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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”

DBI and PI of long-lived animals was first described in mitochondrial as well as in total cellular membranes in
1996 in rat compared to pigeon and human mitochondria tissues of long-lived animals. It can therefore strongly
(36) followed by many studies in mammals and birds (see diminish lipoxidation-derived damage in various cellular
5,6 for review). A total of 23 studies extended the seminal compartments, and especially in the mitochondrial one. At
first observation (36) to many different mammals, various those organelles there is strong abundance of membranes
bird species, and some invertebrates, without finding a together with a nearby and rather constant source of ROS
single exception: low tissue DBI in long-lived animals (6). during mitochondria respiration throughout the whole life
The low degree of fatty acid unsaturation occurs both in span.

Figure 3. Low degree of membrane fatty acid unsaturation in tissues of long-lived animal species. A) Double bond index (DBI) in
the heart of 8 mammals with widely different longevities; B) Levels of the highly unsaturated docosahexaenoic acid (22:6n-3) in liver of

8 mammals; C) Levels of the much less unsaturated linoleic acid (18:2n6) in liver of 8 mammals. DBI (and PI) (part A) and 22:6n-3 (part
B) are low in long-lived animals, whereas 18:2n-6 is higher in long-lived ones (part C). In studies in some tissues or species low 20:4n-6
and high 18:1n-9 are also typical of long-lived animals. Similar results were obtained in skeletal muscle, and in mitochondria from the
three mammalian tissues. Three birds also showed lower DBI than mammals of similar body size. Reviewed in Refs. 5,6, and Physiol.
Reviews 87:1175-213, 2007.

Among the different fatty acids composing the not change among species with different longevities.
different cellular membranes many are responsible for the Instead it is the unsaturation degree of the polyunsaturated
strong decrease in DBI (and PI) as longevity increases fatty acids present what decreases from short- to long-lived
among species. But the most important ones, both due to animals. Long-lived animals have fatty acids with a lower
their content in double bonds (low or high) as well as for degree of unsaturation, with less double bonds per fatty
their larger quantitative presence and variation among acid molecule. With this kind of fatty acid redistribution
species, are 18:2n-6, 18:3n-3 and 22:6n-3 in mammals long-lived animals obtain a strong decrease in the
(Figure 3B,C), and in some phylogenetic groups also sensitivity of their cellular membranes to the destructive
18:1n-9 (at least in the studied birds) and 20:4n-6. As and mutagenic process of lipid peroxidation, while likely
longevity increases across mammalian species tissue avoiding strong changes in the fluidity of their membranes,
18:1n-9, 18:2n-6 (Figure 3C) and 18:3n-3 significantly the so called homeoviscous–longevity adaptation (5). In
increase, and 20:4n-6 and especially 22:6n-3 (Figure 3B) addition, it has been recently shown that feeding 18:1n-9
significantly decrease in skeletal muscle, liver, and heart reverses the increases in 20:4n-6 and 22:6n-3 and the
cellular membranes. Among them, the decrease in 22:6n-3 decreases in 18:1n-9 and 18:2n-6 and complexes I and IV
in long-lived animals usually is the most important to activities observed in the skeletal muscle of old rats (37).
quantitatively explain their low DBI and PI values (Figure Recent confirmation of the low tissue fatty acid
3A,B). Interestingly, the final result is that the total unsaturation of long-lived animals has been obtained
percentage of unsaturated and saturated fatty acids does through shotgun lipidomic analysis of mitochondrial

@Real Academia Nacional de Farmacia. Spain 55