Molecular genetics of aging and longevity.

Our research has focused on understanding the molecular, cellular and genetic mechanisms underlying the process of aging and the determination of life span using the fruit fly, Drosophila melanogaster, as a model system.

Biography

Dr. Helfand received his BS at Stanford University where he worked with Dr. Norman K. Wessells and discovered the neuronal growth factor Ciliary NeuroTrophic Factor. Dr. Helfand obtained his MD degree from Albert Einstein College of Medicine, completed his Medical Internship at Montefiore Medical Center and his Neurology Residency at the Massachusetts General Hospital. He is Board Certified in Neurology.

After Postdoctoral training with Drs. Corey Goodman and David Hogness at Stanford and Drs. John Carlson
and Doug Kankel at Yale he took a position at the University of Connecticut Health Center where he worked from 1990 to 2005.

In 2005 he moved to Brown University where he is Professor in the Department of Molecular Biology, Cell Biology and Biochemistry in the Division of Biology and Medicine. His laboratory focuses on understanding the molecular genetic mechanisms underlying aging and longevity using the model system, Drosophila melanogaster. Dr. Helfand is an Ellison Medical Foundation Senior Scholar and recipient of a MERIT award from the National Institute on Aging.

Research Description

Determining the molecular genetic underpinnings of the process of aging promises to be one of the next great frontiers in biomedical science. Despite our understanding of many of the intricacies of how a single fertilized egg develops into a mature individual, up until recently, we knew very little about the mechanisms by which we age--a subject of great scientific interest for several millennia. We are interested in understanding the molecular mechanisms underlying the development, maturation, and aging of adult animals using the fruit fly, Drosophila melanogaster, as a model system. In our laboratory we make use of a combination of molecular, genetic, cellular, neurobiological, pharmacological, immunological, and behavioral approaches to understand the process of aging and how life span is determined. By combining the powerful molecular genetic techniques available in the Drosophila melanogaster with knowledge of the fly's physiology, anatomy, behavior, and life span altering interventions, we have helped develop an unparalleled model for studying the molecular genetic elements of aging.

We discovered that mutations that decrease the activity of a single gene, Indy (I'm not dead yet), dramatically extends life span in flies without reducing reproduction, physical activity, or metabolic rate. The function of the Indy protein as a transporter of Krebs cycle intermediates and its localization to regions of the fly important in uptake, utilization and storage of nutrients, suggest that reductions in the level of Indy protein alters the metabolic state of the fly in a way that favors life span extension. We are studying how mutations in Indy extend life span in Drosophila and whether manipulation of Indy-like gene activity in mammals will extend healthy lifespan in mammals.

A reduction in Indy activity induces the fly to assume a physiological state similar to calorie restriction, an intervention known to extend life span in mammals, invertebrates, and yeast. But how does calorie restriction extend life span? We have shown that the histone deacetylatase enzymes Rpd3 and Sir2, known to deacetylate histone proteins as well as other proteins such as p53, are responsible for mediating the life span extending effect of calorie restriction in the fly. The conservation of the calorie restriction pathway and the role of Rpd3 and Sir2 in mediating life span extension in a variety of organisms (yeast, nematode, fly) indicate that knowledge of this biochemical/genetic pathway should assist in the development of genetic and pharmacological interventions for the extension of life span. In collaboration with Marc Tatar at Brown University and David Sinclair at Harvard Medical School, we used this knowledge to show that small compounds that enhance Sir2 activity, such as resveratrol, extend the life span in nematodes and flies through a Sir2 dependent calorie restriction pathway. We are continuing to investigate the molecular mechanisms by which Rpd3 and Sir2 cause life span extension starting with studies on p53, the well-known tumor suppressor protein that is inactivated by Sir2. Mice with hyperactive p53 activity are resistant to tumor formation, but surprisingly have a shortened life span with signs of premature aging. Our recent results indicate reduction of p53 activity is one of the mediators of the Sir2/calorie restriction life span extending pathway in flies.

Our studies have led to the proposal of a genetic/biochemical pathway for the life span extending effects of calorie restriction. Mutations in Indy or other triggers that similarly alter the metabolic state of the fly decrease Rpd3 activity, increase Sir2 activity, reduce p53 activity, and extend life span. Our success in predicting the life span extending effect on flies of the Sir2 activator resveratrol suggest that knowledge of this pathway will be valuable for identifying additional interventions for extending life span in flies and other species, including humans.

Projects in the laboratory include: (i) the use of a newly developed rapid method for identifying genes and drugs that slow aging and extend life span; (ii) determining at a biochemical and whole animal physiological level how the single gene mutation, Indy, causes a near doubling of the life span of the fly without a significant tradeoff in physiological functioning; (iii) development of a biochemical/genetic pathway for the life span extending affect of calorie restriction, which includes delineating how alterations in the histone deacetylases rpd3 and Sir2 and sirtuin activator, resveratrol, mediate life span extension; (iv) developing modifications in metabolic activity through transgenic approaches that alter mitochondrial uncoupling and extend healthy life span; (v) defining the role of the well known tumor suppressor p53 in the life span determination; (vi) and the development of the fly as a model for studying disorders of human aging such as neurodegeneration, obesity, and diabetes.

Awards

1975 Distinction, Departmental Honors (Biology)
1975 National Science Foundation (NSF) Undergraduate Fellowship (Advisor: N.K. Wessells)
1983-1984 National Institutes of Health (NIH) Postdoctoral Fellowship
1984-1989 NIH Physician Scientist Award
1986 Diplomate American Board of Psychiatry and Neurology
1992-1995 National Science Foundation Award
1992 American Federation of Aging Research Award
1993 Sandoz Award for Gerontogical Research
1995 American Federation of Aging Research Award
1995 Nathan W. and Margaret T. Shock Aging Foundation Award
1999-2004 National Institute on Aging-RO1
2000-2001 The Donaghue Foundation Investigator Program for Health-Related Research Award
2001-2005 Ellison Medical Foundation Senior Investigator Award in Aging
2004- R37 MERIT Award, National Institute of Aging
2004- National Institute on Aging-RO1
2005- National Institute on Aging-RO1
2007- Glenn Award for Research in Biological Mechanisms of Aging

Affiliations

Ellison Medical Foundation Senior Scholar in Aging
Genetics Society of America
Gerontology Society of America

Funded Research

AG-SS-0716 (Helfand), PI 10/1/2001-9/30/2006 5%
Ellison Foundation
Isolation of Single Gene Mutations in Drosophila Melanogaster

1R01 AG025277 (Helfand), PI 9/30/2005-6/30/2010 15%
National Institutes of Health/National Institute on Aging (NIH/NIA)
Oxidative Damage, Aging, and Life Span

2 R37 AG16667-06 (Helfand), PI 4/1/2004-3/31/2009 15%
NIH/NIA
Single Gene Mutants that Confer Longevity in Drosophila

1RO1 AGO224353 (Helfand), PI 9/30/2004-7/31/2009 15%
NIH/NIA
Control of Gene Expression and Life Span

Courses Taught

• Current Topics in Developmental Biology: The Biology of Aging (Biol 232)
• Development of Scientific Theories: Context and the Individual (Biol 0190P)

Selected Publications

• Bauer J.H., Morris SNS, Chang C, Flatt T, Wood JG and Helfand SL. (2009) dSir2 and Dmp53 interact to mediate aspects of CR-dependent life span extension in D. melanogaster. Impact Aging 1: 38-48.(2009)
• Neretti N, Wang PY, Brodsky AS, Nyguyen HH, White KP, Rogina B, Helfand SL. (2009) Long-lived Indy induces reduced mitochondrial reactive oxygen species production and oxidative damage. Proc Natl Acad Sci U S A. Feb 17;106(7):2277-82. Epub 2009 Jan 21.(2009)
• Helfand, S. L., Bauer, J. H. and Wood, J. G. (2008) Calorie Restriction in lower organisms in Molecular Biology of Aging edited by L. Guarente, L. Partridge, and D. Wallace. Cold Spring Harbor Laboratory Press, New York.(2008)
• Bauer JH, Chang C, Morris SNS, Hozier S, Andersen S, Waitzman JS, Helfand S.L. (2007) Expression of dominant-negative Dmp53 in the adult fly brain inhibits insulin signaling. Proc. Natl. Acad. Sci. (USA), 14; 104(33):13355-60Aug 8; [Epub ahead of print](2007)
• Bauer, JH and Helfand, SL. (2006) New tricks of an old molecule: lifespan regulation by p53. Aging Cell 5: 437-40.(2006)
• Knauf F, Mohebbi N, Teichert C, Herold D, Rogina B, Helfand SL, Gollasch M, Luft FC, and Aronson, PA. (2006) The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates. Biochemical Journal, Epub ahead of print April 12, 2006.(2006)
• Sanchez-Blanco A, Fridell YW, Helfand S.L. (2006) "Involvement of Drosophila Uncoupling Protein 5 in Metabolism and Aging." Genetics 172:1-12.(2006)
• Bauer, JH and Helfand, S. L. (2006) The humble fly: what a model system can reveal about the human biology of aging. Rhode Island Medical Journal, 89(9): 314-5.(2006)
• Bauer JH, Poon PC, Glatt-Deeley H, Abrams JM, Helfand S.L. (2005) "Neuronal Expression of p53 Dominant-Negative Proteins in Adult Drosophila melanogaster Extends Life Span." Curr Biol. 15:2063-8.(2005)
• Bross, TG, Rogina, and Helfand S. L. (2005) Behavioral, physical, and demographic changes in Drosophila populations through dietary restriction. Aging Cell. 4: 309-17. (Cover picture)(2005)
• Fridell, Y-W, Sanchez-Blanco, A., Silvia, B. and Helfand, S. L. (2005) Targeted Expression of the Human Uncoupling Protein 2 (hUCP2) to Adult Neurons Extends Life Span in the Fly. ." Cell Metabolism 1: 145-152.(2005)
• Zheng, J-Y, Mutcherson, R, and Helfand, S. L. (2005) Calorie restriction delays lipid oxidative damage in Drosophila melanogaster. Aging Cell. 4: 209-16.(2005)
• Fridell, Y-W., Sánchez-Blanco, Silvia, B. A. and Helfand, S. L., (2004) Functional Characterization of a Drosophila Mitochondrial Uncoupling Protein. Journal of Bioenergetics and Biomembranes, 36 (3): 219-228.(2004)
• Bauer, J., Goupil, S., Garber, G., and Helfand, S. L. (2004) An accelerated assay for the identification of life span extending interventions in Drosophila melanogaster. Proc. Natl. Acad. Sci. (USA), 101:12980-12985.(2004)
• Wood, J, Rogina, B, Lavu, S., Howitz, K., Helfand, S. L, Tatar, M., and Sinclair, D. (2004) Sirtuin activators mimic calorie restriction and delay aging in metazoans. Nature, 430 (7000): 686-9.(2004)
• Rogina, B. and Helfand, S. L. (2004) Sir2 mediates longevity in the fly through a pathway related to calorie restriction. Proc. Natl. Acad. Sci. (USA), 101: 15998-16003).(2004)
• Marden, J.H., Rogina, B., Montooth,K.L. and Helfand,S.L. (2003) Conditional tradeoffs between aging and organismal performance of Indy long-lived mutant flies. . Proc. Natl. Acad. Sci. USA 2003, 100(6): 3369-3373.(2003)
• Rogina, B., Helfand, S. L. and Frankel, S. (2002) Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction, Science, 298: 1745.(2002)
• Hoopengardner, B and Helfand, S. L. (2002) Temperature Compensation and Temporal Expression Mediated by an Enhancer Element in Drosophila. Mechanisms of Development , 110: 27-37.(2002)
• Knauf, F., Rogina, B., Jiang, Z., Aronson, P. A., and Helfand, S. L. (2002) Functional Characterization and Immunolocalization of the Novel Transporter Encoded by the Life-Extending Gene Indy. Proc. Natl. Acad. Sci. (USA), 99:14315-14319.(2002)
• Rogina, B. Reenan, R. A., Nilsen S. P. and Helfand, S. L. Extended life-span conferred by cotransporter gene mutations in Drosophila. (2000) Science, 290: 2137-40.(2000)
• Rogina, B. and Helfand, S.L. (2000) Cu, Zn superoxide dismutase deficiency accelerates the time course of an age-related marker in Drosophila melanogaster. Biogerontology 1: 161-167.(2000)
• Rogina, B., Vaupel, J.W., Partridge, L. and Helfand, S.L. (1998) Regulation of gene expression is preserved in aging Drosophila melanogaster. Current Biology 8: 475-478.(1998)
• Rogina, B. and Helfand, S.L. (1997) Spatial and Temporal Pattern of expression of the wingless and engrailed genes in the adult antenna is regulated by age-dependent mechanisms. Mech. of Develop. 63: 89-97.(1997)
• Rogina, B., Benzer, S. and Helfand, S.L. (1997) Drosophila drop-dead mutations accelerate the time course of age-related markers. Proc. Natl. Acad. Sci. USA 94: 6303-6306.(1997)
• Rogina, B. and Helfand, S.L. (1996) Timing of expression of a gene in the adult Drosophila is regulated by mechanisms independent of temperature and metabolic rate. Genetics 143:1643-1651.(1996)
• Helfand, S. L. and Naprta, B. (1996) The expression of a reporter protein, ß-galactosidase, is preserved during maturation and aging in some cells of the adult Drosophila melanogaster. Mech of Development 55:45-51.(1996)
• Blake, K. J., Hoopengardner, B., Centurion, A. and Helfand, S. L. (1996) A molecular marker shows that adult maturation is independent of the rate of pre-adult development in Drosophila melanogaster. Developmental Genetics 18:25-130.(1996)
• Rogina, B. and Helfand, S. L. (1995) Regulation of gene expression is linked to life span in the adult Drosophila. Genetics 141:1043-48.(1995)
• Blake, K.J., Rogina, B., Centurion, A. and Helfand, S. L. (1995) Changes in gene expression during post-eclosional development in the olfactory system of Drosophila melanogaster. Mec.h of Develop. 52:179-185.(1995)
• Helfand, S.L., Blake,K.J., Rogina, B., Stracks, M.D., Centurion, A. and Naprta, B. (1995) Temporal patterns of gene expression in the antenna of the adult Drosophila melanogaster. Genetics 140:549-555.(1995)
• Peer-review Publications (since 1995)(1995)