Aging and the decline in health

doi:10.4236/health.2010.26092

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Vol.2, No.6, 615-619 (2010) Health

doi:10.4236/health.2010.26092

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.

ABSTRACT

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

1. INTRODUCTION

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).

2. THE BIOLOGICAL REASONS FOR

AGING

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

616

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

reserve.

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.

3. CAUSES OF 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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617

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.

4. MULTIPLE EVENTS

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].

5. THE LOSS OF MOLECULAR FIDELITY

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

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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.

6. CONCLUSIONS

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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