Andrew (Andy) Samuelson
Ph.D. 2002 State University of New York at
Assistant Professor of Genetics, Department of Biomedical Genetics (BMG)
The Samuelson lab is interested in understanding aging at the genetic, molecular, cellular, and organismal level. Aging is conserved across species and single mutations within orthologous genes in nematodes, flies, and mice regulate longevity and age related phenotypes, implying that aging is influenced by common genetic mechanisms. Classical genetic analysis in C. elegans has identified the daf-2/insulin-like signaling pathway as the most potent regulator of aging, a finding which has since been confirmed in flies and mice. The C. elegans daf-2 signaling pathway is an endocrine system homologous to the mammalian insulin and insulin-like growth factor 1 signaling pathways. The daf-2 gene encodes the worm homologue of the insulin/IGF-I receptor and couples to the AGE-1 phosphatidylinositol 3-kinase (PI3K) and AKT-1/2 kinases, to repress DAF-16, a forkhead transcription factor orthologous to human FoxO. The insulin-like-signaling pathway regulates longevity, metabolic function, development, stress resistance, innate immunity, and the expression of free radical detoxifying enzymes, consistent with free radical theories of aging and the involvement of mitochondria and reactive oxygen species in aging.
Dr. Samuelson conducted the first comprehensive functional genomic study to discover genes that delay the onset of aging. He used RNA interference (RNAi) to identify genes required for the extension of lifespan induced by decreased insulin/IGF signaling and identified 103 genes with the potential to delay aging (‘progeric gene panel’). Significantly, 17 of these putative aging control genes are predicted to regulate vesicular trafficking to the lysosomes. This finding might explain how accumulation of age pigment occurs during normal aging. Almost all of these genes are conserved across animal phylogeny (96%), raising the possibility that they might control aging in humans as well. The Samuelson lab will decipher the molecular function of genes required for daf-2-mediated increased longevity, further elucidate the role of endosomal vesicular trafficking in aging, and dissect the input of stress response pathways.
Specifically, the Samuelson lab will test the progeric gene panel (by RNAi) in long-lived strains harboring mutations in distinct genetic pathways to elucidate the overlapping requirements between the pathways. Since insulin-like signaling modulates metabolic signaling and protects the integrity of the mitochondrial genome, the lab will determine which progeric gene inactivations disrupt metabolic and/or mitochondrial functions. Aging in C. elegans occurs cell non-autonomously, with the nervous system, intestine, and germ-line stem cells serving as major endocrine signaling centers, therefore expression patterns of the aging genes will determined and those that extend lifespan when overexpressed.
Consistent with published studies on lysosomal function and autophagy in aging, Dr. Samuelson discovered that endosomal vesicular trafficking to the lysosome and proper endosomal protein sorting is essential for the increase of lifespan in conditions of decreased insulin-like signaling. This finding suggests that improper recycling of membrane components can accelerate aging. The Samuelson lab will determine the extent to which disruption of vesicular trafficking correlates with aging. The discovery that vesicular trafficking is critical for the aging process implies that aberrant signaling from transmembrane proteins promotes aging, thus the lab will identify and characterize such putative transmembrane proteins. Aberrant vesicular trafficking may promote ER stress, which has a well-established role in aging.
The broadly conserved correlation between stress resistance and longevity suggests that the integrity of stress response mechanisms would sustain longevity in many organisms. The Samuelson lab will determine the contribution of specific stress response pathways to aging by accessing the contribution of the progeric gene panel to stress resistance. The focus is to first identify the subset of those genes in the panel that are required for enhanced stress resistance seen in conditions of decreased insulin-like signaling. The progeric gene inactivations could negatively impact longevity through two mechanisms linked to stress resistance. One possibility is that inactivating an aging gene is sufficient to cause increased damage, thereby activating the related stress response. Alternatively, a progeric gene inactivation may uncouple a damage signal from the stress response machinery, thereby preventing the recognition or response to stress that occurs during aging. The Samuelson lab will identify the progeric gene inactivations that are sufficient to activate a specific stress response pathway without insult or blocks a response after insult. Specifically, oxidative stress response, DNA damage, heat shock response, and protein homeostasis will be studied in detail to elucidate how stress response pathways influence aging.
Chakraborty A.A., Tworkowski K.A., Samuelson A.V., Seger Y.R., Narita M., Hannon G.J., Lowe S.W.,
and Tansey W.P. Adenovirus E1A targets p400 to induce the cellular oncoprotein Myc (2008). Proc. Natl.
Acad. Sci. 105:6103-8. View article in PubMed
Samuelson A.V., Klimczak R.R., Thompson D.B., Carr C.E., and Ruvkun G. Identification of Caenorhabditis elegans Genes Regulating Longevity Using Enhanced RNAi-sensitive Strains (2007). Cold Spring Harb Symp Quant Biol. 72:489-497 View article in PubMed
Samuelson A.V., Carr C.E., and Ruvkun G. Gene activities that mediate increased lifespan of C. elegans insulin-like signaling mutants (2007). Genes and Development 21:2976-94. View article in PubMed
Graduate Program Affiliations
University of Rochester
601 Elmwood Ave., Box 633
Rochester, NY 14642
Office: MRB 2-9631
|Jesse Llop, technician|
|Lindsay Stolzenburg, undergrad student|
|John Dawson, undergrad student|
|Eric Dong, undergrad student|
|Pooja Patel, undergrad student|
|Ariel Chez, undergrad student|
The lab is happy to accept rotation students at this time. A variety of projects in aging are available to students.