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Gustavo Barja de Quiroga

reproduce only afterwards, when the levels of protein DBI is consistent again with a healthy and pro-longevity
availability increase again in the ecological niche. That is effect of membranes containing a low number of fatty acid
why, at 80 % protein (methionine) restriction both a low double bonds.
mitROSp and a low DBI response are recruited. In relation
to this, recent comparison among DR diets containing fish Finally, since mitROSp is lower in DR than in the ad
oil, soybean oil or lard as lipid source, showed that the lard libitum-fed control animals, oxidative damage should also
containing diet (with less unsaturated fatty acids) was the be lower in the nearby, or even in contact situated, mtDNA
one maximizing the beneficial effects of DR on mitROSp, of the restricted animals. In agreement with this, it was
proton leak, ETC, lipid peroxidation, mitochondrial found that the level of 8-oxodG in mtDNA was
structure or mitochondrial apoptotic signaling, likely due significantly lower in the liver, heart and brain of the long-
in part to increases in monounsaturated fatty acid content term DR rats in which mitochondrial ROS production was
in the tissues (54). This improvement in mitochondrial also diminished (reviewed in 55). Depending on the organ
functionality of diets promoting some decrease in tissue studied, such decrease in 8-oxodG occurred only in
mtDNA, or both in mtDNA and nDNA (Table 1).

TABLE 1. Summary of changes on free radical related parameters induced by all manipulations known that consistently increase or not
longevity in mammals laboratory rodents

Experimental manipulation mtROSp mtVO2 FRL 8oxodG 8oxodG mtDNAFragments
Longevity (at CxI) in mtDNA in nDNA inside nDNA

(at CxI)
(MLSP)

DR ! "! !" nd #
PR
LR ! "! !" nd #
CHR
MetR " "" "" nd "
Rapamycin
" "" "" nd "

! "! !" nd #

! "! !(ns) nd !#

DR= dietary restriction; PR = Protein restriction; LR = lipìd restriction; CHR = Carbohydrate restriction; MetR = methioninerestriction; Rapamycin
(14mg/kg diet). The effects of DR,PR, and MetR on oxidative stress related parameters were obtained at a level of 40% restriction, and also at 80%
MetR. The effect of MetR on longevity has been studied always restricting methionine by 80% in the diet (56,57,59). The rapamycin effect of
mitochondrial oxidative stress was studied on B6D2F1 mice (139); the rest of the experiments were performed on Wistar rats. While DR, PR and MetR
decreased mitROSp and 8-oxodG in mtDNA in all the vital organs studied (liver, heart and brain), rapamycin (at 14mg/Kg diet) did it in liver but not in
heart of mice; mtDNA fragments inside nDNA were studied in the liver.For other Refs. see text. mtVO2 = mitochondrial oxygen consumption; FRL = %
free radical leak from CxI of functional mitochondria; nDNA = nuclear DNA; MLSP = maximum life span potential. DR, PR, MetR and rapamycin all
increase both mean lifespan, and maximum longevity (up to 40% in DR, by 20% in PR and DR, and by 11% with rapamycin) in rats and mice.

6. PROTEIN AND METHIONINE RESTRICTION increases in longevity (Table 1). Ten out of eleven protein
restriction (PR) investigations in rats or mice (16 out of 18
6.1. Effect on longevity different life-long survival experiments) reported increases
in longevity (58), although the mean magnitude of this
It has been generally agreed for a long time that calorie increase (around 19 %) was lower than that usually found
intake per se would be exclusively responsible for the in 40 % DR (up to 40 % increase). Thus, PR would be
increase in lifespan induced by DR in rodents. However, responsible for around half of the life-extension effect of
now many studies question this classical consensus. The
results of many investigations indicate that part of the life- dietary restriction.
extending effects on DR are due to the decreased intake of
particular components of the diet, such as proteins, and Among the different dietary amino acids, which is the
more specifically the amino acid methionine (56-60). The one/s responsible for the increase in longevity induced by
few available studies do not support the possibility that PR? It is consistently known that isocaloric 80 %
either life-long isocaloric carbohydrate or lipid restriction methionine restriction (MetR) increases longevity in F344
increase rodent life span. Two investigations of rats (56) and mice (57-59; Table 1) to a similar extent than
carbohydrate restriction or supplementation reported PR. The mean increase in (maximum) longevity in the
opposite and minor changes in rat longevity (61, 62), and it three available MetR life-long experiments taken together
was found that the longevity of Fisher 344 rats does not was around 18 % increase. This occurred even when MetR
change after life-long lipid restriction (63). In contrast, the was started as late as at 12 months of age in C6BF1 mice
large majority of the investigations on the effects of (59). Studies performed in D. melanogaster have also
isocaloric protein restriction (PR) in rats and mice found shown that casein restriction (64) and methionine
restriction (65) extend longevity independently of the

58 @Real Academia Nacional de Farmacia. Spain