2.
Oxidative metabolic damage
Longevity
of homozygote twins is statistically different, but this difference is less
important than between dizygote twins, proving that life expectancy is only
partially genetically determined (6, 20). These data explain why some of the
most interesting current problems are to understand how the genetic factors
influencing aging and longevity respond to a fluctuating environment (6). The
rate of random chemical damage to the genome is considered as the major factor
determining lifespan in species. The free radical theory of the aging process
is based on the hypothesis that with increasing age, mutations of the
mitochondrial DNA will accumulate and will at last lead to a loss of function
with subsequent acceleration of cell death (21).
As
a result of aerobic metabolism, aging is primarily the cumulative sum of
oxidative damages to the cells and tissues of the body. Several lines of
evidence have been used to support this hypothesis including the claims that:
(1) free radical damage at cellular level increase with age, (2) variation in
species life span is correlated with metabolic rate and protective antioxidant
activity, (3) reduced calorie intake leads to a decline in the production of
reactive oxygen species (ROS) and an increase in life span and (4) enhanced
expression of anti-oxidative enzymes in experimental animals can produce a
significant increase in longevity (22).
The
free radical theory may also be used to explain many of the structural
features that develop with aging, including the lipid per-oxidation of
membranes, formation of age pigments, cross-linkage of proteins, DNA damage
and decline of mitochondrial function (22).
The mitochondrial respiratory chain is a powerful source of ROS (23) sensitive
to the oxidative stress in mitochondria which provokes: 1) a decrease in
mitochondria respiratory function, 2) an increase in the rate of production of
ROS, 3) an accumulation of mitochondrial DNA (mtDNA) mutations, 4) an increase
in the levels of oxidative damage to DNA, protein, and lipids and 5) a
decrease in the capacities of degradation of damaged proteins and other
macromolecules (24). Indeed, the
role of mitochondria is essential in cellular aging. The rate of oxidant
production by mitochondria correlates inversely with maximal life span of
species. In many species, females live longer than males, because
mitochondrial oxidant production by females is significantly lower than that
of males. However, mitochondria from ovariectomized females have a similar
oxidant production as those of males (25).
To confirm this discovery, longevity of
ovariectomized women has now to be investigated.
Moreover,
responses to oxidative stress and their subsequent interactions in tissues
result in the deleterious effect of ROS on the cellular function, principally
accumulation of oxidatively altered proteins, lipids, and nucleic acids.
Oxidatively modified proteins have been shown to increase as a function of
age. Furthermore, a number of age-related diseases (cataract for example) have
been shown to be associated with elevated levels of oxidatively modified
proteins (26). Mutations of the mitochondrial DNA and its consequences
(production of oxidatively damaged proteins, lipids, and nucleic acids) will
accumulate and will ultimately lead to a loss of function with subsequent
acceleration of cell death (21).
The chronic exposure to oxidants and an
increased activation of mitochondrial permeability transition pores accelerate
apoptotic mechanisms which can be documented by a significant loss of cardiac
and skeletal myocytes during aging (27).
At
this stage of knowledge, it appears impossible to delimitate the respective
roles of genetics and oxidative metabolic damage in human longevity.
To make progress
in the understanding of these complex interactions, more detailed studies
are needed on how population specific variables, such as life styles, risk
factors and diseases, influence the selection forces that shape the life history
(6).