Research Interests

 

Aging is one of the greatest mysteries in biology, and arguably its next frontier. Old age is the main risk factor for many diseases, including cardiovascular disease, cancer, diabetes, and Alzheimer’s disease. Yet our understanding of aging is still rudimentary because aging is an extraordinarily complex process that defies many conventional rules in biology.

Key unanswered questions that fascinate us are: How do external stimuli that impact aging exert long-lasting effects? Do the mechanisms of aging differ in differentiated cells vs. somatic stem cells vs. germline cells? Can aging features be reversed? Is the aging rate of one individual affected by the presence of other individuals? How have vastly different lifespans evolved, and can this teach us something new about aging?

To address these questions while reflecting the complexity of aging, we have developed a vibrant research program based on a multi-organismal genetic approach. Our lab is deconstructing aging into its most fundamental questions using the invertebrate C. elegans. To explore more complex questions about aging, we employ mammalian models, including mouse and human cells. Importantly, our lab has broken new ground by pioneering the naturally short-lived African killifish as a model to identify new principles underlying vertebrate aging.

Examples of exciting phenomena we have discovered include the epigenetic regulation of lifespan, a ‘non-organismal autonomous’ mode of aging regulation between the sexes, and the existence of vertebrate-specific loci that regulate lifespan. In the future, we want to model aging in complex systems to better understand aging and the evolutionary forces that shape lifespan. Our work has the promise to transform our understanding of aging, which is at the heart of many human diseases.

Projects

1) Metabolic pathways that impact aging

We have had a long-standing interest in the role of metabolic pathways in aging and longevity. As a post-doctoral fellow, I discovered the mechanism of regulation of FOXO transcription factors by the insulin signaling pathway. In our lab, we developed a line of investigation combining C. elegans and mammalian cells to identify the role of the nutrient-sensing pathways such as the insulin-FOXO pathway and the AMP kinase (AMPK) pathway in longevity and associated cellular functions.


1. Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, Anderson MJ, Arden KC, Blenis J, Greenberg ME (1999) Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell, 96: 857-868. Abstract PDF

2. Greer EL, Dowlatshahi D, Banko MR, Hoang K, Blanchard D, and Brunet A (2007) An AMPK-FOXO pathway mediates the extension of lifespan induced by a novel method of dietary restriction in C. elegans. Curr Biol,17: 1646-1656. Abstract PDF

3. Greer EL and Brunet A (2009) Different dietary restriction regimens extend lifespan by both independent and overlapping genetic pathways in C. elegans.  Aging Cell, 8: 113-127. Abstract PDF

4. Banko MR, Allen JJ, Schaffer BE, Wilker EW, Tsou P, White JL, Villen J, Wang B, Kim SR, Sakamoto K, Gygi SP, Cantley LC, Yaffe MB, Shokat KM and Brunet A (2011) Chemical genetic screen for AMPKalpha2 substrates uncovers a network of proteins involved in mitosis. Mol Cell, 44:878-892. Abstract PDF

5. Schaffer BE, Hertz NT, Levin RS, Maures TJ, Schoof ML, Hollstein PE, Benayoun BA, Banko MR, Shaw RJ, Shokat KM, and Brunet A. (2015) Identification of AMPK phosphorylation sites reveals a network of proteins involved in cell invasion and facilitates large-scale substrate prediction. Cell Metab, 22: 907-922. Abstract PDF

6. Webb A, Kundaje A, and Brunet A. (2016) Characterization of the direct targets of FOXO transcription factors through evolution. Aging Cell, 15: 673-685. Abstract PDF

2) Epigenetic regulation of lifespan

Our lab seeks to understand how external signals that impact aging such as food and sex are integrated in a stable, yet reversible manner. One of our most exciting discoveries is the importance of epigenetic modifiers in longevity and the transgenerational inheritance of longevity by chromatin modifiers. We have discovered that epigenetic modifiers that catalyze the trimethylation of lysine 4 in histone H3 (H3K4me3) and H3K27me3 both influenced lifespan. Interestingly, H3K27me3 modifiers can protect against normal aging and aging in response to males. We are interested in how epigenetic modifiers integrate environmental stimuli (food, sex, pathogens, etc) to regulate lifespan.


1. Greer EL, Maures TJ, Hauswirth AG, Green EM, Leeman DS, Maro, GS, Han S, Banko MR, Gozani O and Brunet A (2010) Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans. Nature, 466: 383-387. Abstract PDF

2. Maures TJ, Greer EL, Hauswirth AG, and Brunet A (2011). H3K27 demethylase UTX-1 regulates C. elegans lifespan in a germline-independent, insulin-dependent, manner. Aging Cell, 10: 980-990. Abstract PDF

3. Greer EL, Maures TJ, Ucar D, Hauswirth AG, Mancini E, Lim JP, Benayoun BA, Shi Y and Brunet A (2011) Transgenerational epigenetic inheritance of longevity in Caenorhabditis elegans. Nature, 479: 365-371. Abstract PDF 

4. Maures TJ, Booth LN, Benayoun BA, Izrayelit Y, Schroeder FC and Brunet A (2014) Males shorten the life span of C. elegans hermaphrodites via secreted compounds. Science 343:541-544. Abstract PDF

5. Benayoun BA*, Pollina EA* and Brunet A (2015) Epigenetic regulation of aging: linking environmental input to genomic stability. Nature Review Mol Cell Biol, 16:593-610. Abstract  PDF

6. Booth LN and Brunet A (2016) The aging epigenome. Mol Cell, 62:728-44. Abstract PDF

3) Interaction between epigenetic and metabolic pathways in stem cell aging

Our lab is using mammalian models to address complex questions about aging in cells absent in C. elegans, such as adult regenerative stem cells. Key questions we are asking include: how are metabolic pathways and epigenetic modifiers involved in impacting stem cell aging,? Are stem cells are their differentiated progeny aging in the same manner? We are examining the role of metabolic signaling pathways and FOXO transcription factors in neural stem cells and cognitive function. An ongoing project is to evaluate the role of epigenetic modifications in stem cell aging.


1. Renault VM, Rafalski VA, Morgan AA, Salih DAM, Brett JO, Webb AE, Villeda SA, Thekkat PU, Guillerey C, Denko NC, Palmer TD, Butte AJ, and Brunet A (2009) FOXO3 regulates neural stem cell homeostasis. Cell Stem Cell, 5: 527-539. Abstract PDF

2. Rafalski VA, Ho PO, Brett JO, Ucar D, Dugas JC, Pollina EA, Chow LML, Ibrahim A, Baker SJ, Barres BA, Steinman L, and Brunet A (2013) Expansion of oligodendrocyte progenitor cells upon SIRT1 inactivation in the adult brain. Nat Cell Biol, 15: 614-624. Abstract PDF

3. Webb AE, Pollina EA, Vierbuchen T, Urban N, Ucar D, Leeman D, Sewak M, Rando TA, Guillemot F, Wernig M, and Brunet A (2013) Genome-wide interaction between the pro-longevity factor FOXO3 and the neuronal determinant ASCL1 in adult neural stem/progenitor cells. Cell Rep 4: 477-491. Abstract PDF

4. Benayoun BA, Pollina EA, Ucar D, Mahmoudi S, Karra K, Wong E, Devarajan K, Daugherty AC, Kundaje A, Mancini E, Rando TA, Snyder MP, Baker JC, Cherry M and Brunet A (2014) H3K4me3 breadth is linked to cell identity and transcriptional consistency. Cell 158: 673-688. Abstract PDF Database

5. Brunet A and Rando T. Interaction between epigenetic and metabolism in stem cell aging. Curr Opin in Cell Biol, 24;45:1-7. Abstract PDF

4) Brain aging

We are interested in understanding the determinant of cognitive aging, and if there are aspects of brain aging that can be rejuvenated. Our work in neural stem cells has led us to identify pathways that could be critical for neural stem cells

1. Salih DA, Rashid AJ, Colas D, de la Torre-Ubieta L, Zhu RP, Morgan AA, Santo EE, Ucar D, Devarajan K, Cole CJ, Madison DV, Shamloo M, Butte AJ, Bonni A, Josselyn SA, Brunet A  (2012) FoxO6 regulates memory consolidation and synaptic function. Genes & Dev 26:2780-801. Abstract PDF Supplemental PDF 

2. Rafalski VA, Ho PO, Brett JO, Ucar D, Dugas JC, Pollina EA, Chow LML, Ibrahim A, Baker SJ, Barres BA, Steinman L, and Brunet A (2013) Expansion of oligodendrocyte progenitor cells upon SIRT1 inactivation in the adult brain. Nat Cell Biol (Article) 15: 614-624. Abstract PDF

3. Webb AE, Pollina EA, Vierbuchen T, Urban N, Ucar D, Leeman D, Sewak M, Rando TA, Guillemot F, Wernig M, and Brunet A (2013) Genome-wide interaction between the pro-longevity factor FOXO3 and the neuronal determinant ASCL1 in adult neural stem/progenitor cells. Cell Rep 4: 477-491. Abstract PDF

4. Dulken BW, Leeman DS, Boutet SC, Hebestreit K, and Brunet A (2017). Single cell transcriptomic analysis defines heterogeneity and transcriptional dynamics in the adult neural stem cell lineage. Cell Rep 18: 777-790. AbstractPDF

5) Development of the African turquoise killifish as a new model for aging biology

Our lab is pioneering the naturally short-lived African turquoise killifish as a new model for aging and longevity in vertebrates. We have sequenced the genome of this fish and have developed genome-editing of several aging and longevity genes. We are excited to ask unique questions about vertebrate aging in this new system: are there vertebrate-specific genes that regulate lifespan? What is responsible for the vast differences in lifespan between species?


1. Valenzano DR, Kirschner J, Kamber RA, Zhang E, Weber D, Cellerino A, Englert C, Platzer M, Reichwald K and Brunet A (2009) Mapping loci associated with tail color and sex determination in the short-lived fish Nothobranchius furzeri. Genetics, 183: 1385-1395. Abstract PDF

2. Valenzano DR, Sharp S and Brunet A (2011) Transposon-mediated transgenesis in the short-lived African killifish Nothobranchius furzeri, a vertebrate model for aging. G3, Genes Genome Genetics, 1: 531-538. PDF

3. Harel I, Benayoun BA, Machado M, Singh PP, Hu CK, Pech MF, Valenzano DR, Zhang E, Sharp SC, Artandi SE and Brunet A (2015) A Platform for rapid exploration of aging and diseases in a naturally short-lived vertebrate. Cell, 160: 1013-1026. Abstract  PDF

4. Valenzano DR, Benayoun BA, Singh PP, Zhang E, Etter PD, Hu CK, Clément-Ziza M, Willemsen D, Cui R, Harel I, Machado BE, Yee MC, Sharp SC, Bustamante CD, Beyer A, Johnson EA, and Brunet A  (2015) The African turquoise killifish genome provides insights into evolution and genetic architecture of lifespan. Cell, 163: 1539-1554. Abstract PDF African Killifish Genome Browser

5. Harel I, Valenzano DR, and Brunet A (2016) Efficient genome engineering approaches for the short-lived African turquoise killifish. Nature Protocols, 11: 2010-2028. Abstract PDF