Hansen Lab Research

Introduction

How do organisms age? While aging is a fundamental biological reality that is familiar to all of us, it is not yet clear how aging occurs at the molecular level. Several genes and processes have been identified that affect the rate of aging, many of which are conserved from yeast to humans. However, how these genes and processes affect aging at the cellular and molecular level to influence organismal aging are not fully understood. The research in the Hansen lab is directed towards understanding the regulation and function of the molecular mechanisms, which play central roles in the process of aging. As such, our research aims to advance our understanding of important signaling pathways and processes relevant to aging. Such insight can also contribute to our knowledge of age-related disorders, including diabetes and cancer.

C. elegans is an excellent system for studying organismal aging

To gain new insight into the mechanisms that modulate aging, we are taking advantage of the unique experimental features of the microscopic soil nematode Caenorabditis elegans (Figure 1) that have made it a leading model organism in a number of modern biological research areas, including aging. Chief among these features research are a short lifespan (~2-3 weeks), highly tractable genetics, including extremely facile gene knockdown (e.g., by feeding RNAi, available for genome-wide gene inhibition), and knockout, and transgenic technology. The transparent body of C. elegans allows the visualization of tissues and cells, as well as fluorescently labeled molecules, in the physiologically relevant context of an intact, living organism. Moreover, biochemical techniques are becoming important tools for systematically analyzing the transcriptional, translational, and post-translational profile of this multi-cellular animal.

A conserved modulaTOR of aging

A key interest of our lab is the nutrient sensor and kinase TOR (Target Of Rapamycin). TOR is emerging as a key regulator of lifespan and healthspan, and the mechanism(s) by which TOR operates to affect organismal aging is currently under intense investigation. TOR regulates several important biological processes that may modulate aging in a conserved fashion, these include protein synthesis and the cellular recycling process autophagy. In our lab, we are investigating how TOR and TOR-regulated processes contribute to the aging process in C. elegans. You will find a couple of these interesting projects outlined below!

Autophagy

An important focus of the lab is to elucidate the role and regulation of autophagy in aging. Autophagy is a cellular process by which the cell can degrade and recycle cytoplasmic material (Figure 2), and we and others have shown that autophagy is important for the longevity effects of at least some long-lived C. elegans strains, including animals subjected to dietary restriction. Nutrient limitation is a potent environmental method of health- and lifespan improvement observed in a multitude of different model organisms, including monkeys. We have observed that dietary-restriction triggers autophagy, and genes with functions in this process are required for dietary-restricted animals to live long (Hansen et al., PLoS Genetics, 2008). However, the mechanisms by which autophagy modulates longevity are not yet understood. To address this critical question, we are using a combination of genetic and molecular approaches to understand how and where in the organism the autophagy process functions to modulate longevity. We are also investigating the mechanisms by which the cytoplasmic material/cargo, yet to be characterized as non-specific or selective in nature, is degraded during the aging process.

We also use mammalian cell culture to characterize conserved regulators of the autophagy process. Autophagy has been linked to many age-related diseases as well as aging, and new molecular insights on how autophagy functions in aging may facilitate future treatments of age-linked disorders, including cancer and neurodegenerative diseases.

Protein synthesis

Our lab also studies the TOR-regulated process of mRNA translation. We and others have found that inhibition of the translational machinery or of regulators of protein synthesis, including the ribosomal S6 kinase (S6K) and translation initiation factors (eIFs), can extend lifespan and improve healthspan (Hansen et al., Aging Cell, 2007), possibly in a conserved fashion. We are using biochemical and genomic approaches to elucidate the mechanisms by which key translational regulators of protein synthesis affect aging and age-related diseases.