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phosphatidylcholine, phosphatidylethanolamine, and Gustavo Barja de Quiroga
phosphatidylserine in skeletal muscle, liver and brain of
mammals with widely different longevities (38). calorie restriction (DR) increases not only mean but also
maximum longevity (up to 40 %) and decreases and delays
The low DBI of long-lived animals likely protects not the incidence of degenerative diseases in most animal
only the lipids but also other kinds of cellular components. species including rotifers, flies, spiders, worms, fish,
Since lipid peroxidation is a relatively massive process laboratory rodents and many other mammals (40; Table 1).
compared to oxidative damage to other kinds of In a 20 years-long adult-onset study in rhesus monkeys 30
macromolecules, long-lived animals, due to their low DBI, % DR strongly decreased age-related mortality (from 37 %
will produce far smaller amounts per unit time of highly to 13 %), the incidence of many age-related diseases
toxic and mutagenic lipid peroxidation products like including diabetes, cancer, cardiovascular disease, and
hydroxynonenal, malondialdehyde, and many others. brain atrophy (41). Many effects of DR have been
These, having carbonyl groups, can modify free amino discovered involving lowered GH and insulin/IGF-1-like
groups in proteins and DNA. Lipid peroxidation-derived signalling, modifications in nutrition and amino acid-
protein modification seems to be involved also in aging, sensing pathways, changes in sirtuins (42), apoptosis, and
since comparisons among different mammalian species signalling proteins and transcription factors like
have found that the amount of malondialdehyde-lysine mTOR,S6K, AKT, PKA, or FOXO and tissue-specific
adducts in heart proteins negatively correlates with changes in gene expression profiles. Many of these
longevity (39). changes and others are interrelated and seem to be part of
an integrated cellular aging regulation system (see section
What is the metabolic mechanism responsible for the 9) which includes mitochondria oxidative stress-related
negative correlation between the fatty acid unsaturation damage, and sensitivity to lipid peroxidation, as two of its
degree and species longevity? A role for main aging effectors (42).
acylation/deacylation of the constitutive membrane fatty
acids can not be discarded. However, since the more In the previous sections it was described that long-lived
unsaturated 20:4n-6 and 22:6n-3 are essential fatty acids animals have lower rates of mitROSp and lower mtDNA
synthesized from their dietary precursors 18:2n-6 and oxidative damage than short-lived ones (29). But what
18:3n-3 respectively, the enzymatic processes that control occurs in DR? If the MFRTA is correct also inside species,
the n-3 and n-6 biosynthetic pathways seem to be those two parameters should also decrease during DR.
involved. In this respect, in various comparative studies Initial studies, like in the case of the comparison between
relating the degree of fatty acid unsaturation to longevity different species, focused mainly on antioxidants. They
the results suggest that desaturase and elongase enzymatic showed that DR in rodents does not lead to a generalized
activities in the n-3 and n-6 series (which are rate limiting increase in antioxidants. Instead increases, decreases or
for those biosynthetic pathways) are constitutively low in lack of changes, depending on the particular antioxidant
long-lived animals. In some cases decreases in measured, have been reported even within the same study
peroxisomal beta-oxidation could also be involved. It is (43). Therefore, similarly to what happens in the inter-
now considered that this last process is responsible for the species comparative case, the key to longevity again is not
last steps in the synthesis of the highly unsaturated 22:6n-3 based on the antioxidants levels during DR.
in the n-3 pathway. The low delta-5 and delta-6 desaturase
activities (which are rate limiting enzymes in the n-3 and A different situation concerns mitochondrial ROS
n-6 fatty acid synthesis pathways) of long-lived animals generation. The effect of DR on the rate of mitROSp was
will decrease the conversion of the less unsaturated 18:2n- repeatedly investigated in mice, and especially in rats, by
6 and 18:3n-3 diet-derived precursors to the highly many different laboratories. The results of these
unsaturated 20:4n-6 and 22:6n-3 products. Thus, 18:2n-6 investigations consistently agreed that long-term standard
and 18:3n-3 would accumulate and 20:4n-6 and 22:6n-3 (40 %) DR, as well as short-term (e.g.: 7 weeks) DR,
will diminish, which is just the general kind of fatty acid significantly decrease the rate of mtROS generation in rat
profile observed in long-lived animals. organs including skeletal muscle, kidney, liver, heart and
brain (44, Table 1). This agrees again with the concept that
In summary, the membrane fatty acid unsaturation lowering mitROSp contributes to increase longevity. The
degree is low in tissues of long-lived animals. This is the decrease in mitROSp during DR was found in freshly
only other known factor, in addition to mitROSp, which isolated functional mitochondria exposed to similar
correlates with longevity in the right sense. Importantly, incubation conditions, including the substrate
this is true concerning the MFRTA as well as any other concentration used to feed electrons to the ETC, in the ad
theory of aging. And the degree of fatty acid unsaturation libitum fed and DR groups. Thus, DR mitochondria are
suggests a plausible mechanism to contribute to the widely different from those obtained from ad libitum fed animals,
different aging rates of the different animal species. And and this difference (due to DR) is responsible for the
what is the situation concerning experiments inducing lowered mitROSp detected in vitro. In addition, classic
increases in longevity in single mammalian species? data suggest that complex I substrates like pyruvate
decrease during DR in tissues (45), which has been
5. DIETARY RESTRICTION recently confirmed by full metabolome analysis (46). The
decrease in pyruvate and other mitochondrial substrates
It is well established that standard (40 %) dietary would decrease the in vivo matrix NADH level in DR thus
56 @Real Academia Nacional de Farmacia. Spain
