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Molecular Theories of Aging
Aging is the most universal of biological phenomena known to man. It has been
studied since the beginning of man. Million of books have been written to try and
explain it. People have devoted their lives to conquer it. The Bible explains aging as a
result of sin and our separation from God.
Some religions believe that aging is
completely natural and that when you die you will become transformed into anther
“being”. Yet until the past few years the basic mechanisms involved in this process have
been completely unknown. We are finally getting some insight into this biological
phenomena, and it is the purpose of this paper to explore a few theories, and the way in
which these ideas apply to the specific problems encountered in the various branches of
biology.
To understand the theories of aging we must first know a little about the nature of
aging. It is obvious to a biology student that biological aging can be described at a
phenomenological level as a process that is observed in all living things. It consists of a
systematic, continuous alteration of individuals, leading last to their death. According to
Strehler (1959), The aging process can be characterized by the following four main
features:
1. It is destructive, i.e., it decreases the functional ability.
2. It is progressive, i.e., irreversible.
3. It is intrinsic, i.e., it is determined by the internal characteristics of the
living being or is does not exclusively on any external factor.
4. It is universal, i.e., individuals of the same species display more-or-less
uniform aging pattern, and on the other hand, all living beings show the aging
phenomena.
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There are numerous theories of aging, none of which have been proven beyond a shadow
of a doubt. These theories are just explanations of how some scientists view the aging
process. Some of the molecular theories and hypothesis of aging are:
1. The free-radical hypothesis
10. Theory of decomposed
2. The error catastrophe
(expired) programs
hypothesis
11. Theory of autoimmunization
3. Theory of somatic mutations
12. Evolutionary explanations of
4. Theory of genetic mutations
aging.
5. Wear-and-tear explanations
13. Mathematical theories
6. Cross-linking explanation
14. The cellular interaction
7. Accumulation theories
theory
8. Program theory of aging
15. The collagen theory
9. Membrane hypothesis
16. The waste product theory
17. The calcium theory
You can see how varied the theories are and that they extend into every area in biology
and even into mathematics (Austad, 1998. and Kirkwood, 1998). Since it would take
many books to completely describe in detail each theory and hypothesis, I will only
explain the basics of a few theories.
The first theory that I will discuss is called the disposable soma hypothesis. This
hypothesis suggests that aging has evolved as a byproduct of optimization of energy and
resources for the various works performed by the organism. It assumes that energy
resources are better spent for maintenance of reproductive cells which are resposible for
species survival. To maintain, repaire, and replace all of the bodies somatic cells would
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take too much energy and thus it is not cost effective. It is too expensive in terms of
energy and thus the nonreproductive cells of the body are expendable (Kirkwood, 1986).
Therefore aging results from a progressive accumulation of somatic defects and damage.
This theory relates to evolutionary survival and selection in a unique way. Maintenance
and repair include the prevention and removal of damaged DNA, accuracy in
macromolecular sythesis, and degradation of defective proteins. Life-span of different
species depends on the differential level of somatic maintenance and repair. We can
conclude that long-lived species in general have a greater level of maintenance and repair
systems compared to short-lived species. Scientists have done many studies on this
concept. A study don by Tarin (1994) showed that
from several congenic mouse strains and mammalian species
suggest that there may be an association between cleavage rate of concepti
and longevity, in such a way that concepti from species, strains or the sex
(male) with the fastest cleavage rates have shorter life spans.
Tarin goes on to say that a short lifespan my be due to the fact that fast repoducing cells
tend to make more mistakes in their DNA and structure. Thus somatic mutations build
up and aging occurs at a faster rate. Niedermuller and Hofecker in 1992 did a study
which answered the question: Is selection for extended life expectancy possible by
regularity in aging? They found that in later evolution appearing species of mammals
have longer maximum life span potentials.
According to their data, a nonadaptive
hypothesis of aging was the most plausible and the best hypothesis that fit was the
disposable soma.
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Later species are adapted better to changing environmental
conditions by their other development, their ecological niches are larger,
their environment contains specifically lesser dangers and risks, because
they better cope with them--therefore it is worth while to spend more
energy for the maintenance of their soma than for their reproduction…(
Niedermuller and Hofecker, 1992).
The disposable soma hypothesis balances the maintenance and repair of somatic cells on
one side and the reproduction and fertility on the other. If more energy is used for
maintenance of soma, less will be available for reproduction, and vice versa. This
hypothesis treats senescence as a price paid for sexual reproduction (Kirkwood, 1981).
There is a correlation between time taken to reach reproductive maturity and the species
life-span. Experimental animals whose reproductive age is delayed tend to live longer
than normal animals (Sengall et al, 1991). As you can see there is considerable support
for this hypothesis. Many studies have shown that animals with exhaustive reproductive
activity seem to expend much more energy than is allocated for this purpose. They are
left with little to maintain and repair the somatic cells and therefore they die soon after
their single reproduction. This theory also can draw support from the free radical theory
of aging which will be soon discussed. The maintenance and repair of free radical
damage to various structural and functional molecules play an important role in
determining the aging of an organism. Accumulation of these negative effects occurs
because of failure of prevention and repair systems for such damages.
The free radical hypothesis is probably one of the most popular and widely known
aging mechanisms. People spend millions of dollars per year on products which are
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“supposed” to help prevent free radicals from damaging cells and cell components. But
what is a free radical? I have asked members of my family and some friends who are not
in a science program and they could not give me a reasonable definition. Thus the free
radical hypothesis could be one of the least understood mechanism. Free radicals are
chemical species which contain an unpaired electron in an outer orbital. This unpaired
electron makes them very reactive.
Free radicals can be produced as transient
intermediates in the course of normal cell metabolism. An example of this is found in
oxidative process of the mitochondria.
Since free radicals may attack important
molecules such as DNA, proteins, and lipids, and since they also tend to be selfpropagating, they are capable of generating considerable damage. According to Stanley
Pine (1987), free radicals can be formed in just about any possible reactions such as
fragmentation, substitution, addition, oxidation, and reduction. The process of oxidation
is believed to produce the most free radicals because oxidation-reduction reactions or
organic compounds proceed by free-radical pathways.
Examples of reactive free radicals include the following:
 The very reactive hydroxyl radical (OH), which is produced when ionizing radiation
passes through water.
 The moderately reactive thiyl radical (RS), which is formed when reactive radicals
like the hydroxyl radical react with sulfhydryl groups, e.g., cysteine side chains in
proteins.
 The weakly reactive nitric oxide (NO) radical, which is found in polluted urban air.
Free radicals exhibit some of these patters:
 Attack other molecules indiscriminately.
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 Produce oxygen-consuming chain reactions, such that a single free radical effectively
damages a large number of other molecules.
 Cause fragmentation or cross-linking of molecules, including vital molecules like DNA
and critically important enzymes (Mehlhorn, 1994, and Kirkwood, 1998).
Due to the randomness of the reactions that can occur some products of free radical
chemistry are completely foreign to repair or for reuse into the cell by turnover enzymes
of the cell. An example of this could be that when two proteins become cross-linked,
they might become resistant to attack by proteolytic enzymes and these new molecules
can accumulate progressively in cells just like age pigments which increase with age in
the cells of animals.
One of the most common free radicals is oxygen. Ordinary oxygen has two
electrons with unpaired spins so sometimes it can be called a biradical. Normally the
oxygen radical is quite stable but it can be extremely reactive when other free radicals are
present or in collisions with molecules that very reducing. Although oxygen is inert
towards most nonradical molecules (it can’t initiate free radical chain reactions) it can
react with an organic radical whose unpaired electron is associated with a carbon atom.
This results in peroxyl radical molecules which are moderately reactive which will
remove hydrogen atoms from many different molecules. This can lead to chain reactions
and an accumulation of hydroperoxides.
Chemical products of most free radical
reactions involving oxygen can also be very reactive and many of them have earned the
term “active oxygen” molecules. Several of the most popular species are:
1. Hydroxyl radical, OH
2. Superoxide radical, O2 and two non radicals
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3. Singlet oxygen, O 2
4. Hydongen peroxide, H 2 O2
The most reactive is the hydroxyl radical. No biological molecule is immune to its
attack. Thus organisms have evolved to have major defenses to ensure that this radical
arises as infrequently as possible. Singlet oxygen which can arise from peroxyl radical
reactions is also reactive but not as reactive as the hydroxyl radical. In the presense of
freely dissolved or lossely bound iron or copper and mild reducing agents like ascorbic
acid, hydrogen peroxide can be used to form hydroxyl radicals.
Because of the destructiveness of hydroxyl radicals, hydrogen
peroxide decomposition could be a major source of biological damage
under conditions or iron or copper release from protein binding sites.
Hydrogen peroxide can also interact with heme proteins to produce highly
oxidizing products (ferryl species) that can initiate free radical reactions
(Mehlhorn, 1994).
One of the topics we have not yet discussed is what specific damage does a free
radical do to our body. Nagy in 1994 said that the polymerizing effect of OH radicals
on organic molecules is strongly dependent on the physical density of the system. If the
density of the system is low, a radical will capture an electron from the nearest possible
electron shell which can be refilled only rom the orbits of the same molecule (only
intramolecular cross-links may from). If the density is high, refilling of the electron shell
becomes more possible from other organic molecules (intermolecular cross-link
formation becomes higher). These statements have two very important points hidden in
them.
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First, the density of the cell components is a priori variable, e.g.,
the cytosol is more diluted than the membranes, ect.; therefore, the highest
rate of free radical-induced damage is to be expected in the membranes.
Second, the age-dependent loss of intracellular water content may result in
a higher rate of damage even from fewer free radicals, because the overall
density of the cellular mass increases (Nagy, 1994).
As we near the end of our discussion, I would like to comment on the membrane
hypothesis theory of aging. This little known theory is based on many aspects of cellular
and membrane interactions. I will talk about one main aspect of this theory. Nagy
(1994) said that the cell membrane should be considered the weakest point of the cell. In
addition to free radical-induced damage is exposed to another serious damaging factor
called residual heat. Residual heat is absent in all other membranous components of the
cell. The plasma membrane behaves as a resistance and a capacitance in parallel. The
resting membrane potential (reaching values up to –100 mV) is built up on the membrane
which is 10 nm thick. To us this polarization is very small but at the molecular level it is
very large with voltage reacting up to –100 kV/cm.
For people who know about
electricity, the discharge of such polarity results in considerable heat production just as
we can observe on the condensers used in electronic circuits. Heat productions is due to
the free energy changes and a decrease in entropy in the dielectric when the polarized
electronic field across it is removed. Polarization of the cell membrane discharges at a
rate of 1 to 2 msec during each action potential. This is very frequent when compared to
nerve cells which discharge up to 5- to 100 times per second. Thus the membrane is
exposed to considerable amount of heating all the time. Studies have shown that 90% of
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the heat is not dissipated and the residual heat is left in the membrane. Obviously, the
energy of the residual heat can remain in the membrane only in the form of chemical
bonds which are most likely to be covalent.
The formation of such covalent bonds may be one of the main
factors determining the shortest useful life span of the cell plasma
membrane among all cellular components.
This type of membrane
alteration can be considered as a true “wear and tear” phenomenon which
certainly contributes to the velocity of plasma membrane deterioration
(Nagy, 1994).
Data to support this theory is massive. Shinitzky (1984) wrote a two volume
book which gives a extensive survey of some available data. The data indicates:
1. Microviscosity of the membrane lipid layers is increased.
2. A serious shift of molecular weight distributions of the synaptosomal
membrane proteins toward higher values was observed. This indicates an
increased cross-linking of proteins.
3. Diffusion is lower in most cells.
As you can see, just the heating of the cell membrane can cause major
accumulative damage which will hamper cell function which will then correspond
to body function. It should be noted that this is only a very small portion of the
membrane hypothesis theory. If we were to completely cover this theory we
would look at the decrease of passive monovalent ion permeabilities, the changes
of intracellular colloids and loss of water, the effect of increased density enzyme
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activities, the decrease of rates of RNA and protein synthesis, and the
accumulation of waste products. This would take many text books.
Many scientists are looking for the many and exact mechanisms of aging.
They will never achieve their goals because if we ever did find out what really
causes aging, we could then stop the aging process. As Christians we know that
God created science. Without God science will not make sense. The aging
process is due to the causes of Sin. All around us there is decay. The very
elements are decaying with age. Humans will forever die, age, and grow old until
the day when God will restore order, peace, and harmony which will forever reign
in his kingdom.
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References
Austad, S.N., 1998, Theories of aging: an overview. Aging (Milano), Apr;10(2):146-7.
Kirkwood, T. B. L., and Holliday, R., Aging as a consequence of natural selection, in The
Biology of Human Aging, Bittles, A. H. and Collins, K. J., Eds., Cambridge University
Press, Cambridge, 1986, 1.
Kirkwood, T. B. L., 1998, Biological theories of aging: an overview. Aging (Milano).
1998 Apr;10(2):144-6.
Kirkwood, T. B. L. 1986, repair and its evolution: survival versus reproduction, in
Physiological Ecology. An Evolutionary Approach to Resources Use, Townsend, C. R.
and Calow, P., Eds., Blackwell Scientific Publications, Oxford, 1981, 165.
Mehlhorn, J, Rolf., 1994, Oxidants and antioxidants in aging. CRC Press, London. p6173.
Nagy, Zs, Imre., 1994. The membrane hypothesis of aging. CRC Press, London.
Niedermuller, H., Hofecker, G., 1992, Is selection for extended life expectancy possible
by regularity in aging? Am J Clin Nutr, Jun;55(6 Suppl):1191S-1195S
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Sengall, P. E., Timiras, P. S., and Walton, J. R., 1991, Low tryptophan diets delay
reproductive aging, Mech. Ageing Dev., 23, 245.
Strehler, B.L. (1959): Origin and comparison of the effects of time and high energy
radiations on living systems, Q. Rev. Biol., 34, 117-142.
Pine, H, Stanley., 1987, Organic Chemistry. McGraw-Hill, Inc. New York, p909-940.
Tarin, J. J., 1995, Do the fastest concepti have a shorter life span? Z. Gerontol, MayJun;27(3):166-71.