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8, sections 7-9).
Concerning mechanism “iii”), decreased NADH, it is
more likely in DR than in MetR, due to the decreased
ingestion of a large number of metabolites in DR than in
(isocaloric) MetR. Substrates like pyruvate, malate, and
succinate, as well as NADH and the NADH/NAD+ ratio
are indeed decreased in the tissues of rodents subjected to
DR (45, 46). This will decrease matrix NADH and
NADH/NAD+ ratio, and therefore the degree of electronic
reduction of the complex I ROS generator and its rate of
mitROSp (see section 5). Treatment with a precursor of the
oxidized form of the coenzyme, NAD+, also rejuvenates
the skeletal muscle, improves mitochondrial and stem cell
function in aged mice, and increases their lifespan (117).
This could be due to a decrease in complex I electronic
reduction, or to a sirtuin-dependent effect.
In summary, DR, PR and MetR are nutritional
interventions that increase longevity in rodents, although
the magnitude of the longevity extension of MetR and PR
is around 50 % that of DR. This lower -but significant- life
extension effect in MetR than in DR would agree with the
notion that various different environmental signals target
the cell to modify its aging rate. Restriction of methionine
intake can be responsible for part of the aging-delaying
effects of DR by decreasing mitROSp at complex I and
oxidative damage to mtDNA and macromolecules acting,
at least in this sense, as a “DR-mimic”. The information
available strongly indicates that methionine is the single
dietary substance responsible for the beneficial changes of
DR on mitochondrial oxidative stress. The remaining
effects of DR on aging rate could be due to decreases in
other dietary components, or in the calories themselves,
acting through different additional signaling mechanisms
(Figure 4) that could recruit different gene clusters of the
aging program in the cell nucleus (see section 9), changing
their gene expression levels with different intensities (see
section 9). Among those additional longevity-extending
mechanisms during DR, increased autophagy is emerging
as most important. In any case, it is interesting that not
only 80 % MetR, but also 40 % MetR and 40 % PR
decrease mitochondrial oxidative stress, because PR does
not involve the stronger behavioral and nutritional stress of mixed age mice (123). Therefore, rapamycin is widely
caloric restriction and therefore seems a much more
feasible option for wide application to human populations.
Negative effects such as delays in puberty and decreases in
growth rate and final body size are shared by (40 %) DR
and 80 % MetR but do not occur at 40 % MetR. 40 %
methionine restriction (implemented through PR) could be
the best kind of dietary restriction for humans because it
lowers mitROSp and 8-oxodG in mtDNA to a similar
extent than 80 % MetR, without decreasing at all body and
organ weight, growth rate, maturation, and likely final
body size, at variance with what occurs in 80 % MetR and
40 % DR.
Humans can obtain health benefits consuming
“prudent” diets based on the intake of vegetables
containing proteins rich in essential amino acids but low in
the sulphur-containing amino acids methionine and
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Gustavo Barja de Quiroga
cysteine (like pulses), or almost totally lacking methionine
and cysteine (like many fruits and other vegetables), and
avoiding the presently excessive intake of animal proteins
and fats typical of western diets. The results already
available after many years of PR intervention in humans
seem to be positive for human health and of similar
character than those found in MetR and DR rats (118).
These studies also suggest that DR and PR can protect
from obesity, mortality, and degenerative diseases
including at least cardiovascular ones, diabetes and cancer,
and can increase the human healthspan.
7. RAPAMYCIN, MITOCHONDRIAL OXIDATIVE
STRESS, AND LONGEVITY
Although it is well known that DR increases longevity
in many different animals including mammals, and
seemingly also in monkeys (41), it is difficult to apply to
large human populations due to subnutrition risks
especially in children, very old people, individuals with
limited cultural knowledge and education, and those with
some chronic pathologies. Due to this, there is strong
interest in developing drugs than can increase longevity
without the need to restrict the human diet (119, 120). The
USA National Institute of Aging Interventions Testing
Program (ITP) evaluates the effects of different candidate
molecules to be candidate antiaging drugs in mice
(http://www.nia.nih.gov/research/dab/interventions-
testing-program-itp/compounds-testing). These include
known drugs, antidiabetics, antibiotics and others, like
aspirin, resveratrol, simvastatin or metformin. While the
rest of studied compounds have not shown reproducible
positive effects on longevity (119), rapamycin
significantly increased both mean lifespan, as well as
maximum lifespan (at age of 90 % mortality, mean of the
three sites) by 9 % in males and by 14 % in females in
heterogeneous strains of mice (121). That experiment was
reproduced under the NIA ITP at three different sites.
Posterior studies have confirmed those results and have
shown that dietary rapamycin extends lifespan when
initiated in young (119) or middle aged mice (122), or in
recognized as the first drug known that consistently
increases longevity in mammals. Rapamycin also increase
longevity in yeast (124), C. elegans (125) and Drosophila
(126) through inhibition of the TOR protein complex,
equivalent to mTOR (mammalian target of rapamycin).
This indicates that this longevity pathway is highly
conserved in evolution. The mTOR complex also shows
signs of rapid evolution in amniotes and signs of positive
selection (127).
Although it is clear that rapamycin increases
mammalian longevity, the final effector mechanisms
involved were unknown, although decreases in
mitochondrial damage, increases in autophagy, or
modifications in cell growth/proliferation could be
implicated. Rapamycin also inhibits the mTOR signaling
pathway in mammals (128). Interestingly, the longevity
extending nutritional intervention DR also decreases
@Real Academia Nacional de Farmacia. Spain