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incorrect while believing at the same time that proteins
like mTOR, AMPK or S6K, et cetera, control longevity.
Looking at Figure 8 it is evident that the three parts of the
CARS work together in a highly integrated manner to
determine species longevity.
On the other hand, it is logical to suspect that the same
gene clusters of aging central to the PAP and reacting to
the DRs or rapamycin, plus others additional ones, are also
involved in the control of longevity between different
species. It is already known that different genes can
change their expression at different tissues in response to
the different kinds of dietary restrictions (DR, PR, MetR,
or IF-intermittent feeding) or pro-longevity drugs. These
responses include both quantitative and qualitative
changes concerning the genes involved in each case as
well as their levels of gene expression. The same is
expected between species with much bigger differences in
longevity than in the DRs. Between species, the same
genes involved in response to the DRs would be involved,
plus additional inter-species genes. The degree of
expression of the longevity genes involved is expected to
vary more intensely in different species than in the DRs.
Since the number of genes involved in the response to DR
is already large (up to 1.000) in relation to the total
structural genes (around 20.000 genes), it would be a
prohibited luxury for evolution to use totally different
genes to control aging rate in the case of the different
species than in the DRs. Instead, the same genes would be
used, plus additional inter-specific ones. One well known
example is the case of oxidative stress. While both
mitROSp and cell membrane DBI (global fatty acid
unsaturation) varies between species, in the case of (40 %)
DR and (40 %) MetR mitROSp at complex I is decreased
while the DBI does not change (see section 5). However,
at 80 % MetR, the DBI is also lowered (97). Thus, the
implication of a given effector in a response depends on
whether: a) the longevity difference occurs at the
individual or at the species level; and b) the intensity of the strict proportion to the amount of calories eaten. If this
signal reaching the PAP. In addition, there can be also
inter-individual differences involved. Transcriptions
factors like FOXO1 reacting to DR show polymorphisms
in relation to differences in longevity in human
populations (158).
Although a large part of the change in aging rate is
controlled by the flow of information through the PAP in
the nucleus, at least in the case of mitochondria part of the
control can directly flow from the dietary substances and
derived substrates to modify mitROSp bypassing the PAP.
This occurs in DR, that decreases metabolites like
pyruvate and others, which in turn lower matrix NADH
and then mitROSp at complex I (Figure 8 top). Or the case
of MetR, in which direct control of mitROSp by post-
translational modification of complex I could occur.
Reaction with complex I thiol cysteine groups could
decrease the degree of electronic reduction of the complex
I ROS generator - like the lowered NADH in DR- and then
its rate of mitROSp (159). On the other hand, components
of CARS are interrelated in more complex ways than
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Gustavo Barja de Quiroga
delineated in Figure 8. Thus, the mitochondrial uncoupler
2,4-dinitrophenol lowers mitROSp, which is expected
since it accelerates electron flow at ETC, like during the
state 4 (without ADP) to state 3 (with ADP) energy
transition. However, it also lowers mTOR activity and
insulin-PI3K-MAPK signaling, and increases autophagy
(160).
Another example is the recent description that lowering
mitROSp decreases the amount of damaged mitochondria
and the cellular level of lipofuscin (161), again relating
two main cellular effectors of longevity of post-mitotic
cells, mitochondria and autophagy. Mitochondria have
been repeatedly observed half digested inside secondary
lysosomes under the electron microscope, these vesicles
contributing afterwards to form lipofuscin granules
Strikingly, many genes controlling autophagy are the same
involved in the increase in longevity induced by lowering
mitochondrial respiration (154).
9.2. Intermittent food restriction (IF): is the Aging
Program functioning gradual or not?
It would be most interesting to know whether the PAP
works in a graded form in response to DR or like an ON-
OFF switch. The last possibility is supported by the fact
that DR can also be performed by intermittent fasting (IF)
instead of decreasing the calories or methionine eaten per
day by the DR animals. It is known that IF rodents
increase longevity even in strains that gorge the days that
they receive food. In this last case, even though the total
number of calories eaten is roughly the same in the IF
animals and the controls, longevity still increases in IF.
This apparently paradoxical result would be explained if
the PAP genes react to DR (Figure 8), at least to a certain
extent, in an ON-OFF fashion, instead of responding in
were the case, when the animal eats a certain amount of
food and a threshold of calories is reached, the PAP would
increase its activity output (increase its aging effectors)
from a low (called “OFF” for simplicity) to a higher
(“ON”) level, irrespective of the amount of calories eaten
above the threshold. The PAP will never be at zero activity
in mammals because a minimum activity (here called
“OFF”) is needed to give a PAP output that generates the
mean rate of aging of each species. This “OFF” aging rate
would be maintained when there is no food available.
Shortly after eating, food is digested and absorbed and
tissue PAP activity would jump in a qualitative leap to the
“ON” higher output level. When the animal reaches the
postprandial state and the substrates ingested have been
fully metabolized, PAP activity will go back to the lower
"OFF" resting level of aging effector (PAP output)
activity.
Further research is sorely needed to clarify whether the
PAP output is graded or “all-or-none”, because this could
have important implications concerning which is the
healthiest way of eating to be recommended for human
beings. If PAP works qualitatively (ON/OFF) rather than
gradually, the classical recommendation of the last decade,
eating 5 times per day, would not be the best. On the
@Real Academia Nacional de Farmacia. Spain