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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”
lowering electron feeding of complex I by NADH. This
would in turn decrease the degree of electronic reduction
of the complex I ROS generator, and then its rate of
oxygen radical production. Indeed, DR also decreases the
NADH concentration (45, 46), a change that is known to
strongly decrease the rate of mitROSp (16). This will lead
to a further decrease in the rate of mitROSp in vivo which
would add to that due to the lowered capacity of DR
mitochondria to generate ROS detected in vitro.
Interestingly, the decrease in mitROSp in DR rats
specifically occurred at complex I in all the organs studied
(47-49). Thus, a low rate of mitROSp at complex I is a trait
both of long-lived species and of DR mammals. A recent
study showed that a single nucleotide mutation in complex
I suppresses mouse fibroblast aging (50), and inhibition of
this complex by the antihyperglycemic and proposed
antiaging modulators biguanides lowers its rate of
mitROSp (51). Many studies have shown that
mitochondrial functionality and even morphology is
detrimentally altered in tissues of old animals (52).
Recently, proteomic analysis of 57 out of the 96 known
mouse ETC proteins (and 67 % of complex I proteins),
showed that low abundance of the "matrix domain-only" of
complex I, independent from the rest of the complex,
lowers mitROSp and is related to increased longevity both
in DR and in longer-lived mouse strains, while it increases
during mouse aging (53). That is highly interesting since
we and others have located the ROS generator relevant for
aging precisely inside that matrix domain of complex I, and
likely corresponds to one of the FeS clusters of that
domain (15,18,47).
Dietary restriction, in addition to lowering mitROSp,
also decreases the FRL (Table 1). This indicates that the
efficiency of the mitochondrial respiratory chain in
avoiding ROS generation increases in DR animals. Birds
(pigeons, canaries and parakeets, Refs. 12,17) , which are
especially long-lived homeothermic animals for their body
size and metabolic rate, also show lower FRL values than
the much shorter-lived rats or mice. This suggests that a
low FRL can be a conserved mechanism of life span
extension both between and within species that can be
obtained without the need to decrease mitochondrial
oxygen consumption. That is relevant when it is necessary
to increase longevity without decreasing the general level
of animal activity and thus competitiveness in the
ecological niche. A decrease in FRL can be obtained
through qualitative changes in the redox mid point
potential of the complex I ROS generator related to aging.
This would lead to a decrease in the degree of electronic
reduction of that generator and thus in complex I mitROSp
without decreasing electron flow in the ETC and thus
mitochondrial oxygen consumption. Both a low mitROSp
and a low FRL at complex I have been reported repeatedly
at my laboratory in many different investigations in long-
lived animals (11,12,14,17,18,29,47; Table 1).
Interestingly, a recent extensive proteomic analysis of the
full ETC in mice showed that partial assembly of the
"matrix domain-only" of complex I also occurs during ad
@Real Academia Nacional de Farmacia. Spain
libitum (in addition to the whole complex I protein), but to
a much lower extent during DR (53). That can help to
explain both the decrease in mitROSp and the decrease in
FRL at complex I in DR. Moreover rapamycin, the only
drug known that consistently increases mouse longevity
(see section 7), also lowers mitROSp and FRL at complex I
and decreases the amount of its "matrix domain-only" in
the mitochondria of mouse liver (53; Table 1). It is that
matrix domain which seems to contain the subunits
responsible for the decrease in mitROSp at complex I
related to species longevity (15,16,18,29) and decreased
both by DR (44,47) and rapamycin treatment (see below).
During ad libitum feeding the extra copies of the
"matrix domain-only" complex I would take electrons
from NADH but could not pass them to ubiquinone and
the following complexes of the ETC. This would strongly
fill up that domain with electrons and would thus strongly
reduce with electrons the complex I ROS generator/s. This
would increase mitROSp at this "matrix domain-only"
complex. The result would be a strong increase in
mitROSp without any ATP generation, because electrons
in matrix domain only complex I can not reach the other
separated complexes. In this way the AL animal would
have a high FRL because it has both complete complex I
copies, plus “matrix domain-only” complex I copies that
increase mitROSp but not oxygen consumption or ETC
electron flow. In contrast, the DR and the rapamycin-
treated animals have complete fully assembled complex I
copies and reduced abundance (20-50 % decrease) of
“matrix domain-only” complex I copies. The DR mice
would thus exhibit decreases in mitROSp without
decreases in mitochondrial oxygen consumption (lower
FRL) with a normal ATP production. Therefore, a
quantitative decrease in the amount of the "matrix domain-
only" of Complex I can lead to a qualitative change
(decreased FRL) in DR and rapamycin-treated rodents.
Lowering of the mid point redox potential of the complex I
ROS generator would be another (qualitative in this case)
mechanism than can also contribute to decrease mitROSp
in long-lived animals (14,17,18,29,47).
In contrast to mitROSp, which is low both in long-
lived species and in DR rodents, a low DBI occurs in long-
lived species (see the previous section) and in 80 %
methionine restricted (MetR) rats, but not in 40 % MetR
(see section 6) or 40 % DR rats. Therefore a low DBI, like
a low mitROSp, can contribute to decrease aging rate
during evolution of long-lived animal species. But, in a
single species, the membrane needs to decrease its
sensitivity to oxidative damage by lowering fatty acid
unsaturation only when the level of protein restriction in
the available food is very strong, whereas the decrease in
mitROSp is a response already recruited at milder (40 %)
levels of DR. This makes sense, in principle, since dietary
protein availability is essential for growing of the
offspring. At 80 % MetR there is not enough protein for
adequate growing, and the competitiveness of the offspring
in the wild would be very low. Therefore it is even more
important than in 40 % DR to post-pone aging to
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