Andrew (Andy) Samuelson
Ph.D. 2002 State University of New York at
Assistant Professor of Genetics, Department of Biomedical Genetics (BMG)
Probably the most transformative finding in aging research was the discovery just over 20 years ago that single genetic mutations can drastically alter the rate of aging in Caenorhabditis elegans. A growing body of evidence has demonstrated these changes often occur in highly conserved gene products that function as sensors of metabolic status, examples include: altered insulin/IFG-1 signaling (ILS), sirtuins, AMP kinase (AMPK), and the target of rapamycin (TOR). Alternatively, the transcriptional effectors of these metabolic signals, including DAF-16 (FoxO), PHA-4 (FoxA), SKN-1 (Nrf2), and HSF-1 (heat shock transcription factor) are also responsive to a wide variety of stresses and play key roles in activating many cellular protective mechanisms, which work in part to facilitate the maintenance of protein homeostasis (proteostasis). Proteostasis is the ability of the cells to maintain proper folding of the proteome, which declines during normal aging and may be an underlying basis for many age-associated proteostatic diseases.
In some cases how changes to metabolic signaling are well known. For instance, the canonical C. elegans daf-2/ILS signaling pathway influences aging and constitutes 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 antagonize DAF-16, the orthologue of the mammalian FoxO forkhead transcription factor. Decreased ILS extends longevity, increases resistance to a wide array of stressors, and extends proteostasis, all in a daf-16 dependent manner. Thus DAF-16 function as the canonical transcriptional effector for changes in ILS. Collectively these and other discoveries consistently demonstrate that sensors and effectors of metabolic status and stress response are closely interrelated and regulate a wide variety of adaptive and cytoprotective programs whose decline ultimately determines the progression of aging.
While some signal transduction pathways have been studied in great detail, metabolic and stress signaling occurs through a complex and dynamic network that remains poorly understood. Many questions remain: what are the mediators of these signals, whose activity in turn do they regulate, and what is the cross talk between these signals? Thus identifying mediators of pro-longevity signals and subsequently linking them to essential effectors of cytoprotective programs is critical to understanding aging at the molecular, cellular, and organismal level and is a central focus of the Samuelson laboratory.
To begin to unravel the genetic complexities of aging, we previously conducted the first comprehensive functional genomic study in C. elegans to discover genes that normally function to delay the onset of aging. Towards this end we identified 103 progeric genes (the progeric gene panel (PGP)), which are required for the extension of longevity induced by decreased insulin/IGF signaling. We have completed an extensive analysis of the PGP in the context of many phenotypes related to aging and from this analysis there are currently two main areas of focus within the Samuelson laboratory.
A. One member of the PGP we have been studying in greater detail is apk-1, (aging protein kinse-1), which functions within the nucleus to regulate transcription. Mammalian homologs have important roles in cell growth, development, differentiation, and apoptosis. Significantly, activation of mammalian homologs have been linked to both metabolism and stress response, yet our discovery is the first to directly link this family to aging. We find that APK-1, is both necessary and sufficient to alter lifespan and proteostasis. APK-1 functions in a common genetic pathway with HSF-1 and is induced by thermal stress, implying that APK-1 is a bona fide heat shock response gene. Consistent with this notion, apk-1 null mutant animals have compromised thermotolerance, which is accompanied with reduced induction of heat shock responsive chaperones after thermal stress. Additionally, apk-1 mutants fail to the obtain the hormetic benefit conferred by a transient heat stress, which in wild-type animals manifests as increased lifespan, implying that the roles of APK-1 in the heat shock response, proteostasis, and aging are intimately connected. Lastly, we have discovered that decreased TORC1 signaling induces APK-1. Collectively, we demonstrate that APK-1 is responsive to metabolic as well as stress signaling, and is an essential component of the heat shock response whose function ultimately influences both protein homeostasis and aging.
B. We have discovered a vital role for the Myc family of transcription factors in regulating transcriptional programs that set the progression of aging in Caenorhabditis elegans. Myc and the related Myc family members have well known roles in diverse biological contexts including: cellular proliferation, growth, senescence, metabolism, and apoptosis, but our discovery is the first to directly link the Myc family to aging. We find that in C. elegans two heterodimeric complexes have opposing roles in aging and transcriptional control (homologous to mammalian Myc-Mondo and Mad complexes) (Figure 1). ChREBP, one of two mammalian Mondo homologs, is one of 26 genes lost in Williams-Beuren Syndrome (WBS), which among other symptoms causes metabolic dysfunctions, silent diabetes, and premature aging. Furthermore, Mondo and ChREBP function as non-hormonal sensors of carbohydrate availability. Thus, our discovery that the Myc family plays a role in aging is consistent with a nutrient-sensing paradigm.
Das R., Kim J.H., and Samuelson A.V. APK-1 is induced by metabolic and stress signals to activate the heat shock response and influence aging (In Preparation for submission to Cell Metabolism, 2015)
Llop J.R., Salzman P., and Samuelson A.V. Assessing changes in C. elegans lifespan through the replica set methodology is more accurate than the traditional approach. (Under revision for consideration at Aging Cell, 2015).
Johnson D.W., Llop J.R., Farrell S.F., Yuan J., Stolzenburg L.R., and Samuelson A.V. The Caenorhabditis elegans Myc-Mondo/Mad Complexes Integrate Diverse Longevity Signals (2014) PLoS Genetics 10(4):e1004278. PMCID: PMID24699255.
Sykiotis G.P., Habeos I.G., Samuelson A.V., and Bohmann D., The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation (2011) Current Opinion in Clinical Nutrition and Metabolic Care. 14:41-48. PMCID: PMID21102319.
Ruvkun, G., Samuelson, A.V., Carr, C.E., Curran, S.P., and Shore, D.E. Signaling Pathways that Regulate C. elegans Life Span (2009). In Research and Perspectives in Endocrine Interactions. IGFs: Local Repair and Survival Factors Throughout Life Span. pp. 69-84.
Samuelson A.V., Carr C.E., and Ruvkun G. Gene activities that mediate increased lifespan of C. elegans insulin-like signaling mutants (2007a). Genes and Development 21:2976-94. PMCID: PMID18006689.
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 (2007b). Cold Spring Harb Symp Quant Biol. 72:489-497 PMCID: PMID18419309.
Graduate Program Affiliations
University of Rochester
601 Elmwood Ave., Box 633
Rochester, NY 14642
Office: MRB 2-9631
Manju Thondamal, Ph.D.
|Jesse Llop, Computer Programmer|
The lab is happy to accept rotation students at this time. A variety of projects in aging are available to students.