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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”
caloric intake. Moreover, other recent studies link essential
amino acids, and again especially methionine, with the
positive effect of DR on longevity in yeast (66) and D.
melanogaster (67). Interestingly, PR results in profound
changes in methionine and serine metabolism (including
lowering cystathionine ß-synthase and cystathionine ?-
lyase activities) and increases the oxidation of fatty acids
in rat liver (68).
In addition to extending lifespan, 80 % MetR also
decreases disease-associated markers and the incidence of
age-related degenerative diseases (69, 70). The beneficial
effects of this intervention in rodents include decreases in
serum glucose, insulin, IGF-1, cholesterol, triglycerides
and leptin. Besides, MetR protects against age-related
changes in immunity, slows cataract development (57),
improves colon tight junction barrier function (71) and
improves metabolic flexibility, increasing respiratory
uncoupling (72). MetR may be also used in the future to
inhibit tumor growth, particularly in many cancers that
exhibit the known phenomenon of “methionine
dependence”. These include bladder, breast, colon, glioma,
kidney, melanoma, prostate and other cancers in which
tumor cells have a much greater reliance on methionine
than normal cells do (73). They need this amino acid for
survival and proliferation and their growth seems seriously
limited or inhibited in the absence of methionine (74, 75).
MetR (80 %) also decreases total adipose tissue mass
and lowers visceral fat by 70 % (by more than 40 % after
correcting for the decrease in body mass) in association
with an improvement in insulin sensitivity (76). In
addition, MetR decreases leptin and increases adiponectin
in rodents in agreement with the decrease in visceral
adiposity and the size of white adipose tissue depots.
These beneficial effects seem to be mediated by tissue-
specific responses that favor increased mitochondrial
function and biogenesis, fatty acid oxidation and total
energy expenditure possibly mediated by ß-adrenergic
receptor signaling and changes in lipid homeostasis (77).
Metabolomics and genomic MetR studies found changes
in the expression of a large number of genes and proteins
that led the authors to conclude that MetR increases lipid
metabolism in adipose tissue and muscle whereas it
decreases lipid synthesis in the liver (78). These changes in dietary restriction.
lipid metabolism seem to be involved in the strong
decrease in adiposity and increased insulin sensitivity
observed in isocaloric restriction of dietary methionine.
Altered levels of sulfur-containing amino acids have
been also described in MetR: serum levels of methionine,
cysteine, cystathionine, and taurine decrease in MetR rats,
whereas homocysteine levels (79) and glutathione (56)
increase. Interestingly, adding cysteine to the MetR diet
reverses most of the studied beneficial changes on
adiposity and insulin resistance (79) and increases the
transcription of various genes associated with
inflammation and carcinogenesis (78). Therefore, the
beneficial changes of the MetR diet have been attributed to
the decrease of cysteine in serum (80) or liver (78)
observed in animals subjected to MetR.
@Real Academia Nacional de Farmacia. Spain
On the other hand, excessive intake of dietary
methionine is toxic. This toxicity far exceeds that
produced by any other amino acid (81), leading to damage
in some vital organs and increases in tissue oxidative stress
(81, 82) with similar negative effects to those observed in
rats fed diets with a high protein content. Chronic and
excessive methionine supplementation increases plasma
hydroperoxides and LDL-cholesterol (83), induces
vascular (84) and kidney damage with tubular hypertrophy
(85), raises iron accumulation and lipid peroxidation, and
leads to liver dysfunction (86), besides other alterations in
other organs. In addition, methionine supplementation
increases methionine and its two more nearly derived
methionine cycle metabolites, S-adenosylmethyonine and
S-adenosylhomocysteine in rat liver and kidney (87).
Some of the harmful effects of methionine
supplementation have been attributed to methionine-
related metabolites like S-adenosylmethyonine, S-
adenosylhomocysteine, or homocysteine, rather than to
methionine itself, although in other investigations a direct
methionine toxic effect has been suggested (80, 84). This
last case fits well with the observation that direct addition
of methionine to isolated mitochondria in vitro increases
their rate of mitROSp in liver and kidney mitochondria
(87).
Oxidation of methionine residues in proteins generates
methionine sulfoxide, depriving them of their function as
methyl donors and may lead to loss of their biological
activity (88). This modification can be repaired by
methionine sulfoxide reductase in a thioredoxin-dependent
reaction. In this context it is interesting that over-
expression of methionine sulfoxide reductase increases
lifespan in D. melanogaster (89) and the opposite
manipulation, knocking out the same enzyme, increases
protein carbonyls and decreases longevity (90). There is
evidence that this enzyme plays an important role in
protection against oxidative, cold, and heat stress and
seems to be involved in the regulation of aging in D.
melanogaster (91). Also in agreement with a methionine
role in aging, it has been reported that long-lived Ames
dwarf mice have an altered methionine metabolism
showing a marked increase in the transulfuration pathway
compared to their wild-type siblings (92). All the above
results point to methionine as the single dietary factor
responsible for part of the longevity extension effect of
6.2. Role of mtROS generation and oxidative damage
DR decreases oxidative stress in mitochondria. But,
what is the specific dietary component responsible for the
decreases in mtROS production and oxidative damage to
mtDNA during DR? In agreement with their lack of effect
on longevity (61-63), neither isocaloric 40 % lipid
restriction (93) nor isocaloric 40 % carbohydrate
restriction (94) change mitROSp or 8-oxodG in mtDNA
(Table 1). However, isocaloric 40 % PR during 7 weeks
decreases mitROSp and oxidative damage to mtDNA in rat
liver (95) in a strikingly similar way, quantitatively and
qualitatively to 40 % DR (Table 1). The effect of PR was
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