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| Development of Novel Anti-aging Drugs |
| Fumiaki Uchiumi1,2*, Takahiro Oyama1, Kensuke Ozaki1 and Sei-ichi Tanuma2,3 |
| 1Department of Gene Regulation, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda-shi, Chiba-ken, Japan |
| 2Research Center for RNA Science, RIST, Tokyo University of Science, Noda-shi, Chiba-ken, Japan |
| 3Biochemistry, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda-shi, Chiba-ken, Japan |
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| *Corresponding author: |
Dr. Fumiaki Uchiumi, Ph.D.
Department of Gene
Regulation
Faculty of Pharmaceutical Sciences
Tokyo University of Science,
Tokyo University of Science,
2641 Yamazaki, Noda-shi, Chiba-ken 278-8510,
Japan
Tel: +81-4-7121-3616
Fax: +81-4-7121-3608
E-mail: uchiumi@
rs.noda.tus.ac.jp |
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| Received August 25, 2011; Accepted August 25, 2011; Published August 27,
2011 |
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| Citation: Uchiumi F, Oyama T, Ozaki K, Tanuma SI (2011) Development of Novel
Anti-aging Drugs. Pharm Anal Acta 2:106e. doi:10.4172/2153-2435.1000106e |
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| Copyright: © 2011 Uchiumi F, et al. This is an open-access article distributed under
the terms of the Creative Commons Attribution License, which permits unrestricted
use, distribution, and reproduction in any medium, provided the original author and
source are credited. |
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| Abstract |
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| It has been thought that cellular senescence is regulated by the total amount of damage to chromosomes,
including telomeric regions. Another explanation is that cellular senescence is attributed to oxidative stresses
mainly generated in mitochondria. At present, several compounds, such as 2-deoxy-D-glucose (2-DG) and trans-
Resveratrol (Rsv), are expected to be used as anti-aging drugs for extending life-span. Our previous study indicated
that promoter activities of the telomere-maintenance factor-encoding genes are activated by both compounds. The
mechanism might be implicated in the concept of hormesis - that the application of low doses of toxic substrates
strengthens DNA-repair system. Effective anti-aging drugs could be found by screening compounds that up-regulate
expression of the telomere associated genes. |
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| Keywords |
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| Caloric restriction; Cellular senescence; 2-deoxy-Dglucose;
Oxidative stress; Resveratrol |
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| Introduction |
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| All higher organisms, including humans, experience aging and
have limited life spans. It has been explained that the aging process is
controlled by damage to chromosomes [1] and oxidative stress [2,3].
Telomeres, which are the ends of chromosomes, are composed of
TTAGGG repeats with the maintenance factor complex [4]. Repeated
replication shortens telomeres [5] and causes chromosomal instability
to arise [4]. Mutations of specific genes, such as WRN and LMNA, are
known to cause premature aging syndromes [6,7]. The proteins that are
encoded on these genes are thought to regulate chromosomal stability
and probably the telomere maintenance system. From studies of model
organisms, several genes that encode anti-oxidative enzymes, insulinsignaling
proteins, sirtuin (Sir2 in yeast, and SIRT1 in mammalian
organisms), tumor suppressor p53, and transcription factor FoxO
were shown to affect lifespan [8,9]. These lines of evidence raised the
question: how do chromosomal damage and oxidative stress associate
with each other to properly regulate the aging process and how can
expanding our knowledge of these processes and their association aid
in the development of effective anti-aging drugs? |
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| Reactive oxygen species (ROS), which are mainly generated from
mitochondria, are thought to cause DNA damage [10]. Recently, it was
revealed that telomere dysfunction exerts a signal to mitochondria by
reducing transcription of the PGC-1α and PGC-1β genes that encode
mitochondrial regulators [11]. These observations suggest that there is
mutual communication between mitochondoria and telomeres |
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| To date, several candidates for anti-aging drugs have been
investigated. For example, 2-deoxy-D-glucose (2DG), which is a
potent inhibitor of glucose metabolism, has a caloric restriction (CR)
mimetic effect [12]. The natural compound Resveratrol (Rsv), which
is contained in grape skins and red wine, activates sirtuin-mediated
deacetylation [13]. The life spans of various organisms might be
extended by administration of these drugs [12,14]. Besides affecting
glucose metabolism and sirtuins, these CR mimetic compounds have
the effect of inducing transcription of telomere-associated genes. Our
previous study indicated that 2DG and Rsv up-regulate the promoter
activities of the WRN, TERT, and shelterin-encoding genes, along with
moderately stimulating telomerase activity [15-17]. This might be a
favorable side effect, and may shed light in the search for anti-aging
drugs. The anti-aging effect might come from the concept of hormesis [18], the stimulation of the DNA repair or telomere-maintenance
system through low doses of toxic substrates. By analyzing the
stimulation of telomerase and the gene expression of the telomeremaintenance
factors, effective anti-aging drugs might be discovered,
isolated, and synthesized in the future. |
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| References |
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- Vijg J (2007) Chapter 5: Genome instability and accelerated aging. In: Aging
of the Genome: The Dual Role of DNA in Life and Death, Oxford University
Press, NY: 151-180.
- Robb EL, Page MM, Stuart JA (2009) Mitochondria, cellular stress resistance,
somatic cell depletion and lifespan. Curr Aging Sci 2: 12-27.
- Benz CC, Yau C (2008) Ageing, oxidative stress and cancer: paradigms in
parallax. Nat Rev Cancer 8: 875-879.
- O'Sullivan RJ, Karlseder J (2010) Telomeres: protecting chromosomes against
genome instability. Nat Rev Mol Cell Biol 11: 171-181.
- Blackburn E (2006) Chapter 1: A history of telomere biology. In: Telomeres
(2nd edn) (de Lang T, Lundblad V, Blackburn E, Eds.), Cold Spring Harbor
Laboratory Press, NY: 1-19.
- Chu WK, Hickson ID (2009) RecQ helicases: multifunctional genome
caretakers. Nat Rev Cancer 9: 644-654.
- Eriksson M, Brown WT, Gordon LB, Glynn MW, Singer J, et al. (2003)
Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford
progeria syndrome. Nature 423: 293-298.
- Kuningas M, Mooijaart SP, van Heemst D, Zwaan BJ, Slagboom PE, et al.
(2008) Genes encoding longevity: from model organisms to humans. Aging
Cell 7: 270-280.
- van der Horst A, Burgering BTT (2007) Stressing the role of FoxO proteins in
lifespan and disease. Nat Rev Mol Cell Biol 8: 440-450.
- Oberdoerffer P, Sinclair DA (2007) The role of nuclear architecture in genomic
instability and aging. Nat Rev Mol Cell Biol 8: 692-702.
- Sahin E, Colla S, Liesa M, Moslehi J, Müller FL, et al. (2011) Telomere
dysfunction induces metabolic and mitochondrial compromise. Nature 470:
359-365.
- Roth GS, Ingram DK, Lane MA (2001) Caloric restriction in primates and
relevance to humans. Ann N Y Acad Sci 928: 305-315.
- Stefani M, Markus MA, Lin RC, Pinese M, Dawes IW, et al. (2007) The effect of
resveratrol on a cell model of human aging. Ann N Y Acad Sci 1114: 407-418.
- Kaeberlein M (2010) Resveratrol and rapamycin: are they anti-aging drugs?
Bioessays 32: 96-99.
- Zhou B, Ikejima T, Watanabe T, Iwakoshi K, Idei Y, et al. (2009) The effect of
2-deoxy-D-glucose on Werner syndrome RecQ helicase gene. FEBS Lett 583:
1331-1336.
- Uchiumi F, Watanabe T, Hasegawa S, Hoshi T, Higami Y, et al. (2011) The
effect of resveratrol on the Werner Syndrome RecQ helicase gene and
telomerase activity. Curr Aging Sci 4: 1-7.
- Uchiumi F, Oyama T, Ozaki K, Tanuma S (2011) Characterization of 5'-flanking
regions of various human telomere maintenance factor-encoding genes, In:
DNA Repair (Kruman I, Ed.), InTech-Open Access Publisher, Inc, Rijeka,
Croatia, in press.
- Schumacher B (2009) Transcription-blocking DNA damage in aging: a
mechanism for hormesis. Bioessays 31: 1347-1356.
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