IUBMB Life, 59(4 – 5): 249 – 254, April – May 2007
Critical Review
Theories of Ageing
Jose Viña1, Consuelo Borrás2 and Jaime Miquel3
1
Department of Physiology, School of Medicine, University of Valencia
2
Catholic University of Valencia
3
Department of Biotechnology, University of Alicante, Spain
Summary
Ageing is a universal, intrinsic, progressive and deleterious
process. Understanding it is of major interest to scientist, physicians
as well as to the general population. Critical to this understanding is
to formulate comprehensive theories of aging with high predictive
and explanatory power. More than 300 theories have been postulated
and are reviewed here. The free radical theory of ageing is one of the
most prominent and well studied. It was further developed by one of
us (JM) in what has become known as the mitochondrial theory of
ageing. These theories provide new experimental approaches to
further develop our understanding of the phenomenon of ageing.
IUBMB Life, 59: 249–254, 2007
Keywords Senescence; longevity; oxidative stress; free radicals.
THE CONCEPT OF AGEING
So far we do not have a universally accepted definition of the
process of ageing. Denham Harman postulates that ageing is the
result of the progressive accumulation of changes in the body
which occur with the passing of time and which cause the
increase in the probability of disease and death of the individual.
It can also be defined as the wearing of the structures and
functions that reach a peak or plateau during development and
maturations of the individuals of a given species. Bernard
Strehler, a very well-known American gerontologist, defines
ageing by means of four postulates (see Fig. 1):
. Ageing is universal: a phenomenon associated with the
process of ageing must occur in different degrees in all
individuals of a species.
Received 2 November 2006; accepted 6 November 2006
Address correspondence to: Dr Jose Viña, Department of
Physiology, Universidad de Valencia, Avda. Blasco Ibáñez 17,
46010 Valencia, Spain. E-mail: jose.vina@uv.es
ISSN 1521-6543 print/ISSN 1521-6551 online Ó 2007 IUBMB
DOI: 10.1080/15216540601178067
. Ageing must be intrinsic: the causes that are the origin of
ageing must be endogenous; they must not depend on
extrinsic factors.
. Ageing must be progressive: changes that lead to ageing must
occur progressively throughout the life span (they must also
occur in young individuals, albeit in a small proportion).
. Ageing must be deleterious: i.e., a phenomenon associated
with ageing will only be considered as part of the ageing
process if it is ‘bad’ for the individual.
CONSEQUENCES OF AGEING
Virtually all physiological functions lose efficiency with
ageing. In general terms, we accept that ageing causes a loss in
the capacity to maintain the internal milieu of the individual
when faced by changes in the external atmosphere. Thus the
individual loses the capacity to maintain homeostasis. A good
example of this is the lower capacity of elderly persons to
endure extreme temperatures, infections, or in general the
situations in which stress occurs. Thus, the force and elasticity
of the skeletal muscular system are deteriorated; there is a
lower glomeral filtration in the kidneys, lower pulmonary
ventilation, and a lower maximal blood flow through the heart.
We can also find intolerance to glucose associated with ageing.
It must be noted that the glycaemia in the elderly is similar to
that of the young. What we lose with ageing is the capacity of
maintaining glycaemia after hyperglycaemic insults such as
overdoses of oral glucose. This is a good example of the loss of
the capacity to maintain homeostasis with ageing. Critically
important, ageing causes losses in vision, hearing capacity,
memory, motor co-ordination, and other neural functions of
physiological importance. The majority of vital organs will
suffer phenomena associated with atrophy or degeneration.
Among the most notable ones are organs which are composed
of post mitotic cells such as neurons, myocardial cells, or
muscle. Moreover, ageing causes a degradation of intercellular
matter. For instance, there is a decrease in the number of elastic
fibers, as well as cross links of collagen fibers in the dermis.
250 VIÑA ET AL.
Ageing is also associated with an increased susceptibility
to trauma, infections and many other forms of stress. The
functioning of the immune system is impaired and this gives
rise to both an increase in auto-immune disease as well as an
increased susceptibility to infections.
The incidence of cancer increases exponentially with age.
And the same happens with the incidence of degenerative
diseases, of which the neurodegenerative ones are the most
prominent.
LONGEVITY
The term longevity includes two different concepts: max-
imal and mean longevity. Mean longevity is defined as the
mean life expectancy at birth of individuals of a given species
(1). Maximal longevity is the maximal age of any individual of
a given species that can be recorded. In this way, it is well
known that the mean longevity of the human species has
increased considerably during recorded history. This has
happened especially thanks to a decrease in infantile mortality,
to the discovery of vaccines, antibiotics, and in general to an
improved control of infectious diseases as well as to improved
nutrition. Of special note is the critical relevance of the
increase in hygiene and in general of public health in the
improvement in average life span that has occurred in the 20th
century.
In fact, the increase in mean longevity which occurred
during the 20th century, which changed from approximately
33 years to approximately 80 (always higher in females than in
males) has never previously occurred in recorded history and is
very unlikely to occur again. Indeed, we have not found an
increase in maximal longevity in the human species. Long ago
there were persons who reached the age of 80 or 90 years,
although the per cent of these persons is much lower than
Figure 1. Characteristics of the ageing process.
nowadays. The consequence of the increase in average
longevity is that the population from 60 to 100 years has
risen. Thus, the incidence of degenerative diseases such as
Alzheimer’s, Parkinson’s, and atherosclerosis has increased
enormously.
The advances in research on longevity bring the same kind
of results, albeit in animal species. Many manipulations (such
as dietary supplementations of vitamins, the practice of
physical exercise and others) have been successful in increasing
average or mean longevity in experimental animals, such as
rats, mice or Drosophila, but only very few manipulations have
been successful in increasing maximal longevity. The most
thoroughly studied intervention to increase longevity is dietary
restriction. In 1934, McKay et al. (2) published that dietary
restriction (but taking great care to maintain adequate intake
of proteins and of micronutrients) increased longevity, both
average, and to a certain extent, maximal longevity in rodents.
Walford and Weindruch (3, 4) reported that even late onset
establishment of dietary restriction was efficient in increasing
longevity of animals. The effect of calorie restriction on gene
expression, antioxidant status, and many other metabolic
parameters has been thoroughly studied but falls out of the
scope of this review.
THEORIES OF AGEING
There are many theories of ageing (see Fig. 2). In 1990
Mevdevev (5) in an excellent review stated that there were more
than 300 theories of ageing and the number is increasing. This
is a natural consequence of the fact that we are quickly
improving our understanding of the natural phenomena that
are associated with ageing using new experimental methods
and ideas. In fact, almost any major discovery in cellular and
molecular biology has given rise to a new family of theories of
ageing or to improved versions of old ones. Thus, the task of
reviewing these theories is becoming more and more difficult
because they are either very selective or they are now
old fashioned. However, as pointed out by Vijg and Müller
Figure 2. Theories of ageing. Classification.
 THEORIES OF AGEING
(6) some of the old hypotheses of ageing laid the ground for the
big scientific revolution in our understanding of ageing, which
occurs in our days. We believe that the expectation of a unified
theory which includes all the phenomena associated with
ageing is, at the present time, unrealistic. Moreover, it is gen-
erally accepted that we do not have all the pieces to the puzzle
of ageing. However, it is indeed possible, as we attempt to do in
this review, to offer a preliminary solution to the problem of
offering satisfactory theories of ageing, which can guide new
experiments that will of course increase our understanding of
ageing at the various levels of biological organization.
THE FREE RADICAL THEORY OF AGEING
One of the most prominent theories to explain ageing is the
free radical theory of ageing which was initially proposed by
Harman in the 1950s (7). The free radical theory of ageing as
stated by Harman proposes that free radicals derived from
oxygen are responsible for damage associated with ageing. The
antioxidant systems are unable to counterbalance all the free
radicals continuously generated during the life of the cell. This
results in oxidative damage in the cell and thus in tissues. There
is a great deal of experimental proof in support of this theory.
Old animals show a higher index of oxidation than young ones
and indeed they accumulate oxidized proteins, oxidized DNA
forms, and oxidized lipids (8, 9). The damage can be attributed
to an increased rate of free radical production in older
organisms. Other experimental evidence supports this theory
as a cause of ageing. For instance, increasing antioxidant
defences results in an increase in the average life span. In a
similar fashion, reactive oxygen species are involved in
degenerative diseases associated with age (10). Similarly,
antioxidant administration increases average life span in
Drosophila (11, 12). Moreover, Orr and Sohal have found
hard experimental evidence in support of the free radical theory
of ageing: Drosophila over-expressing both Cu/Zn-superoxide
dismutase and catalase, show an increase in both average and
maximal life span (13). However, the same authors published
later that Drosophila over-expressing both Mn-superoxide
dismutase and catalase, don’t show an increased life span,
although the transgenic flies displayed an enhanced resistance
to experimental oxidative stress. This observation suggests that
modification of life span not only depends on resistance against
oxidative stress, but also on the specific manipulation of
antioxidant pool which is modified (14).
Reactive oxygen species are continuously generated in the
mitochondrial electron transport chain (15, 16). Approxi-
mately 1 – 2% of all oxygen used by mitochondria in
mammals, in state 4 does not yield water but reactive oxygen
species. Under physiological conditions this ROS production
should be lower, because 2% is the maximum production of
reactive oxygen species by mitochondria under non-physiolo-
gical conditions, when respiratory chain is inhibited by
Antimycin A (15, 16).
251
Based on these facts, Miquel and co-workers proposed in
1980 the mitochondrial theory of free radicals in ageing (11).
The theory suggests that senescence is the result of damage
caused by reactive oxygen species to the mitochondrial
genome in post mitotic cells (11). Mitochondria from post
mitotic cells use oxygen at high speeds, thus producing ROS
which cause oxidative stress as they overwhelm the antiox-
idant cellular defences (17).
The mitochondrial theory of ageing has been recently tested
in various laboratories and there are many published papers in
support of this theory. For instance, data from the laboratory
of Sohal and from our own laboratory have shown that
mitochondria from old animals produce more ROS than those
from young ones (18). Moreover, there is an inverse relation-
ship between mitochondrial peroxide production and long-
evity in mammals (19, 20). These results support the
hypothesis that the rate of the oxidant generation by
mitochondria is a critical factor in ageing (19). Furthermore,
oxidative damage to mitochondrial proteins and mitochon-
drial lipids occurs during ageing (21 – 24). Interestingly, the
rate of peroxide generation increases with age. Corbisier and
Remacle performed an interesting experiment in support of
this idea. These authors micro-injected isolated mitochondria
from fibroblasts of old rats into cells of young ones and so the
ones who had received ‘old’ mitochondria rapidly entered
senescence (25).
Thus, the continuous ROS generation by mitochondria
during the whole life span, causes a chronic oxidative stress,
associated with age, which plays a critical role in ageing. In
addition, the rate of oxidant production by mitochondria from
short-lived species is much higher than that of longer-lived
ones (18 – 20). It appears, therefore, that the rate of oxidant
production by mitochondria is a key determinant of maximal
life span potential.
Mitochondria are not only involved in the fundamental
ageing process, but also in the loss of functional properties
associated with ageing (11, 22). We have observed that
respiratory activity of mitochondria decreases with age in
liver, muscle, and brain. Mitochondrial membrane potential
also decreases with age. Interestingly, the rate of transcription
of some mitochondrial genes decreases with age in rats and
Drosophila (26). Prominent amongst these is 16S rRNA. This
RNA molecule is highly susceptible to oxidative stress (27).
Indeed the expression of this mitochondrial gene decreases with
age in parallel with the survival curve of Drosophila (26). Thus,
16S rRNA can be considered as a biomarker of cellular ageing.
The activity of other important proteins, such as transport
proteins, is also associated with age. Prominent amongst these
proteins are diphosphate and the dicarboxylate transport in
liver mitochondria.
The rate of oxidant production by mitochondria is rather
difficult to study. Moreover, although the general agreement is
that it increases with age, some laboratories are unable to
confirm this fact. Consequently, studying biomarkers of
252 VIÑA ET AL.
oxidative stress appears more adequate than studying the rate
of oxidant production. For instance, lipid peroxidation can be
studied using different biomarkers such as ethane or penthane
exhalation in expired air (28). Lipid peroxidation is associated
with the pathogenesis of a number of age-associated diseases
(29). Protein oxidation is another interesting biomarker of
oxidative stress. Twenty years ago, Vitorica et al. (30) studied
enzyme specific damage associated with age. As a result, they
found that not all enzymes are inactivated, or damaged, at the
same rate with ageing and that some are more susceptible to
damage than others. Earl Stadtman and his co-workers in a
notable series of papers, reported that many of the post-
translational modifications found in old cells are due to the
deleterious effects of free radicals (8). In fact, some key amino
acids such as proline, arginine or lysine are oxidised to yield
carbonyl derivatives, i.e., aldehydes.
DNA may be the most critical target molecule for age-
associated oxidative stress. Bruce Ames and his co-workers, in
California, have calculated that reactive oxygen species modify
approximately 10,000 bases of DNA per cell (31). DNA
repairing enzymes are able to repair the vast majority of these
lesions, but not all. Therefore, DNA lesions that go un-
repaired, such as 8-oxo-dG accumulate with age. It is well
known that mitochondrial DNA is much more oxidized with
age than nuclear DNA (21). Our group, in 1996, showed that
oxidative damage to mitochondrial DNA correlates with
oxidation of mitochondrial glutathione (22).
To sum up, the free radical theory of ageing, and
especially the mitochondrial theory of ageing, is particularly
attractive not only because they appear to be supported by a
vast number of experiments, but also because they suggest a
rational intervention therapy: the administration of anti-
oxidants which could retard age-associated damage. More-
over, these two theories could explain almost all the
phenomena explained by previous theories of ageing such
as the loss of immune response, the accumulation of lipo-
fucsine, of somatic mutation, or even Orgell’s catastrophic
theory of ageing.
WEAR AND TEAR THEORIES
These theories are based on the idea that ageing is a
‘secondary effect’ of physiological work of cells (32, 33). They
are based on data obtained in the early part of the 20th
century (34, 35) essentially in Drosophila melanogaster. These
data were later confirmed by Miquel and co-workers in the
1970s (36 – 38). They show that within the range of tempera-
ture in which these insects can live, life span is inversely
proportional to room temperature.
Moreover, the idea that proteins can be denatured by heat
and that this could be involved in accelerated ageing in insects
and other poiquiloterms has been proposed (37). However,
Strehler pointed out the fact that the high activation theory of
this reaction makes it unlikely that they are relevant in the
ageing process. In fact, in the early 20th century (39) it was
proposed that the activation energy of the ageing process in
Drosophila is more similar to that of enzyme catalysed
reactions than to non-enzymatic chemical reactions. These
wear and tear theories coincide with the rate of living theory of
ageing of Pearl (33) in that changes in room temperature affect
longevity in Drosophila, and that this is due to the modulation
on the oxygen consumed by these flies (36, 38). Essentially, the
rate of oxygen utilization when referred to milligram of body
weight in Drosophila is inversely correlated with the maximal
life span of these flies at a room temperature of 258C (40). This
inverse relationship between aerobic metabolism and longevity
is preserved even when Drosophila are without gravity, flying
in space satellites (41).
THE ROLE OF ANTIOXIDANTS IN THE
MODULATION OF THE AGEING PROCESS
Richard Cutler observed that several antioxidants such as
vitamin E, uric acid, cellular plasmin or superoxide dismutase
in several organisms show an inverse relationship with the
basal metabolic rate and with the maximal longevity of species
(42). Thus, he proposed that the maximal life span should be
correlated with the antioxidant capacity of cells. In keeping
with this line of thought Orr and Sohal observed that double
transgenic Drosophila over-expressing Cu/Zn-superoxide dis-
mutase and catalase show less oxidative stress and more life
span, both mean and maximal (13). Moreover, they found that
the process of ageing was slowed. Indeed, the transgenic
Drosophila showed a lower loss in physical activity and less
markers of damage in proteins. However, they did not observe
an effect on life span when each of these two enzymes was
separately over-expressed (43). A critically important point is
the relationship between the various antioxidants in cells.
Persons with defects in absorption of vitamin E or with low
glutathione levels show different conditions but not an
accelerated ageing. In fact, using high doses of vitamin E in
some age-related diseases such as Alzheimer’s, is being lately
questioned after the publication of some studies which show
that its administration is detrimental for the patients (44).
However, there are also some recent reports which state that
high doses of vitamin E improve survival, neurological
performance and brain mitochondrial function (45). Thus,
there is a controversy in the use of high doses of vitamin E in
age-related diseases such as Alzheimer’s disease.
The group of Barja, in Madrid observed that by inhibiting
catalase in frogs, an over-expression of superoxide dismutase
and glutathione reductase occurs and an increase in the
synthesis of glutathione also takes place. This in fact gave rise
to an increased longevity of the frogs (1). Thus organisms tend
to maintain homeostasis and it is very difficult to visualize that
cellular antioxidants may act separately. In fact, they are
chemically related and changes in one antioxidant will affect
the activity of others (1, 42).
 THEORIES OF AGEING
INTEGRATION OF THEORIES OF AGEING
Some of the more than 300 theories of ageing mentioned by
Medvedev in his 1990 classical review paper (5) have been
abandoned as they could not be ratified when submitted to the
appropriate experimental tests whether in human beings or
laboratory animals. Others, like the free radical theory of
ageing have found stronger experimental support. In fact,
Pearl’s theory of wear and tear, which indicates that ageing, is
a ‘secondary effect’ of metabolism has indeed been supported
by experiments. On the contrary, Orgel’s theory of the
catastrophic error in the synthesis of protein, which was
widely accepted in the 1960s could not be confirmed by
experimental research. Equally, the theory of the limited
number of cell divisions, as proposed by Hayflick, is now being
questioned based on recent experimental evidence, particularly
in multi-cellular organisms.
In fact, it is generally accepted that ageing is linked with this
organization in cells probably caused by oxidative stress
associated with the deleterious effect of reactive oxygen species.
On the other hand, many of the more recent hypotheses
proposed a relationship between ageing, genetic programming,
the loss of telomeres, and apoptotic cell death and even if all
these processes are probably linked with age-associated diseases,
their role on normal ageing has still not been fully clarified.
The importance of postulating comprehensive theories of
ageing lies in the fact that it lays the ground for new
experiments, which will help us to understand more fully the
process of ageing, and thus to improve longevity and quality
of life of animals, and in the last instance of human beings.
ACKNOWLEDGEMENTS
Laboratory work reported here was supported by grant
SAF2004/ 03755 to JV.
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