Brian Kennedy
	Associate Professor of Biochemistry PhD 1996, MIT BA 1989, Northwestern University 206.685.0111 V 206.685.1792 F bkenn@u.washington.edu

Why do we age and what can we do about it? Should anything be done about it? Philosophers and scientists, wealthy and indigent, everyone has considered these questions at one time or another and numerous thoughts are available on the internet. Ancient proverbs often relate to aging. The Greeks pondered it. Shakespeare wrote about it. Darwin and Wallace puzzled over it. Benjamin Gompertz work out mathematical tables to predict it. And for the last century, modern scientists have tried to understand its underlying causes. Yet the molecular changes that underlie aging have remained largely refractory to inquiry. However, scientific discoveries related to aging are increasing dramatically in recent years, making it feasible that aging can finally be understood. Moreover, the concept of healthspan, the period of an individual’s life during which they are healthy and functional, has emerged. As interventions that slow aging are being identified, it is becoming clear that targeting aging directly may be an effective broad spectrum approach to age-related conditions including cardiovascular, neurodegenerative, metabolic and metastatic diseases. The big questions are not yet answered, but it feels likely that they will be shortly.

Aging is a primary focus of research in the Kennedy lab. The strategy started with comparative genomics using invertebrate model systems (Smith et al., Genome Research, 2008). By identifying and comparing the genes that affect aging in more tractable eukaryotes, we have identified a set of conserved longevity pathways that are likely to affect mammalian longevity. Approaches currently are centered on (1) studying these pathways using invertebrates in an attempt to identify the molecular changes that drive aging and (2) testing whether these pathways affect mammalian aging using mouse models.

1. The TOR pathway, protein translation and aging – Reduced TOR signaling leads to lifespan extension in yeast, worms, flies and mice, making it the most highly conserved aging pathway known to date. Our studies using yeast are focused on why reduced TOR signaling leads to lifespan extension. Our studies indicate that one major benefit of TOR inhibition is altered translation, which has multiple effects. One of these is, paradoxically, the enhanced translation of GCN4, which encodes a transcription factor that regulates stress response genes (and others). A current focus is to identify key downstream targets of GCN4 relevant to aging. Studies also indicate that reduced TOR signaling leads to lifespan extension through GCN4-independent mechanisms and several approaches are being taken to identify these alternate mechanisms. Results from yeast are being compared to those from similar studies in C. elegans, performed in the Kennedy lab and in collaboration with Matt Kaeberlein in the Department of Pathology, University of Washington.

We have generated and are characterizing several mouse gene knockouts of components of the mTOR pathway and are studying the phenotypes of these mice related to aging and age-related disease. Mice lacking a number of ribosomal protein subunits are also being characterized. Reduced expression of ribosomal protein genes leads to lifespan extension in both worms and yeast. These mouse models will not only be used to study aging, but also as a platform for testing mechanistic hypotheses developed in invertebrates.

2. Sirtuins and aging – Overexpression of SIR2 in yeast and its ortholog in worms, Sir-2.1, leads to lifespan extension. Moreover, evidence indicates that elevated activity of the mammalian ortholog, SIRT1, may beneficial in a number of age-related disease models. While mechanisms of action of SIR2 orthologs related to aging have been proposed in each organism, there is no unifying model across species. We have discovered in yeast studies that SIR2 extends lifespan through a second mechanism unrelated to extrachromosomal rDNA circles. Since regulation of ERC formation may be a yeast-specific mechanism, we are actively characterizing the ERC-independent mechanism in the hope that it will be conserved in other eukaryotes.

3. S6 kinase and aging – Reduced S6kinase activity leads to lifespan extension in yeast, worms and flies. We are actively pursuing S6 kinase studies in invertebrates, but more recently have focused on S6 kinase in mice. We are characterizing properties of mice lacking S6K1 and are in the process of generating tissue-specific S6K1 knockouts. Tissue-specific knockouts will be used to determine where reduced S6K1 activity leads to enhanced lifespan and protection from age-related diseases.

4. A-type nuclear lamins – For a number of years, the Kennedy lab has been focused on how A-type nuclear lamins facilitate nuclear functions. Lamins are the only intermediate filaments that localize to the nucleus, and their function is required for nuclear integrity and proper regulation of both replication and transcription. A-type lamins are targets for mutations in a range of diseases including muscular dystrophy, cardiomyopathy and progeria, which resembles premature aging. Our recent studies are focused on determining how A-type lamins promote normal cardiac and skeletal muscle function as well as determining how A-type lamin mutations promote Hutchinson-Gilford progeria syndrome. These studies use primary cell culture and mouse models.