Research Topics
| Leonard P GuarenteSummaryAffiliation: Massachusetts Institute of Technology Country: USA Publications
Research Grants
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Publications
Calorie restriction--the SIR2 connectionLeonard Guarente
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Cell 120:473-82. 2005....- Calorie restriction, SIRT1 and metabolism: understanding longevityLaura Bordone
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Nat Rev Mol Cell Biol 6:298-305. 2005..In this review, we summarize recent findings that are beginning to clarify the mechanisms by which CR results in longevity and robust health, which might open new avenues of therapy for diseases of ageing... - Calorie restriction and SIR2 genes--towards a mechanismLeonard Guarente
Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Mech Ageing Dev 126:923-8. 2005..I then summarize what is known about the mammalian Sirt1 as it relates to physiological changes during CR, and discuss how this mechanism may impact on life span, as well as diseases of aging... - A role for SIR-2.1 regulation of ER stress response genes in determining C. elegans life spanMohan Viswanathan
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Dev Cell 9:605-15. 2005..1-mediated repression of ER stress genes. Our findings demonstrate that abu-11 and other members of its ER stress gene family are positive determinants of C. elegans life span... 
Metabolic and neuropsychiatric effects of calorie restriction and sirtuinsSergiy Libert
Glenn Laboratory for the Science of Aging, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139 email
Annu Rev Physiol 75:669-84. 2013..We review the molecular understanding of CR; the role of sirtuins in CR; and the effects of sirtuins on physiology, mood, and behavior...
Sirtuins, aging, and metabolismLeonard Guarente
Paul F Glenn Laboratory and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Cold Spring Harb Symp Quant Biol 76:81-90. 2011..Finally, I discuss emerging data showing protection by sirtuins against most of the common diseases of aging. It is possible that sirtuins will be novel targets to combat these diseases pharmacologically...- Molecular mechanisms of yeast agingD A Sinclair
Department of Biology, Massachusetts Institute of Technology, Cambridge 02139, USA
Trends Biochem Sci 23:131-4. 1998..However, recent discoveries might have validated one aging model in which the triggering of a molecular aging clock results in the replication and accumulation of a senescence factor that eventually overwhelms old cells... - Sirtuins as potential targets for metabolic syndromeLeonard Guarente
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Nature 444:868-74. 2006..Sirtuins and other important metabolic pathways that affect calorie restriction may serve as entry points for drugs to treat metabolic syndrome... - Forever youngLeonard Guarente
Paul F Glenn Lab, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Cell 140:176-8. 2010..Liu et al. (2010) now describe a new mechanism of cell renewal in budding yeast, in which damaged protein aggregates are transported out of the daughter buds along actin cables to preserve youthfulness... - The logic linking protein acetylation and metabolismLeonard Guarente
Paul F Glenn Laboratory, Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Cell Metab 14:151-3. 2011..A picture is presented in which protein acetylation is linked to available energy via the NAD-dependent deacetylases. This model suggests that protein acetylation regulates metabolic strategy and also helps store energy in cells... - Mitochondria--a nexus for aging, calorie restriction, and sirtuins?Leonard Guarente
Department of Biology, Massachusetts Institute of Technology, Cambridge MA 02139, USA
Cell 132:171-6. 2008..In this Essay, I speculate on how an increase in mitochondrial activity might provide benefit and discuss how diet, mitochondria, and sirtuins might interact in a pathway to slow aging and associated diseases... - SIR2 and aging--the exception that proves the ruleL Guarente
Dept of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Trends Genet 17:391-2. 2001..Here, I discuss a way of reconciling these two views that could have major implications for healthcare... - Sir2 links chromatin silencing, metabolism, and agingL Guarente
Department of Biology, Massachusetts Institute of Technology (MIT, Cambridge, Massachusetts 02139 USA
Genes Dev 14:1021-6. 2000 - Diverse and dynamic functions of the Sir silencing complexL Guarente
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
Nat Genet 23:281-5. 1999..I speculate that the Sir proteins may be capable of enzymatic modification of chromatin and other substrates, which enables them to carry out a broad range of cellular functions... - Calorie restriction extends Saccharomyces cerevisiae lifespan by increasing respirationSu-Ju Lin
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Nature 418:344-8. 2002..We discuss how this metabolic strategy may apply to CR in animals... - SIR2: a potential target for calorie restriction mimeticsDanica Chen
Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Trends Mol Med 13:64-71. 2007..The SIR2 family represents an evolutionarily conserved lifespan regulator. Modulating the activity of SIR2 might provide effective CR mimetics to combat diseases of aging... - Neuronal SIRT1 regulates endocrine and behavioral responses to calorie restrictionDena E Cohen
Paul F Glenn Laboratory, Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Genes Dev 23:2812-7. 2009..We conclude that Sirt1 in the brain is a link between somatotropic signaling and CR in mammals... - SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cellsMarcia C Haigis
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
Cell 126:941-54. 2006..These results indicate that SIRT4 functions in beta cell mitochondria to repress the activity of GDH by ADP-ribosylation, thereby downregulating insulin secretion in response to amino acids, effects that are alleviated during CR... - The Sir2 family of protein deacetylasesGil Blander
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Annu Rev Biochem 73:417-35. 2004..We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging... - Mammalian sirtuins--emerging roles in physiology, aging, and calorie restrictionMarcia C Haigis
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Genes Dev 20:2913-21. 2006..The current findings sharpen our understanding of sirtuins as potential pharmacological targets to treat the major diseases of aging... - Sirt1 promotes fat mobilization in white adipocytes by repressing PPAR-gammaFrederic Picard
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Nature 429:771-6. 2004..As a reduction in fat is sufficient to extend murine lifespan, our results provide a possible molecular pathway connecting calorie restriction to life extension in mammals... - The role of calorie restriction and SIRT1 in prion-mediated neurodegenerationDanica Chen
Department of Biology, MIT, Cambridge, MA 02139, USA
Exp Gerontol 43:1086-93. 2008..Taken together, our results suggest a more complex interplay between CR, SIRT1, and neurodegenerative diseases than previously appreciated... - C. elegans SIR-2.1 interacts with 14-3-3 proteins to activate DAF-16 and extend life spanAla Berdichevsky
Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, 02139, USA
Cell 125:1165-77. 2006..We propose the existence of a stress-dependent pathway in which SIR-2.1 and 14-3-3 act in parallel to the insulin-like pathway to activate DAF-16 and extend life span... - Tissue-specific regulation of SIRT1 by calorie restrictionDanica Chen
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Genes Dev 22:1753-7. 2008..Our findings suggest that designing CR mimetics that target SIRT1 to provide uniform systemic benefits may be more complex than currently imagined... - Mutations in Saccharomyces cerevisiae gene SIR2 can have differential effects on in vivo silencing phenotypes and in vitro histone deacetylation activityChristopher M Armstrong
Department of Biology, Massachussetts Institute of Technology, Cambridge, MA 02139, USA
Mol Biol Cell 13:1427-38. 2002..We also show that the histone deacetylase activity of Sir2p is necessary for the proper localiztion of the SIR complex to the telomeres... - SIRT1 transgenic mice show phenotypes resembling calorie restrictionLaura Bordone
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Aging Cell 6:759-67. 2007..Our findings suggest that increased expression of SIRT1 in mice elicits beneficial phenotypes that may be relevant to human health and longevity... - How does calorie restriction work?Jana Koubova
Department of Biology, MIT, Cambridge, Massachusetts 02139, USA
Genes Dev 17:313-21. 2003 - Genetic links between diet and lifespan: shared mechanisms from yeast to humansNicholas A Bishop
Department of Biology, 77 Massachusetts Avenue, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Nat Rev Genet 8:835-44. 2007..Evidence is mounting that the brain has a crucial role in sensing dietary restriction and promoting longevity in metazoans... - Two neurons mediate diet-restriction-induced longevity in C. elegansNicholas A Bishop
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Nature 447:545-9. 2007.... 
Sirt1 regulates insulin secretion by repressing UCP2 in pancreatic beta cellsLaura Bordone
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
PLoS Biol 4:e31. 2006..Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in beta cells to affect insulin secretion...- Nicotinamide adenine dinucleotide, a metabolic regulator of transcription, longevity and diseaseSu-Ju Lin
Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, MA 02139, USA
Curr Opin Cell Biol 15:241-6. 2003..Many human diseases are associated with changes in NAD level and/or the NAD : NADH ratio, raising the possibility that the Sir2p family might play a role in these diseases... - SIRT1 shows no substrate specificity in vitroGil Blander
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
J Biol Chem 280:9780-5. 2005..This result brings us one step closer to understanding how SIRT1 and possibly other protein deacetylases chose their substrate... - Mammalian SIRT1 represses forkhead transcription factorsMaria Carla Motta
Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Cell 116:551-63. 2004..We speculate how down-regulating these two classes of damage-responsive mammalian factors may favor long lifespan under certain environmental conditions, such as calorie restriction... - Mouse Sir2 homolog SIRT6 is a nuclear ADP-ribosyltransferaseGregory Liszt
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
J Biol Chem 280:21313-20. 2005..These results provide the first characterization of a Sir2 protein from phylogenetic class IV... - Saccharomyces cerevisiae MPT5 and SSD1 function in parallel pathways to promote cell wall integrityMatt Kaeberlein
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Genetics 160:83-95. 2002..This work also provides evidence that post-transcriptional regulation is likely to be important both for maintaining cell integrity and for promoting longevity... - SIRT1 deacetylates and positively regulates the nuclear receptor LXRXiaoling Li
Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Mol Cell 28:91-106. 2007..Our findings suggest that deacetylation of LXRs by SIRT1 may be a mechanism that affects atherosclerosis and other aging-associated diseases... - Neurogenesis directed by Sirt1Sergiy Libert
Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
Nat Cell Biol 10:373-4. 2008..These findings link a longevity gene to the activity of neuronal stem cells and their response to stress... - 3-Ketoacyl thiolase delays aging of Caenorhabditis elegans and is required for lifespan extension mediated by sir-2.1Alina Berdichevsky
Department of Biology, Paul F Glenn Laboratory, Howard Hughes Medical Institute, Cambridge, MA 02139, USA
Proc Natl Acad Sci U S A 107:18927-32. 2010..Our findings suggest that defects in fatty acid oxidation can limit lifespan and accelerate aging in C. elegans and that kat-1-mediated fatty acid oxidation is crucial for overexpressed sir-2.1 to delay aging... - Aging and disease: connections to sirtuinsGizem Donmez
Paul F Glenn Laboratory and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Aging Cell 9:285-90. 2010..Here we discuss several diseases of aging for which SIRT1 has been recently shown to confer protection. These findings suggest that manipulating sirtuin activity pharmacologically may be a fruitful area to improve human health... - SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycleTakashi Nakagawa
Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, USA
Cell 137:560-70. 2009..Similar effects occur during long-term calorie restriction or a high protein diet. These findings demonstrate SIRT5 plays a pivotal role in ammonia detoxification and disposal by activating CPS1... - Calorie restriction extends yeast life span by lowering the level of NADHSu Ju Lin
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Genes Dev 18:12-6. 2004..A genetic intervention that specifically decreases NADH levels increases life span, validating the model that NADH regulates yeast longevity in response to CR... - Acute oxidative stress can reverse insulin resistance by inactivation of cytoplasmic JNKAlina Berdichevsky
Novartis Institute for Biomedical Research, Cardiovascular and Metabolism Disease Area, Cambridge, Massachusetts 02139, USA
J Biol Chem 285:21581-9. 2010..We propose that the contrasting effects of acute and chronic stress on insulin sensitivity are driven by changes in subcellular distribution of MKP7 and activated JNK... - Urea cycle regulation by mitochondrial sirtuin, SIRT5Takashi Nakagawa
Paul F Glenn Laboratory for the Science of Aging and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
Aging (Albany NY) 1:578-81. 2009..Similar effects are also observed on high protein diet or calorie restriction. These data indicate SIRT5 also has an emerging role in the metabolic adaptation to fasting, high protein diet and calorie restriction... - A stress response pathway involving sirtuins, forkheads and 14-3-3 proteinsAla Berdichevsky
Department of Biology, Massachusetts Insitute of Technology, Cambridge, Massachusetts 02139, USA
Cell Cycle 5:2588-91. 2006..In this prospective we review recent literature highlighting the role of SIR-2.1, 14-3-3 and other DAF-16 co-factors in DAF-16 activation... - Increase in activity during calorie restriction requires Sirt1Danica Chen
Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Science 310:1641. 2005..In mammals, calorie restriction induces a complex pattern of physiological and behavioral changes. Here we report that the mammalian Sir2 ortholog, Sirt1, is required for the induction of a phenotype by calorie restriction in mice... - Mammalian Sir2 homolog SIRT7 is an activator of RNA polymerase I transcriptionEthan Ford
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Genes Dev 20:1075-80. 2006..Depletion of SIRT7 stops cell proliferation and triggers apoptosis. Our findings suggest that SIRT7 is a positive regulator of Pol I transcription and is required for cell viability in mammals... - Separation of mother and daughter cellsPeter U Park
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Methods Enzymol 351:468-77. 2002 - SIRT1 promotes differentiation of normal human keratinocytesGil Blander
Genstruct Inc, One Alewife Center, Cambridge, Massachusetts 2140, USA
J Invest Dermatol 129:41-9. 2009..We conclude that SIRT1 functions in normal human keratinocytes to inhibit proliferation and to promote differentiation... - Superoxide dismutase 1 knock-down induces senescence in human fibroblastsGil Blander
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
J Biol Chem 278:38966-9. 2003..Together, these findings support the notion that in normal human cells the SOD1 protein may play a role in the regulation of cellular lifespan by p53 and may also regulate the death signals in cancer cells... - Genetics and the specificity of the aging processSiegfried Hekimi
Department of Biology, McGill University, Montreal, Quebec H3A 1B1, Canada
Science 299:1351-4. 2003..Thus, the aging process may be more specific than previously anticipated on evolutionary grounds... - Scientific community. Aging research's family feudJennifer Couzin
Science 303:1276-9. 2004 - Saccharomyces cerevisiae SSD1-V confers longevity by a Sir2p-independent mechanismMatt Kaeberlein
Department of Genome Sciences, University of Washington, Seattle, Washington 98195, USA
Genetics 166:1661-72. 2004..We propose that SSD1-V defines a previously undescribed pathway affecting cellular longevity and suggest that future studies on longevity-promoting genes should be carried out in long-lived SSD1-V strains... - Genomic instability and aging-like phenotype in the absence of mammalian SIRT6Raul Mostoslavsky
Howard Hughes Medical Institute, The Children s Hospital, CBR Institute for Biomedical Research, Harvard University Medical School, Boston, MA 02115, USA
Cell 124:315-29. 2006..We conclude that one function of SIRT6 is to promote normal DNA repair, and that SIRT6 loss leads to abnormalities in mice that overlap with aging-associated degenerative processes... - High osmolarity extends life span in Saccharomyces cerevisiae by a mechanism related to calorie restrictionMatt Kaeberlein
Longenity, Inc, Waltham, Massachusetts 02451, USA
Mol Cell Biol 22:8056-66. 2002..This metabolic shift likely increases NAD levels, thereby activating Sir2p and promoting longevity... - Increased life span due to calorie restriction in respiratory-deficient yeastSu-Ju Lin
PLoS Genet 2:e33; author reply e34. 2006 - Life-span extension in yeastDavid A Sinclair
Science 312:195-7; author reply 195-7. 2006 - NO link between calorie restriction and mitochondriaLeonard Guarente
Nat Chem Biol 1:355-6. 2005 - Model organisms as a guide to mammalian agingHeidi A Tissenbaum
Program in Gene Function and Expression, University of Massachusetts Medical School, New Research Building Suite 604, 364 Plantation Street, Worcester, MA 01605, USA
Dev Cell 2:9-19. 2002..Here we review these findings with a focus on the nematode Caenorhabditis elegans and the budding yeast Saccharomyces cerevisiae and highlight general features of the regulation of aging that may have implications for mammals... - Science fact and the SENS agenda. What can we reasonably expect from ageing research?Huber Warner
Buck Institute for Age Research, Novato, CA, USA
EMBO Rep 6:1006-8. 2005 - SIRT1 inhibits transforming growth factor beta-induced apoptosis in glomerular mesangial cells via Smad7 deacetylationShinji Kume
Department of Medicine, Shiga University of Medical Science, Otsu, Shiga 520 2192, Japan
J Biol Chem 282:151-8. 2007..Our results suggest that up-regulation of SIRT1 deacetylase activity is a potentially useful therapeutic strategy for prevention of TGFbeta-related kidney disease through its effect on cell survival... - Telomere shortening exposes functions for the mouse Werner and Bloom syndrome genesXiaobing Du
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA
Mol Cell Biol 24:8437-46. 2004..These findings indicate that telomere dysfunction may contribute to the pathogenesis of Werner syndrome and Bloom syndrome... - Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondriaMalcolm A Leissring
Center for Neurologic Diseases, Department of Neurology, Harvard Medical School and Brigham and Women s Hospital, Boston, MA 02115, USA
Biochem J 383:439-46. 2004..Our results identify new mechanisms regulating the subcellular localization of IDE and suggest previously unrecognized roles for IDE within mitochondria...
Research Grants
- MOLECULAR STUDY OF YEAST SGS1 AND RDNA CIRCLES IN AGINGLeonard Guarente; Fiscal Year: 2003..The overarching goal is to slow down aging in at least some organs to provide a higher quality of life as people enter their twilight years. ..
- Molecular Study of sir-2 genes and Aging in C. elegansLeonard Guarente; Fiscal Year: 2006..elegans. They also may shed light on a molecular mechanism of CR in an animal. These findings may have direct relevance to aging and the extension of life span by CR in mammals. ..
- CELL SENESCENCE IN SACCHAROMYCES CEREVISIAELeonard Guarente; Fiscal Year: 2007..Importantly, CR is known to forestall orprevent many diseases of aging in rodent models. Therefore, drugs that are developed against targets we identify may open new strategies to treat diseases of aging. ..
- Function of Mammalian SIRT1 in AgingLeonard Guarente; Fiscal Year: 2007..This project will enable us to understand the regulation of aging in mammals by SIRTI. It may also have implications for diseases of aging, such as cancer, cardiovascular disease, diabetes, and neurodegenerative disease. ..
- Function of Mammalian SIRT1 in AgingLeonard P Guarente; Fiscal Year: 2010..We plan to determine the functions of mammalian sirtuins, with emphasis on SIRT1, in multiple cell types in mice. These studies may suggest new strategies to treat diseases of aging. ..
- CELL SENESCENCE IN SACCHAROMYCES CEREVISIAELeonard Guarente; Fiscal Year: 2001....
- CELL SENESCENCE IN SACCHAROMYCES CEREVISIAELeonard Guarente; Fiscal Year: 1993..The genes identified in these various genetic selections and screens will be cloned and sequenced. Functional relevance of these genes to aging, senescence, and cell death in higher organisms will be evaluated...
- MOLECULAR ANALYSIS OF TRANSCRIPTIONAL ADAPTORSLeonard Guarente; Fiscal Year: 2001..Finally, a possible link between this coactivator and TBP will be investigated genetically and biochemically. ..
- Molecular Study of sir-2 genes and Aging in C. elegansLeonard P Guarente; Fiscal Year: 2010..elegans that will identify new genes, mechanisms and pathways driving this process. Our findings may lead to new therapeutic approaches to diseases of aging in humans. ..