the researchers set out to determine whether the declining mitochondrial function and increased intracellular fat content seen with aging could be traced back to deficiencies of AMPK. They compared AMPK activity in young and old rats following three "perturbations" that normally stimulate the enzyme and, in turn, mitochondria production. The treatments included acute exposure to an AMPK-stimulating chemical, chronic exposure through feeding of another chemical that induces AMPK by mimicking an energy shortage, and exercise.

In every case, older rats showed a decline in AMPK activity compared to younger animals. Young rats infused with a stimulatory chemical showed an increase in muscular AMPK activity not seen in old rats, they found. Similarly, the muscle of exercise-trained young rats showed more than a doubling in AMPK activity. In older rats, that AMPK hike with exercise was "severely blunted." The muscles of young rats fed the AMPK-stimulating chemical also showed an increase in AMPK and a 38% increase in mitochondrial density, they reported. In contrast, older animals' AMPK activity and mitochondrial numbers held steady.

As we get older exercise becomes less effective. Plus, a low level of AMPK might put us at greater risk of type 2 insulin insensitive diabetes.

Would a drug or gene therapy that stimulates AMPK production increase muscle strength and decrease fat? Would it come at some cost? Does the body slow down AMPK production because the muscle cells become too aged to do as much? Or would higher AMPK increase cancer risk?

Share |      Randall Parker, 2007 February 06 11:22 PM  Aging Mechanisms

bbm said at February 7, 2007 10:47 AM:

I wonder if L-carnitine was the stimulant, and if not, if it is somehow involved. IIRC, L-Carnitine helps fatty acids cross the mitochondrial membrane for oxidation.

velopismo said at February 7, 2007 6:32 PM:

ALCAR and Beta-GPA were the two stimulants. http://www.sciencedirect.com/science?_ob=MImg&_imagekey=B7MFH-4N0GXBM-B-8&_cdi=23259&_user=10&_coverDate=02%2F07%2F2007&_sk=%23TOC%2323259%232007%23999949997%23643678%23FLA%23display%23Volume_5,_Issue_2,_Pages_81-156_(7_February_2007)%23tagged%23Volume%23first%3D5%23Issue%23first%3D2%23date%23(7_February_2007)%23&view=c&_gw=y&wchp=dGLbVtz-zSkWW&md5=4fdc0090bab5fbfdd79b7dfb540599a7&ie=/sdarticle.pdf

From Sinclair's Cell study:
"AMPK is a metabolic regulator that promotes insulin
sensitivity and fatty acid oxidation. Its activity correlates tightly
with phosphorylation at Thr 172 (p-AMPK). Chronic activation of
AMPK occurs on a calorically restriction diet and has been proposed
as a longevity strategy for mammals20. Consistent with this idea,
additional copies of the AMPK gene are sufficient to extend lifespan
in C. elegans21. Because we and others22 have observed that resveratrol
can activate AMPK in cultured cells through an indirect mechanism
(Fig. 2e; see also Supplementary 3ad), we examined whether AMPK
activation occurred in the livers of the resveratrol-fed group. Resveratrol
showed a strong tendency towards inducing phosphorylation
of AMPK (Fig. 2f), as well as two downstream indicators of
activity, namely phosphorylation of acetyl-coA carboxylase at Ser 79
and decreased expression of fatty acid synthase"

Randall Parker said at February 7, 2007 6:51 PM:


Thanks a lot for finding that.

Okay, here's yet another reason to take resveratrol. The fact that CR boosts AMPK suggests that boosting AMPK might provide a net benefit. I wonder how big a dose of resveratrol is needed to boost AMPK.

Also, is Acetyl L Carnitine better or worse than resveratrol for AMPK boosting?

bbm said at February 8, 2007 7:01 AM:

I wonder if this would have benefits in diseases where mitochondrial function is thought to play a central role...

I also wonder if this would potentiate the tumor apoptosis effects of DCA by further stimulating the mitochondria that are switched off in tumor cells...

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