Extending Life in Mice With Artificially Shortened Life Spans is Rarely Directly Relevant or Useful

There are numerous examples of studies that use mice genetically engineered to suffer forms of shortened life span with the appearance of accelerated aging. One has to be very cautious in reading anything into this sort of work, however: it is rarely of any great relevance to normal aging, as it creates and then attempts to ameliorate an entirely artificial situation. The appearance of accelerated aging is not in fact accelerated aging, but is rather often caused by mechanisms that are of little importance in normal aging. Even when the mechanisms are relevant, the overall metabolic circumstances can render it impossible to determine whether or not a partial treatment will be of any use in normal aging. The gold standard for relevance when evaluating new methods is the extension of life in unmodified mice, but unfortunately this is expensive and slow.

The publicity materials quoted below are a good example of research in animals exhibiting shortened life spans. Here scientists are investigating a protein involved in the induction of cellular senescence. As is often the case, however, from the structure of the work it is impossible to tell whether or not their drug candidate will be of any use as a treatment to lower levels of cellular senescence in normal aging and thus produce benefits such as extended health and life span. Those tests will still have occur:

When cells or tissue age - called senescence - they lose the ability to regenerate and secrete certain proteins, like a distinctive fingerprint. One of those proteins, PAI-1 (plasminogen activator inhibitor) has been [a focus of] research, originally as it relates to cardiovascular disease. "We made the intellectual leap between a marker of senescence and physiological aging. We asked is this marker for cell aging one of the drivers or mechanisms of rapid physiological aging?"

For the study, [researchers] used mice bred to be deficient in a gene (Klotho) that suppresses aging. These mice exhibit accelerated aging in the form of arteriosclerosis, neurodegeneration, osteoporosis and emphysema and have much shorter life spans than regular mice. [These] rapidly aging mice produce increased levels of PAI-1 in their blood and tissue.

Then scientists fed the rapidly aging mice TM5441 - the experimental drug - in their food every day. The result was a decrease in PAI-1 activity, which quadrupled the mice's life span and kept their organs healthy and functioning. "This is a completely different target and different drug than anything else being investigated for potential effects in prolonging life. It makes sense that this might be one component of a cocktail of drugs or supplements that a person might take in the future to extend their healthy life."

Link: http://www.northwestern.edu/newscenter/stories/2014/04/experimental-drug-prolongs-life-span-in-mice.html


It seems that what these studies in age-accelerated mice did prove, however, is that the diseases of aging can be combated. This would not increase the maximum lifespan because of senescence, however it would greatly increase the normal lifespan- in humans by about 20 to 40 years if we actually lived to the limits that senescence allows.

Posted by: Gear Mentation at May 2nd, 2014 1:06 PM

All this experiment proves unfortunately is that mice bred to be deficient in the gene Klotho which results in an increased level of PAI-1 are more diseased than regular mice, and die younger. And that this disease can be counteracted by the drug TM5441.

It does not prove that PAI-1 causes aging (it could well just increase as a result of aging, like wrinkles). And it does not prove that decreasing PAI-1 with TM5441 increases median or maximal lifespan in normal mice (or humans).

You could do exactly the same experiment in humans were you withheld vitamin C, then watched them get scurvy and die younger, called scurvy 'aging', then gave them vitamin C and watched it halt or even partially reverse the effects of scurvy, and claim (falsely) that you had halted or reversed aging.

Posted by: Jim at May 2nd, 2014 4:52 PM

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