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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”

summarized in the present review? How a probe reacting Studies in mammals and other vertebrates clearly
only to pH could consistently vary with longevity always indicate beyond reasonable doubt that the rate of mitROS
in the right sense in 55 mutant or environmental longevity generation importantly contributes to determine longevity,
models? And most importantly, what is the hypothesis whereas antioxidants do not (23, 24, 29, 32). This is
relating H+ to longevity? To the best of my knowledge counterintuitive only if we erroneously consider the cell as
none has been proposed. Perhaps proton gradient and a homogeneous system without compartmentation. But
mitochondrial membrane potential are indirectly related to cells are not like that. The global cellular level of oxidative
longevity through changes in mitROSp, and this stress should depend both on the rates of ROS production
relationship would add to a possible reaction of some ROS and ROS elimination. Both contribute to determine cell
with cpYFP. If this were true, both the critics and the survival or cell death according to the general “balance”
authors of the study (31) would be right, and the between them, and likely affect mean lifespan. However,
impressive results would have a strong value for the ROS concentration in particular compartments like
biogerontology. In any case, these important physiological mitochondria, and most especially very near to the places
questions have not been resolved and still wait for of mitROS generation like complex I, should be much
adequate answers. I consider most important to fully more dependent on mitROSp than on antioxidants as the
clarify this issue. The availability of a technique (mitoflash free radical generation site relevant for aging is
or any other better one?) that could reliably estimate how approached at micro level. At such places, it is mitROSp
much mitochondrial ROS are produced in a mouse in vivo what would mainly determine the local ROS concentration
would be, no doubt, of paramount value for researchers (Figure 2). This is especially important because the main
and a most fundamental advance for gerontology. target for aging, mtDNA, is located very close in the
vicinity, perhaps even in contact with the free radical
3.5. The Contact Hypothesis of Aging. mitROSp instead of generation source.
defences or repair control aging

Figure 2. Low ROS local concentration near mtDNA in long-lived species. Long-lived animals show both low rates of mitROS

production (Figure 1B) and low antioxidant levels (Figure 1A), and the reverse is true in short-lived-lived ones (7,10). Therefore, both
kinds of animals have a similar and moderate level of mean oxidative stress (and H2O2 concentration) at most cellular sites. This is
necessary for general cell homeostasis and survival both in animal species with high and low longevities. But the local concentration of
ROS at the site of ROS production is much lower in long-lived than in short-lived species due to their low rates of mitROS production.
This causes the lower oxidative damage to mtDNA (Figure 1C and Ref. 20) of long-lived species because mtDNA is situated nearby or
even in contact with the site of ROS production at complex I relevant for aging. The model predicts the existence of a gradient of H2O2
concentration from mitochondria to the surrounding cytoplasm. The size of the stars, lower in long-lived species, represents the local ROS
concentration at the sites of mitROSp at complex I, which is lower in long-lived species.

@Real Academia Nacional de Farmacia. Spain 53