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Mitochondrial ROS and mtDNA fragments inside nuclear DNA as a main effector of ageing: the “cell aging regulation system”
be eliminated unless aging is defeated. Treating all the
degenerative diseases one by one will never eliminate
them. However, defeating aging, all of them will be
eliminated with a single manipulation. This will restart
evolution of increasing longevity, which has been among
the main causes of the great success of our species in the
planet, from our last common primate ancestors, the early
small Plesiadapiformes-like Purgatorius which lived only
around 10 years, to the 122 years that we can live now at
best, a 10 fold (1.000 %) life extension. In order to
accomplish this major goal, that will free us from most of
those terrible illnesses and restart our evolutionary path
towards an even higher complexity, we must first
understand what are the fundamental basic mechanisms of
aging down to the cell level. Once we know these, the
large capacity of modern molecular biology and
pharmacological techniques will finally allow
accomplishing the old dream of decreasing, for the first
time in history, human aging rate.
After truly decreasing aging rate, it will be possible in
the future for human beings to reach e.g. 100 years with a
biological age equivalent to that of a young person of
today of 30 years of age ("only" around 3 fold lifespan
extension). That would be properly called "healthy aging",
which is clearly not the case for most human centenarians
nowadays. The previous approach implemented in the past
century, merely to protect many people from death but not
from aging, increased the percentage of people that
reached old age, so that they are alive but they are
biologically old and therefore weak and with a ever
increasing exponential chance of suffer sooner or later
degenerative diseases and death. The result is the ever
increasing percentage of aged people in our societies,
generating an enormous load for social security and health
care systems, and strongly increasing the proportion of
fragile, disabled, and long time suffering old individuals in parameters like these two, that correlate in the right sense
the population. Our aged societies and their high economic
burden constitute the frequently called huge
socioeconomic "aging problem". All this can be solved by
progressively attaining negligible senescence with the help
of gerontological science. Biogerontology has the key to
this solution that will help to propel humanity to a brighter explain is why longevity and aging rate vary so widely
future on its committed evolutionary path from simplicity
to complexity, from dust to bacteria, to eukaryotic cells, to
multicellular life, to better society, and then to new
achievements that few can nowadays even wonder.
Therefore, what causes aging? While many different
theories of aging have been proposed, the mitochondrial
free radical theory of aging (MFRTA) is one of the few
current main explanations of aging and longevity in
mammals, birds and multicellular animals in general. Any
aging theory must explain why maximum longevity
(referred here throughout as “longevity”) varies so widely
in animals: 30 fold from mice to men, 200 fold from
shrews to the longest-living whales, or more than 5,000
fold from perhaps a few days of life in some invertebrates
to Arctica islandica mussels (longevity around 500 years).
Such huge differences indicate that longevity is markedly
@Real Academia Nacional de Farmacia. Spain
regulated and flexible during species evolution. Copying
only a small fraction of this natural capacity would make
possible in the future to reach negligible senescence in
humans. Animals closely related by phylogeny, like Mus
musculus (longevity 4 years) and Peromyscus leucopus
(longevity 8 years) mice have very different maximum
lifespans, indicating that evolution of longevity is also a
relatively easy and quick process. Therefore, substantially
decreasing the aging rate in mammals including humans
will be relatively easy once the underlying basic
mechanisms controlling longevity at physiological, cellular
and molecular levels are elucidated.
Mean lifespan and the life expectancy at birth of the
individuals of a population depends more on the
environment than on the genes. On the contrary
(maximum) longevity, and its inverse -the species aging
rate -, depends more than 90 % on the genotype, as it is
also the case for any other species-specific trait. Longevity
and aging rate are the parameters that matter concerning
the endogenous process of aging.
Up to now, only two known factors have demonstrated
to correlate in the right sense with animal longevity in
vertebrates including mammals and birds: a) the rate of
mitROSp (mitochondrial reactive oxygen species
production, Refs. 1-4); and b) the degree of fatty acid
unsaturation (calculated as the double bond index, DBI) of
tissue cellular membranes including the mitochondrial
ones (5, 6). The longer the longevity of a species, the
smaller the value corresponding to these two parameters.
The low mitROSp of long-lived animal species decreases
their generation of endogenous (free radical) damage at
mitochondria. The low fatty acid DBI and peroxidizability
index (PI) decrease the sensitivity of the cellular and
mitochondrial membranes to free radical attack and lipid
peroxidation. No other theory of aging focuses on
with longevity across animal species (and also within
single species), and offers plausible mechanistic
explanations for the final accumulation of damage from
endogenous origin leading to aging. This is relevant, since
the most important fact that any theory of aging must
among different animals.
2. ANTIOXIDANTS AND LONGEVITY
Studies about MFRTA first focused in antioxidants,
mainly because they could be measured with rather simple
methods. In 1993 it was found at my laboratory that both
enzymatic and non-enzymatic endogenous tissue
antioxidants, including superoxide dismutase, catalase,
GSH-peroxidases, GSH-reductases, GSH, or ascorbate,
strongly correlated with longevity across vertebrates.
However, and rather surprisingly, such correlation was
negative, instead of positive as it was until that time widely
believed. Our review on the relationship between
endogenous antioxidants and vertebrate longevity (7)
included all the available published data on the subject
obtained in vertebrates including mammals by my as well
as other laboratories.
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