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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”
recapitulates phylogeny” (e.g. presence of gills or tail in mtDNA fragments, have been found inserted into nDNA
human embryo or foetus), in this case applied to inside the nucleus. Therefore, we should look both at the
mitochondria and to the nucleus to understand aging,
programmed aging as a continuation of development. as much as we should look at the mitochondria and at the
nucleus to understand the creation and further evolution of
The lack of increase to phenotypic threshold (minimum the eukaryotic cell.
of around 60 %-80 % deleted) of mtDNA deletions due to
the very high copy number of mtDNA in heteroplasmia 9. THE CELLULAR AGING REGULATION
per cell was a strong problem for the validity of MFRTA, SYSTEM (CARS)
similarly to the main origin of mtDNA point mutations
from replication/repair instead of from mitROSp as 9.1. Signaling, the nuclear Aging Program, and aging
deduced from the relative frequency of base transversions Effectors
vs. transitions. However, now there is evidence that
mtDNA fragments accumulate inside nDNA with age in The integrated Cellular Aging Regulation System, for
yeast and mammals, and that this promotes aging (147). convenience called CARS here for the first time, is
Furthermore, the longevity increasing drug rapamycin composed of three main parts (Figure 8):
reverses such age-related accumulation in mouse liver
strongly paralleling what happens for complex I mitROSp A) Cytoplasmic Pre-nuclear Signaling (mostly
(Figure 5A,B; Ref.139). All that means that MFRTA can signaling proteins)
not be considered “dead” any more except by those not
aware of the recent breakthrough discoveries of mtDNA B) The nuclear genetic Pro Aging Program (PAP)
transfer from mitochondria to the nucleus during the including the Gene Clusters of Aging (153); and
lifetime of the individual. On the contrary MFRTA, like
the bird phoenix, emerges again well alive and all pristine C) Post-nuclear Effectors (executors) of Aging.
from its ashes. Perhaps the failure to detect mtDNA
mutations relevant for aging has been due to looking at the This CARS occurs both in post-mitotic and in mitotic
wrong place. The ROS related to aging should be looked at tissue cells. Mitotic cells could harbour, in addition, other
mitochondria. However, what could be more important for additional hypothetical aging effectors specific for such
aging would not be the (remaining) deleted mtDNA, but kinds of tissues, like telomere shortening or perhaps
what is lacking at mtDNA after the deletion: the mtDNA apoptosis, but these are not expected to be relevant in cells
fragments. The consequences likely relevant for aging, the that do not divide. Especially, if the cell does not divide,
the telomeres would not shorten. And the most important
tissues for mammalian aging are those mainly composed
of post-mitotic cells, skeletal muscle, heart and brain.
Figure 8. Cell Aging Regulation System (CARS). The working model of the CARS (including the Pro Aging Program-PAP lying inside the
@Real Academia Nacional de Farmacia. Spain 67
