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This would explain why lowering the rate of mitROSp Gustavo Barja de Quiroga
instead of increasing antioxidants was selected for during
the evolution of longevity in mammals, birds, and other Mitochondria can vary the percentage free radical leak
species. And it would be consistent with the view that (FRL = % mitROSp/mitO2 consumption) in the respiratory
mitochondria are causal players in the aging process. chain. They decrease such percentage (the FRL) in
Contact between mtDNA and specific mitochondrial especially long-lived animals, like birds or dietary
proteins agrees with classic electron microscopic studies restricted rats. They lower the FRL to decrease mitROSp
(33). Mitochondrial nucleoid structure has been long (to age slowly), while their mitochondrial oxygen
debated, with an estimation of about 2-10 mtDNA consumption is not depressed to be able to continue
molecules coated by an unspecified number of proteins mitochondrial ATP generation at the rates needed for the
(34). However, using high-resolution microscopy, the normal activity level of the animal. If ROS leakage were
structure of the nucleoids has been further clarified as an "unavoidable by-product" of the mitochondrial electron
single mtDNA circular molecules compacted by transport chain, the FRL would be a rather constant % of
mitochondrial transcription factor A (TFAM, 35), which electron flux at the ETC. Instead, the FRL is decreased
forces mtDNA to undergo a U-turn, thus collapsing the especially long-lived animals like birds, that live 2-3 fold
mtDNA molecule. longer than mammals of the same body size and specific
metabolic rate. Contrarily to the "by-product" unproven
3.6. Low mitROSp, and then low endogenous antioxidant heavily repeated assumption, mitROSp is finely tuned
defences and DNA repair, in long-lived animals (regulated) in each animal, and if necessary, it varies
independently of the rate of mitochondrial oxygen
In order to decrease damage to mtDNA it is much more consumption and the total rate of electron flow at the ETC.
efficient to lower the rate of generation of damage than to Thus, the FRL varies in many cases to contribute to
have a higher rate of generation of damage and, determine the aging rate and the longevity of the species
afterwards, try to intercept the generated ROS using (birds), or the individual (during the DRs). The lazy
antioxidants, or try to repair the damaged already inflicted assumption currently present in too many scientific articles
on mtDNA. This last approach would not make sense if that mitROS are "unavoidable by-products of the ETC"
generation of damage can be controlled on the first place. should be avoided because the measurements on functional
This is why long-lived species have not used high isolated mitochondria data have demonstrated it to be false
(antioxidant) defence (7,8,10,11,23,24,29,32) or high on too many occasions. The use of this "by-product"
repair of endogenous DNA damage (reviewed in 29) to concept should be exclusively limited to particular
increase longevity. In addition, it would be very costly to situations on which it is known to be correct, but not as a
continuously maintain high levels of antioxidant or repair generalization for every situation. This is important
enzymes in long-lived mammals to counteract a high rate because this wrong concept is making enormous damage
of damage generation. Instead, lowering mitROSp: i) is to the scientific gerontological advance concerning
much easier; ii) is 100 % efficient; and iii) avoids much MFRTA, and therefore towards solving the aging problem.
damage at around zero cost. This view is fully consistent
with the idea that aging is generated (evolutionarily 4. LONGEVITY AND MEMBRANE FATTY ACID
speaking) "on purpose" by the organism itself, that aging UNSATURATION
has an adaptive value, likely for the group (2), and
possibly to speed up evolutionary pace because it increases In addition to mitROSp, there is a second known
diversity and thus evolvability (2). This is why it has been parameter that also correlates with longevity in the right
selected for during evolution and programmed in the sense, the fatty acid unsaturation degree of tissue cellular
genotype to be expressed at widely different rates in (including mitochondrial) membranes. This is also well
agreement with the fecundity, population size, and many known since it has been studied many times in more than
other traits of each particular species on its ecological 20 well controlled different investigations and concordant
niche (see section 9.2). The association between fecundity results were always obtained. The degree of fatty acid
and longevity is not physiological, as the Disposable Soma unsaturation can be summarized as the double bond index
Theory of aging assumes without evidence and lacking any (DBI), or alternatively, as the peroxidizability index (PI).
physiologically plausible mechanism that could support it, The longer the longevity of the species, the smaller the
but genetic. Because fecundity must be necessarily linked total number of tissue fatty acid double bonds (the smaller
to longevity in the cell Aging Program (see section 9), the DBI, Figure 3A, and PI). A constitutively low DBI
otherwise population size would oscillate too much strongly decreases the sensitivity of the cellular and
endangering the survival of the group. mitochondrial membranes to lipid peroxidation, a highly
destructive process. Lipid peroxidation, in addition to
3.7. FRL is not a constant percent, and mitROS are not membrane damage, produces mutagenic and toxic
simple "by-products", of the ETC metabolites. Peroxidation of lipids quantitatively is the
most intense destructive process produced in cells by ROS.
The fact that mitROSp is low in long-lived species Fatty acids containing a high number of double bonds (like
irrespective of the value of their specific metabolic rate is 20:4n-6 and especially 22:6n3) are the cellular molecules
clearly against the common belief that mitROS production most sensitive to lipid peroxidation, and their sensitivity to
is an unavoidable "by-product" of the respiratory chain. lipid peroxidation increases exponentially as the number of
double bonds per fatty acid molecule increases. The low
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@Real Academia Nacional de Farmacia. Spain
