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[A1CR]

The role that http://en.wikipedia.org/wiki/Hormesis has in
various
biological systems, including CR, is discussed in the below
paper.

Hayes DP.
Nutritional hormesis.
Eur J Clin Nutr. 2006 Aug 2; [Epub ahead of print]

PMID: 16885926 http://tinyurl.com/hm73c

... Hormetic and other dose-response relationships are
categorized,
depicted, and discussed. Evidence for nutritional hormesis
is presented for
essential vitamin and mineral nutrients, dietary
restriction, alcohol
(ethanol), natural dietary and some synthetic pesticides,
some herbicides,
and acrylamide. Some of the different hormetic mechanisms
that have been
proposed are reviewed. ... The credence and relevance of
hormesis to
nutrition are considered to be established. The roles of
hormesis in
nutritional research and in formulating nutritional
guidelines are
discussed.

... The analyses of Calabrese's group revealed the
uncovered biphasic
dose-response relationships to be quite common and broadly
generalizable;
that is such responses do not appear to be restricted to
biological model,
end point measured, or stressor agent, and appear to
represent a basic
feature of biological responsiveness to chemical and
physical stressors.
Furthermore, the quantitative features of the hormetic-like
dose responses
are remarkably similar with respect of response amplitude
and width, and the
relationship of the maximum response to the
'quasi-threshold' NOEL. Such
similarities across models, end points and stressor agents
suggest a similar
type of adaptive strategy possibly related to resource
allocation. In
addition, the biphasic dose-response was also found to be
more common than
other competing models, even the long-pre-eminent
toxicological threshold
model (Calabrese and Baldwin, [the free to all full text
http://tinyurl.com/mh44e and http://tinyurl.com/mwlxz ].

Hormetic dietary restriction
... (DR) ... (1) every-day caloric restriction (CR)
with the restricted
animals being typically being given 20-40% fewer calories
than the ad
libitum (AL) fed control animals, and (2) intermittent
fasting (IF) with the
restricted animals typically going a whole day without food
and then
permitted to eat AL on the following day. ... Both the CR
and IF laboratory
DR regimens provide essential nutrients and vitamins,
thereby avoiding
confounding effects of malnutrition. In fact, CR and IF
animals are almost
always healthier, sleeker, and more active than their AL
counterparts, who
tend to develop obesity in mid-life. While the CR laboratory
regimen
administered throughout life is generally more protective
than adult-onset
CR, both prevent adult-onset obesity, significantly extend
lifespan and
suppress tumorgenesis. Laboratory caloric restricted diets,
which as noted
are designed to provide adequate micronutrient coverage,
have been found to
produce reduced oxidative DNA damage (Haley-Zitlin and
Richardson, 1993).
Contrast this result with laboratory reports that
micronutrient deficiencies
produce DNA damage both through oxidative lesions and
single- and
double-strand breaks (Ames, 1998).

DR by either the CR or IF regimen can significantly
extend the life
span of rodents by some 30-40% (Mattson et al., 2002).
Life-extending CR
effects have been observed in, amongst others, protozoa,
yeast, nematode,
several insect species including fruitfly, mouse, rat,
hamster, guinea-pig,
dog, cow and in several non-human primate species. CR is a
potent and
broadly acting cancer-prevention regimen in laboratory
experimental
carcinogenic models, being effective in several species, for
a variety of
tumor types, and for spontaneous and chemically induced
neoplasias. For
example, CR inhibits spontaneous neoplasias in several
knockout and
transgenic mouse models, it suppresses the carcinogenic
action of several
classes of chemicals in rodents, and also inhibits several
forms of
radiation-induced cancer. CR in animal models also reduces
age-associated
neurodegenerative disorders, prevents age-assisted declines
in psychomotor
and spatial memory tasks, improves the brain's plasticity
and ability for
self-repair, as well as retarding age-associated
physiological deterioration
and delaying and, in some cases, preventing age-assisted
diseases. These
salutary effects have been found to arise from either CR
(i.e., energy) or
meal frequency rather than from restriction of specific
toxic dietary
contaminants or specific macro- or micronutrients (Yu,
1994). They occur
without a reduction of mass-specific metabolic rate or level
of physical
activity (Hursting et al., 2003).
Observational studies suggest that dietary restriction
has beneficial
effects on human morbidity and mortality. Participants in
the Harvard Alumni
Health Study and the Nurse's Health Study with body mass
indexes (a possible
biological marker of CR) some 15-20% below the national
average (a hallmark
of 'chronic but mild undernutrition') had reduced mortality.
Their
peripheral blood lymphocytes had higher DNA repair capacity
and exhibited no
appreciable age-dependent decline in DNA-repair potential
vis-à-vis normal
subjects (Raji et al., 1998). Moreover, physiological
changes analogous to
those observed in CR monkeys, including high-density
lipoprotein (HDL)
cholesterol increases, are reported in Muslims who fast
during the holy
month of Ramzan. Residents of Okinawa, Japan, who are known
to consume fewer
calories than residents of the main Japanese islands,
display lower death
rates from cerebrovascular disease, cancer, and heart
disease. Food
shortages in some North European countries during World War
II led to a
sharp fall in mortality from coronary artery disease
followed by sharp rise
in mortality with the war's end, although these observations
are difficult
to interpret because of confounding factors such as
malnutrition (Strom and
Jensen, 1951). There are some other more controlled human
demonstrations,
such as the Biosphere 2 studies (Verdery and Walford, 1998),
which also
suggest positive effects but which unfortunately suffer from
a dearth of
subjects and non-optimum controls. On a more encouraging
note, emerging
evidence from human population studies (as well as
laboratory experimental
data) indicate that low calorie intake can reduce risk of
Alzheimer's
disease, Parkinson's disease and stroke, three of the most
devastating
neurodegenerative conditions in the elderly (Roth et al.,
1999; Mattson et
al., 2002). In addition, some as of yet small-scale clinical
studies have
reported that long-term CR ameliorates diastolic function
and reduces
atherosclerosis (Fontana et al., 2004; Meyer et al., 2006).
Anti-aging and life-prolonging effects of laboratory
CR studies are
accompanied by stimulation of various maintenance
mechanisms, including
increased efficiency of DNA repair, increased fidelity of
genetic
information transfer, more efficient protein synthesis, more
efficient
protein degradation, more efficient cell replacement and
regeneration,
improved cellular responsiveness, as well as fortification
of the immune
system. Among the specific mechanisms proposed to account
for the antiaging
and life-prolonging actions of CR are oxidative damage
attenuation,
alteration of the glucose-insulin system and alteration of
the IGF-1, which
ubiquitously acts on tissues to regulate growth, cell death,
and development
(Hursting et al., 2003; Masoro, 2003). As an additional and
more general
explanation, Masoro (1998) has proposed hormesis as the
beneficial action(s)
resulting from the response of an organism to low-intensity
stress. In this
context, 'stress' is operationally defined as a signal
generated by a
physical or chemical factor, the stressor, which in a living
system
initiates a series of events in order to counteract, adapt
and survive. Some
moderate intensity long-term stressors have been reported to
delay aging and
prolong life and include temperature shock (heat and cold),
irradiation
(UV-, gamma- and X-rays), heavy metals, prooxidants,
alcohol, exercise, as
well as CR (Rattan, 2004). Stress exposure induces various
regulatory stress
response proteins (e.g., glucocorticoids glucose-regulated
stress proteins
and/or hsps heat shock proteins) that protect cellular
components as well as
allow a better degradation of damaged proteins during
stress. The heat shock
protein system is known to protect cells against the
damaging action of a
broad spectrum of physiological stresses in addition to heat
and CR, for
example, cold, amino acid analogues, heavy metals, free
radicals, exercise
activity, etc. (Lindquist, 1986). These stress response
proteins repair
exposure-caused cellular damages and potentially even the
damages present
before the stress, so that organisms may be in better
conditions after the
stress and live longer. Other stress response mechanisms
that have been
proposed include induction of detoxification enzymes, cell
proliferation/apoptosis, DNA repair, protein turnover and
antioxidative
response (Yu and Chung, 2001; Klaunig, 2005).

In support for the hormesis hypothesis, Masoro (2003)
has cited
findings that single-gene mutations that extend the life of
invertebrate
species also increase the ability of these organisms to cope
with damaging
agents. Recent neurodegenerative laboratory studies lend
additional strong
support to hormetic stress mechanisms (Mattson et al., 2002;
Anson et al.,
2003). It was found that stress induced by every-other-day
feeding (IF, with
the laboratory animals going a whole day without food and
then eating AL on
the next day) sometimes produced even more positive results
than CR feeding
every day. The observed reductions in neurodegenerative
disorders were
attributed to activation at the cellular and molecular
levels of hormetic
responses in which neurons increased production of
neurotropic factors and
stress proteins (specifically hsps heat shock proteins and
glucose-regulated
stress proteins). The intriguing possibility that the
beneficial effects of
IF can at least in part be dissociated from caloric intake
is further
supported by the finding that targeted deletion of the
insulin receptor in
adipose cells results in increased longevity without a
reduction in caloric
intake (Bluher et al., 2003).

... stress has been suggested as a
hormesis-inducing agent and has
been invoked to explain hormesis arising from dietary
restriction, natural
dietary pesticides and ethanol consumption. ...