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(The following
is an invited discussion piece submitted by Dr.
Edrward J. Masoro. Commentaries on this piece are invited
from all readers of this Newsletter for
publication in the next issue.
Submit comments to nico@worldeventsforum.com.)
The Basis of Food Restriction-Induced
Life Extension:
A Contentious Subject
Edward J.
Masoro
 Dr.
Masoro
is Professor Emeritus in the
Department of Physiology at the
University of Texas Health Science
Center at San Antonio (UTHSCSA) where
from September of 1973 though May of
1991 he served as Chairman. He was the
founding Director of the Aging Research
and Education Center of UTHSCSA, which
as of 2004 became the Barshop Institute
of Longevity and Aging Studies. He now
serves as a member of that institute. He
was the recipient of the 1989
Allied-Signal Achievement Award in Aging
Research. In 1990, he received a
Geriatric Leadership Academic Award from
the National Institute on Aging (NIA)
and the Robert W. Kleemeier Award from
the Gerontological Society of America.
In 1991, he received a medal of honor
from the University of Pisa for
Achievements in Gerontology, and in
1993, the Distinguished Service Award
from the Association of Chairmen of
Departments of Physiology. In addition,
he received the 1995 Irving Wright Award
of Distinction of the American
Federation for Aging Research and the
1995 Glenn Foundation Award. He has
served as President of the
Gerontological Society of America,
President of the Association of Chairmen
of Departments of Physiology, Chairman
of the Aging Review Committee of the
NIA, and Chairman of the Board of
Scientific Counselors of the NIA. Dr.
Masoro has held faculty positions at
Queen’s University (Canada), Tufts
University School of Medicine,
University of Washington, and Medical
College of Pennsylvania. Since 1975, his
research has focused on the influence of
food restriction on aging. He has served
or is serving in an editorial role for
10 journals and from January 1992
through December 1995, he was the Editor
of the
Journal of
Gerontology: Biological Sciences.
When I first started
to work on food restriction and aging in
the mid-1970s, I was under the mistaken
impression that its life-extending and
anti-aging actions were due to an
attenuated fasting state. I find that
many investigators still hold to this
belief today. Indeed, it wasn’t until
our group began to analyze our first
study that I realized this view was not
valid, at least for the rats we were
studying. We found that rats on a 40%
reduction of food intake starting at 6
weeks of age had a caloric intake per
gram of body weight below that of the
ad libitum--fed animals that lasted
for only a week or so; for the rest of
life, it was slightly greater than that
of the ad libitum-fed group
(1). In that study, the food
restriction regime markedly extended
life: the age of the 10th
percentile survivors increased from 797
days for the ad libitum-fed group
to 1,236 days for the food-restricted
group (2). In addition, for most of
their long lives, the restricted rats
exhibited a gradual increase in body
mass involving both the fat mass and
lean mass (2,3). Thus, unlike the
fasting state in which a negative energy
balance drives the metabolic processes,
our food-restricted rats were in a
positive energy balance. Moreover, we
found that food restriction had its
major life-extension impact during the
positive caloric balance portion of life
(4).
In that first study,
both the food-restricted and the ad
libitum-fed rats received a diet in
which 60% of the calories were from
carbohydrate, 20% from fat, and 20% from
protein (2). Based on respiratory
quotient findings, the fuel mix utilized
by both the food-restricted and ad
libitum-fed rats during most of life
span was the same as that eaten (5, 6).
In contrast, when animals are fasted,
there is at first a rapid depletion of
glycogen stores and then body fat and to
a lesser extent protein are the major
energy sources utilized.
In the recent
literature, it has been frequently
suggested that alterations in fat
metabolism during food restriction
underlie its life-prolonging action.
Most of these suggestions are based on
the view that food restriction has
metabolic effects similar to fasting.
For instance, several investigators have
suggested that food restriction
increases the length of life by
increasing the use of fat relative to
other fuels. Clearly that was not the
case during most of the life span of the
rats in our studies. It has also been
claimed that food restriction increases
longevity by affecting fatty acid
biosynthesis; this is an unlikely
possibility in our studies because fatty
acid biosynthesis is a minor metabolic
pathway in rats fed diets in which fat
accounts for 20% of the energy intake
(7). Still others relate the increased
longevity to the decrease in the intake
of dietary fat. We found that decreasing
fat intake by 40% without reducing total
energy intake had no effect on the
longevity of the rats (8). It has also
been suggested that food
restriction-induced reduction in body
fat content underlies its
life-prolonging action. This suggestion
ignores our rat study (3) and the mouse
study of Dave Harrison’s group (9); both
studies dissociate the effects of food
restriction on longevity from its
effects on body fat content.
Clearly, many
of these suggestions are based on the
false premise that the metabolic
characteristics of food restriction are
similar to those of the fasting state.
Many hold this misconception because
they have not adequately reviewed the
literature, particularly papers that are
not available on-line. Also, many
investigators make such claims without
measuring the process that is the basis
of their suggestions. Thus, rather than
measuring the rate of fatty acid
oxidation or fatty acid biosynthesis,
what is measured is either the mRNA
level or the protein level or both of an
enzyme or transcription factor involved
in the process and then making claims
about the entire process from these
fragmentary data.
It has recently
been suggested that decreased intake of
a specific nutrient, such as protein,
rather than total calories may be the
basis of the life-extending action of
food restriction (10). Support for this
view comes from the finding that diets
with a markedly reduced methionine
content extend the life span of rats
(11) and mice (12). This view ignores
our study showing that reduction of
energy intake by 40% is as effective in
extending life whether or not the intake
of methionine and protein are also
reduced by 40% (13). Moreover, the
marked restriction of only one of the
essential amino acids is likely to
distort protein metabolism and thereby
stress the organism. The intensity of
the stress will vary from low to high,
depending on the level of the imbalance.
As will be discussed below, if the
stressor intensity is low, it may well
extend life via a hormetic action; if
the intensity is high, it will decrease
the length of life. The findings on mice
by Miller et al (12), mentioned above,
are consistent with methionine-restriction
having such actions. The marked
restriction of another essential amino
acid, tryptophan, also increases the
longevity of rats (14), a finding in
accord with this view.
In addition to
mechanisms based on the belief that food
restriction extends life by inducing an
attenuated fasting state, many other
mechanisms have been proposed in the
more than 70 years since McCay et al
(15) reported their findings. Suggested
mechanisms include the following:
retardation of growth and development,
decreased metabolic rate, decreased body
temperature, increased physical
activity, enhanced apoptosis, attenuated
apoptosis, increased protein turnover,
decreased oxidative stress, attenuated
glycation and glycoxidation, decreased
insulin-like signaling, and others.
Indeed, it is likely that many of these
hypotheses have identified processes
that are frequently, if not invariably,
involved in the life-prolonging action
of food restriction. What is needed is
an overall hypothesis that embraces the
many frequently and/or invariably
involved components of the
life-prolonging action of food
restriction.
The hormesis
hypothesis, which was independently
proposed by me (16) and by Turturro and
colleagues (17) in 1998, provides such a
unifying concept. Hormesis refers to
phenomena in which the response of an
organism to a chemical or physical agent
is qualitatively different when the
agent is of high intensity than when it
is of low intensity. Within the province
of toxicology, hormesis has come to mean
the beneficial action of a substance at
a low concentration that is toxic at
higher concentrations. Rattan (18) has
further modified the definition for use
in biological gerontology: hormesis
in aging is characterized by the
beneficial effects resulting from the
cellular responses to mild repeated
stress. He further proposes that the
concept of hormesis as an aging
retardant is based on the principle that
repeated exposure to mild stress
stimulates maintenance and repair
processes (19).
Is there reason
to believe that the level of food
restriction that induces life extension
has a hormetic action? The answer is
yes. First, the level of food
restriction that extends life is a
low-intensity stressor. It is generally
accepted that an elevated level of
plasma glucocorticoids is a marker of
stress in mammalian organisms (20).
Sabatino et al (21) found that food
restriction causes a lifelong, modest
daily elevation in the peak afternoon
concentration of plasma free
corticosterone; in contrast, restraint
stress, a high intensity stressor,
causes a marked elevation. These
findings provide strong evidence that
food restriction is a low-intensity
stressor. The second issue is whether
this level of food restriction also has
a hormetic action. Again, the answer is
yes. Food restriction increases the
ability of rats and mice to cope with
intense stressors, such as surgery (16),
inflammatory agents (22), heat stress
(23), and toxic chemicals (24).
Many
biogerontologists, myself included,
believe aging results from the long-term
action of endogenous and environmental
damaging agents. If this view is valid,
then it is to be expected that the
hormetic action of food restriction
should slow aging and thereby extend
life. And there is, indeed, abundant
evidence that food restriction both
enhances protective processes (e.g., the
heat shock protein response to damage)
and up-regulates repair processes such
as enhanced DNA repair and increased
protein turnover (25).
Although there
is much evidence in support of the view
that hormesis plays an important role in
food restriction-induced life extension,
many issues still need to be addressed.
A major unanswered question is the
pathway that links the long-term
restriction of food intake to the
hormetic effectors (i.e., the enzymes
that inactivate damaging agents,
proteins with protective functions, and
molecular repair processes). In 2000,
Guarente’s group reported that SIR2, a
sirtuin protein, is required for caloric
restriction-induced replicative life
extension in the yeast species, S.
cerevisiae (26). Sinclair’s group
extended this line of investigation and
appeared to have made great progress in
describing the pathway that links
caloric restriction and other low
intensity stressors to SIR2 in this
yeast species (27). In addition, reports
that sirtuin proteins are components of
the food-restriction-induced life
extension in C. elegans (28) and
D. melanogaster (29) provide
further support for a likely key role of
these proteins in all species that
exhibit this life-extending phenomenon.
However, the Kennedy group (30) has
challenged this view for S.
cerevisiae; they have shifted the
focus to a decrease in the activity of
nutrient-responsive kinases Sch9 and TOR.
Thus, in the case of yeast, the pathway
linking the low-intensity stressor
action of energy restriction to
replicative life extension is currently
in debate. In addition, recently
reported research indicates that sirtuin
proteins may not be involved in food
restriction-induced life extension in
C. elegans (31). Thus, at this time,
whether sirtuin proteins are components
of the caloric restriction hormetic
pathway is an open question.
It is also an
open question whether the daily
elevation in the peak concentration of
plasma free corticosterone induced in
rodents by food restriction plays a role
in the life-prolongation or merely
serves as a marker for a daily repeated
low-intensity stressor. Some support for
the former comes from the fact that
there is abundant evidence for
glucocortoids playing an important role
in enhancing the ability of mammals to
cope with stressors (20). Thus, the
daily elevation of the plasma free
corticosterone level is probably an
important component of the hormetic
action of food restriction.
The signal that
links the decreased availability and/or
intake of food to the hormetic pathway
is also a perplexing problem. During the
initial phase of food restriction, the
occurrence of a negative energy balance
could well result in a hormetic response
or a specific nutrient-deprivation
response (e.g., response of the TOR
pathway) or both. However, as food
restriction continues, the animals are
no longer in a negative energy balance;
rather, they are in a positive energy
balance for the major part of their
life. During this long and important
phase of food restriction’s
life-prolonging action, what is
signaling the adrenal cortical system or
a specific nutrient-deprivation
response? The study of Anson et al (32)
suggests that rather than reduced energy
intake, intervals of fasting resulting
from the periodic availability of food
is the signal. This is an interesting
but unlikely possibility; we found that
providing food-restricted rats their
daily food allotment in one feeding at
1500h or in two feedings at 0700h and
1500h did not affect the magnitude of
life extension or the retardation of
age-associated diseases (33). Moreover,
rats fed ad libitum eat primarily
during the dark phase of the light
cycle. The concept of molecular
hysteresis, proposed by Mobbs et al
(34), is another possibility that
warrants further study. However, it is
hard to believe that a signal initiated
during the brief period of negative
energy balance following the beginning
of food restriction can, through
molecular hysteresis, last a lifetime.
Recently, Libert et al (35) reported
that an olfactory signal plays a role in
food restriction-induced life extension
in Drosophila melanogaster. A
role for olfaction in the response of
rodents to food restriction has yet to
be demonstrated. In my opinion, it is
unlikely to play a role for the
following reason. In our rat studies,
semi-synthetic diets were the food
source. The components of the diet were
individually decreased or increased.
Also, the source of protein was changed
from casein to soy protein. Through all
of these alterations in dietary
composition, life extension continued to
relate primarily to the reduced intake
of energy per rat.
Although food
restriction has been found to extend the
life of a spectrum of species, ranging
from yeast to mammals (36), the question
of whether the same mechanisms are
involved has yet to be adequately
addressed. Indeed, it is not even clear
whether the mechanisms are always the
same within the same species. In some
mouse studies, food restriction extends
life by slowing the age-associated
exponential increase in population
mortality. In other mouse studies, it
acts by delaying the age at which this
increase begins, but does not affect it
once underway (37). Can these two very
different patterns of mortality result
from the same mechanisms?
Do other dietary
manipulations that extend life utilize
the same mechanisms as food restriction?
Returning to life extension due to the
marked reduction in dietary methionine,
it is likely that this results from the
stressor effect of an imbalanced intake
of essential amino acids; i.e., at
certain levels, this imbalance acts as a
low intensity stressor and thus has a
hormetic action. Indeed, there may well
be additional nutritional conditions
that extend life because of a hormetic
action. In fact, several low intensity
stressors other than diet have been
found to extend the life of some
invertebrate species (38). However, it
is an open question whether the hormetic
pathway used in response to methionine
deficiency or other low intensity
stressors is the same as that occurring
in response to food restriction.
Moreover, it is
likely that hormesis is not the sole
basis of life extension induced by food
restriction. Indeed, only the enhanced
protective and repair processes are
within the scope of hormesis. In
addition, there is evidence that food
restriction decreases the generation of
harmful agents. For example,
mitochondria isolated from
food-restricted rodents exhibit a
decreased generation of reactive oxygen
molecules (39). However, Brian Merry
(40) points out that caution is required
in regard to the ability of food
restriction to decrease organismic
reactive oxygen molecule formation since
this has not yet been shown in the
intact organism. Thus, although it is
likely that food restriction decreases
the intensity of damaging processes,
such as oxidation and glycation, further
research is needed to establish the
quantitative role of this action in
regard to life extension.
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