Anne Brunet

Research/Lab website:   Brunet Lab Home Page

The overall goal of our lab is to understand the molecular mechanisms of longevity. Organismal longevity is regulated by a combination of genetic and environmental factors. The searches for genes that play a central role in the control of lifespan in several species have converged on components of the signaling pathway that connect insulin to FOXO transcription factors (FOXOs). However, how this pathway functions to regulate lifespan is not understood yet.

A first goal of the laboratory is to determine the molecular mechanisms by which FOXOs translate environmental stimuli into changes in gene expression programs that in turn mediate organismal longevity. We use a combination of chromatin immunoprecipitation and genomic approaches to analyze the recruitment of FOXO to specific promoters in response to environmental conditions that are critical for longevity. In addition, we recently found that FOXOs functionally interact with Sir2/SIRT1, a deacetylase that has been shown to promote longevity in a range of species. Using proteomic approaches, we are embarking on the systematic identification of novel partners of FOXOs and Sir2 in response to a variety of environmental stimuli in cultured cells and in intact tissues. These experiments will give crucial insight into the molecular machinery that regulates the overall aging process.

A second project of the laboratory is to determine the role of FOXOs in organismal longevity by generating mouse mutants for this family of transcription factors. We use a combination of the Cre/loxP recombination system and RNA interference approaches to abrogate the expression of the FOXO family in mice. We are also generating mouse mutants in which the endogenous FOXO gene is replaced by a series of specific mutants of FOXO, in “knock-ins” experiments. We use these FOXO mutant mice to assess the roles of these transcription factors in organismal longevity and in diseases that are associated with age.

A third focus of the laboratory is to understand the importance of the central nervous system in the control of organismal longevity. Longevity, like body weight or growth, is an integrated and synchronous process, suggesting that it may be centrally controlled by the nervous system. However, whether the nervous system plays an important role in conveying longevity signals to the entire organism is an open question. We are developing a series of genetic tools to test the importance of specific regions of the nervous system in the regulation of longevity. These experiments have the potential to identify FOXO-dependent and independent pathways in the control of aging.

Together with our studies of FOXO transcription factors, these approaches will advance our understanding of the regulation of organismal longevity. As a large number of diseases have a striking age-dependent onset, we hope that identifying important regulators of the aging process may help prevent the occurrence of age-dependent diseases.