cron-web.org

[A1CR]

From: CRONie_A


> Alas, it costs $30 to view.
>
> From: CRON4healthyfuture
>
>> There is a recent study in the journal Experimetnal Gerontology that
>> indicates that calories from protein may be "worse" than calories from
>> sugar.
>>
>> This isn't an entirely new idea, but so many bleat "calories, calories,
>> calories" that I thought it bears at least a double-take.
>>
>> Go to the link below, and click on "Articles in Press". Find the one
>> about Counting Calories in Drosophila. That is the article. In the
>> full-text, Marc Tatar's team recapitulates the findings previously
>> published in PLoS Biology. Rock on, dudes.
>>
>> http://www.sciencedirect.com/science/journal/05315565

Min KJ, Flatt T, Kulaots I, Tatar M.
Counting calories in Drosophila diet restriction.
Exp Gerontol. 2006 Nov 22; [Epub ahead of print]
PMID: 17125951

Drosophila continues to be a model system of choice to study
the genetics of
aging. It has a short lifespan and small genome size, but
nevertheless
contains a complex organ and endocrine system that allows
studying the role
of conserved signal transduction pathways with sophisticated
genetic tools.
Oxidative stress and metabolic changes along with
intersecting signaling
systems Insulin Receptor (InR), Target of Rapamycin (TOR)
and Jun N-terminal
Kinase (JNK) have emerged as some of the major players in
aging. Sleep and
organ-specific aging has also been the subject of recent
progress in
understanding aging.

1. Starvation resistance and the regulation of lifespan: InR
and TOR
pathways
In many species, reducing nutrient intake extends lifespan.
The insulin
signaling pathway is a widely conserved mechanism implicated
in the control
of nutrient sensing and has been shown to regulate growth,
size, as well as
lifespan in higher eukaryotes. In Drosophila, the
functionally conserved
components of the insulin pathway, like the Insulin Receptor
(InR),
phosphoinositide 3-kinase (PI3K) and the forkhead
transcription factor
dFOXO, have been shown to regulate aging. One of the known
targets of dFOXO
is d4E-BP, a regulator of the translation initiation factor
eIF4E activity.
A recent report suggests that d4E-BP is a critical
downstream effector of
dFOXO for surviving under dietary restriction and that it is
also linked to
lifespan (Tettweiler et al., 2005). Other studies examined
the role of the
Target of Rapamycin (TOR) pathway, another signaling pathway
that responds
to changes in various energy states and amino acids, is also
known to
regulate growth and size, as well as lifespan. Furthermore,
dTOR seems to
act downstream of dFOXO, in addition to be interconnected
with the InR
pathway, in regulating metabolism as well as lifespan (Luong
et al., 2006).
In addition to InR and TOR pathways' involvement in
regulating lifespan, the
stress-responsive JNK pathway also regulates aging dependent
on the
InR-associated transcription factor FOXO (Wang et al.,
2005), again
highlighting the crosstalk between InR, TOR as well as JNK
signaling in
aging.

2. Oxidative stress, mitochondria and aging
The free radical theory of aging posits that the
accumulation of
macromolecular damage induced by toxic reactive oxygen
species (ROS) plays a
central role in the aging process and that reducing the
metabolic
consumption of molecular oxygen by suppressing energy
utilization would
reduce ROS (mainly H2O2, and ONOO?) generation and increase
lifespan
correspondingly. The mitochondria are the principal
generator of ROS during
the conversion of molecular oxygen to energy production
where approximately
0.4-4% of the molecular oxygen metabolized by the
mitochondrial electron
transport chain is converted to ROS (Aguilaniu et al.,
2005). However,
numerous studies carried out in Drosophila aimed at reducing
mitochondrial
ROS production, which included overexpression of
antioxidants such as
superoxide dismutase (SOD) and catalase, failed to validate
this theory
(Magwere et al., 2006). In contrary, some studies even
yielded opposing
results, where upregulating the levels of antioxidants led
to a decline of
lifespan (Bayne et al., 2005). On the other hand, targeted
overexpression of
human uncoupling protein 2 (hUCP2) in the mitochondria of
adult fly neurons
as well as human SOD in adult fly motoneurons led to a
decrease in ROS
generation, a decrease in oxidative damage and an extension
of lifespan
(Fridell et al., 2005). These findings support the notion
that reducing
mitochondrial oxidative damage in neurons is sufficient to
increase lifespan
and also revealed the advantage of using Drosophila as a
system for
examining the functions of human proteins. However, another
study showed
that functional knockout of UCP5 in Drosophila led to flies
living longer on
low-caloric diets but no increased respiratory rate and ATP
production in
their mitochondria, suggesting that mitochondrial activity
is not
necessarily linked to longevity (Sanchez-Blanco et al., 2006).

The correlation between the free radical theory of aging and
caloric
restriction is also an interesting and important aspect of
senescence that
has been studied. The prediction that mitochondrial
production of ROS
determines organismal aging would suggest that dietary
restriction should
promote longevity since fewer ROS are produced. Indeed,
caloric restriction
is one of the most successful manipulations in extending
life across
numerous vertebrate and invertebrate species. However, flies
under caloric
restriction showed no significant difference in
mitochondrial ROS production
and no reduction in metabolic rate compared to controls,
even though their
lifespan is increased (Partridge et al., 2005). Therefore,
no conclusion can
yet be reached as to whether dietary restriction prolongs
lifespan via a
decline in mitochondrial ROS generation.

The vertebrate apolipoprotein D (ApoD) protein is a
lipocalin secreted from
glia and neurons during neural development and is
upregulated in the aging
brain and under numerous nervous system pathologies. The
Drosophila homolog
of human ApoD, Glial Lazarillo (Glaz) is also primarily
expressed in subsets
of adult glial cells and its absence reduces the organism's
ability to
counter oxidative stress and starvation and also shortens
male lifespan
(Sanchez et al., 2006). Conversely, overexpression of Glaz,
by means of
ubiquitous and tissue-specific drivers, confers resistance
to hyperoxia and
increases lifespan under normoxia (Walker et al., 2006).
Taken together,
these results support the notion that Glaz has a protective
function in
stress conditions and in doing so, promotes lifespan
extension. The levels
of mitochondrial ROS in the Glaz deficient and
overexpressing flies remain
to be examined.

In addition to overall lifespan extension, other parameters
of Drosophila
aging could also be employed in understanding the
relationship between
mitochondrial oxidative stress and aging. Parkinson's
disease (PD) is an
age-dependent neurodegenerative disease and is thought to be
triggered, at
least in part, by mitochondrial dysfunction and increased
susceptibility to
oxidative stress and toxins. The Drosophila PTEN-induced
kinase 1 (PINK1)
protein is localized to mitochondria and associated with
sporadic forms of
PD (Clark et al., 2006, Park et al., 2006, Wang et al., 2006
and Yang et
al., 2006). Removal of PINK1 results in mitochondrial
fragmentation and
increased sensitivity to multiple stresses, including
oxidative stress,
whereas treatment of PINK1 knockdown flies with antioxidants
protects flies
against PD-associated neurodegeneration (Wang et al., 2006).
These findings
underline the importance of mitochondrial oxidative stress
in PD
pathogenesis, which can be regarded as another indicator of
the aging
process.

3. Tissue-specific manipulation of aging
How the aging process within an organism is coordinated
between different
organs and how the decline in organ physiology is regulated
continues to be
one of the pressing question in aging research but has been
difficult to
address. Recently, changes in sleep patterns, heart function
and stem cell
biology with age have received some attention in Drosophila.

3.1. Sleep and aging
In humans, sleep consolidation is a well-known physiological
function that
deteriorates in the elderly. This is manifested by an
increase in daytime
sleep, accompanied by an increase in nighttime wakefulness.
Flies display
remarkably similar characteristics of sleep (e.g., Shaw et
al., 2000). Using
Drosophila to further analyze age-associated sleep-wake
cycle perturbations,
it has been reported that the sleep-wake cycles become less
robust and that
sleep is increasingly fragmented with age (Koh et al.,
2006). By analyzing
sleep-wake cycles at different temperatures (a parameter
known to modify
lifespan), this study provides evidence that the rate of
sleep consolidation
breakdown correlates with lifespan, in that the breakdown is
accelerated
under conditions that cause a shortening of lifespan. This
suggests that
irregular sleep-wake cycles are linked to physiological
aging. Similar
alterations of sleep consolidation were associated with
increased oxidative
stress, consistent with the idea that oxidative stress
accumulation
contributes to sleep deterioration with age. Interestingly,
the adult
mushroom bodies (a part of the fly CNS known to be involved
in learning and
memory) appear to function as a central regulator of sleep
in Drosophila
(Joiner et al., 2006 and Koh et al., 2006). This is likely
the beginning of
an exiting new direction of investigation, aimed at
elucidating the genetic
and molecular basis of the influence of aging on sleep and
its control by
nervous system components.

3.2. Cardiac aging
Recent efforts in elucidating the cellular and molecular
basis of cardiac
function in Drosophila suggest that in addition to the
evolutionary
conservation of embryonic heart specification there may also
be similarities
in the molecular control of heart physiology and aging.
Indeed, like in
humans, cardiac senescence in Drosophila is characterized by
a reduction of
heart rate increase upon stress, an increase in rhythm
disturbance and
pacing stress-induced cardiac failure (Wessells et al.,
2004). In addition,
genetic manipulation of InR signaling cell autonomously
impinges on heart
performance senescence, thus providing a cardiac model for
genetic studies
of organ-specific aging (Wessells et al., 2004). The dTOR
branch of the InR
pathway is also involved in regulating age-dependent decline
of cardiac
function (Luong et al., 2006). How exactly individual organs
integrate
positive or negative systemic 'aging' signals and what
pathway endpoint
effectors (such as FOXO) are going to be relevant in
different organs is
still largely unresolved. Drosophila is very well suited to
address such
questions of epistasis and tissue specificity.

In the heart, pathway effectors that directly affect its
performance with
age must also impinge on components of the heart's
electrical and
contractile system. Indeed, characterization of the
age-related phenotype of
an ATP-sensitive potassium channel encoded by the dSUR gene
revealed that
its RNA levels are significantly decreased in hearts of old
flies, and that
RNAi-mediated knockdown in young hearts causes compromised
heart function
reminiscent of old flies (Akasaka et al., 2006), supporting
an involvement
of these potassium channels in the cardiac aging phenotype.

3.3. Stem cells
Due to their potential role in tissue repair and in the
treatment of
degenerative diseases, stem cells' research has been given
much attention
and Drosophila has emerged as an important model for
studying stem cell
biology. In addition to the well-known germ stem cells that
decrease their
self-renewal potential with age, a new set of self-renewing
cells have been
discovered in Drosophila: the intestinal stem cells
(Micchelli and Perrimon,
2006 and Ohlstein and Spradling, 2006). They are dispersed
throughout the
length of the midgut and are slowly dividing, thereby giving
rise to
intestinal and enteroendocrine cells. Human intestinal cells
are well known
to be continuously renewed by stem cells, thus the
Drosophila midgut
epithelium may turn over similarly. Both labs identified
adult intestinal
stem cells by lineage tracing experiments, and demonstrated
that Notch
signaling regulates the differentiation of enteroendocrine
cells, again
reminiscent of vertebrates. The identification of Drosophila
intestinal stem
cells now offers the opportunity to study intestinal stem
cell renewal and
aging in vivo.