As we age, our cells suffer a progressive and permanent loss of genetic information due to the accumulation of mutations. The mounting genetic deficits may limit cellular function or lead to cell death, thereby contributing to the loss of tissue homeostasis that occurs during aging. This proposal seeks to test the influence of mutation burden on aging of diploid yeast. We have evidence that excessive mutation rates can cause extinction of haploid yeast, due to random inactivation of essential genes.
In Aim 1 we will define the upper limits of mutation burden for diploids.
In Aim 2 we will transiently elevate mutation rates and then measure replicative lifespan, chronological aging, and competitive fitness in the presence and absence of oxidative damage and caloric restriction.
In Aim 3, we will monitor cells for altered protein homeostasis as a possible consequence of mutation load. By these studies we hope to establish whether random mutation burden contributes to cellular aging and gain sufficient preliminary data to apply for an R01 to extend our studies into animals.
The somatic mutation accumulation theory of aging posits that the progressive loss of genetic information in our cells leads to declining tissue homeostasis with age. Our preliminary data suggest that high mutation rates can cause extinction of dividing diploid yeast populations. Here we propose to define whether mutation burden enhances aging of diploid yeast.
|Herr, Alan J; Kennedy, Scott R; Knowels, Gary M et al. (2014) DNA replication error-induced extinction of diploid yeast. Genetics 196:677-91|
|Kennedy, Scott R; Loeb, Lawrence A; Herr, Alan J (2012) Somatic mutations in aging, cancer and neurodegeneration. Mech Ageing Dev 133:118-26|