Download In support

Mary McDonald, MD
Assistant Professor
Division of Geriatric Medicine and Palliative Care,
Department of Family Medicine
Learning Objectives
Every student should be able to...
 Differentiate chronological age from biological age.
 Explain what is meant by the heterogeneity of aging in humans and
describe its clinical implications.
 Discuss the multiple coexisting forces which may work in concert to
affect the aging process.
 Compare life expectancy and lifespan.
 Describe the general characteristics of aging
 Describe what is meant by homeostenosis.
 Evaluate the theories of aging presented and outline supporting and
opposing evidence of each.
 Compare and contrast the two theories of lifespan extension and
describe their clinical implications.
CHRONOLOGICAL
AGE
How long have
You lived?
VS
BIOLOGICAL
AGE
How old is
Your body?
CLINICALLY, WE SEE GREAT
VARIATION WITHIN THE BIOLOGICAL
AGE OF OUR OLDER ADULT PATIENTS
Life Expectancy

the average number of years remaining for
a living being (or the average for a class of
living beings) of a given age to live.
Life Expectancy at Birth, 65 and 85 Years of Age, by Sex &
Race: United States, Selected Years 1900-2002
Source: U.S. Census Bureau
Source: U.S. Census Bureau
Life Expectancy


Improved public hygiene and the discovery
of antibiotics in the early to mid 1900s led
to significantly prolonged lifespan
Further prolongation occurred in 1970’s
and 1980’s with improved treatments for
cardiovascular disease
Lifespan
Lifespan - The duration of life of an individual
Average Lifespan - The normal or average
duration of life of members of a given
species.
Wordrefernce.com English Dictionary
Lifespan
Jeanne Calment of Southern France died in
1997 at the age of 122 years and 164 days.
Very active. Took up fencing at age 85 and was
still riding a bicycle at age 100.
Characteristics of Aging (1 of 2)





Mortality increases exponentially
Biochemical composition of tissue changes
Physiologic capacity decreases
Ability to maintain homeostasis diminishes
Susceptibility and vulnerability to disease
increases
Environmental and genetic factors
influence the rate of aging
Characteristics of Aging (2 of 2)

Loss of physiologic reserve and decreased
homeostatic control may result from:
 Allostatic load (persistent activation of normal
neuroendocrine, immune, and autonomic responses to
stress)
 Development of homeostenosis (altered response to
physiologic stresses)

Changes are generally irreversible
Developmental-Genetic Progeria




Progeria is a disease of premature aging
Death typically by age 13 and usually due to
atherosclerotic disease, stroke, heart attack.
Hutchinson-Gilford Progeria linked to
mutations in the nuclear structural protein
lamin A.
caused by a tiny, point mutation in a single
gene, known as lamin A (LMNA).
Werner’s Syndrome
Disease of premature aging. Patients appear
normal for first two decades of life but develop
arteriosclerosis, malignant neoplasms, DMII,
osteoporosis, cataracts very young
Werner’s Syndrome



Disorder isolated to a single gene on
chromosome 8 which encodes for a DNA
helicase
This gene has been cloned and is an area of
great research
DNA helicases are involved in the repair,
replication and expression of genetic
material
Aging research has turned away from a single
gene answer to the cause of aging.
Increasing understanding that aging is a
consequence of complex interactions within
differing systems of the body and the surrounding
environment.
Theories of Aging




Molecular Theories
Cellular Theories
System Theories
Evolutionary Theories
Molecular Theories of Aging




Gene regulation
Codon restriction
Error catastrophe
Dysdifferentiation
Gene Regulation Theory

Aging is caused by changes in gene
expressions, affecting both aging and
development
Gene Expression (1 of 2)

Compared with younger adults, the elderly can have
decreased, unchanged, or increased rates of gene
expression

Mechanisms that influence gene expression with aging:
 Mutations in DNA sequences in/around certain genes
 Latent viral infections (eg, herpes viruses)
 Accumulation of environmentally induced cell damage

It is unknown whether age-related changes in gene
expression are functionally significant
Gene Expression (2 of 2)

Primary changes in gene expression with age:
 Decreased transcription rates for key genes
 Decreased messenger RNA (mRNA) turnover
 Decreased inducibility of genes, such as immediate early genes,
acute phase reactants, and stress genes

Expression of genes related to stress response is upregulated during senescence
 Consequences unknown
 May be adaptations to accumulated environmental or oxidative
stress
Codon Restriction Theory

Accuracy of mRNA translation is impaired due
to inability to decode codons in mRNA
Error Catastrophe Theory

Decline in fidelity of gene expression over time
resulting in increased portion of abnormal
proteins
Dysdifferentiation

A gradual accumulation of random molecular
damage over time impairs regulation of gene
expression
Molecular Theories of Aging


Synopsis: Age-acquired chromosomal instabilities
contribute to gene silencing or expression of diseaserelated genes (eg, cancer genes)
In support:
 Damage by reactive oxygen species causes mitochondrial DNA
(mtDNA) mutations in muscle and brain
 Defective mitochondrial respiration and further oxidant injury creates
a cycle of damage
 Mitochondrial mutations and defective respiration have been linked to
neurodegeneration

In opposition: The practical impact on nondiseased aging
appears to be minimal
Molecular Theories of Aging


mtDNA also undergoes age-related changes

Mutation rate 10,000-fold greater in elderly than in younger
adults

Up to 10% of very old adults have mtDNA deletions
However, mitochondrial and mtDNA are amply
redundant

Age-related changes in respiratory chain activities are subtle, if
detectable at all

Most likely effect of age-related mtDNA changes is reduced
functional reserve of energy production
Cellular Theories of Aging



Cellular senescence theory
Oxidative stress theory
Apoptosis theory
Cellular Senescence Theory



Each cell has a maximum number of divisions
before it enters senescence
The length of the telomere end of the DNA chain
shortens with each division and less telomerase
activity is observed
A telomere is a region of highly repetitive DNA
at the end of a chromosome that functions as a
disposable buffer
Telomere
Telomeres



Aged cells with proliferative potential exhibit
telomere shortening and loss of telomerase
activity
Conversely, telomerase hyperactivity is linked
to cellular transformation and cancer
Telomere length and telomerase activity might
be clinical markers of human aging and
oncogenesis
Oxidative Stress Theory
Oxidative metabolism produces reactive oxygen species which
damage protein, lipids and DNA
Oxidative Stress Theory

In support:
 Mutations
in oxidative stress pathway can extend life
span
 Mutations in other pathways that increase longevity
resist oxidative damage

In opposition: Antioxidants do not delay human
senescence or disease
Apoptosis Theory
Genetically determined, programmed
cell death.
“Genome Crisis”
Systems Theories of Aging


Neuroendocrine
Immune senescence
Neuroendocrine Theory

Changes in the neuroendocrine control of
homeostasis result in aging-related physiologic
alterations
Neuroendocrine Theory

Synopsis: Hypothalamic and pituitary
responses are altered (TRH, GNRH, GHRH,
TSH, LH, FSH, GH, ACTH)

In support: No direct support as causative of
healthy aging, and supplementation does not
alter aging in humans
Immune Senescence Theory

Changes in the immune system with aging lead
to increases in infectious disease and increase
in autoimmune disease in older adults.
Theories of Aging: Immune
Senescence
 Synopsis:
Time-acquired deficits, primarily in Tcell function, increase susceptibility to infections
and cancer
 Slower
onset of lymphocyte proliferation
 Diminished cloning efficiency of individual T cells
 Fewer population doublings of fibroblasts
 In
support: Some diseases are associated with
aging
 In opposition: Immunologic function is apparently
not directly related to healthy aging
Evolutionary Theories of Aging
Aging results from a decline in the force of
natural selection
1.
2.
Mutation accumulation
Antagonistic Pleiotropy
Mutation Accumulation
Mutations that affect health in older ages are not
selected against and therefore accumulate in a
population
Supported by diseases like Huntington’s Disease.
An autosomal dominant, terminal,
neurodegenerative disease that typically presents
at age 30-45, after childbearing age.
Mutation Accumulation
Diseases that are lethal in childhood or early
adulthood are not passed to further generations
and do not accumulate in a population
Antagonistic Pleiotropy
Some genes that code for beneficial effects in
early life may then be detrimental in later years
Discussed as the conflict between fecundity
(reproductive ability) and longevity
Antagonistic Pleiotropy and
Testosterone
Testosterone production in young men supports
reproductive potential
This same hormone in older adults contributes to
the development of prostate cancer
Antagonistic Pleiotropy
Studies have revealed that destroying germ line
cells in both Drosophila and C. elegans can
extend lifespan
Antagonistic Pleiotropy
Insert picture of drosophila
Drosophila
Insert picture of elegans
C. elegans
Can all of this knowledge be
used to extend lifespan?
Life Span Extension:
Metabolic And Insulin Signaling

There appears to be endocrine regulation of aging
 In a range of species, mutations in certain genes,
especially those that appear to play roles in metabolic
and insulin signaling (eg, GH, IGF-1), extend life span
 In contrast, life span is shorter in humans with untreated
isolated GH deficiency (but normal age-related GH
decline may have little to do with healthy aging)
 Low-expressing IGF-1 receptor alleles are more highly
represented among long-lived humans

These pathways are potential targets for drugs to delay or
prevent age-related changes
Life Span Extension:
Caloric Restriction (1 of 2)

Caloric restriction increases average and
maximum life spans in a variety of species

Impact of caloric restriction varies considerably
in mice and flies

Two robust markers of caloric restriction in
rodents (reduced body temperature, reduced
plasma insulin) have been observed in older
men and in caloric-restricted rhesus monkeys
Life Span Extension:
Caloric Restriction (2 of 2)

Sir2, an enzyme in the sirtuin family of proteins, mediates
the benefits of caloric restriction in yeast

Sirtuin-activating compounds (STACs) could conceivably
enhance life span in humans
 Resveratrol, a plant polyphenol in red wine, is a STAC
that prolongs life span in fruit flies and worms
 Resveratrol has anti-inflammatory, antioxidant,
anticancer, and vasoactive effects on human cells

It might be possible to develop calorie restriction mimetics
to increase human life span
What does aging mean to the
physician?



Great heterogenicity in the older population
Increased attention to biological age versus
chronological age
No “one size fits all” approach to treating
older adults
Summary

There are large interindividual variations in the rate of
physiologic aging

Aging appears to have multiple causes, including genetic and
environmental factors

Genetic factors may regulate aging or life span through a
variety of mechanisms (eg, insulin signaling, control of
oxidative damage, DNA maintenance, and altered gene
expression)

It might be possible to extend human life span with caloric
restriction mimetics or drugs targeting the GH/IGF-1 pathway
Acknowledgements
GRS6 Chapter Authors:
Bruce R. Troen, MD
Donald A. Jurivich, DO
© American Geriatrics Society
National Vital Statistics systems
Stedman’s Concise Medical Dictionary. Third Edition. 1997
Wordreference.com English Dictionary
Landon Center on Aging Photo Contest
Landon Center on Aging Photo Contest
Landon Center on Aging Photo Contest
Landon Center on Aging Photo Contest
Landon Center on Aging Photo Contest