Stephen L. Helfand Professor of Biology

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. During this time he spent a year at UC London with Drs. Martin Raff and Av Mitchison. He 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 at Yale with John Carlson and Doug Kankel 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, recipient of a MERIT award from the National Institute on Aging, has twice been awarded the Glenn Award for Research in Biological Mechanisms of Aging and was awarded the Glenn Foundation/American Federation of Aging Research Breakthroughs in Gerontology Award.

Brown Affiliations

Research Areas

scholarly work

PUBLICATIONS

 

Refereed journal articles

 

1) Helfand, S.L., Smith, G.A., and Wessells, N.K.  (1976) Survival and development in culture of dissociated parasympathetic neurons from ciliary ganglia.  Dev. Biol. 50: 541-547.

 

 2) Helfand, S.L., Riopelle, R.J., and Wessells, N.K. (1978) Non-equivalence of conditioned medium and nerve growth factor for sympathetic, parasympathetic and sensory neurons.  Exp. Cell Res. 113: 39-45.

 

3) Helfand, S.L., Werkmeister, J., and Roder, J.C. (1982) The relationship between target cell binding, chemiluminescence and cytolysis.  J. Exp. Med. 156: 492-505.

 

4) Roder, J.C., Helfand, S.L., Werkmeister, J., McGarry, R., Beaumont, T.J., and Duwe, A. (1982)  Oxygen intermediates are triggered early in the cytoytic pathway of human NK cells.  Nature 298: 569-572.

 

5) Werkmeister, J.A., Helfand, S.L., Rubin, P., Haliotis, T., Pross, H., and Roder, J.C. (1982) Tumor cell differentiation modulates susceptibility to natural killer cells.  Cell. Immun. 69:  122-127.

 

6) Roder, J.C., Todd, R.F., Rubin, P., Haliotis, T., Helfand, S.L., Werkmeister, J., Pross, H.F., Boxer, L.A., Schlossman, S.F., and Fauci, A.S. (1983) The Chediak-Higashi gene in humans III.  Studies on the mechanism of NK impairment.  Clinical Exp. Immuno. 51: 359-368.

 

7) Helfand, S.L., Werkmeister, J., Pross, H., and Roder, J.C. (1983) Oxygen intermediates are required for interferon activation of NK cells.  J. Interferon Res.  2: 143-151.

 

8) Werkmeister, J., Helfand, S.L., Roder, J., and Pross, H. (1983) The chemiluminescence response of human natural killer cels.  II.  Association of a decreased response with low natural killer activity.  Eur. J. Immunol.  13: 514-520.

 

9) McGarry, R.C., Helfand, S.L., Quarles, R.H., and Roder, J.C. (1983) Recognition of myelin-associated gylcoprotein by the monoclonal antibody HNK-1.  Nature 306: 376-378.

 

10) Beachy, P.A., Helfand, S.L. Hogness, D.S. (1985) Segmental distribution of bithorax complex proteins during Drosophila development.  Nature 313: 545-551.

 

11) Helfand, S.L. and Carlson, J.  (1989) Isolation and characterization of an olfactory mutant in Drosophila with a chemically specific defect.  Proc. Natl. Acad. Sci. USA  86: 2908-2912.

 

12) Woodward, C., Huang,T., Sun, H., Helfand, S.L., and Carlson, J. (1989) Genetic analysis of olfactory behavior in Drosophila:   A new screen yields the ota mutants. Genetics. 123:  315-326.

 

13) McKenna, M., Monte, P., Helfand, S.L., Woodard, C., and Carlson, J.  A novel chemosensory response in Drosophila and the isolation of the acj mutations which affect it. (1989) Proc. Natl. Acad. Sci. USA   86:  8118-8122.

 

14) Irvine, K.D., Helfand, S.L. and Hogness, D.S. The large upstream control region of the Drosophila homeotic gene Ultrabithorax.  (1991) Development  111:  407-424.

 

15) Helfand, S.L.,  Blake,K.J.,  Rogina, B., Stracks, M.D., Centurion, A. and Naprta, B.  Temporal patterns of gene expression in the antenna of the adult Drosophila melanogaster. (1995) Genetics  140:  549-555.

 

16) Blake, K.J., Rogina, B.,  Centurion, A. and Helfand, S. L.  Changes in gene expression during post-eclosional development in the olfactory system of Drosophila melanogaster. (1995) Mechanisms of Development  52:  179-185.

 

17) Rogina, B. and Helfand, S. L.   Regulation of gene expression is linked to life span in the adult Drosophila. (1995) Genetics 141:  1043-1048.

 

18) Blake, K. J.,  Hoopengardner, B., Centurion, A. and Helfand, S. L.  A molecular marker shows that adult maturation is independent of the rate of pre-adult development in Drosophila melanogaster. (1996) Developmental Genetics 18:  125-130.

 

19) Helfand, S. L. and Naprta, B.  The expression of a reporter protein, ß-galactosidase, is preserved during maturation and aging in some cells of the adult Drosophila melanogaster.  (1996) Mechanisms of Development 55:45-51.

 

20) Rogina, B. and Helfand, S. L.  Timing of expression of a gene in the adult Drosophila is regulated by mechanisms independent of temperature and metabolic rate. (1996) Genetics 143: 1643-1651

 

21) Rogina, B. and Helfand, S. L.  Spatial and temporal pattern of expression of the wingless and engrailed genes in the adult antenna is regulated by age-dependent mechanisms.  (1997) Mechanisms of Development  63:  89 - 97.

 

22) Rogina, B., Benzer, S., and Helfand, S. L.  Drosophila drop-dead mutations accelerate the time course of age-related markers.  (1997) Proc. Natl. Acad. Sci. (USA), 94: 6303-6306.

 

23) Rogina, B., Vaupel, J. W., Partridge, L., Helfand, S. L.  Regulation of gene expression is preserved in aging Drosophila melanogaster.  (1998) Current Biology, 8:  475-478.

 

24) Rogina, B. and Helfand, S.L.  Cu, Zn superoxide dismutase deficiency accelerates the time course of an age-related marker in Drosophila melanogaster. (2000)  Biogerontology 1:  161-167.

 

25) 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.

 

26) Hoopengardner, B and Helfand, S. L.  Temperature Compensation and Temporal Expression Mediated by an Enhancer Element in Drosophila. (2002) Mechanisms of Development, 110:  27-37.

 

27) 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.

 

28) Rogina, B., Helfand, S. L. and Frankel, S. (2002) Longevity regulation by Drosophila Rpd3 deacetylase and caloric restriction, Science, 298: 1745.

 

29) 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), 100: 3369-3373.

 

30) 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.

 

31) Woods, 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. (* co-contributing authors)

 

32) 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.

 

33) 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.

 

34) 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.

 

35) Zheng, J-Y, Mutcherson, R, and Helfand, S. L. Calorie restriction delays lipid oxidative damage in Drosophila melanogaster. Aging Cell 2005;  4: 209-16.

 

36) Bross, TG, Rogina, B, and Helfand S.L. (2005) Behavioral, physical, and demographic changes in Drosophila populations through dietary restriction. Aging Cell. 4:  309-17. (Cover picture)

 

37) Bauer JH, Poon PC, Glatt-Deeley H, Abrams JM, and Helfand S.L. (2005) Neuronal Expression of p53 Dominant-Negative Proteins in Adult Drosophila melanogaster Extends Life Span. Curr Biol. 15:2063-8.

 

38) Sanchez-Blanco A, Fridell YW, and Helfand S.L. (2006) Involvement of Drosophila Uncoupling Protein 5 in Metabolism and Aging. Genetics 172:1-12.

 

39) Knauf F, Mohebbi N, Teichert C, Herold D, Rogina B, Helfand S.L., Gollasch M, Luft FC, and Aronson, PA. (2006) The life-extending gene Indy encodes an exchanger for Krebs-cycle intermediates. Biochemical Journal 397: 25-29.

 

40) 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]

 

41) Bauer J.H., Morris SNS, Chang C, Flatt T, Wood JG and Helfand S.L. (2009) dSir2 and Dmp53 interact to mediate aspects of CR-dependent life span extension in D. melanogaster. Aging 1: 38-48.

 

42) Neretti N, Wang PY, Brodsky AS, Nyguyen HH, White KP, Rogina B, Helfand S.L. (2009) Long-lived Indy induces reduced mitochondrial reactive oxygen species production and oxidative damage. Proc Natl Acad Sci U S A. 2009 Jan 21. [Epub ahead of print]

 

43) Wang PY, Neretti N, Whitaker R, Hosier S, Chang C, Lu D, Rogina B, Helfand SL. (2009) Long-lived Indy and calorie restriction interact to extend life span.  Proc Natl Acad Sci U S A. 2009 Jun 9;106(23):9262-7. Epub 2009 May 22.

 

44) Fridell, Y-W, Hoh, M, Kreneisz, Orsolya, Hosier, S, Chengyi, C, Scantling D, Mulkey, D and Helfand SL. (2009) Increased Uncoupling Protein (UCP) activity in Drosophila Insulin-Producing neurons attenuates Insulin signaling and extends lifespan. Aging Jul 21;1(8):699-713.

 

45) Bauer JH, Chang C, Bae G, Morris SN, Helfand SL.(2010) Dominant-negative Dmp53 extends life span through the dTOR pathway in D. melanogasgter.  Mech Ageing Dev. 2010 Mar;131(3):193-201. Epub 2010 Feb 1.

 

46) Bauer, JH, Antosh, M., Chang, C., Schorl, C., Kolli, S., *Neretti, Helfand SL. Comparative transcriptional profiling identifies takeout as a gene that regulates life span. (2010) Aging May;2(5):298-310.PMID: 20519778

 

47) Wood JG, Hillenmeyer S, Lawrence C, Chang C, Hosier S, Lightfoot W, Mukherjee E, Jiang N, Schorl C, Brodsky AS, Neretti N, Helfand SL.  (2010) Chromatin remodeling in the aging genome of Drosophlia.  Aging Cell. 2010 Dec;9(6):971-8. doi: 10.1111/j.1474-9726.2010.00624.x. Epub 2010 Oct 21.PMID: 20961390

 

48) Antosh M, Whitaker R, Kroll A, Hosier S, Chang C, Bauer J, Cooper L, Neretti N, Helfand SL. (2011) Comparative transcriptional pathway bioinformatic analysis of dietary restriction, Sir2, p53 and resveratrol life span extension in Drosophila.  Cell Cycle. 2011 Mar 15;10(6).

 

49) Antosh M, Fox D, Helfand SL, Cooper LN and Neretti N. (2011) New comparative genomics approach reveals a conserved health span signature across species. Aging (Albany NY). 2011 Jun;3(6):576-83.  PMID: 21775776

 

50) Birkenfeld AL, Lee HY, Guebre-Egziabher F, Alves TC, Jurczak MJ, Jornayvaz FR, Zhang D, Hsiao JJ, Martin-Montalvo A, Fischer-Rosinsky A, Spranger J, Pfeiffer AF, Jordan J, Fromm MF, König J, Lieske S, Carmean CM, Frederick DW, Weismann D, Knauf F, Irusta PM, De Cabo R, Helfand SL, Samuel VT and Shulman GI. (2011) Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metabolism 2011 Aug 3;14(2):184-95. PMID: 21803289

 

51) Chamseddin KH, Khan SQ, Nguyen ML, Antosh M, Morris SN, Kolli S, Neretti N, Helfand SL, Bauer JH. “takeout-dependent longevity in associated with altered Juvenile Hormone signaling”. Mech Ageing Dev. 2012 Nov;133(11-12):637-46. Epub 2012 Aug 30. PMID: 22940452

 

52) Rogina B, and Helfand SL (2013). Indy mutations and Drosophila longevity. Front Genet., 4: 47.doi: 10:3389/fgene.2013.00047. eCollection 2013. PMCID:PMC3619052.

 

53) Whitaker R, Faulkner S, Miyokawa R, Burhenn L, Henriksen M, Wood JG, and Helfand SL (2013). Increased expression of Drosophila Sir 2 extends life span in a dose-dependent manner. Aging, 5(9):682-691. PMID: 24036492.

 

54) Savva YA, Jepson JEC, Chang Y-J, Whitaker R, Jones BC, St. Laurent G, Tackett MR, Kapranov P, Jiang N, Du G, Helfand SL and Reenan RA (2013). RNA editing regulates transposon-mediated heterochromatic gene silencing. Nature Comm., 4:2745. Doi: 10.1048/ncomms3745.

 

55) Jiang N, Du GY, Tobias E, Wood JG, Whitaker R, Neretti N and Helfand SL (2013). Dietary and genetic effects on age-related loss of gene silencing reveal epigenetic plasticity of chromatin repression during aging. Aging, 5(11):813-824 (Cover picture). PMC Journal-in process.

 

56) Zhu CT, Chang C, Reenan JA and Helfand SL (2014). Indy gene variation in natural populations confers fitness advantage and life span extension through transposon insertion. Aging, 6(1): 58-69..

 

57) Ding F, Gil MP, Franklin M, Ferreira J, Tatar M, Helfand SL, Neretti N (2014).  Transcriptional response to dietary restriction in Drosophila melanogaster. J Insect Physiol. May 10. pii: S0022-1910(14)00076-6. Doi: 10.1016/j.insphys.2014.05.002 [Epub ahead of print].

 

58) Whitaker R, Gil MP, Ding F, Tatar M, Helfand SL, Neretti N (2014). Dietary switch reveals fast coordinated gene expression changes in Drosophila melanogaster. Aging May 6(5):355-368. 2014.
PMCID: PMC4069263.

 

59) Pu, M., Ni Z., Wang M., Wang X., Wood J. G., Helfand S. L., Yu H. and Lee S. S. (2015). "Trimethylation of Lys36 on H3 restricts gene expression change during aging and impacts life span." Genes Dev 29(7): 718-731.

 

Refereed reviews/Perspectives

 

1) Goodman, C.S., Bastiani, M.M., Doe, C.Q., du Lac, S., Helfand, S.L., Kuwada, K.Y., Thomas, J.B. (1984)  Neuronal recognition during development:  cellular and molecular approaches.  Science 225: 1271-1279.

 

2) Bastiani, M.J., Doe, C.Q., Helfand, S.L., and Goodman, C.S. (1985) Neuronal specificity and growth cone guidance in grasshopper and Drosophila embryos.  Trends in Neuroscience 84: 257-266.

 

3) Hogness, D.S., Lipshitz, H.D., Beachy, P.A., Peattie, D.A., Saint, R.A., Goldschmidt-Clermont, M., Harte, P.J., Gavis, E.R., and Helfand, S.L. (1985) Regulation and products of the Ubx domain of the bithorax complex.  Cold Spring Harbor Symp. Quant. Biol. 50:  181-194.

 

4)  Helfand, S. L. and Rogina, B.  Regulation of gene expression during aging.  (2000) In “Molecular Genetics of Aging”  Pages 67-80 Results and Problems in Cell Differentiation, Vol. 29, ed. Siegfried Hekimi,  Springer-Verlag, Germany.

 

5)  Helfand, S.L. and Inouye, S.K. Rejuvenating views of the aging process. (2002) Nature Reviews Genetics, 3: 149-153.

 

6)  Helfand, S. L. Chaperones Take Flight. (2002) Science, 295: 809-810.

 

7)  Helfand, S. L. and Rogina, B. Genetics of aging in the fruit fly, Drosophila melanogaster. (2003) Annual Review of Genetics, 37: 329-48.

 

8)  Helfand, S. L. and Inouye, S. L.  Aging, life span, genetics and the fruit fly. (2003) Clinical Neuroscience Research,  2: 270-278.

 

9)  Helfand, S. L. and Rogina, B. “From genes to aging in the Drosophila”(2003) Advances in Genetics, Vol. 49, pp 67-109. Edited by J. C. Hall, J. C. Dunlap and T. Friedman, Academic Press, San Diego.

 

10)  Helfand, S. L. and Rogina, B.  Molecular genetics of aging:  Is this the end of the beginning? (2003) BioEssays 25: 134-141.

 

11) Bauer JH and  Helfand SL  (2006). New tricks of an old molecule: lifespan regulation by p53. Aging Cell, 5: 437-40.

 

12) Bauer JH and  Helfand SL (2006). The humble fly: what a model system can reveal about the human biology of aging. Rhode Island Medical Journal, 89(9): 314-5.

 

13) Bauer JH and  Helfand SL (2009). Sir2 and longevity: the p53 connection. Cell Cycle, 8(12):1821. PMCID:PMC2827152.

 

14) Blagosklonny MV, Campisi J, Sinclair DA, Bartke A, Blasco MA, Bonner WM, Bohr VA, Brosh RM Jr, Brunet A, Depinho RA, Donehower LA, Finch CE, Finkel T, Gorospe M, Gudkov AV, Hall MN, Hekimi S, Helfand SL, Karlseder J, Kenyon C, Kroemer G, Longo V, Nussenzweig A, Osiewacz HD, Peeper DS, Rando TA, Rudolph KL, Sassone-Corsi P, Serrano M, Sharpless NE, Skulachev VP, Tilly JL, Tower J, Verdin E, and Vijg J (2010) Impact Papers on Aging in 2009. Aging, Mar;2(3):111-21. PMCID:PMC2871240.

 

15) Shulman GI and  Helfand SL (2011). Indy knockdown in mice mimics elements of dietary restriction. Aging, 3(8):701. PMCID:PMC3184973.

 

16) Wood JG and Helfand SL (2013). Chromatin structure and transposable elements in organismal aging. Frontiers in Genetics of Aging, 4;4:274 PMCID:3849598.

 

17) Gorbunova, V., Boeke, J.D., Helfand, S.L., and Sedivy, J.M. (2014). Human Genomics. Sleeping dogs of the genome. Science 346: 1187-1188 (PMID: 25477445).

 

Chapters in books

 

1) Helfand, S.L., Werkmeister, J., and Roder, J.C. (1982) The role of free oxygen radicals in the activation of the NK cytolytic pathway.  In: Herberman, R., Editor, NK Cells and Other Natural Effector Cells.  Academic Press. Page: 1011-1020.

 

2) Werkmeister, J., Helfand, S.L., Haliotis, T., Pross, H., and Roder, J.C. (1982) Specificity of natural killer (NK) cells: nature of target cell structure.  In:  Herberman, R., Editor, NK Cells and Other Effector Cells.  Academic Press.  Page:  743-750.

 

3) Helfand, S. L. and Rogina, B.  Regulation of gene expression during aging.  In: Hekimi, Siegfried, editor.  Molecular Genetics of Aging: Results and Problems in Cell Differentiation, vol. 29.  Germany: Springer-Verlag; 2000. p. 67-80.

 

4) Helfand, S. L. and Rogina, B. From genes to aging in the Drosophila.  In: Hall, J.C., Dunlap, J. C., Friedman, T., editors. Advances in Genetics. San Diego: Academic Press; 2003 vol. 49, p 67-109.

 

5) Helfand, S. L. and Rogina, B. Genetics of aging in the fruit fly, Drosophila melanogaster. Annual Review of Genetics 2003; 37: 329-48.

 

6) Helfand, S. L., Bauer, J. H. and Wood, J. G. (2009) Calorie Restriction in lower organisms.  In Molecular Biology of Aging edited by L. Guarente, L. Partridge, and D. Wallace. Vol 51; 73-93. Cold Spring Harbor Laboratory Press, New York.

 

7) Bauer J. H. and Helfand S.L. (2011) The Genetics of Dietary Modulation of Lifespan Book is Mechanisms of Life History Evoluation edited by Thomas Flatt and Andrease Heyland, Oxford University Press, Oxford

 

8) Wood, J.G., Whitaker, R. and Helfand S.L. (2013) Genetic and biochemical tools for investigating sirtuin function in Drosophila melanogaster. Sirtuins: Methods and Protocols, Methods in Molecular Biology edited by Matthew Hirschey, Series Editor John M. Walker. vol. 1077: p57-67. Springer,  Humana Press, New York, Heidelberg, Dordrecht, London.

research overview

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.

research statement

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.

funded research

R01 AG024353  (Helfand, PI)                                                                                                  8/1/09 – 4/30/19

NIH/NIA

Control of Gene Expression and Life Span

The goals of this project are to study the effects of age-related changes in chromatin on gene expression.

The overall goals of this project are to determine how changes in chromatin affect aging, with the intention of developing interventions capable of acting upon chromatin structure to restore a “younger” heterochromatin profile and extend healthy life span.

Role: PI

Glenn AFAR BIG Award  (Helfand, PI)                                                                                   07/01/14-6/30/16

American Federation for Aging Research

Chromatin-regulated activation of retrotransposable elements – a novel molecular mechanism of aging

The major goals are to examine the chromatin mechanisms responsible for transposable element repression and to explore the potential for augmenting these mechanisms as interventions for extending healthy lifespan.

Role: PI

R37 AG016667 (Helfand, PI)                                                                                                   4/1/04 - 3/31/16

NIH/NIA

Single Gene Mutants that Confer Longevity in Drosophila

The goals of this project are to study the molecular genetic mechanisms of life span extension in single gene mutations in Drosophila.

Currently in no-cost extension with Supplement.

Role: PI