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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”
including those of mitochondria, composed of fatty acid
constituents more resistant (with less double bonds) to
ROS induced damage. Now autophagy is emerging as a
third possible aging effector. Macro-autophagy (154) can
eliminate heavily cross-linked, oxidized, and aggregated
mixtures of peroxidized lipids and proteins (155) and even
sometimes whole heavily damaged mitochondria (156).
Thus animals like us seem to age slowly at least because
they "purposely" (in evolutionary sense) produce less toxic
substances (ROS) per unit time, their membrane fatty acids
are more resistant to them, and most of the still remaining
molecular damage is eliminated by the macro-
autophagocytosis machinery. This shows the strong
interrelationship between the three aging effectors. The
materials that can not be digested and eliminated by
autophagy accumulate in the cytosol as lipofuscin
granules, the best known marker of aging at tissue level.
Many different mutant mice with single autophagy
genes knocked out have a decreased life span (reviewed in
154). However, we still lack rigorous evidence that over-
expression of macro-autophagy genes increases longevity.
The same problem affects DBI except for successful
knocking out of desaturase/elongase genes that increased
longevity in C. elegans nematodes. It is known, hoever,
that mitROSp at complex I, consistently decreases in all
the four known experimental manipulations that increase
mammalian longevity: DR, PR, MetR, and rapamycin
feeding. Some positive evidence suggesting that
increasing autophagy increases longevity has been
published, although it was limited to a short-lived mice
strain in which overexpression of the essential
autophagosomal protein ATG5 increased maximum
lifespan from only 781 to 900 days (157). In contrast, in
the first three experiments taken together in which
rapamycin increased longevity the control mice of both
sexes reached 1,086 days and the rapamycin treated ones
reached 1,212 days of age at 90 % mortality (121), a
capacity surpassed by MetR and DR.
The husbandry conditions and the strain used clearly
affect the longevity attained by the animals in aging
experiments. Further aging experiments using longer lived
control mice, approaching 1,000-1,200 days at least, are
needed to identify other drugs that could increase
longevity. It is necessary to use long-lived instead of short- century of intensive gerontological research, ROS continue
lived strains as controls, and to implement husbandry
conditions that maximize longevity and produce more
rectangular and smooth survival curves.
Another key requisite for acceptation of any theory of
aging is that it must be able to explain why different
animals age at so different rates. It is still unknown
whether autophagy is higher or not in tissues of long-lived
animals compared to those of short-lived ones. However,
telomere length is higher in mice than in men, the opposite
of what is expected if telomere shortening were another
causal factor involved in aging. Consistent and
reproducible evidence concerning these aspects is urgently
needed before definitively considering macro-autophagy a
third aging effector. In addition, when those comparative
@Real Academia Nacional de Farmacia. Spain
studies are performed, care must be taken not to correct
the real values by body size because this will erase most of
the real causes of aging responsible for the correlations
between the studied hypothetical mechanism of aging and
longevity. If the authors of a study still doubt whether to
correct or not correct for body size, the best option would
be to show in the publications the correlations with
longevity for both the corrected and the non corrected
values. That is most important. Otherwise, the high
potential of comparative gerontology to facilitate the cheap
and fast possible identification or elimination of
hypothetical causes of aging will be almost fully erased,
which will be a too great loss for gerontology.
Although correlation does not imply causality, the
central parameters of any valid theory of aging must
correlate with the longevity of different species in the right
sense. Thus, mitROSp is low in tissues of long-lived
mammals and birds, which fully fits with the modern
version of MFRTA. On the contrary, antioxidant enzymes
also correlate with longevity but in the wrong sense: they
are up to more than one order of magnitude lower (instead
of higher) in long-lived than in short-lived mammals or
vertebrates (7). The same is true for the repair of DNA
damage of endogenous origin (reviewed in 29, section
3E1). Therefore, both defence (antioxidants) and DNA
repair are discarded as causes of aging. High
"maintenance" of the animal (leading to high longevity) is
not due to defence plus repair contrarily to what the three
mainstream evolutionary theories of aging (mutation
accumulation, antagonist pleiotropy, and disposable soma
theory) wrongly predicted. On the contrary high
maintenance is due to a low rate of generation of
endogenous damage (low mitROSp and low DBI) and,
likely, also to a high rate of elimination of damaged
components (high autophagy). MitROSp and autophagy
are strongly complementary mechanisms, helped also by a
third factor: high resistance of tissue cellular membranes
to lipid peroxidation obtained through a low DBI and PI.
In short, longevity is obtained through a low rate of
production of "damage" (mitROS,), a high rate of
cleaning their consequences (high autophagy), and a
high constitutive resistance to oxidative modification
(e.g., low DBI). The identification of the rate of mitROSp
with the concept of "rate of generation of endogenous
damage" comes from the fact that, after more than one
to be the only know highly damaging substances
endogenously produced by the healthy animal organism
throughout their lives that have the capacity to break
covalent bonds. If any other different family of substances
having that property is discovered in the future, it could be
tested to be added or not to the list of aging effectors.
Meanwhile mitROS continue to be the only toxic highly
damaging substances that the body "purposely" produces
to cause and increase its aging rate.
The Pre-nuclear Signals, the PAP, and the Aging
Effectors, are integrated working together to constitute the
CARS. Therefore, it is illogic to consider MFRTA
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