Aging has been defined in biological terms as the accumulation of changes in an organism over time. In humans this is associated with an increased incidence of ‘age-related’ diseases such as cancer, Alzheimer’s disease and Type II diabetes. Epigenetic modifications play an important role in ‘locking in’ transcriptional and cellular states during the development of an organism. Cues from the environment can be received and remembered, potentially mediating the environmental influence over the rate of aging. The laboratory of Dr Jing-Dong Han at the CAS-MPG Partner Institute of Computational Biology (PICB) is measuring epigenomic profiles during aging of the human brain and relating this to lifestyle and physiological factors. Using systems biology approaches, gene loci are integrated into sub-networks to predict key genes influencing aging and disease susceptibility. .My interest in the study of aging and age-related diseases involves mapping, and characterising, the influence of age-related changes in the mitochondria. Mitochondria are critical to cellular metabolism and are increasingly implicated in age-related diseases. It has been predicted that the accumulation of changes in mitochondrial proteins is an important part of human aging. Although the majority of the 1500 mitochondrial proteins are encoded in nuclear DNA, mitochondria also retain a small genome (mtDNA) encoding 37 essential genes. My research will have three approaches:.1. Epigenetic modification of nuclear-encoded mitochondrial proteins may affect the expression of components of mitochondrial networks. I will use ChIP-chip and Chip-seq to investigate transcription factor binding, and bisulfite sequencing to identify changes in histone methylation patterns, in the genomes of human samples. I will use computational analyses to integrate this data into sub-networks and predict key nuclear-encoded mitochondrial gene loci involved in aging and disease. .2. C. elegans lifespan can be used to validate predicted regulators of lifespan control. I will use RNAi to target short-listed nuclear-encoded mitochondrial gene loci in the C. elegans genome, and then monitor C. elegans morphology and motility during aging. Validation in this model also allows for refinement of the computational analyses. .3. Evidence from mouse models has suggested that the accumulation of detrimental, but non-lethal, changes in mtDNA genes influences aging. Recent evidence demonstrating that DNA methylases are active in mitochondria has questioned long-held beliefs that there is no epigenetic control of mtDNA. I will modify the deep sequencing and epigenetic analyses used at the PICB for mtDNA samples. If epigenetic modification of mtDNA is confirmed, this opens up a previously unknown level of mitochondrial gene regulation to further research..Understanding how aging and mitochondria are related will have a significant impact on the understanding of aging and age-related diseases.