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[A1CR]

Macroautophagy is another name that some use to describe the
role of
http://en.wikipedia.org/wiki/Autophagy on a larger scale.
Many aspects
related to aging are involved in this biological process,
and it appears
that the means whereby CR acts may utilize autophagy
mechanisms. For the (2)
paper, the achieving of 11% CR at 6 months and 10% at 24
months by feeding
every other day; and 32% CR at 6 months and 29% at 24 months
by feeding only
6 days per week was noted.

1. Donati A.
The involvement of macroautophagy in aging and anti-aging
interventions.
Mol Aspects Med. 2006 Sep 12; [Epub ahead of print]
PMID: 16973209 http://tinyurl.com/r3pjt

Macroautophagy is a process that sequesters and
degrades organelles and
macromolecular constituents of cytoplasm for cellular
restructuring and
repair, and as a source of nutrients for metabolic use in
early starvation.
Extensive evidence has been reported that macroautophagy
process declines
with increasing age. This impairment, probably due to ad
libitum feeding,
may cause accumulation of altered structures leading to the
age-related
decline in cell functions. It has been suggested that
caloric restriction
(CR) and disruption of insulin-like signals contrast the
process of aging by
prolonged stimulation of macroautophagy. According to this
hypothesis, it is
shown that life-long weekly administration of an
anti-lipolytic drug
decreases glucose and insulin levels, stimulates autophagy
and intensifies
anti-aging effects of submaximal CR.

1. Introduction and overview

Process of ageing denotes a post-maturational deterioration
of cells and
organisms with the passage of time, that underlies an increased
vulnerability to challenges and a decreased ability to
survive (Masoro,
1999). The issue whether biological ageing is distinct from
age-associated
diseases is still a matter of debate (Holliday, 2004 and
Hayflick, 2004).
The author's opinion is that recent advancements in
Biogerontology may
support the hypothesis that all existing living beings are
affected by
ageing, a fatal inherited disease ("senectus ipsa morbus
est") whose
incubation period is long enough to enable patients to
reproduce
successfully. In this comprehensive view, ageing is a
disease, not a risk
factor for disability and illness, and age-associated
diseases like
atherosclerosis, tumours and neurodegeneration should rather
be seen like
signs or complications of the underlying fundamental
disease, and may share
its mechanism(s) at least in part.

There is a general consensus on the fundamental
mechanisms of ageing:
cell molecules and substructures are subject to a variety of
destructive
forces that originate in both the internal and external
environments of an
organism, and lesions may accumulate in cells and tissues.
At the molecular
level, causes may be found in oxidative damage and not
completed
housekeeping. Both factors are responsible for the progressive
senescence-associated accumulation of deleterious
alterations of
macromolecules and organelles, responsible for cell
misfunctioning, starting
from young-adult age (Weindruch and Sohal, 1997).

In regard to oxidative damage, the hypothesis is that
as much as 1-2%
of the used oxygen molecules might generate reactive oxygen
species (ROS),
endogenously produced by mitochondria and peroxisomes, which
may hit and
alter DNA, protein, cell membranes and organelles as well as
extracellular
components (Weindruch and Sohal, 1997). At an older age,
accumulation of
altered mitochondria and peroxisomes may boost the yield of
ROS per unit of
produced energy (see Bergamini et al., 2004). The effects of
ROS are not
counteracted fully by the antioxidant defenses in the
hydrophylic and in the
lipophylic compartments of the cell. Level of oxidative
stress cannot be
modulated at will by the use of antioxidants because signal
is used to
monitor the rate of cell metabolism, in order to adjust cell
functions and
blood supply. Thus, a long-term administration of excess
antioxidants may
have severe unwanted effects (Yu et al., 1998).

Failure in housekeeping (inadequate ability to repair
or degrade
altered macromolecules, cell membranes and organelles and
replace them with
new) appears to be the concause of ageing, and the
stimulation of turnover
of altered proteins, membranes and organelles (e.g., by
caloric restriction
(Yu, 1995) and physical exercise (Holloszy and Kohrt, 1995)
or drugs
(Bergamini et al., 2003 and Berger et al., 2006)) may be a
remedy and a part
in the mechanism of antiageing interventions. Table 1 shows
mechanisms
responsible for cell maintenance. In summary, repair at the
molecular level
can treat any type of DNA, protein and lipid damage;
autophagy and lysosomal
degradation regulate the turnover rate of macromolecules and
subcellular
structures, and also help maintenance of cell in case of
failure of
molecules repair; in mammals, targeting to lysosomal
degradation provides an
additional degradative pattern of altered proteins and
aggregates, possibly
endowed with anti-ageing effects, whose function may decline
with ageing
(Kaushik and Cuervo, 2006); macroautophagy may also
recognize and dispose
altered organelles quite selectively (Donati et al., 2006 =
reference 3);
failure of repair at the molecular and subcellular level may
trigger
apoptosis (Boya et al., 2005), the last tier of defence
against the
accumulation of irreversibly altered cells in the body. All
cells in the
body must die, including cardiac and muscle cells and
neurons; time-lag
before cell death may be influenced by several factors and
eventually might
be determinated by the time of autophagy failure (Table 2).
Enhanced
apoptosis may precipitate cardiac, muscle and neurodegenerative
age-associated diseases.

[...]

In this issue, attention will be focused on
macroautophagy, the
physiological mechanism that controls cell nutrition and
volume and adapts
cell composition to a changing environment (Stevens and
Lowe, 2000);
mechanism also protects cells from the age-related
accumulation of altered
proteins, membranes and organelles (Stevens and Lowe, 2000;
see also Terman
et al., 2006). Macroautophagy was said to be the putative
mechanism of the
anti-ageing action of caloric restriction (Bergamini and
Gori, 1995).
Macroautophagy is a highly conserved degradation/recycling
system ubiquitous
in eukaryotic cells, in which the cytoplasm, including
excess or aberrant
organelles, is sequestered into double-membrane vesicles and
delivered to
the degradative organelle, the lysosome/vacuole, for
breakdown and eventual
recycling (Wang and Klionsky, 2003). Process generates
nutrients during
fasting under the control of amino acids and pancreatic
hormones (Kanazawa
et al., 2004 and Miotto and Kadowaki, this issue) and gives
place to
resynthesis, turnover and rejuvenation of cellular
components (long-lived
proteins, cytomembranes and organelles) (Bergamini et al.,
2004). This
process has an important role in various biological events
such as
adaptation to changing environmental conditions and cellular
remodeling
during development and differentiation (Yorimitsu and
Klionsky, 2005).
Autophagic degradation has an important role in physiology
of the nervous
system, heart and muscle (Eskelinen, 2006). Autophagy also
samples proteins
in cell (viral, tumour and autoantigens) and generates
peptides which are
then presented on major histocompatibility complex (MHC)
class II (Munz,
2006 and Schmid et al., 2006). Thus autophagy represents a
previously
unrecognized immune mechanism that may act against cells
with intracellular
microbes (Deretic, 2005) and perhaps against cells (e.g.,
cancer cells)
exhibiting abnormal protein synthesis and composition.

It has been known for decades that autophagy regulates
mitochondria
(Pfeifer, 1978) and peroxisome turnover (Veenhuis et al.,
1983 and Locci
Cubeddu et al., 1985; for recent advancements, see
Monastyrska and Klionsky,
2006). Very recent evidence shows that macroautophagy
recognizes and
eliminates older or altered ROS-hypergenerating organelles
quite selectively
(Gu et al., 2004 and Donati et al., 2006 = reference 3). The
molecular
identity of the "opsonizing" mechanism is not known yet
(Klionsky, 2005) but
perhaps ARF might be in the game (Reef et al., 2006). The
accumulation of
altered protein (Yamamoto et al., 2006) and any type of cell
injury,
including ROS (Moore, 2004), ischemic (Hamacher-Brady et
al., in press) and
mechanic (Diskin et al., 2005) injuries can ignite a
nutrition-independent
m-TOR-independent macroautophagy (see Meijer and Codogno,
2006). These two
types (nutrition- and injury-dependent) of activation might
interact
each-other to potentiate protection.

Signalling and autophagy regulation have been
investigated and
clarified (Meijer and Codogno, 2006) and may undergo
progressive
deterioration with increasing age, both in vitro (Cavallini
et al., 2001)
and in vivo (Del Roso et al., 2003). The age-related decline
in functioning
of autophagy might account for the age-dependency of many
age-associated
diseases in ad libitum-fed animals, including
neurodegeneration (Boland and
Nixon, 2006), and for retardation by caloric restriction and
by the
pharmacological intensification of autophagic degradation
(Donati et al.,
2004 = reference 2; and Ravikumar and Rubinsztein, 2006).

2. Conclusions

There may be support to the hypothesis that during
evolution, in order
to promote rapid growth and successful reproduction, Nature
tuned down
autophagic degradation too much and function of cell
maintenance suffered
and determinated lifespan. A dramatically increasing number
of scientific
contributions is being published showing that autophagy is
primarily a
pro-survival mechanism (Levine and Yuan, 2005). Currently
available data
show that the pharmacological intensification of the process
of autophagic
degradation may be a big step towards retardation of ageing
and prevention
and therapy of neurodegenerative diseases.

2. Donati A, Cavallini G, Carresi C, Gori Z, Parentini I,
Bergamini E.
Anti-aging effects of anti-lipolytic drugs.
Exp Gerontol. 2004 Jul;39(7):1061-7.
PMID: 15236765 http://tinyurl.com/jtq9k

... 3-month-old male Sprague-Dawley rats were (a)
given standard
laboratory food ad libitum (AL); (b) fed AL 6 days and
fasted 1 day every
week (FW); (c) fed AL every other day (EOD), (d) fed like FW
and given
Acipimox (50 mg/kg b.w.) on the day of fasting (FWA) by the
gastric tube.
The AL, FW and EOD groups received saline intragastrically.
Treatment with
Acipimox transiently decreased plasma free fatty acids,
glucose and insulin
and increased valine plasma levels, and had no long-term
effect on food
consumption and body weight. By age 6, 12 and 24 months
subgroups were taken
and the age-related changes in liver dolichol and autophagic
proteolysis--which are correlated with life-expectancy--were
measured. Liver
dolichol levels increased and autophagic proteolysis
decreased in mature and
older AL rats; EOD and FWA fully counteracted these changes;
FW rats had
significant but smaller beneficial effects. It is concluded
that life-long
weekly-repeated transient inhibition of insulin secretion by
antilipolytic
drugs may have an anti-aging effect, additive to the
anti-aging effect of a
milder caloric restriction. Speculation is that transiently
lower plasma
insulin levels might stimulate the anti-aging cell-repair
mechanism
autophagy, which has longer lasting effects on cell
housekeeping.