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generation and repair through mtDNA. Its measurement is Gustavo Barja de Quiroga
a useful marker of the rate of generation of mtDNA
deletions and mtDNA fragments. Mutations can also arise hydroxynonenal and many others, which can diffuse from
due to processes unrelated to oxidative stress like mtDNA membrane peroxidized lipids to the cell nucleus. Some of
replication and repair. However, it is highly unlikely that these products have the potential to modify DNA, e.g.,
these last mechanisms of damage generation are related to through direct interaction of the carbonyl group of the
longevity, because their random nature can not explain the aldehydes with free amino groups in mtDNA or nDNA.
determination of longevity during DRs and in different This would add secondary DNA damage to that primarily
animal species. It has been argued that the types of base coming from the complex I mtROS generator relevant for
mutations (transitions or transversions) mainly present in aging. There is a paucity of studies concerning lipid
mtDNA indicate that they mainly come from mtDNA peroxidation-dependent damage to mtDNA and nDNA
replication and repair. This has been taken as evidence (175), especially due to technical limitations. They are
against MFRTA. But this applies only to base substitutions however potentially interesting and should be studied.
and does not concern to mitROS-induced DNA strand
breaks leading to mtDNA large deletions, and to mtDNA 5. DR and MetR also decrease protein oxidation,
fragments insertion inside nDNA. When irreversibly glycoxidation and lipoxidation, perhaps due to the
damaged mtDNA reaches a high threshold level in a cell, decrease in mitROSp at complex I or to an increase in
approaching homoplasmy of mutated mtDNA, protein catabolism during the DRs. Mitochondrial protein
mitochondrial ATP generation through oxidative oxidation-derived modification can also contribute to the
phosphorylation is decreased to levels great enough to accumulation of mtDNA mutations, although this
contribute to aging. There is no consensus if this classical possibility has also been poorly investigated.
concept of MFRTA (176) can contribute to explain aging
and longevity. 6. Many different kinds of evidence converge in the
concept that aerobic tissue cells (both the post-mitotic and
It is now known beyond reasonable doubt that mtDNA the mitotic ones) have a Pro-Aging Program (PAP) lying
fragments accumulate during aging inside nDNA in yeast, inside the cell nucleus, likely composed of hierarquically
rat liver and brain, and mouse liver (139,147-149), causing interrelated gene clusters of aging analogously to the Hox
an increase in chronological aging at least in yeast (147). genes controlling development (153). The PAP is a main
Recent investigations show that such accumulation, as central part of the Cellular Aging Regulatory System
well as the increase in complex I mitROSp and FRL with (CARS). The large amount of pro-aging genes already
age, are fully (100 %) reversed by rapamycin dietary discovered during the last two decades are highly
treatment in the liver of middle age mice (139). This is conserved during evolution from yeast and nematodes to
accompanied by rapamycin-induced strong increases in Drosophila, and mammals, like in the case of the Hox
autophagy fully reverting to young levels, and by partial genes. The PAP reacts to GH/ insulin/IGF-1 like signaling
reversion of lipofuscin accumulation with age (139). and to cytoplasmic signals like those from AMPK, mTOR,
Interestingly, recent studies indicate that the mtDNA and many others, in response to the different
fragments do not enter nDNA randomly. Instead they are environmental types of dietary restrictions or drugs like
directed to the centromeres as a main “entry door” to the rapamycin. The signals entering the nucleus would modify
nucleus. From there, they can potentially disseminate to different PAP master genes through transcription factors
other chromosome regions, perhaps being specifically like FOXO, TFEB and many others. These master genes
directed to nDNA regulatory regions controlling the gene would then modify the expression of different gene
clusters of aging (PAP) residing in the cell nucleus (153), clusters of aging mainly constituting the PAP. These
thus contributing to aging and to accelerate the mortality clusters must be organized in a hierarchical cascade of
rate at old age. Further research is urgently needed to genes interrelated trough transcription factors, enhancers,
clarify this possibility. Alternatively, and more simply, the promoters, et cetera. The target genes situated at the lower
mtDNA fragments can potentially alter the information level in such hierarchy would modify the synthesis of
coded in nDNA. They could be directed specifically to specific proteins which change the activity level of the
structural genes, thus promoting cell malfunction, cell aging effectors (executors of aging).
death, or cellular malignant transformation, and thus aging
and cancer. Among PAP target genes some have been already
identified. These are the ones controlling: i) the synthesis
4. The low fatty acid unsaturation degree of cellular of matrix-only complex I domain; ii) delta 5 and 6
and mitochondrial membranes of long-lived animals leads desaturases and elongases in the n-6 and n-3 pathways of
to relatively low rates of endogenous lipid peroxidation in fatty acid synthesis; iii) many autophagy genes. Some
vivo, which is, quantitatively, the most destructive signals coming from the environment (the DRs) can by-
oxidative stress process to the main different types of pass the nuclear PAP and directly modify the mitochondria
cellular macromolecules. A low rate of membrane lipid (or likely other aging effectors) changing their rate of
peroxidation in long-lived animals also leads to decreases mitROSp at complex I.
in the generation of highly toxic and mutagenic lipid
peroxidation products like malondialdehyde, 7. Among candidate aging effectors in aerobic tissues
(both mitotic and post-mitotic), three emerge at present: 1)
72 Mitochondria (including mitROSp); 2) The degree of fatty
acid unsaturation (DBI) of cellular membranes; and 3)
Autophagy. Decreases in the first two effectors slow aging
@Real Academia Nacional de Farmacia. Spain
