May 31, 2004
Mice With Inefficient Mitochondria Live Longer

Mice which generate more heat and less useful chemical energy from breaking down sugars live longer.

Could mice hold the secret to longer life?

Scientists from the University of Aberdeen, the Aberdeen-based Rowett Research Institute and the Medical Research Council (MRC) in Cambridge have made a major breakthrough in understanding how metabolism affects lifespan.

In a seven-year study of mice they found that those with the highest metabolic rate lived the longest, raising the prospect that the effect could be mimicked in humans.

Scientists have long thought that a high metabolic rate was linked to a shortened life-span. The present discovery turns this century old belief on its head and changes dramatically our understanding of the regulation of life-span.

Metabolism is the means by which nutrients are broken down to smaller building blocks and chemical energy, which are used to make new body materials and to do work.

The researchers discovered that the most metabolically active 25% of the mice studied, far from having shorter life-spans, in fact lived 36% longer than the least active. If the same effects are mimicked in humans then the finding would imply that a higher metabolic rate could add an extra 27 years to the average human lifespan.

When the muscles of the most metabolically active mice were examined, they were found to contain factors that increased their metabolism by making it less efficient.

Although the scientists do not yet fully understand how these factors work, it is suspected that while the make the metabolism less efficient, on the positive side they reduce the generation of toxic by-products called "oxygen free radicals".

Blondie has assured us "Live fast because it won't last". But the leader of this research team says live fast to die old.

"We are really excited by this finding," said Professor John Speakman, leader of the research team. "The result is striking: living fast means dying old."

I asked U Cambridge biogerontologist Aubrey de Grey for some comments on this report and here is his email response: (with his permission)

It's a fine study, but not as much of a revision of existing thinking as the press reports make out. The investigators are talking about efficiency of conversion of proton gradient into ATP, as opposed to conversion of oxygen into water. In other words, the long lived animals are expressing uncoupling proteins that make their mitochondria generate more than the usual amount of heat and less than the usual amount of ATP. A side-effect of this is that the proton gradient is lower, which allows electrons to slide along the electron transport chain more quickly, getting stuck less of the time at points where they can fall out and make ROS, so the ROS production is lower.

Aubrey's reference to ROS is to Reactive Oxygen Species which are damaging molecules generated as a side-effect of oxidation of sugars to make chemical energy. This happens in mitochondria which are organelles found inside of cells where sugars are broken down to create chemical energy molecules.

This latest result is not really unexpected given what is already known about mitochondrial metablism and free radical generation. Still, it is a nice piece of work that underlines the importance of mitochondria in cellullar aging.

These longer lived mice probably have to eat more calories in food to stay alive because a smaller fraction of the sugar they break down gets converted into useful chemical energy in the form of the energy carrying molecule ATP (Adenosine TriPhosphate). The mitochondria make the chemical energy carrying molecule ATP from ADP (Adenosine DiPhosphate) by using the energy unleashed by breaking down sugar to add a phosphate to ADP. This reaction requires a proton gradient but making that proton gradient steep also causes the mitochondria to generate more free radicals that inflict the damage which accumulates to cause aging.

This report is not the only recent piece of evidence for the theories that mitochondrial free radical generation is a major cause of aging. Also read my post Mice With Defective Mitochondrial DNA Repair Gene Age More Rapidly.

We can hope for treatments that will lower the rate at which mitochondria generate free radicals. However, what we need even more is the ability to repair the accumulated damage. We need to develop the means to grow replacement organs, control stem cells, deliver gene therapies, and other Strategies for Engineered Negligible Senescence.

Share |      Randall Parker, 2004 May 31 02:30 AM  Aging Studies


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