about my Ames dwarf project ...

Specific aims

We aim to test if membrane composition is altered in a long-living mutant, the Ames dwarf mouse compared to normal sized, shorter-living heterozygous siblings. If Ames dwarf mice would in fact have low tissue contents of n-3 PUFAs but high n-6 PUFA contents we would confirm our previous findings while reconciling the ’membrane pacemaker hypothesis of ageing’ in its current form. If finally, Ames dwarf mice would have a low n-3 PUFA content but not a particularly low content of docosahexaenoic acid (DHA), we would reject the hypothesis that the effects of membrane composition are due to peroxidisability as previously suggested.

Short final report

Membrane fatty acid composition is correlated with longevity in mammals. The "membrane pacemaker hypothesis of aging" proposes that animals whose cellular membranes contain high amounts of polyunsaturated fatty acids (PUFAs) have shorter life spans because their membranes are more susceptible to peroxidation and harmful oxidative damage. Among PUFAs, especially those from the n-3 class were suggested to limit lifespan through their biochemical properties leading to oxidative stress. Until now it remained to be shown however, that transgenic mice such as the long-lived Ames dwarf mouse indeed have membranes containing fewer PUFAs, as predicted from the "membrane pacemaker hypothesis of aging". Ames dwarf mice are mutants lacking growth hormones while living up to five years contrary to heterozygous control animals that live 3 years only. Here, we show that across four different tissues such as muscle, heart, liver and brain phospholipids as well as liver mitochondria Ames dwarf mice
in fact possess membrane phospholipids being rich in PUFAs (30-60% depending on the tissue) but significantly poorer in n-3 PUFAs than normal- sized, short-lived siblings. This finding therefore generally supports the membrane pacemaker hypothesis of aging, provided that n-3 PUFAs are looked at, not the PUFA class as such. Further, we observed that tissue composition clearly differed between 1, 2 and 6 months of age in both phenotypes. This finding needs to be addressed in further experiments as it might point to an important other role of PUFAs, such as on regulating body temperature of mammals. Interestingly, we observed only small differences between heart, skeletal muscle and liver phospholipids but brain tissue clearly differed from all other tissues in the body with a dominant proportion of n-3 PUFAs in both genotypes the Ames dwarfs and the controls. The fact that brain tissue does not provide any support for the membrane pacemaker hypothesis needs to be addressed in further studies.