Functional Genomic Study of Aging and Aging Interventions

衰老是一种生物学过程，其特征是各种生理功能的逐渐衰退。有许多与年龄相关的变化，包括基因表达的变化，这些变化在酵母菌、蠕虫、苍蝇、啮齿动物、非人类灵长类动物和人类等各种生物中都有。老龄化领域的一个重要问题是这些与年龄相关的变化是否以及如何调节健康寿命和寿命。

Aging is a biological process that can be characterized as a gradual decline of various physiological functions. There are numerous age-related changes, including changes in gene expression, that are shared in various organisms ranging from yeast, worm, fly, rodent, non-human primates and humans. One of the important questions in the aging field is whether and how these age-related changes modulate healthspan and lifespan. Invertebrate models, including C. elegans and D. melanogaster, are in the forefront of studies to determine the molecular mechanisms underlying aging processes. The advantages of using invertebrates for aging studies include not only their relative short lifespan, typically in shorter than a few months for the ease to follow their whole life, but also the availability of rich genetic and genomic resource for powerful genetic and molecular studies. We have summarized the important of invertebrate models in aging research in a review paper published Ageing Research Reviews (2013). We have also detailed aging protocols in Drosophila in a review paper published in Methods in Molecular Biology 2013. These publications should provide valuable guidance for aging research in invertebrates, especially C. elegans and D. melanogaster. Like many other organisms, aging is associated with expression changes of thousands of genes in two powerful invertebrate models, C. elegans and D. melanogaster. A central question related to these molecular changes is whether they provide any molecular insight relevant to human aging. One approach to address this issue is to identify which molecular changes are evolutionarily conserved between C. elegans and D. melanogaster. The conserved changes will likely help understand molecular mechanisms applicable to human aging. However, despite of many bioinformatic approaches available to identify conserved genes and proteins mostly based on sequence homolog, tools are limited to identify genes and proteins with low sequence similarity but conserved function, the latter of which likely consist of a significant portion of genome. To address this issue, in collaboration with several intramural groups directed by Drs. Kevin Becker and Ilya Goldberg, we have developed a bioinformatic tool for high throughput functional analysis of large number of gene sets between C. elegans and D. melanogaster. We have demonstrated the utility of these gene sets in systems biology studies of complex biological phenotypes, including aging. This line of work has been published in BMC Genomics 2013. The tool and database described in this paper will allow us taking better advantage of large amount of genomic data available in many organisms including humans and facilitate the studies of functional conservation in various biological processes, such as aging, in the future studies. Among the conserved proteins related to aging processes are topoisomerases, which are known to be essential to solve DNA topological protein and critical for aging-related biological processes, such as DNA repair. RNA metabolism has been shown to be crucial in almost all biological processes, including aging, and many diseases, such as age-related degenerative diseases. However, none of eukaryotic topoisomerases have been linked to RNA metabolism. In collaboration with Dr. Weidong Wangs group, we identified Top3β as the first eukaryotic RNA topoisomerase, which is present in polyribosome and stress granule in the cell. We further demonstrated that Top3β interacts with Fragile X protein (FMRP) to regulate synaptic formation at the neuromuscular junction (NMJ) in Drosophila. FMRP is a major protein linked to Fragile X syndrome, a common form of intellectual disability, and autism. We have shown that Top3β and FMRP bind a number of common sets of mRNAs, including those encoded by genes with neuronal functions related to schizophrenia and autism. Top3β mutations have been shown to be associated with schizophrenia and intellectual disability in humans. These findings suggest Top3β acts as an RNA topoisomerase in RNA metabolism and interacts with FMRP in promoting neural development and mental health. This line of work has been published in Nature Neuroscience (2013). Demonstration of the first eukaryotic RNA topoisomerase will facilitate determining the role of RNA metabolism, especially topology, in aging and neurological diseases, which opens a novel line of research in the aging field. In summary, we have made significant progress towards understanding molecular mechanisms underlying aging and age-related diseases. We have developed a bioinformatic tool for high throughput functional studies of genomic data. We have identified the first RNA topoisomerase and demonstrated its role in maintaining mental health. These studies are valuable for advancing the objectives of the Translational Gerontology Branch and the mission of the NIA to understand the basic biology of aging and develop efficient interventions for humans.