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Gustavo Barja de Quiroga
Figure 1. Production of ROS at mitochondria (A) negatively correlates with longevity across animal species. Evolutionarily, this is
the cause of the very low endogenous antioxidant (including antioxidant enzymes) levels of long-lived animal species (B). In addition, it
nowadays mechanistically causes the low level of mtDNA oxidative damage of long-lived animals (C). (Refs. 7,20,23,29).
All those data, coming from various different sources species.
consistently agreed: the longer the longevity, the lower
were the levels of most endogenous tissue antioxidants and 3. MITOCHONDRIAL ROS GENERATION, mtDNA
antioxidant enzymes. A later reappraisal of the subject (8) OXIDATIVE DAMAGE, AND LONGEVITY
confirmed the existence of a generally negative correlation
between tissue antioxidants and longevity in all kinds of 3.1. Comparative studies of mitROSp
vertebrate animals (Figure 1A). It was most interesting that
long-lived animals had lower instead of higher antioxidant Why long-lived animals need less antioxidant levels in
levels. Among 27 studied correlations, 21 negatively their vital organs? We proposed (10) that the rate of
correlated with longevity, six did not show significant mitROSp could be negatively correlated with longevity and
differences, and not a single positive correlation with that this would be the critical factor for aging, instead of
longevity was found (7). Superoxide dismutase was among the antioxidants. Long-lived animals would not need to
the antioxidants tending to show no association with maintain high antioxidant enzyme levels, which is
longevity. Previous believe that this enzymatic activity energetically expensive, because they would produce
was positively associated with longevity was due to mtROS at a low pace, and they could transitorily induce
referring the SOD activity values (total SOD, CuZn plus them if needed. This was indeed experimentally
Mn) to the oxygen consumption (VO2) of the whole corroborated comparing mammalian species with different
animal (to the weight-specific metabolic rate). Since longevities (3) (Figure 1B) as well as comparing short-
weight-specific metabolic rate strongly decreases as body lived rodents (rats and mice) with 8 fold longer lived birds
size increases, the larger SOD/VO2 of humans compared to (pigeons, parakeets and canaries) of similar body size and
rats was due to the lower value of the denominator in the weight-specific metabolic rate (11, 12). A posterior
humans (lower weight-specific metabolic rate than rats) investigation studying up to 12 different mammalian
instead of to a higher value of the numerator (SOD). In species confirmed these findings even after correcting for
fact when the tissue SOD values (total SOD, CuZn plus body size (4).
Mn, without dividing by VO2) were plotted against
longevity across species they showed no significant The studies in birds are especially important because
correlation with mammalian longevity in mammals in the the studies performed in mammals used species following
original publication (9). In the brain and lung of vertebrate the Pearl rate of living law of aging: “the lower the weight-
species –but not in liver- the correlation between SOD specific metabolic rate the longer the longevity”. Thus, one
(total SOD, CuZn plus Mn) and longevity was again could not discard, in principle, the possibility that the
negative like for the other antioxidants. Further studies in species with longer longevity included in the comparisons
different mammals including long-lived naked mole-rats, between different mammals could show low rates of
as well as ants, honey bees and marine bivalves also found mitROSp simply because their rates of oxygen
a negative correlation with longevity for this antioxidant consumption were also lower than those of the short-lived
enzyme –SOD (8). In this more recent and comprehensive ones. In fact mitROSp was positively correlated with
review of the subject, among a total of 78 correlations mitochondrial O2 consumption and with global metabolic
between endogenous tissue antioxidants and longevity, 72 rate in those studies (3). It was then important to study the
were negative, six did not show significant differences, problem in some of the many species that deviate from the
and only a single one was positive (8), corroborating Pearl´s rate of living law (an old theory of aging ruled out
global studies performed almost two decades ago (7). long ago). Three groups of warm-blooded vertebrates have
Therefore endogenous antioxidant levels are clearly not much higher longevity than expected for their body size or
the cause of the high longevity of long-lived animal weight-specific metabolic rate compared to most
mammals: birds, bats and primates. Birds have both a
high rate of oxygen consumption per gram of tissue and a
50 @Real Academia Nacional de Farmacia. Spain
