ADDING LIFE TO YEARS
AND YEARS TO LIFE
Sonya Norris, Tim Williams,
Science and Technology Division
27 October 2000
TABLE OF CONTENTS
LIFESPAN AND LIFE EXPECTANCY
HISTORICAL TRENDS IN LIFE
A. Heart and Lungs
C. Immune System
F. Eyes and Ears
AGING AND LIFESTYLE: USE
IT OR LOSE IT
MOLECULAR AND BIOCHEMICAL
RESEARCH INTO AGING
A. Damage With Age
3. DNA Damage
B. Minimizing the Damage
Neutralizing Free Radicals
DNA Protection and Repair
C. Telomeres and Programmed
Longevity through Caloric Restriction
ADDING LIFE TO YEARS
AND YEARS TO LIFE
In 1999, 12.4% of the Canadian
population was 65 years of age or older. In 2026, this age group is expected
to represent 21.4% of the population. During this time, the total population
of people over 90 years of age is expected to more than triple while the
number of people below age 44 is expected to drop by over one million
people. These demographic changes will have a profound impact on society,
ranging from our view of retirement to changing demands on the medical
system. The extent of this impact will depend on the health of our aging
society. This in turn will be heavily influenced by our scientific understanding
of the aging process and the causes of ill health, through which we may
improve the health of the elderly. New research into the longevity of
laboratory animals has also raised the prospect of extending lifespan,
the possibility of which has many ethical and practical implications.
This paper describes the state of our knowledge of the aging processes,
with a particular emphasis on the distinction between normal aging and
AND LIFE EXPECTANCY
Lifespan is the maximum
length of life of an organism. For humans, the longest recorded lives
have been in the vicinity of 120 years, and so this has been taken, somewhat
arbitrarily, to be the lifespan of a human. Life expectancy is the average
length of time a person would live based on current rates of death (mortality).
Currently, the life expectancy from birth for a male in Canada is 75.7
years; for females, it is 81.4 years. The actual average number of years
lived by a population depends on changes to mortality that occur over
their lifetimes. Interpreting published life expectancies between countries
may also be difficult given that reporting and calculation differences
exist. For example, there is some variation between countries concerning
the criteria for reportable live births.
Life expectancy can be calculated
for people at different ages. For instance, life expectancy at age 65
for males is 16.2 years while for women it is 20 years. Comparing this
with the life expectancy from birth it is evident that, if one reaches
the age of 65, the average age of death is higher (81.2 vs. 75.7 for
males, 85.0 vs. 81.4 for females). This is because life expectancy at
birth takes into account infant and young adult death, which brings the
HISTORICAL TRENDS IN LIFE EXPECTANCY
Life expectancy from birth
has increased dramatically since 1900 in Canada. Then, a male had a life
expectancy of 47 years and a female had one of 50 years. Today, these
expectancies have increased by more than 60%. The rate of increase in
life expectancy at birth was great for the first 50 years of the 1900s
but has slowed down since the 1960s. The increase in life expectancy at
the beginning of the 20th century was the result of medical
discoveries, such as vaccinations, and the implementation of such public
health measures as water chlorination. Many infectious diseases that were
common in Canada are now virtually eradicated. With lower death rates
due to infectious diseases of younger people, life expectancy increases
greatly because the death of a young person has a large impact on the
average age of death.
In the past 30 years, the
impact on life expectancy has been largely due to a decrease in unintentional
injuries leading to death as well as through a reduction in cardiovascular
Trends in life expectancy
at greater ages have also increased but not nearly to the extent of life
expectancy at birth. In the United States, life expectancy at age 85 was
4.6 years in 1960, rose to 6.2 years by 1975 and has not changed since.
Thus while great strides have been made in increasing life expectancy
at birth, largely through combating disease, lifespan has risen only minimally.
Medical advances against
disease will almost certainly continue to increase life expectancy but
the lack of any great increase in maximum lifespan suggests that there
may be limits to how old people can get. The question then arises as to
why, in the absence of disease, people age. The process of aging in the
absence of disease is often referred to as normal aging.
There are many misconceptions
about what normal aging processes are and, as we learn more about aging,
it is becoming clear that many of the negative images people have of the
process of growing old are largely a function of disease and changes in
lifestyle, rather than inevitabilities of age. Many of the inconsistencies
regarding aging have arisen because the focus of research on aging has
been on elderly people with disease. Findings from longitudinal studies
of healthy individuals, such as the Baltimore Longitudinal Study on Aging,
are beginning to give a clearer picture of physiological changes associated
with normal aging.
A. Heart and Lungs
Although there are some
changes in cardiovascular function with age, the changes are not nearly
as significant as one might expect. Increases in arterial stiffness can
lead to increased resistance to blood flow and consequent hypertension
as well as some thickening of the walls of the heart. However, the heart
pumps more efficiently. As well, generalized stiffness in the chest cavity
can lead to progressive loss of pulmonary function including a decrease
in the effective volume of air that can be forcibly exhaled from maximum
inhalation. The lungs also lose some capability of clearing foreign particles
and infection. In effect, the capacity to supply oxygen to the body is
not greatly reduced by age alone but can be more easily compromised by
The flow of blood in the
kidneys (renal blood flow) drops by 10% per decade after age 20 so that
an 80-year-old might expect to have half the renal blood flow of a young
adult. The number of filtration structures known as the glomeruli decreases
by 30% to 40% by age 80, and the efficiency of the remaining ones also
declines. Despite this, the kidneys, under unstressed circumstances, retain
the ability to maintain fluid and electrolyte balance. Once again, however,
kidney function is more easily compromised by disease, and its ability
to function under increased loads of some salts is decreased.
C. Immune System
Another common observation
of aging is that infections that would have been tolerable in earlier
years can prove fatal in the later years. Older persons who do not succumb
to diseases such as cancer or cardiovascular disease often die from the
flu or pneumonia. This is a result of the immune system no longer being
capable of fighting a "routine" invasion.
White blood cells (lymphocytes)
fight infections such as bacteria. There are two types of lymphocytes:
B-cell and T-cell lymphocytes. T-cells are produced in the thymus, which
is known to shrink with age. Predictably the level of functioning T-cells
also declines with age. Some T-cells (called helper T-cells) produce substances
called lymphokines which in turn mobilize other immune system components.
Interleukin-2 is one of the lymphokines and is known to decrease with
age. Current research is analyzing the anti-aging effects associated with
It has been known for some
time that the levels of the sex hormones estrogen and testosterone fall
considerably over time. In addition, other hormones such as growth hormone
(GH), melatonin and dehydroepiandrosterone (DHEA) may also decrease with
age. These and other decreases help to explain much of the observed deterioration
of old age. Older women are at increased risk of osteoporosis and breast
cancer for example, as a result of the fall in estrogen levels. Growth
hormone is also linked to bone strength, as well as muscle mass, and as
its level goes down with age, frailty increases. Injections of growth
hormone have been found to reverse some of the signs of aging but may
in fact reduce overall lifespan. Related to GH, researchers are also studying
the effects of growth hormone releasing hormone that results in higher
levels of GH, and of insulin-like growth factor-1 (IGF-1) which is secreted
in response to higher GH levels. Melatonin appears to regulate some seasonal
changes in the body and may be associated also with sleep disturbances
that are common among the elderly. The adrenal hormone DHEA is a precursor
to testosterone and has been proposed as a means to enhance the immune
system of the elderly and to protect against cardiovascular disease, multiple
sclerosis and cancers. DHEA which boosts levels of interleukin-2
(see Immune System above) may be needed for the function and proliferation
of immune cells.
Recent studies have shown
that there is some localized age-related loss of neurons, but that many
neuronal pathways are able to compensate by increasing the number of connections
between cells and by regrowing extensions of the nerve cells such as the
dendrites. As a result, many cognitive functions such as sustained attention,
most linguistic abilities and sensory memory do not change greatly with
Although many functions
of the brain remain uncompromised, neural loss in a region of the brain
known as the suprachiasmatic nucleus is associated with disturbances in
the circadian clock. Older people tend to want to sleep earlier and rise
earlier than do younger people.
F. Eyes and Ears
There is frequently a reduction
in the ability to focus close up and on moving targets, as well as an
increased sensitivity to glare and difficulty seeing at low light. Higher
frequency sounds are more difficult to hear with increasing age.
AGING AND LIFESTYLE: USE IT
OR LOSE IT
The image of debilitating
old age is not necessarily real. If diseases such as atherosclerosis and
other cardiovascular maladies can be avoided, the body continues to function
relatively normally as it ages. Many health problems commonly associated
with aging can, therefore, be avoided through the control of disease.
It is also becoming clear that lifestyle and diet play significant roles
in the creation and avoidance of health problems. As we age, we tend to
become more sedentary and eat less well. This in turn can have significant
health consequences that can be improved by reintroducing activity and
a nourishing diet.
Muscle loss, bone strength,
blood glucose levels and cardiovascular capacity are all common ailments
that are generally associated with old age. They may have little to do,
however, with the processes of biological aging and can be reduced by
remaining active and maintaining good eating habits. When adults, who
have previously led sedentary lives, have an exercise program, it causes
remarkable improvements in, for instance, their ability to ventilate the
lungs and the functioning of blood vessels. Equally, high blood glucose
levels, which are frequently found in the elderly, are commonly the result
of bad nutrition and lack of exercise. Exercise programs for elderly,
glucose-intolerant individuals greatly improve glucose metabolism and
decrease blood insulin levels. Osteoporosis has been shown to have links
to smoking, inadequate calcium and lack of exercise. Exercise can also
help to reset the circadian clock, located in the brain, which dictates
when the body wants to sleep.
In addition to the benefits
of physical exercise, there is now some evidence to suggest that keeping
the mind active can help mitigate against some forms of mental decline.
This idea is supported by studies in which rats that were kept in stimulating
environments had larger cerebral cortexes, larger neurons and more connections
among neurons than did rats kept in non-stimulating environments.
Our understanding of disease
processes and lifestyle influences has greatly improved our capacity to
alleviate some of the physiological problems that we commonly associate
with aging. Medical improvements to fight disease and changes in lifestyle
have thereby increased, and will continue to increase, life expectancy
and the quality of life as we age. Lifespan, however, has been little
affected by these advances. Further improvements in life expectancy, and
the possibility of extending lifespan, may come from improving our understanding
of the more fundamental biochemical and molecular processes behind normal
MOLECULAR AND BIOCHEMICAL
RESEARCH INTO AGING
Throughout the life of an
organism, it faces a constant assault from environmental factors such
as radiation and chemicals that can react with and damage important biological
molecules and processes. Equally, the more times cells reproduce their
genetic material, the more likely that mistakes may be made. Thus over
time, the fundamental structure of cells and the day-to-day activities
of cells can be compromised. The ability to repair structural and metabolic
damage is key to reducing many age-associated effects.
It is also known that the
activity of a variety of genes changes with age. Of particular interest
are a number of genes involved in cell division that are down regulated
with age. Apparent aging rates can also be associated with specific genes.
Diseases such as Werners Syndrome and Hutchinson-Guilford progeria
are associated with single genes, and cause patients to prematurely undergo
genetic and physiologic changes similar to aging. Werners Syndrome
causes death usually by age 50 while the Hutchinson-Guilford disorder
results in death before age 15.
In addition to damage accumulation,
aging appears also to be the result of programmed processes. This specifically
refers to senescence, the state into which cells enter after a pre-determined
number of cell divisions. Finally, calorie-reduced diets are associated
with increased lifespans and involve the interaction of many of the facets
A. Damage With Age
Free radicals are the normal
by-product of the metabolism of fats, proteins and carbohydrates into
energy; in most cases, they are properly disposed of by the cells
own defences. Free radicals are atoms, molecules or compounds with an
extra-unpaired electron. In this unstable state, the compound is highly
reactive and needs to take an electron from somewhere else in order to
become stable. The electron source can be any compound, which is in turn
left unstable and in need of an electron. This sets off a chain reaction
resulting in the formation of some harmful compounds, particularly a class
called reactive oxygen species (ROS), capable of damaging proteins, membranes
Some gerontologists(1) have used diabetes as a model for aging after observing
that diabetics exhibit some signs of premature aging. Diabetics have faster
rates of glucose crosslinking than do normal individuals.
Glucose crosslinking begins
when glucose and proteins combine to produce "glycoproteins,"
a process called glycosylation. These glycoproteins then link together,
or crosslink, to form advanced glycosylation end products (or AGEs). AGEs
appear to toughen tissues and may be involved in the deterioration associated
with aging, such as stiffening of the connective tissue, hardened arteries,
clouded eyes (cataracts), loss of nerve function, and less-efficient kidneys.
All of these changes are common in old age and are observed to occur prematurely
3. DNA Damage
DNA damage can occur as
a result of radiation, including UV, chemicals or as the result of mistakes
made in the DNA replication process. Replication mistakes in particularly
sensitive areas of the yeast genome, for instance, yield small circles
of DNA. The accumulation of these is directly related to cell age. Daughter
cells, which inherit some of these circles, have shorter lifespans.
Radiation and chemicals
can lead to mutations, the placement of a wrong letter of the DNA alphabet
in the genome. These point mutations accumulate in older cells. It is
theorized that the accumulated genetic damage leads to malfunctioning
proteins and cells and ultimately tissues and organs. Such accumulated
damage could explain increased frequencies of cancer and the decline in
immune function in the elderly.
DNA is not exclusively confined
to the nucleus. A very small proportion of our genetic material is contained
within intracellular organelles called mitochondria. These structures
are the energy generators for the cell. The mitochondria contain the DNA
for only a few dozen genes, as compared to tens of thousands of genes
encoded in the nuclear DNA. There is, however, a much higher rate of genetic
mutation in the mitochondria due to the abundant supply of free radicals,
in the form of reactive oxygen species, in these structures. Free radicals
are a by-product of the energy metabolism performed by the mitochondria.
Although higher rates of mutation have been identified in mitochondrial
DNA, the specific mutations that occur may not be entirely random. Recent
studies suggest that specific mutations occur with age. It has also been
suggested that mitochondria may also be the site of a "longevity
gene." Studies have shown that a large proportion of people over
100 years old possess a specific mitochondrial gene.
Left unchecked, the damage
created over time would lead to severe problems in the functioning of
cells and organs. Healthy organisms have, therefore, mechanisms that both
prevent and repair damage. To some extent, the aging process is not so
much related to the production of damage but to the increasing inability
to repair damage once it has occurred.
Neutralizing Free Radicals
Three enzymes exist within
the cell to "disarm" these harmful compounds. These are superoxide
dismutase (SOD), glutathione peroxidase and catalase. Recently it was
shown that anti-oxidant enzyme activity is deficient in some diseases
of premature aging. Conversely, studies using laboratory invertebrates
have shown that increasing the activity of these enzymes may extend lifespan.
Nutrients known as anti-oxidants, such as vitamins C and E as well as
beta-carotene, are also capable of neutralizing free radicals. However,
these defences are not usually able to prevent all the damage that can
be done by free radicals; little by little, the damage accumulates, which
produces some of the tissue and organ deterioration associated with advancing
Diabetics have been observed
to show some signs of premature aging. The increased production of free
radicals through glucose metabolism is one possible reason for this observation.
Free radicals have also been implicated in age-associated disorders such
as cancer, atherosclerosis, cataracts and neurodegeneration. Recent work
suggests that a buildup of nerve cell damage by free radicals triggers
a hormonal response that initiates deterioration and aging. Research has
suggested that boosting anti-oxidant levels may help to slow the aging
Scientists have discovered
that as cells approach senescence, they produce less of a class of protein
called "heat shock proteins" (HSPs). Initially they were discovered
after analyzing the contents of cells that had been subjected to higher
temperatures than normal. In fact, it has been found that these HSPs are
normally produced in cells but that their levels are increased in response
to many stressors including heat, cold, trauma and toxins as part of a
defence system to protect the cell. The ability to produce these surges
in HSPs in response to stress is lost with age. This observation may help
to explain why younger people respond better to stresses than do older
Although the exact role
played by HSPs in the aging process is unclear, scientists do know that
they play a part in breaking down and disposing of damaged proteins, while
also assisting in the production and transportation of new cellular proteins.
These "chaperones" are HSPs that bind and stabilize proteins
at intermediate stages of folding, assembly, translocation across membranes,
HSPs have been linked to
disease via their involvement with the immune system, including presenting
antigens to the immune system for antibody production. They are also capable
of initiating and propagating auto-immune disease. In addition, the HSPs
appear to have a role in innate immunity. Other recent research suggests
that HSPs may be involved in protection against cancer and cardiac failure.
DNA Protection and Repair
The lifespan of an organism
has been shown to be related to its ability to prevent and repair certain
types of DNA damage. Many DNA repair mechanisms are designed to find the
errors, remove the segment containing the error, and re-constitute the
DNA from the complementary strand.
Another aspect of DNA damage
involves the enzyme DNA helicase. This enzyme is responsible for "unwinding"
the double helix of the DNA strand during replication. Improperly functioning
helicases have been implicated in some hereditary diseases of premature
aging. This research is in its early stages and it has not yet been shown
that the same mechanism is at work in normal individuals as they age.
Many of the errors of DNA
replication occur in areas of the genome that are read frequently, or
that have highly repetitive sequences, such as those which encode the
ribosomes, the machinery for assembling proteins. Silent information regulator
(SIR) proteins reduce the frequency with which stretches of the genome
are expressed and, in yeast, are associated with increased lifespan.
The body has its own defences
against AGE (advanced glycosylation end products) formation, as it does
against DNA damage and free radical formation. Macrophages (immune cells
that are capable of engulfing and destroying certain foreign structures)
can attach themselves to AGEs. They then engulf the complex, break it
down, and eject the remnants into the bloodstream for excretion via the
kidneys. This system cannot prevent AGE accumulation completely, however,
and AGEs accumulate with age.
Research is currently pursuing
a means to artificially prevent AGE formation as well as destroy existing
AGEs. A compound called aminogaunidine is being studied for its ability
to prevent AGE formation. This substance has been shown to boost cardiovascular
and kidney function in laboratory animals. Another pharmaceutical agent
called ALT-711 is being investigated for its ability to break apart existing
AGEs and reverse the signs of aging such as reduced lung elasticity.
A decreasing ability to
prevent or repair damage results in its accumulation. This can lead to
the inability of cells and organs to perform their functions properly.
In turn, this can lead to a weakened ability to maintain homeostasis and
to fight off disease.
C. Telomeres and Programmed
Human cells, as well as
many other organisms, have finite lifespans. In fact, until recently,
it was believed that immortal cells, with infinite lifespans, were cancerous.
After a certain number of divisions, normal cells enter a state of senescence.
In this state, cells do not divide or proliferate and there is no DNA
synthesis. Scientists have found links between senescence and human lifespans.
One aspect of senescence
research is the discovery of a physical barrier that results in a finite
number of cell divisions. Every chromosome has a long non-coding genetic
tail called a telomere, which protects the unstable ends of coding DNA.
Each time the DNA strand is copied (i.e., the cell divides), the telomere
becomes shorter. Once the entire telomere is lost, the cell is no longer
capable of dividing because further divisions would produce chromosomes
that lack some information.
Human cells cultured in
the laboratory have been notoriously difficult to work with because they
die after a certain number of divisions. However, human cells genetically
transformed to contain the enzyme telomerase do not die, as this enzyme
maintains telomere length. Telomerase has also been found in some cancerous
cells, which has led to a great deal of research on the possibility of
controlling cancer growth by interfering with telomerase activity. It
is unlikely, however, that telomeres will be the silver bullet against
cancer. The immortal human telomerase-transformed cells have been shown
not to be cancerous and some mice without telomerase activity have still
developed cancer, so factors other than the existence of telomerase are
involved in cancer cells immortality.
The exact relationship between
cell senescence and the aging process is not well defined and is an area
of intense focus. Scientists have observed that the cells of cloned animals
can have the telomere length of the genetic donor. The telomeres on the
chromosomes of Dolly, the first cloned animal, were shorter than anticipated
for her chronological age, leading to speculation that cloned animals
would age prematurely. Clones are produced using cells from adult animals,
thus the cloned animal can begin life with telomeres considerably shorter
than in a conventional embryo. Recently, a cloning procedure was developed
that resulted in lengthened telomere size in clones. It is too early to
conclude whether the lifespan of any of these clones has been significantly
D. Increased Longevity
through Caloric Restriction
Caloric restriction (CR),
without malnutrition, is the focus of a considerable amount of current
research. In both single-celled organisms such as yeast and in mammals
such as rodents, CR has been shown to consistently extend life expectancy.
The manner by which CR may increase life expectancy is proving to be somewhat
complex. It appears as though CR may have an influence on DNA repair rates,
free radical levels, hormonal balance and cell senescence as well as possibly
other mechanisms. Another phenomenon associated with CR is the observation
in laboratory rodents that the development of disease and tumours is prevented
or slowed down. Research into CR may provide further insight into the
mechanisms responsible for age-associated disease.
One of the manners by which
CR may slow the aging process is by causing a reduction in the accumulation
of free radicals. This is because free radicals are by-products of metabolism,
the rate of which is reduced when calories are restricted. This, in turn,
would result in less protein and tissue damage caused by these compounds
and less DNA damage.
A connection has also been
made between CR and genetic stability in yeast, a model organism from
which much has been learned about fundamental aging processes. CR reduces
the level of free radicals molecules that can damage the cells
energy-producing machinery. Cells with undamaged machinery have more active
SIR proteins, which in turn slow down the aging process through changes
in gene expression.
A third proposed means of
reducing DNA damage is based on the observation that CR lowers core body
temperature. This could result in less DNA damage, and better DNA repair
than at normal body temperatures. Some age-associated diseases such as
cancer and cardiovascular disease have been linked to free radical and
DNA damage, which may help to account for CRs observed effect on
disease progression. A possible mechanism for CRs anticarcinogenic
effects is the observation that the level of insulin-like growth factor-1
(IGF-1) affects tumour growth. CR inhibits production of IGF-1, and this
may be how CR prevents or slows the progression of cancer.
In addition, CR appears
to somehow moderate the decline in growth hormone. This could have the
effect of postponing the frailty associated with old age. Researchers
have noted that CR appears to have an effect on the immune system by postponing
the decline normally observed in aging. The means by which CR accomplishes
this is not yet known but may also be linked back to the reduction in
damage accumulation. Free radical damage results in the loss of function
of some proteins and could include those produced in the immune response.
Finally, CR results in reduced consumption of glucose and so it may be
reasonable to theorize that CR may result in less AGE formation. This
could therefore delay disease progression and other changes associated
with normal aging.
It is not practical to carry
out human studies in this area. Instead, scientists are studying the effects
of CR on primates. Even so, these studies will take several decades and
are far from being complete. Preliminary observations of these monkeys
suggest that CR does delay aging in primates. Research into caloric restriction
does not promote the aim of severely restricting the caloric intake of
humans in order to extend life. What is hoped is that clarification of
the mechanisms involved will help to provide a means of improving health
in later years.
Life expectancy has increased
by more than 50% in the past 100 years, and the health of the elderly
has also improved as the result of disease treatment and prevention. Further
improvements in life expectancy and health will inevitably arise out of
research into the fundamental understanding of aging in the absence of
disease. It is also possible that an increase in human lifespan may result
from this research. Such an increase may involve many practical and ethical
questions. The possibility of greatly increased human lifespan, however,
will not occur for a long time. That time should be used to carefully
address the socio-economic implications of an older, healthier population.
Provincial and Territorial Advisory Committee on Population Health, Toward
a Healthy Future, Second Report on the Health of Canadians, 1999.
Institute on Aging (NIA), In Search of The Secrets of Aging,
NIA internet site at: www.nih.gov/nia/health/pubs/secrets-of-aging/
Quest to Beat Aging," Scientific American special edition,
Michael R. "Can Human Aging Be Postponed?" Scientific American,
December 1999, pp. 106-111.
Gerontologists are scientists who study aging.