Leonard P. Guarente

Last updated

Leonard P. Guarente
Born1952 (age 70–71) [1]
Revere, Massachusetts, U.S. [1]
Alma mater Harvard University
Scientific career
Thesis Genetics of Transcription Termination  (1979)
Doctoral students Brian K. Kennedy
Matt Kaeberlein
Website web.mit.edu/biology/guarente/

Leonard Pershing Guarente (born 1952) is an American biologist best known for his research on life span extension in the budding yeast Saccharomyces cerevisiae , roundworms ( Caenorhabditis elegans ), and mice. [2] [3] He is a Novartis Professor of Biology at the Massachusetts Institute of Technology. [4]

Contents

Early life and education

Leonard Guarente was born and raised in Revere, Massachusetts and was the first person in his family to attend college, when he started his undergraduate work at MIT in 1970. [5] He earned his Ph.D. at MIT, studying under Jon Beckwith and Mark Ptashne. [6] He did a post doc at Harvard. [7]

Science

MIT hired Guarente and he opened his own lab in 1981; [6] he earned tenure there in 1986. [5] For the first nine years, his lab studied gene regulation in yeast. [5] [6]

In 1991 his lab started to study genes involved in aging. [5] In 1993, Cynthia Kenyon's lab at UCSF discovered that a single-gene mutation in (Daf-2) could double the lifespan of C. elegans. That same year, David Sinclair joined the Guarente lab, and they developed the hypothesis that caloric restriction slows aging by activation of sirtuins. [8] The Kenyon and Guarente labs came to lead the field studying the genetics of aging. [9]

In 1995 the Guarente lab identified the gene SIR4 (Silent information regulator 4) as a longevity regulator. When SIR4 was mutated in a single cell organism S. cerevisiae longevity was extended. [10] It was later determined that the complex of SIR2 and SIR4 are responsible for longevity phenotype, [11] and that over-expression of SIR2 alone was sufficient to extend lifespan. Moreover, scientists in Guarente laboratory determined that SIR2 is necessary for longevity extension by calorie restriction. [12]

In 1999, Guarente and Kenyon became co-founders of Elixir Pharmaceuticals, which aimed to develop drugs targeting sirtuin; [8] Guarente left the company seven years later after he disagreed with venture capitalists who had gained control of the company about the focus of the company. [13]

In 2000 the Guarente laboratory published work identifying SIR2's activity as a NAD+-dependent protein deacetylase. This NAD dependence explained how SIR2 could connect diet to physiology and suggested the mechanism by which calorie restriction could extend the lifespan of some organisms. [14]

Guarente made the case that involvement of SIR2 in metabolism and lifespan is conserved in other organisms. In round worm, Guarente reported that Caenorhabditis elegans, expression of SIR2 (sir2.1) is sufficient to extend longevity [15] and in the fruit fly, Drosophila melanogaster , overexpression of SIR2 was also reported to extended lifespan. [16] However, other groups have disputed this finding and showed that SIR2-expression does not cause lifespan extension in worms or flies. [17] Overexpression of SIRT1 (mammalian sir2 homolog) does not extend lifespan. [18] Several of Guarente's high profile publications on SIRT1 have been retracted or corrected. [19]

Guarente wrote an autobiography in 2003 titled Ageless Quest: One Scientist's Search for Genes That Prolong Youth.

Guarente's rivalry with Sinclair, which began in 2002 when Sinclair challenged Guarante's description of how sir2 might be involved in aging at a scientific meeting at Cold Spring Harbor Laboratory, was the subject of an article in Science in 2004. [20]

In 2014 Guarente co-founded the dietary supplement company Elysium Health. [13] [21]

Related Research Articles

<span class="mw-page-title-main">Nicotinamide adenine dinucleotide</span> Chemical compound which is reduced and oxidized

Nicotinamide adenine dinucleotide (NAD) is a coenzyme central to metabolism. Found in all living cells, NAD is called a dinucleotide because it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine nucleobase and the other, nicotinamide. NAD exists in two forms: an oxidized and reduced form, abbreviated as NAD+ and NADH (H for hydrogen), respectively.

Calorie restriction mimetics (CRM), also known as energy restriction mimetics, are a hypothetical class of dietary supplements or drug candidates that would, in principle, mimic the substantial anti-aging effects that calorie restriction (CR) has on many laboratory animals and humans. CR is defined as a reduction in calorie intake of 20% to 50% without incurring malnutrition or a reduction in essential nutrients. An effective CRM would alter the key metabolic pathways involved in the effects of CR itself, leading to preserved youthful health and longer lifespan without the need to reduce food intake. The term was coined by Lane, Ingram, Roth of the National Institute on Aging in a seminal 1998 paper in the Journal of Anti-Aging Medicine, the forerunner of Rejuvenation Research. A number of genes and pathways have been shown to be involved with the actions of CR in model organisms and these represent attractive targets for drug discovery and for developing CRM. However, no effective CRM have been identified to date.

The DAF-2 gene encodes for the insulin-like growth factor 1 (IGF-1) receptor in the worm Caenorhabditis elegans. DAF-2 is part of the first metabolic pathway discovered to regulate the rate of aging. DAF-2 is also known to regulate reproductive development, resistance to oxidative stress, thermotolerance, resistance to hypoxia, and resistance to bacterial pathogens. Mutations in DAF-2 have been shown by Cynthia Kenyon to double the lifespan of the worms. In a 2007 episode of WNYC’s Radiolab, Kenyon called DAF-2 "the grim reaper gene.”

Calorie restriction is a dietary regimen that reduces the energy intake from foods and beverages without incurring malnutrition. The possible effect of calorie restriction on body weight management, longevity, and aging-associated diseases has been an active area of research.

<span class="mw-page-title-main">Sirtuin</span> Enzyme

Sirtuins are a family of signaling proteins involved in metabolic regulation. They are ancient in animal evolution and appear to possess a highly conserved structure throughout all kingdoms of life. Chemically, sirtuins are a class of proteins that possess either mono-ADP-ribosyltransferase or deacylase activity, including deacetylase, desuccinylase, demalonylase, demyristoylase and depalmitoylase activity. The name Sir2 comes from the yeast gene 'silent mating-type information regulation 2', the gene responsible for cellular regulation in yeast.

<span class="mw-page-title-main">David A. Sinclair</span> Australian geneticist

David Andrew Sinclair is an Australian-American biologist and academic known for his research on aging and epigenetics. Sinclair is a professor of genetics at Harvard Medical School and is the co-director of its Paul F. Glenn Center for Biology of Aging Research. He is the president of the non-profit Academy for Health & Lifespan Research and an officer of the Order of Australia (AO).

<span class="mw-page-title-main">Cynthia Kenyon</span> US molecular biologist

Cynthia Jane Kenyon is an American molecular biologist and biogerontologist known for her genetic dissection of aging in a widely used model organism, the roundworm Caenorhabditis elegans. She is the vice president of aging research at Calico Research Labs, and emeritus professor of biochemistry and biophysics at the University of California, San Francisco (UCSF).

<span class="mw-page-title-main">Michael Ristow</span> German medical researcher (born 1967)

Michael Ristow is a German medical researcher who has published influential articles on biochemical aspects of mitochondrial metabolism and particularly the possibly health-promoting role of reactive oxygen species in diseases like type 2 diabetes, obesity and cancer, as well as general aging due to a process called mitohormesis.

<span class="mw-page-title-main">Sirtuin 1</span> Protein

Sirtuin 1, also known as NAD-dependent deacetylase sirtuin-1, is a protein that in humans is encoded by the SIRT1 gene.

<span class="mw-page-title-main">Sirtuin 3</span> Protein-coding gene in the species Homo sapiens

NAD-dependent deacetylase sirtuin-3, mitochondrial also known as SIRT3 is a protein that in humans is encoded by the SIRT3 gene [sirtuin 3 ]. SIRT3 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein. SIRT3 exhibits NAD+-dependent deacetylase activity.

<span class="mw-page-title-main">Sirtuin 5</span> Protein-coding gene in the species Homo sapiens

Sirtuin 5 , also known as SIRT5 is a protein which in humans in encoded by the SIRT5 gene and in other species by the orthologous Sirt5 gene.

<span class="mw-page-title-main">Sirtuin 6</span> Protein-coding gene in the species Homo sapiens

Sirtuin 6 is a stress responsive protein deacetylase and mono-ADP ribosyltransferase enzyme encoded by the SIRT6 gene. In laboratory research, SIRT6 appears to function in multiple molecular pathways related to aging, including DNA repair, telomere maintenance, glycolysis and inflammation. SIRT6 is member of the mammalian sirtuin family of proteins, which are homologs to the yeast Sir2 protein.

<span class="mw-page-title-main">SRT-1720</span> Organic compound, experimental pharmaceuticum

SRT-1720 is an experimental drug that was studied by Sirtris Pharmaceuticals intended as a small-molecule activator of the sirtuin subtype SIRT1. The compound has been studied in animals, but safety and efficacy in humans have not been established.

Sirtris Pharmaceuticals, Inc. was a biotechnology company based in Cambridge, MA that developed therapies for type 2 diabetes, cancer, and other diseases. Conceived in 2004 by Harvard University biologist David Sinclair and serial entrepreneur Andrew Perlman, and founded that year by Sinclair and Perlman, along with Christoph Westphal, Richard Aldrich, Richard Pops, and Paul Schimmel, the company was focused on developing Sinclair's research into activators of sirtuins, work that began in the laboratory of Leonard P. Guarente where Sinclair worked as a post-doc before starting his own lab.

Sirtuin-activating compounds (STAC) are chemical compounds having an effect on sirtuins, a group of enzymes that use NAD+ to remove acetyl groups from proteins. They are caloric restriction mimetic compounds that may be helpful in treating various aging-related diseases.

<span class="mw-page-title-main">Daf-16</span> Ortholog

DAF-16 is the sole ortholog of the FOXO family of transcription factors in the nematode Caenorhabditis elegans. It is responsible for activating genes involved in longevity, lipogenesis, heat shock survival and oxidative stress responses. It also protects C.elegans during food deprivation, causing it to transform into a hibernation - like state, known as a Dauer. DAF-16 is notable for being the primary transcription factor required for the profound lifespan extension observed upon mutation of the insulin-like receptor DAF-2. The gene has played a large role in research into longevity and the insulin signalling pathway as it is located in C. elegans, a successful ageing model organism.

<span class="mw-page-title-main">Genetics of aging</span> Overview of the genetics of aging

Genetics of aging is generally concerned with life extension associated with genetic alterations, rather than with accelerated aging diseases leading to reduction in lifespan.

The disposable soma theory of aging states that organisms age due to an evolutionary trade-off between growth, reproduction, and DNA repair maintenance. Formulated by Thomas Kirkwood, the disposable soma theory explains that an organism only has a limited amount of resources that it can allocate to its various cellular processes. Therefore, a greater investment in growth and reproduction would result in reduced investment in DNA repair maintenance, leading to increased cellular damage, shortened telomeres, accumulation of mutations, compromised stem cells, and ultimately, senescence. Although many models, both animal and human, have appeared to support this theory, parts of it are still controversial. Specifically, while the evolutionary trade-off between growth and aging has been well established, the relationship between reproduction and aging is still without scientific consensus, and the cellular mechanisms largely undiscovered.

<span class="mw-page-title-main">Mitochondrial theory of ageing</span> Theory of ageing

The mitochondrial theory of ageing has two varieties: free radical and non-free radical. The first is one of the variants of the free radical theory of ageing. It was formulated by J. Miquel and colleagues in 1980 and was developed in the works of Linnane and coworkers (1989). The second was proposed by A. N. Lobachev in 1978.

<span class="mw-page-title-main">Age-1</span> Gene

The age-1 gene is located on chromosome 2 in C.elegans. It gained attention in 1983 for its ability to induce long-lived C. elegans mutants. The age-1 mutant, first identified by Michael Klass, was reported to extend mean lifespan by over 50% at 25 °C when compared to the wild type worm (N2) in 1987 by Johnson et al. Development, metabolism, lifespan, among other processes have been associated with age-1 expression. The age-1 gene is known to share a genetic pathway with daf-2 gene that regulates lifespan in worms. Additionally, both age-1 and daf-2 mutants are dependent on daf-16 and daf-18 genes to promote lifespan extension.

References

  1. 1 2 Bolino, August C. (2012). Men of Massachusetts: Bay State Contributors to American Society. p. 426. ISBN   978-1-4759-3376-5.
  2. ↑ "Popular paper by famous longevity researcher gets mega-correction". Retraction Watch. March 8, 2016. Retrieved August 13, 2017.
  3. ↑ "Leonard Guarente". Big Think. Retrieved August 13, 2017.
  4. ↑ "Leonard P. Guarente | MIT Biology". biology.mit.edu. Retrieved August 13, 2017.
  5. 1 2 3 4 Trafton, Anne (September 15, 2009). "In Profile: Leonard Guarente". MIT News Office.
  6. 1 2 3 Wade, Nicholas (September 26, 2000). "Scientist at Work: Leonard Guarente; Searching for Genes to Slow the Hands of Biological Time". The New York Times.
  7. ↑ Johnson, Thomas E. (April 2004). "Book Reviews: The Start of Anti-Aging Medicine?". The Gerontologist. 44 (2): 270–273. doi: 10.1093/geront/44.2.270 . ISSN   1758-5341.
  8. 1 2 Duncan, David Ewing (August 15, 2007). "The Enthusiast". MIT Technology Review.
  9. ↑ Solomon, Lewis D. (2017). The Quest for Human Longevity: Science, Business, and Public Policy. Routledge. ISBN   978-1-351-47559-4.
  10. ↑ Kennedy, B.K.; et al. (1995). "Mutation in the silencing gene SIR4 can delay aging in S. cerevisiae". Cell. 80 (3): 485–96. doi: 10.1016/0092-8674(95)90499-9 . PMID   7859289.
  11. ↑ Kaeberlein, M., M. McVey, and L. Guarente (1999). "The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms". Genes Dev. 13 (19): 2570–80. doi:10.1101/gad.13.19.2570. PMC   317077 . PMID   10521401.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ↑ Lin, S.J., P.A. Defossez, and L. Guarente (2000). "Requirement of NAD and SIR2 for life-span extension by calorie restriction in Saccharomyces cerevisiae". Science. 289 (5487): 2126–8. Bibcode:2000Sci...289.2126L. doi:10.1126/science.289.5487.2126. PMID   11000115. S2CID   26330861.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. 1 2 Wallace, Benjamin. "An MIT Scientist Claims That This Pill Is the Fountain of Youth". New York Magazine.
  14. ↑ Imai, S.; et al. (2000). "Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase". Nature. 403 (6771): 795–800. Bibcode:2000Natur.403..795I. doi:10.1038/35001622. PMID   10693811. S2CID   2967911.
  15. ↑ Tissenbaum, H.A.; L. Guarente (2001). "Increased dosage of a sir-2 gene extends lifespan in Caenorhabditis elegans". Nature. 410 (6825): 227–30. Bibcode:2001Natur.410..227T. doi:10.1038/35065638. PMID   11242085. S2CID   4356885.
  16. ↑ Rogina, B.; S.L. Helfand (2004). "Sir2 mediates longevity in the fly through a pathway related to calorie restriction". Proc Natl Acad Sci U S A. 101 (45): 15998–6003. Bibcode:2004PNAS..10115998R. doi: 10.1073/pnas.0404184101 . PMC   528752 . PMID   15520384.
  17. ↑ Burnett, Camilla; Valentini, Sara; Cabreiro, Filipe; Goss, Martin; Somogyvári, Milán; Piper, Matthew D.; Hoddinott, Matthew; Sutphin, George L.; Leko, Vid (September 21, 2011). "Absence of effects of Sir2 over-expression on lifespan in C. elegans and Drosophila". Nature. 477 (7365): 482–485. Bibcode:2011Natur.477..482B. doi:10.1038/nature10296. ISSN   0028-0836. PMC   3188402 . PMID   21938067.
  18. ↑ Bordone, L.; et al. (2007). "SIRT1 transgenic mice show phenotypes resembling calorie restriction". Aging Cell. 6 (6): 759–67. doi:10.1111/j.1474-9726.2007.00335.x. PMID   17877786. S2CID   16071943.
  19. ↑ Palus, Shannon (March 8, 2016). "Popular paper by famous longevity researcher gets mega-correction". Retraction Watch. Retrieved April 2, 2019.
  20. ↑ Couzin, J (February 27, 2004). "Scientific community. Aging research's family feud". Science. 303 (5662): 1276–9. doi:10.1126/science.303.5662.1276. PMID   14988530. S2CID   161459205.
  21. ↑ Ramsey, Lydia. "A startup that's developed an anti-aging supplement just raised $20 million". Business Insider.
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