Membrane Pacemaker Hypothesis and Ames Dwarf Mice

Ames dwarf mice lack growth hormone and as a consequence live much longer than their peers. Here the biochemistry of this lineage is considered in light of the membrane pacemaker hypothesis of aging, which suggests that the degree of resistance to oxidative damage in cell membranes is a driving factor in determining longevity. Thus similar species with different proportions of more resistant and less resistant molecules making up their cell membranes have different life spans. Is it possible that this can happen within a species thanks to genetic engineering of the sort that produced the Ames dwarf mouse lineage?

Membrane fatty acid (FA) composition is correlated with longevity in mammals. The "membrane pacemaker hypothesis of ageing" proposes that animals which cellular membranes contain high amounts of polyunsaturated FAs (PUFAs) have shorter life spans because their membranes are more susceptible to peroxidation and further oxidative damage. It remains to be shown, however, that long-lived phenotypes such as the Ames dwarf mouse have membranes containing fewer PUFAs and thus being less prone to peroxidation, as would be predicted from the membrane pacemaker hypothesis of ageing.

Here, we show that across four different tissues, i.e., muscle, heart, liver and brain as well as in liver mitochondria, Ames dwarf mice possess membrane phospholipids containing between 30 and 60 % PUFAs (depending on the tissue), which is similar to PUFA contents of their normal-sized, short-lived siblings. However, we found that that Ames dwarf mice membrane phospholipids were significantly poorer in n-3 PUFAs. While lack of a difference in PUFA contents is contradicting the membrane pacemaker hypothesis, the lower n-3 PUFAs content in the long-lived mice provides some support for the membrane pacemaker hypothesis of ageing, as n-3 PUFAs comprise those FAs being blamed most for causing oxidative damage. By comparing tissue composition between 1-, 2- and 6-month-old mice in both phenotypes, we found that membranes differed both in quantity of PUFAs and in the prevalence of certain PUFAs. In sum, membrane composition in the Ames dwarf mouse supports the concept that tissue FA composition is related to longevity.

At some point a research group will find a way to alter only membrane constituent molecules and no other factors in laboratory mice, which should go some way towards quantifying the effect on aging and longevity. The challenge with using any of the well known long-lived lineages of mice is that many aspects of their metabolism are different - it is difficult to point to any one of those and talk about how important it may or may not be to extended longevity given the presence of the others.



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