Vol.2, No.6, 615-619 (2010) Health
Copyright © 2010 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Aging and the decline in health
Robin Holliday
Australian Academy of Science, Canberra, Australia; RandL.Holliday@bigpond.com
Received 4 November 2009; revised 14 December 2009; accepted 17 December 2009.
The biological reasons for aging are now un-
derstood. Aging is the result of multiple sto-
chastic events in molecules, cells, tissues and
organs. These together produce the aged phe-
notype, senescence and ultimately death. Many
of these changes can be directly linked to spe-
cific age-associated disease. However, there are
also age-related changes that are not patho-
logical. It can be said that aging has multiple
causes, or is instead due to a general loss of
molecular fidelity, that is, an increase in disor-
der. The complexity of organism means that
they develop as ordered structures by obtaining
energy from the environment. These ordered
structures must be maintained by a wide variety
of mechanisms which also depend on energy
resources. Eventually these mechanisms fail,
and senescence sets in. It is known that the ef-
ficiency of maintenance is correlated directly
with the lifespan of different mammalian species.
Also, these lifespans are inversely correlated
with fecundity or reproductive potential. There
is a trade off between investment of resources
in maintenance of the body, or soma, and in-
vestment in reproduction.
Keywords: Aging; Senescence; Disease;
Pathologies; Evolution
It is now evident that aging is no longer an unsolved
biological problem [1-6]. However, the relationship be-
tween natural aging in humans to age-associated dis-
eases is controversial. Most books and reviews about
aging completely ignore the vast literature on human age
related pathologies. Also, most research on each of these
pathologists is done by specialists who have no particu-
lar knowledge or interest in the process of ageing per se.
An exception that relates late onset disease to aging is
the excellent monograph The Oxford Textbook of Geriat-
ric Medicine [7]. Hayflick [8] has argued that aging is an
intrinsic process occurring in almost all animals, and that
it is not directly related to particular age-associated pa-
thologies. Instead, he states that aging makes an animal
susceptible to these pathological events. In contrast, it is
argued here and elsewhere [2,5,9] that the process or
processes of aging are responsible for most of these
pathological changes. This leads to the loss or decline of
health that is eventually lethal. Many diseases are the
result of multiple molecular or cellular events. These
events may occur over a long period of time, and it is
their multiplicities that eventually produce the symptoms
of disease. In other words many diseases can be due to
time dependent multiple “hits” which are stochastic
random events. There is an intermediate position which
states that “senescence gives rise to disease, but disease
does not give rise to senescence” [10], and also that the
distinction between senescence and disease is blurred.
At the outset it is important to define some key words.
Health is the state of being free from illness or injury.
Aging is the process of growing old. Senescence is the
condition or process of deterioration with age. Aging
(ageing) and senescence are often used interchangeably.
Disease is a disorder of structure or function which is not
simply the result of specific injury. Pathology is the sci-
ence of the causes and effects of diseases. (It is also the
branch of medicine that deals with the laboratory ex-
amination of samples of body tissue for diagnostic or
forensic purposes, but this is not relevant to the discus-
sion here).
To understand aging one must first explain its biological
origin and function. Organisms develop from the fertil-
ized egg to become adults that are capable of reproduc-
tion. In the natural environment in which evolution oc-
curred, animals are confronted with various hazards, for
example, predators, insufficient food and water, or para-
sites and pathogens. Mortality is therefore high, so that
R. Holliday / HEALTH 2 (2010) 615-619
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most offspring are born to young adults rather than old
ones. In this situation there is little, if any, natural selec-
tion for a long lifespan. Instead, Darwinian fitness is
increased if resources are channeled into reproduction
rather than preserving the body indefinitely [11-13]. It
has been shown that in 47 mammalian species there is an
inverse relationship between fertility and fecundity and
longevity in a non-hazardous environment such as a zoo
or under domestication [2,14]. (In the case of humans,
longevity is highest in developed countries with good
health care). It has also become evident that longevity is
directly related to the maintenance of function of the
various tissues and organs of the body.
There are many maintenance mechanisms, which will
be listed but not reviewed here: 1) The repair of damage
in DNA; 2) The degradation of abnormal protein mole-
cules; 3) The defences against reactive oxygen species
(ROS); 4) The immune system which provides defences
against pathogens and parasites; 5) The detoxification of
harmful chemicals in the diet; 6) Proofreading in the
synthesis of macromolecules, which removes errors; 7)
Wound healing, including the clotting of blood and the
repair of broken bones; 8) Epigenetic controls for normal
cell functions, and which also prevent the development
of cancer; 9) Apoptosis, which removes potentially
harmful cells; 10) Physiological homeostasis co-ordi-
nating the functions of different cells, tissues and organs;
11) The grooming of hair and skin to remove harmful
pests and parasites; 12) The storage of fat as an energy
In this list there is no reference to a central component
of cell function, namely, RNA (apart from proofreading
in its synthesis). This is largely due to lack of informa-
tion. RNA transmits information in DNA to proteins,
The translation of RNA into proteins depends on transfer
RNAs and ribosomes (which consist of proteins and
RNA). There is also the accurate splicing of RNA tran-
scripts. The regulatory role of small RNAs has recently
been demonstrated in normal cells. It would be surpris-
ing if 1) there were not important controls of all these
functions, and 2) there were no age-related changes in
RNA metabolism and function. However, they remain to
be discovered.
Most of the listed maintenance mechanisms are scien-
tific disciplines in their own right, and together they de-
pend on a considerable proportion of the resources
available to an animal. It should also be noted that a
large number of genes are necessary to code for all the
proteins and enzymes that are needed for each mecha-
nism. These genes in one way or another have an effect
on the process of aging.
There have been many comparative studies that
clearly demonstrate that long-lived species have more
efficient maintenance mechanisms than short lived ones.
These have been comprehensively reviewed elsewhere
[2], and since that time more evidence has been pub-
lished [5,15-17]. Only a few examples can be mentioned
here. The same chemical cross links occur more rapidly
in bovine skin than human skin [18]. In rats, carcinomas
are far more frequently than they do in humans, with an
approximately 30-fold difference in the rate of onset [19].
Also, somatic mutations in lymphocytes increase about
10 fold during the lifespan of mice and humans. How-
ever, this increase occurs over about three years in mice
and 80 years in humans [20]. It has been shown that the
defences against ROS correlate with mammalian life-
span [16,21,22]. It has also been shown that these de-
fences are much more efficient in the pigeon, which is
long lived, than the rat, a short lived animal of similar
size and metabolic rate [23]. A similar difference was
demonstrated between small long-lived birds (canary
and parakeet) and the short lived mouse [24]. From all
these studies it can be concluded that it is the eventual
decline in maintenance that brings about aging.
How does the decline or loss of maintenance give rise to
aging? To answer this question we need to consider
many of the events that actually occur during aging
(2,15). It is known that chromosomal changes and also
mutations increase during aging. There may be addi-
tional damage to DNA which is not recognized by repair
enzymes and simply accumulates with time [25]. Many
studies document deletions in mitochondrial DNA. Ab-
normalities in nuclear DNA can result in age-associated
carcinomas. Altered proteins appear in many locations.
Collagen and elastin become cross-linked, which is a
cause of hardening of the arteries. The loss of elasticity
of artery walls can increase blood pressure, and this can
result in kidney damage and also strokes. Many types of
protein react with glucose and other carbohydrates to
produce advanced glycation products (AGEs). These are
high molecular weight aggregates that can occur in many
locations. There is also the accumulation of lipofuscin,
also known as the “age pigment”, which is a complex
mixture of many degradation products. This is also seen
in many tissues during aging. Recently there has been
much interest in epigenetic events during aging, and
particularly “epigenetic drift” [26-28]. These events may
be due to changes in DNA methylation and histone
modification, which in turn can change gene expression.
There may be irregularities in hormone function or me-
tabolism, for example, late onset diabetes is caused by a
failure of the normal controls of insulin levels, or to
changes in insulin receptors. In the brain, neurons may
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be lost or become abnormal, producing the amyloid
plaques and neurofibrillary tangles which give rise to
Alzheimer’s disease and other dementias. In the vascular
system, atheromatous plaques can form on the inner wall
of the major arteries and these impair normal blood flow.
This is a major cause of heart disease. The valves of the
heart can become calcified, which is another component
of the disease. Although muscle tissue can to some ex-
tent repair itself, over a long period of time cells are lost
and not replaced. Aging is frequently associated with
loss of hearing and sight. The long lived protein crystal-
lin becomes denatured and loses transparency, and this
result in the appearance of lens cataracts. Retinopathy is
largely due to the failure to remove protein aggregates
that are the end products of the continual turnover of
photoreceptors in the cells of the retina. The age-associ-
ated diseases of osteoporosis and osteoarthritis, are due
to a decline in normal bone metabolism and the accu-
mulation of damage in bone joints. Another example of
multiple events giving rise to disease is the gradual loss
of kidney glomeruli and eventually renal failure.
The previous section is only a summary of some of the
changes that can occur during aging. They are sufficient
to demonstrate that multiple events at the molecular and
cellular level can bring about very significant changes in
tissues and organs. These in turn can bring about ill
health and disease during ageing. However, not all age
associated multiple events are pathological. A good ex-
ample is the whitening of hair. This is due to the loss of
melanocytes in hair follicles, and the loss of hair follicles
themselves results in baldness. One of the most obvious
effects of aging is on the skin, and this provides a rough
measure of a person’s age. Skin changes are due to loss
of elasticity, wrinkling, and often the accumulation of
pigmented “age spots”. Leaving aside skin cancers, these
cumulative effects are simply part of the aging pheno-
type, and do not impair health. A third example is the
loss of muscle strength with age, which by itself is not a
harmful change, but is can lead to other problems such
as falls and broken bones, particularly if the individual
also has osteoporosis.
It is interesting that these outward manifestations of
aging are not pathological. It is the internal changes that
eventually produce age-associated disease and a senes-
cent phenotype. The longevity of identical twins is more
similar that the longevities of sibs. Also, inbred mice
which are genetically identical and live in the same en-
vironment have quite variable lifespans, and the survival
curve of a population of these mice is an S-shaped curve.
There is a plateau with no deaths, then slowly increasing
mortality, followed by a steeper increase in mortality.
Finally, the slope of the curve flattens out and a few
“outliers” achieve the longest lifespan [29] If this curve
is plotted on a logarithmic scale, there is again a plateau
followed by an exponential decline in surviving animals.
This is very similar to observations in radiology, where,
for example, a population of viruses is irradiated. Again
there is a plateau in survival, followed by an exponential
decline in survival. This is an example of a multiple hit
survival curve. The same can be said of many of the
vulnerable components of the body, and taken together
this constitutes aging of the whole body. Obviously,
there is not complete synchrony in the change and loss
of function of one or another tissue or organ system.
This can gives rise to a common misconception. For
example, it has frequently been said that dementia has
nothing to do with ageing because many old people re-
tain their mental facilities throughout their lifespan. The
same can be said of carcinomas, cardiovascular disease,
and so on. A further related and interesting point is that
death certificates must specify a particular cause or
causes of death, it is not permissible for a physician to
use the term “natural aging”.
During long periods of evolution some animal species
reduce their lifespan, whereas others increase it. Since
aging is multi-causal, the evolved changes in the effi-
ciency of maintenance must depend on a degree of syn-
chrony in the rate that tissues and organs gradually be-
come senescent. There would be no selective advantage
if one organ system increased (or reduced) its survival
time, whilst others did not. This was first clearly stated
by John Maynard Smith nearly fifty years ago [30].
In his book What is Life? Schrodinger [31] discussed the
complexity of living organisms. The second law of
thermodynamics states that ordered states of atoms and
molecules will eventually become disordered. Schrod-
inger wrote about organisms feeding on negative entropy.
This means that they depend on energy to maintain their
complex structures, which is a contravention of the sec-
ond law. It is obvious that this is not a permanent situa-
tion because aging eventually results in death, and it is
after this that disorder prevails. Instead of stating that
there are multiple causes of aging, one can instead re-
gard the whole process of aging to have just one cause,
and this is the loss of molecular fidelity, and gain in en-
tropy. This is the viewpoint of Hayflick [4,8].
There is, however, no radical distinction between this
one cause of aging and the multiple causes that have
been discussed here. The analogy of a motor car helps to
explain this. The car is a complex machine that requires
R. Holliday / HEALTH 2 (2010) 615-619
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continual service and maintenance. With time it is sub-
ject to wear and tear in its component parts which are to
some extent independent of each other, but are also es-
sential for its normal function.
We can equate the loss of molecular fidelity or in-
creasing molecular disorder with wear and tear. The
component parts of a car cannot be expected to last in-
definitely, for example, the gearbox, the electrical sys-
tem, the cooling system, the engine, and so on. With
time the defects increase and are more and more expen-
sive to repair. At a given point in time the car is not
worth repairing and reaches the end of its working life.
We can conclude that the multiple parts of a car deterio-
rate at a given rate, and its life ends as a result on innu-
merable cumulative defects, which are the equivalent of
“molecular infidelity” in an organism. It is also signifi-
cant to note that a vintage car can be maintained indefi-
nitely, but at huge expense. Similarly an animal body
could, in principle, be maintained indefinitely, but a cost
in resources that would be selectively disadvantageous.
Thus all animals, except a few of the simplest, have fi-
nite lifespan.
The biological reasons for aging are no longer a mystery.
The adult organism is a structure capable of reproduction
for a given period, but in a natural environment, most
offspring are born to young adults because environ-
mental hazards limit the lifespan of parents. The energy
resources available to every animal are used for general
metabolism, for reproduction and also to maintain the
body, or soma. Normal metabolism is obviously essen-
tial for life, but there is a trade off between the invest-
ment of resources in reproduction and in body mainte-
nance, which varies between species. Thus, short lived
small species, such as rodents, can have many offspring,
whilst large long lived species have few offspring.
In the case of the human species, a great deal is
known about the changes that occur with aging. Many of
these changes affect vital functions which result in a
decline in health and eventually to events that cannot be
treated at all. Nevertheless, the last few months of life
very often depend on medical resources that are increas-
ingly expensive, especially in developed countries. In
the end, all care and treatments fail, and the elderly indi-
vidual dies. It is true to say that aging is almost always
associated with a decline in health leading to death.
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