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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”
contrary, putting all the food in a single early meal, or deacetylases like SIRT1, and the mitochondria-specific
perhaps, in two big meals one at around 15:00 and the SIRT3 are involved in the decrease in oxidative damage
other at around 20:30, together with a very frugal breakfast and antiaging effects induced by DR in mice (170).
-as it is typical in Mediterranean countries which are Interestingly, SIRT3 deacetylates various Complex I
among the most long-lived worldwide- would be an subunits (171) which could modulate the nearby placed
adequate option. In this way, people would expend most of sites of mitROSp. It is also of interest that epigenetics
the day (19 hours) fasting (the PAP working in OFF seems to influence two main effectors of PAP, the
position), and their PAP will be turned ON for a few hours mitochondria (172-174) and the autophagy system (154).
only once or twice per day. If this were correct, the
habitude of eating small amounts of food, so typical of 10. CONCLUSIONS
some western countries, but with high frequency at almost
every time during the day should be avoided. Food that 1. Long-lived mammals and birds have species-specific
strongly signals to PAP, like simple carbohydrates (sugar) low mitochondrial ROS generation rates at complex I, low
or sweetened beverages generating high insulin peaks levels of mtDNA oxidative damage, and low fatty acid
should be specially avoided, while complex carbohydrates unsaturation degrees in their cellular and mitochondrial
that are slowly absorbed would lead to much lower insulin membranes. After almost two decades of research, the rate
peaks. High amounts of methionine, an amino acid that of mitROSp and the fatty acid unsaturation of cellular
specifically signals the PAP, could be prevented avoiding membranes continue to be the only two known traits
excessive consumption of meat and restricting the intake correlating with animal longevity in the right sense and
of total protein to around 0.6 g of protein/Kg of body offering a plausible mechanism to cause aging. This is true
weight per day (0.8 is the current RDA at USA and many not only concerning MFRTA but also all theories of aging
other countries). in general so far proposed. The close vicinity or even
contact between the site of ROS generation and mtDNA
9.3. Epigenetics, aging and PAP avoids antioxidants to interfere with the ROS produced at
the mitROS generator relevant for aging, which is situated
A further complication involves interactions within the at complex I. This is likely why antioxidants do not modify
cell nucleus functionally affecting the nuclear gene longevity. The ROS-dependent final forms of mtDNA
clusters of aging PAP genes. In addition to varying their damage most relevant for aging –mtDNA deletions, and
expression in response to cytoplasmic, hormonal, and mtDNA fragments inside nDNA- seem finely tuned and
environmental signals, there can be nuclear feed-back controlled by the rate of mitROS production of each
among these genes due to epigenetic modifications (Figure animal species. This significantly contributes to determine
8). Epigenetic changes like DNA methylation, acetylation the species-specific aging rate and longevity.
or phosphorylation and histone modifications seem to be
important factors in aging. Epigenetic marks establish 2. It is well known that DR also decreases mitROSp
changes in gene expression in response to environmental and FRL at complex I and oxidative damage to mtDNA.
stimuli (like the different DRs) and drugs (like rapamycin) This is exclusively due to the lower methionine intake
and can be even part of the PAP itself (162). Some authors (MetR) of the animals subjected to DR. Around 50 % of
even support the existence of an "epigenetic clock"(163, the longevity extension effect of DR and PR is due to
164). This would be essentially different from the MetR, and seems to increase longevity in part through
"epigenetic drift" during aging which would correspond to decreases in mitROSp at complex I; the other 50 % effect
stochastic changes that will be of small or not interest for of DR on longevity would act through other mechanisms
the control of longevity (164). There is a decrease in like, perhaps, increased macro-autophagy. Rapamycin, the
global DNA methylation during aging, whereas there is an only known drug that consistently increases longevity in
increase with aging in local methylation at CpG islands mammals also decreases mitROSp at complex I and FRL,
and specific promoters (164-166). like all the different types of DRs. Interestingly, all the
four known experimental manipulations that have proven
A recent analysis of human body epigenome has found to increase mammalian longevity decrease mitROSp at
widespread tissue-specific differential CG methylation, complex I, FRL, and mtDNA damage (either 8-oxodG in
allele-specific methylation and transcription, and the mtDNA, or mtDNA fragments insertion inside nDNA).
unexpected presence of non-CG methylation in almost all
human tissues which correlates with tissue-specific 3. The constantly produced mtROS throughout life at a
functions (167). Changes in specific histones have been different rate in each species leads to the generation of
also described during aging, including global increases in oxidative damage in mtDNA (e.g. 8-oxodG) which is
H4K20 trimethylation and H3S10 phosphorylation, and repaired and can lead to point mutations in the process.
decreases in H3K9 and H3K27 trimethylation and H3K9 But mitROS, substances produced by the organism that
acetylation (168), which would contribute to modulate have capacity to break covalent bonds, also generate
aging rate. Such DNA modifications modulate gene single and double strand breaks in mtDNA. This leads to
expression through regulation of chromatin structure, irreversible forms of damage (mutations) like mtDNA
which is known to change during aging. Many age- deletions, and mtDNA fragments which enter the
dependent histone methylations are reversed by both DR chromosomes through the centromeres and accumulate in
and rapamycin treatments in mouse brain (169). Histone nDNA during aging. The steady-state level of 8-oxodG in
mtDNA is a marker of the flow of ROS-dependent damage
@Real Academia Nacional de Farmacia. Spain 71
