| Current
Drug Targets
ISSN: 1389-4501
Current Drug Targets
Volume 7, Number 11, November 2006
Contents
GSK-3 in Health and Disease
Guest Editor: H. Eldar-Finkelman
Editorial Pp. 1375
Glycogen Synthase Kinase-3 – An Overview
of An Over-Achieving Protein Kinase Pp. 1377-1388
L. Kockeritz, B. Doble, S. Patel and J.R. Woodgett
[Abstract]
Multiple Roles for Glycogen Synthase Kinase-3
as a Drug Target in Alzheimer’s Disease Pp.
1389-1397
H.-C. Huang and P.S. Klein
[Abstract]
Targeting Glycogen Synthase Kinase-3 in the CNS:
Implications for the Development of New Treatments for Mood
Disorders Pp. 1399-1409
T.D. Gould, A.M. Picchini, H. Einat and H.K. Manji
[Abstract]
GSK3 at the Edge: Regulation of Developmental
Specification and Cell Polarization Pp. 1411-1419
L. Kim and A.R. Kimmel
[Abstract]
Glycogen Synthase Kinase-3 (GSK3) in Psychiatric
Diseases and Therapeutic Interventions Pp. 1421-1434
R.S. Jope and M.-S. Roh
[Abstract]
Role of Glycogen Synthase Kinase-3 in Insulin
Resistance and Type 2 Diabetes Pp. 1435-1441
E.J. Henriksen and B.B. Dokken
[Abstract]
Protein Kinase Inhibition: Different Approaches
to Selective Inhibitor Design Pp. 1443-1454
G. Scapin
[Abstract]
The Saccharomyces cerevisiae GSK-3β
Homologs Pp. 1455-1465
Y. Kassir, I. Rubin-Bejerano and Y. Mandel-Gutfreund
[Abstract]
Ageing
Guest Editors: H.-P. Deigner and R. Kinscherf
Editorial Pp. 1467-1468
Foreseeable Pharmaceutical Repair of Age-Related Extracellular
Damage Pp. 1469-1473
A.D.N.J. de Grey
[Abstract]
The Pharmacology of Ageing in Drosophila
Pp. 1479-1483
M. Jafari, A.D. Long, L.D. Mueller and M.R. Rose
[Abstract]
Premature Ageing Prevention: Limitations and Perspectives
of Pharmacological Interventions Pp. 1485-1503
V.N. Anisimov
[Abstract]
The Deficit in Low Molecular Weight Thiols as
a Target for Antiageing Therapy Pp. 1505-1512
W. Dröge, R. Kinscherf, W. Hildebrandt and T. Schmitt
[Abstract]
Therapeutic Efficacy of Selegiline in Neurodegenerative
Disorders and Neurological Diseases Pp. 1513-1529
M. Ebadi, H. Brown-Borg, J. Ren, S. Sharma, S. Shavali,
H. El ReFaey and E.C. Carlson
[Abstract]
Towards a Life Prolonging Pill? Small Molecules
with Anti-Ageing Properties Pp. 1531-1537
G. Wagner
[Abstract]
The Endocannabinoid System in Ageing: A New Target
for Drug Development Pp. 1539-1552
A. Paradisi, S. Oddi and M. Maccarrone
[Abstract]
The Role of NAD+
Dependent Histone Deacetylases (sirtuins) in Ageing
Pp. 1553-1560
J. Trapp and M. Jung
[Abstract]
Abstracts
[Back
to top]
Editorial
Protein kinases play essential roles in cellular processes
and are well recognized as important therapeutic targets in
many human diseases. The serine/threonine protein kinase Glycogen
synthase kinase-3 (GSK-3) is an extraordinary example in this
regard. This enzyme, which was characterized originally as
a glycogen synthase kinase, has emerged, unexpectedly, as
a drug-discovery target in several pathological disorders,
including diabetes, affective disorders, and Alzheimer's disease.
The unique biochemical and cellular features of GSK-3, which
distinguish it from other protein kinases, are most likely
the key to understanding the sophisticated function of GSK-3
in biological systems. These features justify the efforts
invested toward the development of selective GSK-3 inhibitors
as a promising therapeutic treatment.
In this issue of Current Drug Targets,
articles are gathered from eight groups with different expertise
areas that, together, uncover the multiple aspects of GSK-3.
This gives the reader a unique, special opportunity to gain
a panoramic view in the filed, and to uncover the challenges
that still wait to be resolved
Hagit Eldar-Finkelman
[Back to top]
Glycogen Synthase Kinase-3 – An Overview
of An Over-Achieving Protein Kinase
L. Kockeritz, B. Doble, S. Patel and J.R. Woodgett
Glycogen synthase kinase-3 (GSK-3) has attracted much
scrutiny due to its plethora of cellular functions, novel
mechanisms of regulation and its potential as a therapeutic
target for several common diseases. In mammals, GSK-3 is encoded
by two genes, termed GSK-3α
and GSK-3β,
that yield related but distinct protein-serine kinases. GSK-3
is unusual in that its protein kinase activity tends to be
high in resting cells and cellular stimuli, such as hormones
and growth factors, result in its catalytic inactivation.
Further, many of the substrate proteins of GSK-3 are functionally
inhibited by phosphorylation. Thus, signals that inhibit GSK-3
often cause activation of its diverse array of target proteins.
Regulation of GSK-3 is important for normal development, regulation
of metabolism, neuronal growth and differentiation and modulation
of cell death. Dysregulation of GSK-3 activity has been implicated
in human pathologies such as neurodegenerative diseases and
type-2 diabetes. In this introductory chapter we provide a
primer on the modes of GSK-3 regulation and a description
of the various signaling pathways and cellular processes in
which GSK-3 is an active participant.
[Back to top]
Multiple Roles for Glycogen Synthase Kinase-3
as a Drug Target in Alzheimer’s Disease
H.-C. Huang and P.S. Klein
Alzheimer’s disease (AD) is a common neurodegenerative
disorder that presents clinically as inexorable cognitive
impairment and decline in performance of activities of daily
living. AD is characterized pathologically by neuronal depopulation,
extracellular amyloid plaques, and intraneuronal accumulation
of neurofibrillary tangles (NFTs). Accumulation of these polypeptide
aggregates is generally believed to be integral to the pathogenesis
of AD. Recent evidence implicates the protein kinase glycogen
synthase kinase 3 (GSK-3) in the regulation of both of these
processes. GSK-3 has long been studied as one of several tau
protein kinases, and has more recently been shown to be involved
in the generation of Aβ
peptides. GSK-3 activity may also promote cell death and conversely,
inhibition of GSK-3 has been associated with increased cell
survival under a variety of cytotoxic conditions. Thus drugs
that target GSK-3 could attack AD pathogenesis on multiple
fronts simultaneously. Here we will briefly review the molecular
understanding of AD pathogenesis as it stands at this point,
and then discuss the emerging role of GSK-3 in regulating
these processes.
[Back to top]
Targeting Glycogen Synthase Kinase-3 in the CNS: Implications
for the Development of New Treatments for Mood Disorders
T.D. Gould, A.M. Picchini, H. Einat and H.K. Manji
There exists an immediate need to develop novel medications
for the treatment of mood disorders such as bipolar disorder
and depression. Initial interest in glycogen synthase kinase-3
(GSK-3) as a target for the treatment of mood disorders arose
from the finding that the mood stabilizing drug lithium directly
inhibited the enzyme. More recent preclinical evidence implicates
the modulation of GSK-3 in either the direct or downstream
mechanism of action of many other mood stabilizer and antidepressant
medications currently in use. One of the cellular targets
of GSK-3, which may mediate some of the effects of lithium
and other drugs, is β-catenin,
a transcription factor that is rapidly degraded when GSK-3
is active. Recent rodent behavioral data (both genetic and
pharmacological) supports GSK-3 representing a therapeutically
relevant target of lithium. This includes antidepressant-like
behavior in the forced swim test and antimanic-like response
to amphetamine following administration of the GSK-3 inhibitor
AR-A014418, a findings that is concomitant with an increase
in brain β-catenin.
The evidence described in this review suggests that regulating
GSK-3 may represent a target for novel medications to treat
mood disorders.
[Back to top]
GSK3 at the Edge: Regulation of Developmental Specification
and Cell Polarization
L. Kim and A.R. Kimmel
GSK3 is a multifunctional protein kinase that is pivotal for
the regulation of metabolism, the cytoskeleton, and gene expression.
Multicellular eukaryotes utilize GSK3 as a molecular switch
to specify distinct cell fates, but also to organize these
cells spatially within the developing organism. We discuss
the central role of GSK3 in control of the Wnt, Hedgehog,
cAMP (in Dictyostelium), and other signaling pathways,
but also focus on significant new evidence that GSK3 is required
to establish cell polarity.
[Back to top]
Glycogen Synthase Kinase-3 (GSK3) in Psychiatric Diseases
and Therapeutic Interventions
R.S. Jope and M.-S. Roh
Glycogen synthase kinase-3 (GSK3) has recently been linked
to mood disorders and schizophrenia, and the neurotransmitter
systems and therapeutic treatments associated with these diseases.
GSK3 is a widely influential enzyme that is capable of phosphorylating,
and thereby regulating, over forty known substrates. Four
mechanisms regulating GSK3 (phosphorylation, protein complexes,
localization, and substrate phosphorylation) combine to provide
substrate-specific regulation of the actions of GSK3. Several
intracellular signaling cascades converge on GSK3 to modulate
its activity, and several neurotransmitter systems also regulate
GSK3, including serotonergic, dopaminergic, cholinergic, and
glutamatergic systems. Because of changes in these neurotransmitter
systems and the actions of therapeutic drugs, GSK3 has been
linked to the mood disorders, bipolar disorder and depression,
and to schizophrenia. Inhibition of GSK3 may be an important
therapeutic target of mood stabilizers, and regulation of
GSK3 may be involved in the therapeutic effects of other drugs
used in psychiatry. Dysregulated GSK3 in bipolar disorder,
depression, and schizophrenia could have multiple effects
that could impair neural plasticity, such as modulation of
neuronal architecture, neurogenesis, gene expression, and
the ability of neurons to respond to stressful, potentially
lethal, conditions. In part because of these key actions of
GSK3 and its associations with mood disorders and schizophrenia,
much research is currently being devoted to identifying new
selective inhibitors of GSK3.
[Back to top]
Role of Glycogen Synthase Kinase-3 in Insulin Resistance
and Type 2 Diabetes
E.J. Henriksen and B.B. Dokken
A reduced ability of insulin to activate glucose transport
in skeletal muscle, termed insulin resistance, is a primary
defect leading to the development of impaired glucose tolerance
and type 2 diabetes. Glycogen synthase kinase-3 (GSK-3) is
a serine/threonine kinase with important roles in the regulation
of glycogen synthesis, protein synthesis, gene transcription,
and cell differentiation in various cell types. An emerging
body of evidence has implicated GSK-3 in the multifactorial
etiology of skeletal muscle insulin resistance in obese animal
models and in obese human type 2 diabetic subjects. Overexpression
and overactivity of GSK-3 in skeletal muscle of rodent models
of obesity and obese type 2 diabetic humans are associated
with an impaired ability of insulin to activate glucose disposal
and glycogen synthase. New insights into the importance of
GSK-3 as a regulator of insulin action on glucose transport
activity in muscle have come from studies utilizing selective
and sensitive inhibitors of GSK-3. These studies have demonstrated
that selective inhibition of GSK-3 in insulin-resistant skeletal
muscle causes improvements in insulin-stimulated glucose transport
activity that are likely caused by enhanced post-insulin receptor
insulin signaling and GLUT-4 glucose transporter translocation.
An additional important action of these GSK-3 inhibitors in
the context of obese-associated type 2 diabetes is a reduction
of hepatic glucose production, likely via downregulation
of genes associated with gluconeogensis. It is clear from
these studies that selectively targeting GSK-3 in skeletal
muscle may be an important new strategy for the treatment
of obesity-associated insulin-resistant states characterized
by GSK-3 overactivity in insulin-sensitive tissues.
[Back to top]
Protein Kinase Inhibition: Different Approaches to
Selective Inhibitor Design
G. Scapin
Protein kinases represent a large family of enzymes involved
in regulating complex molecular machineries that control many
cellular functions, from survival and proliferation to apoptosis.
Abnormal protein kinase activity has been involved in a variety
of patho-physiologic states, including cancer, inflammatory
and autoimmune disorders, and cardiac diseases, and protein
kinases have become one of the major therapeutical targets
of the past 10 years. The major problem associated with ATP-competitive
kinase inhibition is target specificity, since many other
enzymes, kinases and not-kinases alike, utilize ATP: less
specific inhibitors would be expected to exhibit undesirable
toxicities that would limit their potential utility as therapeutic
agents. The purpose of this review is to offer the reader
an idea of the evolution of the methodologies utilized in
the quest for selective kinase inhibitors, from the more traditional,
screening-based methods to the newer technology of chemogenomics,
proteomics and chemical genetics.
[Back to top]
The Saccharomyces cerevisiae GSK-3β
Homologs
Y. Kassir, I. Rubin-Bejerano and Y. Mandel-Gutfreund
Yeast cells carry four homologs of GSK-3β,
RIM11, MCK1, MRK1 and YGK3.
The significant homologs are RIM11 and MCK1
that presumably arose from a recent genome duplication followed
by a rapid divergence. Accordingly, these homologs phosphorylate
specific substrates. Rim11 is essential for entry into meiosis,
whereas Mck1 is essential for growth at elevated and low temperatures.
Both kinases transmit nutrient signals, but Mck1 transmits
additional signals including stress signals such as, temperature,
osmotic shock and Ca2+. Consequently, Mck1 plays
a role in multiple functions, including cell wall integrity,
meiosis and centromere function. The other two homologs, MRK1
and YGK3 that belong to the RIM11 and MCK1
phylogenetic trees, respectively, show no distinct phenotype.
These paralogs posses redundant roles, though less important,
with Rim11 and Mck1 functions. This review summarizes the
cellular roles of these kinases, their mode of regulation,
and the signals that they transmit.
[Back to top]
Editorial
Ageing is an issue, which inevitably affects all of us, and
conditions that accompany ageing - such as cardiovascular
disease, cancer, neurodegenerative disorders and diabetes
- account for the majority of healthcare costs. This is a
rapidly increasing problem, as, average life expectancy worldwide
has increased by 20 years since 1950, to stand at 66 years
now and the number of people over 65 is expected to double
until 2025 in many industrialized countries in Europe and
the US. It can be expected that the trend towards an increased
lifespan - independent of the intake of specially designed
treatment - has not come to an end yet. Drs. Oeppen and Vaupel
(Cambridge University, United Kingdom and Max Planck Institute
for Demographic Research, Germany) have observed that maximum
life expectancy has steadily increased for the past 160 years.
The increase in the record expectation of life should be slowing,
when close to a natural maximum, an observation which, however,
has not been made.
While the magnitude of the consequences of these world-wide
demographic changes, however, is not reflected by existing
therapeutic options, there is an increasing interest and awareness
in the scientific community for the treatment of age-related
disorders, dysfunctions and diseases; furthermore, an increasing
emphasis is placed on basic research witnessing unprecedented
growth and acceptance. Although the fountain of youth certainly
is out of reach, the recent past has seen exciting developments
bringing us closer to the identification of causes of ageing
and to the generation of agents increasing longevity. Exciting
innovations have been described in biotechnology including
conditions to regrow damaged or diseased tissues and organs,
in stem cell technology to permit development of a supply
source for human cells, tissues, and organs and genetic engineering
advancements. The view dominated by evolutionary research
considering ageing as a general deterioration, thus precluding
monogenetic causes of longevity, has been changed dramatically
within the last decade, which has seen spectacular increases
of lifespan in model organisms as a result of single-gene
mutations. These findings have fuelled the screening for specifically
interfering agents and will prompt the search for further
single-gene targets employing timely screening technologies
such as high-throughput tests using RNAi. The latter is also
being used to correct defective RNA splices that, when expressed,
cause disease. Screening for potential treatments, however,
requires appropriate models and feasible assays. Whereas lifespan
studies are performed in simple organisms like yeast, worms
(C. elegans) or flies (Drosophila) requiring
several days or weeks, an evaluation in a mouse model may
take several months or years. Recent genetic studies on these
animals revealed that the lifespan of these species can be
dramatically increased by the mutation of one or a few genes.
The identification of these genes, however, suggests that
ageing can be manipulated, because many genes that affect
longevity in model organisms have human homologs. However,
it still remains to be shown to which extent these or other
gene activities represent drugable targets.
With regard to low molecular weight agents, medicinal chemistry
has developed efficient toolkits and e.g. Chemical Genetics,
a phenotype-driven research targeting the lifespan of model
systems and animal models, appears to be fruitful. Given the
lack of knowledge on life-extending mechanisms a random or
biased screening approach is reasonable besides attempts to
address distinct known targets for interference based on mechanistic
considerations. For instance, a lifespan directed screening
of agents with known pharmacological activities such as the
testing of anticonvulsive drugs by Kerry Kornfeld and colleagues
provides highly interesting data pointing to a previously
unknown connection between neural function and longevity.
Alternative underlying mechanisms are expected to include
the preservation or the restoration of important functions
in cellular control and repair mechanisms or of pathways affecting
the expression and function of proteins controlling the levels
of reactive oxygen species and improving stress resistance
such as antioxidant enzymes like catalase or administration
of the glutathione precursor cysteine, which might reduce
age-associated degeneration. Drugs mimicking caloric restriction
decrease weight, may decrease oxidative stress, increase insulin
sensitivity, modulate the neuroendocrine system and prolong
life in ways similar to caloric restriction.
This special issue presents selected aspects of timely ageing
research. A screening for agents capable of repairing age-related
extracellular damage as suggested by A. de Grey,
notwithstanding mechanisms involved, appears as an intriguing
concept. Alternatively, however, having identified potential
key compounds with significant impact on lifespan, it can
be fruitful to determine how these agents can bring organisms
extra time. The paper of Jafari et al.
analyses the pharmacology of molecules tested in C. elegans
or Drosophila focussing on anticonvulants, antioxidants
(sirtuin activating, superoxide dismutase/catalase mimetics),
vitamins and histone deacetylase inhibitors.
Intermittent fasting, i. e. reduced meal frequency,
and caloric restriction extend lifespan and increase resistance
to age-related diseases in mammals and improve the health
of overweight humans. Caloric restriction is the only experimental
manipulation known to extend the lifespan of a number of organisms
including yeast, worms, flies and possibly non-human mammals.
In this context Anisimov critically
analyses data on the lifespan extension and adverse effects
of chemicals and drugs suggested as geroprotectors including
antidiabetic drugs, growth and thyroid hormones, glucocorticoids,
DHEA etc.
Differential insulin responsiveness in skeletal muscle and
fat cells may potentially be used to favour anabolic processes
in muscle tissues. The importance of insulin-receptor signalling,
a low basal insulin receptor kinase activity and the role
of tumour necrosis factor-α
is reviewed by Dröge et al..
The therapeutic approaches include cysteine supplementation,
potentially counteracting age-related decrease in glutathione
and cysteine concentrations, consequences and possibly causes
of increasing oxidative stress during ageing.
The neuroprotective and lifespan extending effects of a selected
neuroprotective compound, selegiline, comprising increase
of the striatal superoxide dismutase, protection against peroxynitrite-
and nitric oxide-induced apoptosis, and protection of dopaminergic
neurons from toxicity induced by glutathione depletion is
the topic addressed by Ebadi et al..
As mentioned, a series of recent genetic studies on worms,
flies, and rodents revealed that the lifespan of these species
can be dramatically increased by mutation of a single gene.
In these cases, increased lifespan is frequently associated
with an increased resistance to oxidative stress. The review
of Wagner highlights the potential
of small molecules and their effects on enzymatic and non-enzymatic
antioxidants in the context of their potential influence on
longevity.
New targets of high interest for anti-ageing drug development
further involve the control and modulation of histone deacetylases
and of the endocannabinoid system as outlined by Paradisi
et al.. Longevity genes, like NAD+
dependent histone deacetylases (sirtuins) are involved in
regulating the responses to cellular stress and caloric restriction.
In model organisms, lifespan could be expanded by mutations
in homologs of insulin and insulin-like growth factor 1 signaling
genes. Alternative candidates comprise genes regulating inflammatory
responses and mitochondrial DNA. The potential role of sirtuin
family members and their respective functions as well as available
drug-like inhibitors / activators of sirtuin activity are
reviewed by Trapp and Jung.
Ageing certainly is a complex process in which deterioration
of multiple cellular functions rule out the identification
of a golden bullet or panacea. With high probability, however,
we will experience multitherapeutic interventions capable
of slowing or reversing the process of ageing including associated
dysfunctions in the near future.
Hans-Peter Deigner
Ralf Kinscherf
[Back to top]
Foreseeable Pharmaceutical Repair of Age-Related Extracellular
Damage
A.D.N.J. de Grey
Various molecular and cellular alterations to our tissues
accumulate throughout life as intrinsic side-effects of metabolism.
These alterations are initially harmless, but some, which
we may term "damage", are pathogenic when sufficiently
abundant. The slowness of their accumulation explains why
decline of tissue and organismal function generally does not
appear until the age of 40 or older. Aging is thus best viewed
as a two-part process in which metabolism causes accumulating
damage and sufficiently abundant damage causes pathology.
Hence, a promising approach to avoiding age-related pathology
is periodically to repair the various types of damage and
so maintain them at a sub-pathogenic level. Some examples
of such types of damage are intracellular and others extracellular.
Several types of intracellular damage are highly challenging
– sophisticated cellular and genetic therapies will
be needed to combat them, which are surely at least 20 years
away and maybe much more. Extracellular damage, by contrast,
generally appears more amenable to pharmaceutical repair which
may be feasible in a shorter timeframe. In this article, the
major types of age-related extracellular damage and promising
avenues for their repair are reviewed.
[Back to top]
The Pharmacology of Ageing in Drosophila
M. Jafari, A.D. Long, L.D. Mueller and M.R. Rose
Recent research indicates that aging is affected by many genes
and thus many biochemical pathways. This has led to a failure
to find pharmaceuticals that significantly ameliorate the
human aging process. Progress in evolutionary and genetic
research, however, suggests the possibility of combining experimental
evolution, genomic analysis, and mass screening of pharmaceuticals
and botanicals to produce effective therapeutics for human
aging. The starting point for this strategy is model systems
that have outbred populations with substantially increased
lifespan. These are easily produced by tuning the force of
natural selection in the laboratory. Such biological material
is then a good candidate for genomic analysis, leading to
the identification of numerous biochemical pathways involved
in increased lifespan, in the model system. These biochemical
pathways would then be available for pharmaceutical development,
first in fruit flies, then in rodents, and eventually in a
clinical human population. We include a discussion of the
pharmacological methods appropriate to this strategy of drug
discovery.
[Back to top]
Premature Ageing Prevention: Limitations and Perspectives
of Pharmacological Interventions
V.N. Anisimov
A significant increase of the elderly in populations of developed
countries is followed by increase morbidity and mortality
from main age-related diseases – cardiovascular and
neuro-degenerative, cancer, diabetes mellitus, declining in
a resistance to infections. Obviously, the development of
means of the prevention of the premature ageing and these
diseases in humans are crucial at present. However, data on
such type means rather scarce, contradictory and often not
reliable from the points of view of the adequacy of the experiments
to current scientific requirements, as well as the interpretation
of the results and safety. Available data on the life span
extension and adverse effects of chemical compounds and drugs
suggested as geroprotectors are critically analyzed: antidiabetic
drugs, growth and thyroid hormones, glucocorticoids, DHEA,
sex steroids and contraceptives, melatonin and peptide preparations
modulating the pineal gland, antioxidants, chelate agents
and lathyrogens, adaptogens and herbs, neurotropic drugs,
inhibitors of monoamine oxidase, immunomodulators and some
other. Most of the results could not convincingly evidence
the life span extension and safety of the suggested geroprotectors.
We believe that it is necessary to establish an international
program for the expert evaluation of the life span extension
potential of pharmacological interventions for humans. The
scope of the program should be to evaluate chemical, immunological,
dietary and behavioural interventions that may lead to life
span extension or retard premature ageing and the objective
– preparation of critical reviews and evaluations on
evidence of the life span extending properties of a wide range
of potential geroprotectors and strategies by international
groups of working experts. The program may assist national
and international authorities in devising programs of health
promotion and premature ageing prevention.
[Back to top]
The Deficit in Low Molecular Weight Thiols as a Target
for Antiageing Therapy
W. Dröge, R. Kinscherf, W. Hildebrandt and T. Schmitt
The popular use of antioxidative vitamins illustrates the
growing awareness of oxidative stress as an important hazard
to our health and as an important factor in the ageing process.
Superoxide radicals and superoxide-derived reactive oxygen
species (ROS) are constantly formed in most cells and tissues.
To ensure that ROS can function as biological signaling molecules
without excessive tissue damage, ROS are typically scavenged
by antioxidants such as glutathione and the vitamins A, C,
and E. “Oxidative stress“ occurs if the production
of ROS is abnormally increased or antioxidant concentrations
are decreased. Genetic studies in mice, Drosophila,
and C.elegans suggested that ageing may be mechanistically
linked to oxidative stress. Several manifestations of oxidative
stress were shown to increase with age, whereas tissue levels
of vitamin E, plasma concentrations of vitamin C, and intracellular
glutathione concentrations decrease with age. In at least
two independent studies, cysteine supplementation on top of
the normal protein diet has shown significant beneficial effects
on each of several different parameters relevant to ageing,
including skeletal muscle functions. As the quality of life
in old age is severely compromised by the loss of skeletal
muscle function, and as muscle function can be measured with
satisfactory precision, loss of muscle function is one of
the most attractive surrogate parameters of ageing. The mechanisms
by which a deficit in glutathione and its precursor cysteine
contributes to various ageing-related degenerative processes
appears to be related largely but not exclusively to the dysregulation
of redox-regulated biological signaling cascades.
[Back to top]
Therapeutic Efficacy of Selegiline in Neurodegenerative
Disorders and Neurological Diseases
M. Ebadi, H. Brown-Borg, J. Ren, S. Sharma, S. Shavali,
H. El ReFaey and E.C. Carlson
Selegiline inhibits the activity of monoamine oxidase B, enhances
the release of dopamine, blocks the uptake of dopamine, acts
as a calmodulin antagonist, and enhances the level of cyclic
AMP, which in turn protects dopaminergic neurons. It possesses
cognition-enhancing functions, rejuvenates serum insulin-like
growth factor I in aged rats, and enhances life expectancy
in rodents. Selegiline possesses neurotrophic-like actions,
and rescues axotomized motorneurons independent of monoamine
oxidase B inhibition. It enhances the synthesis of nerve growth
factor, protects dopaminergic neurons from glutamate-mediated
neurotoxicity, and protects dopaminergic neurons from toxic
factors present in the spinal fluid of parkinsonian patients,
and the said effect may be mediated via elaborating
brain derived neurotrophic factor. Selegiline increases the
striatal superoxide dismutase, protects against peroxynitrite-
and nitric oxide-induced apoptosis, and guards dopaminergic
neurons from toxicity induced by glutathione depletion. It
stimulates the biosynthesis of interleukin 1-β
and interleukin-6, is an immunoenhancing substance, possesses
antiapoptotic actions, and is neuroprotectant in nature. Selegiline
has been shown to be efficacious in Parkinson's disease, global
ischemia, Gille de la Tourette syndrome, and narcolepsy. Its
therapeutic efficacy in Alzheimer's disease remains uncertain.
In Alzheimer’s disease, short term studies of selegiline
suggest a beneficial effect; whereas long term studies are
less convincing.
[Back to top]
Towards a Life Prolonging Pill? Small Molecules with
Anti-Ageing Properties
G. Wagner
While at present there is no scientific consensus on the reasons
for cellular and organismal ageing – or indeed on a
comprehensive definition for ageing – scientific efforts
to unravel the complex biochemistry behind the ageing process
have recently met with considerable success. Despite a still
somewhat fragmented understanding of the phenomenon of ageing,
a distinction has therefore become possible between those
biochemical and physiological events that are causal
to ageing, and those that merely accompany the process.
Such a distinction is an important prerequisite for the selection
of targets for pharmacological intervention, and for the design
of “anti-ageing drugs” directed against these
targets. This review looks from a chemical viewpoint at currently
used model systems for the ageing process, at small molecules
showing anti-ageing properties in these screens, and at their
mechanisms of action.
[Back to top]
The Endocannabinoid System in Ageing: A New Target
for Drug Development
A. Paradisi, S. Oddi and M. Maccarrone
Endocannabinoids are a new class of lipids, which include
amides, esters and ethers of long chain polyunsaturated fatty
acids. Anandamide (N-arachidonoylethanolamine; AEA)
and 2-arachidonoylglycerol are the main endogenous agonists
of cannabinoid receptors able to mimic several pharmacological
effects of Δ9-tetrahydrocannabinol,
the active principle of Cannabis sativa preparations
like hashish and marijuana. AEA is released “on demand”
from membrane lipids, and its activity at the receptors is
limited by cellular uptake followed by intracellular hydrolysis.
Together with AEA and congeners, the proteins which bind,
synthesize, transport and hydrolyze AEA form the “endocannabinoid
system”. Endogenous cannabinoids are present in the
central nervous system and in peripheral tissues, suggesting
a physiological role as broad spectrum modulators. This review
summarizes the main features of the endocannabinoid system,
and the latest advances on its involvement in ageing of central
and peripheral cells. In addition, the therapeutic potential
of recently developed drugs able to modulate the endocannabinoid
tone for the treatment of ageing and age-related human pathologies
will be reviewed.
[Back to top]
The Role of NAD+
Dependent Histone Deacetylases (sirtuins) in Ageing
J. Trapp and M. Jung
Histone deacetylases (HDACs) are enzymes that are able to
deacetylate lysine side chains in histones and certain non-histone
proteins which leads to altered states of conformation and
activity for the proteins in question. Three classes of histone
deacetylases have been recognized in humans. Class I and II
are zinc-dependent amidohydrolases and eleven subtypes have
been discovered (HDAC1-11). Class III enzymes depend in their
catalysis on NAD+ and subsequently, O-acetyl ADP
ribose and nicotinamide are formed as a consequence of the
acetyl transfer. Due to the homology to the yeast histone
deacetylase Sir2p the NAD+-dependent deacetylases
are also termed sirtuins and seven members (Sirt1-7) are known
in humans. Sirtuins are found from bacteria to eukaryotes
and altogether about 60 isoforms have been characterized in
different organisms. Sirtuins have been implicated in the
regulation of molecular mechanisms of aging. The overexpression
of sirtuin enzymatic activity leads to an increase of lifespan
in Saccharomyces cerevisiae and Caenorhabditis elegans that
can also be reached by calorie restriction. Sirtuins have
been proposed to act as sensors for glucose uptake that respond
to the levels of NAD+ but more complex ways of
action have been suggested as well. This article will present
the members of the human sirtuin family with their respective
functions and review the existing druglike inhibitors and
activators of sirtuin activity.
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