Theory of Aging Process

Prof.dr.Hardi Darmawan, MPH&TM, FRSTM

1
DEFINITION OF AGING
Old and aging depends on the age and
experience of the speaker.
Chronological age - number of years
lived
Physiologic age - age by body function
Functional age - ability to contribute to
society
CHRONOLOGICAL CATEGORIES
Young-Old - (ages 65 - 74)
Middle-Old - (ages 75 - 84)
Old-Old - (age 85 and older)
Doh!
Chronologic age is not an accurate predictor of
physical condition or behavior
Sue Saxon & Mary Jean Etten, Physical
Change & Aging
Rather,
Physical condition seems to be driven by:
Lifestyle choices
exercise
nutrition
stress management
Genetics
Environment
Demographics of Aging
6
Americans over the age of 65 will rise from
approximately 12% in 2000 to 20% in 2030
Over 85 year-olds are the most rapidly
increasing demographic group.
Baby-boomers are rapidly approaching
retirement age
AAAAAAHHHHHHH!!!!
US Census Bureau Data for US population of
adults age 65 and older
1990 30 million
2030 70 million
2050 96 million
Significance of Human Aging
People live longer now than ever before
By 2030, 20% of the US population will be 65 and older
Significant challenge to medicine-ethical, financial, etc.
8
Significance of Human Aging
What is normal in the
aging process primary
aging
More susceptibility to
disease secondary
aging
More heterogeneity in
the elderly population
Onset indeterminable
and progression varied
Genetic and
environmental factors
9
Significance of Human Aging
Gender is a significant factor
Lifestyle a primary factor
Various theories of aging attempt to explain the process
bottom line, there is disruption of homeostasis.
10
Stages of Life
Chronological age typically used to note lifes transitions
Indonesian Life Expectancy
2000 2005 : 67.8 years
2020 2025 : 73.6 years
12
Saparman,Sragen (143 yrs)
Mak Encuh, Bandung (131 yrs)
Aging is not an inevitable
process leading to disease and
deterioration
13
14
Normal aging
Characteristic of aging
Theories of aging
Genetic molecular, cellular / tissue change
Functional changes
Common disease
Physiology of aging
Effects of aging on the different organ
Metabolics disorder in aging
15
NORMAL AGING
Despite stereotype most of the elderly age well !
Most of our images are based on the frail sub-
set who frequently use medical services
16
Normal Aging
Generally normal
aging in
associated with a
reduction in
functional reserve
capacity in
tissues and
organs.
17
Normal Aging
At advanced age more
common to see
evidence of impaired
homeostasis and
response to external
insults e.g. illness.
18
Temperature Regulation and Aging
19
Risk Factors for Hypothermia in
Elderly
Decreased thermogenesis
Decreased vasoconstriction in response to cold
Decrease in intensity of shivering
Medications e.g. Chlorpromazine
Socio-economic (nutrition, heating, etc)
Co-morbidities including falls / immobility
20
Decreased ability to
sweat
Decreased ability to
redirect heat :
Reduced capacity for
vasodilation peripherally
Modest ability to
increase cardiac output
21
Risk Factors
for Hypothermia in Elderly
Summary of Normal Aging Changes
Despite stereotype most of the elderly age well!
Most of our images are based on the frail sub-set
who frequently use medical services
Generally normal aging in associated with a
reduction in functional reserve capacity in tissues
and organs
At advanced age more common to see evidence of
impaired homeotasis and reponse to external
insults eg. Illness.
22
Characteristic of Aging
Mortality increases exponentially
Biochemical composition of tissue changes
Physiologic capacity decreased
Ability to maintain homeostasis diminishes
Susceptibility and vulnerability to disease increases
Environmental and Genetic factors influence
the rate of age
23
Characteristic of Aging
Loss of physiologic reserve and decreased
homeotatic control may result from :
Allostatic load (persistent activation of normal
neuroendrocrine, immune and autonomic
responses to stress)
Development of homeostasis (altered
response to physiologic stresses)
Changes are generally irreversible
24
Physiological Theories of Aging
Genetic Theories
Gene
Error
Somatic mutation
Programmed
Nongenetic Theories
Immunologic /
Autoimmune
Free Radical
Wear & Tear
Cross link or Collagen
http://prolongyouth.com/theories.h
tml
Psycho-Social Theories of Aging
Disengagement
Theory
Activity Theory
Continuity Theory
Theories of Aging :Genetic
Synopsis : senescence results from activation
or suppression of specific aging genes
In support :
1. Longevity appears to be hereditable
2. Some genetic disorders lead to accelerated
aging
In opposition :
1. Evolutionary pressures appear to select for
reproductive fitness rather than senescence
2. Little direct evidence of genetic
programming of senescence in humans.
27
Theories of Aging :
Chromosomal Alterations
Synopsis: Age-acquired chromosomal instabilities
contribute to gene silencing or expression of disease
related genes (eg. Cancer genes)
In support :
Damage by free radicals 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 non-diseased aging
appears to be minimal
28
Theories of Aging : Immunologic
Synopsis: time-acquired deficits, primarily
in T-cell function, increase susceptibility to
infections and cancer
In support : no direct support as causative
of healthy aging, supplementation does not
alter aging in humans
29
Theories of Aging : Oxidative Stress
Synopsis : Oxygen converted during
metabolism causes protein, lipid and DNA
damage over time
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
30
CELLULAR CHANGES
Loss of proliferative potential, e.g.:
Slower onset of lymphocyte proliferation
Diminished cloning efficiency of individual T
cells
Fewer population doublings of fibroblasts
Proliferative potential does not invariably
diminish with age
Changes in gene expression, signal transduction
and telomere length contribute to cellular aging.
31
Cell Death
Age-dependent problems with apoptosis could
result in leukemias, lymphomas and abnormal
tissue repair.
Apoptosis may play a role in age-related
neurodegeneration, e.g.:
Neuronal loss in Alzheimers disease may be due to
cytotoxicity of -amyloid, which can induce apoptosis
in cultured cells
Putative toxins such as free radicals have been
implicated in neuronal loss in Parkinsons disease
32
Physiology of Aging
Why do we need to know the
physiology of aging?
to tell the difference between
physiological and pathological
phenomena in the geriatric population
To appreciate the impact of normal
age-related degeneration on diseases
and their management.
33
Successful Aging
Chronologic age and physiologic age not the same
Due to complex interactions of genetics and
environment
Individuals age at different rates and there is
significant variability
Successful Aging
Prevalence of disease increases with age
Proposed pathways of aging:
Aging with disease and disability
Usual aging; absence of pathology but presence of
decline in function
Healthy aging; no pathology or functional loss
Pathway goals:
De-emphasize aging characterized by decline
Emphasize heterogeneity among elderly
Underscore positive pathway of aging
Highlights possible avoidance of disease associated with
aging
Successful Aging - homeostasis less efficient, but
still present
Goals of
Successful Aging
Compression of
debilitating disease into
final portion of life
Maintain high-level of
function until end of life
Death with dignity and
comfort
37
Aging and Disease
Aging is associated with
increase in incidence
and severity of disease
Factors predispose
individuals to
functional losses later
in life
39
Integrative
Physiology of
Aging
Why do we age?
Who do we need to
know the physiology
of aging?
2 categories of theories :
Aging events occur randomly and accumulate
in time : Stochastic Theory
Accumulated errors in making bodily and
cell proteins Error Catastrophe Theory
Cross-linking of big molecules such as
proteins accumulates over time Cross-
linking theory
Repeated damage to DNA and incomplete
repair wear and Tear Theory
Aging is inevitable : Nonstochastic Theory
40
Why do we age?
2 categories of theories :
Aging is inevitable : Nonstochastic Theory
Certain organ-systems such as
hypothalamus, immune and
neuroendocrine systems have in-built
pacemakers that involute with age
pacemaker theory
There is familiar predisposition for longevity
and thus there may be a genetic basis for
aging genetic theory
41
Cell Senescence and Death
Cell senescence much like apoptosis
Occurs throughout life
Arresting growth of damaged/dysfunctional cells
Beneficial early in life; may contribute to aging later
Cell Senescence and Death
Inducers can cause cancer
Senescence allows cells to respond to inducers,
but cells withdraw from growth cycle -
incapable of tumorigenesis
Contribution of cell senescence to aging:
Altered secretions of cells
Proteases, inflammatory cytokines, growth factors
Erosion of structure and integrity of tissues
SKIN AND AGING
44
Hillary Clinton
Albert Einstein
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Skin and Aging
In general, the skin is drier, thinner and wrinkled
Other age-related changes include :
Loss of the inter-digitations between the epidermis and
dermis
Decline in the vascular supply
Decline in the immune cells of the integument
Decline in the activation of vitamin D
Clinical consequences include :
Vulnerable to tearing, bruising and breakdown
Pressure ulcers (decubiti) more likely
Delayed response to topically-administered toxic agents
Sunlight exposure results in premature age-related changes
in the skin.
45
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Age Related Changes in Immune System
Age related changes include :
The thymus involutes with age
T-cell immunity tends to decline
Cytokine level and function may change with age
Humoral (B-cell) immunity declines with age
Changes in neutrophil function with increased
margination, reduced migration to site of
inflammation/infection and altered phagocytosis
Autoantibodies increase with age
Clinical Consequences :
Decline in cell mediated immunity may result in
TB reactivation and shingles
Vaccine response may be impaired
Altered presentation of infection
46
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Sight and Aging
Reduction of pupil size slows
adjustment to light changes
Corneal surface flattens
admitting less light into the
eye
Reduced lens transparency
interferes with reception of
colour wavelengths
Reduced blood supply and
radiation damage to retinal
area.
47
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Smell and Aging
48
eardrum and
ossicles thicken
and becomew
less flexible
Loss of hair
cells in the organ
of the corti
Loss of cochlear
neurons
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Taste with Aging
49
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Examples of Clinical
Relevance
Older adults may need longer to adjust to changes
in lighting and may need increased contrast to
facilitate depth perception
Loss of high frequency sounds, which include
consonants, make what is heard unintelligible,
leading to the frequent complaint, I can hear you
but I cant understand what you are saying
It is important to recognize, that a response that
does not correspond to a question may relate to
sensory, rather than cognitive, impairment
50
Cortical Changes and Aging
There is some selective loss in the
number and size of neurons
Dendritic connections may decrease
A number of neurotransmitters changes,
which may result in neurotransmitter
imbalances
51
EFFECTS OF AGING ON THE DIFFERENT ORGANS
CT Scan Changes and Aging
52
Memory and Aging
May have more difficulty
with certain components of
memory
Typically, older adults need
more time to process
information
May have difficulty coming
up with names
spontaneously (retrieval)
For healthy older adults,
these changes represent
more inconvenience than
significant functional
impairment
53
EFFECTS OF AGING ON THE DIFFERENT ORGANS
TURMERIC
54
BANANA
55
Sleep and Aging
Sleep patterns tend to
change, resulting in :
A decrease in Stage IV
(deep) sleep
An increase in Stage I
(light) sleep
An increase in the
number of nighttime
awakenings
56
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Sensation and Peripheral Nervous
Function
Increased threshold observed for peripheral
sensory modalities
Nerve conduction time slows with age
secondary to loss of the myelin sheath
The net effect of these changes is a decrease in
both amount and speed of afferent information
conduction to the spinal cord and higher
centers.
57
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Spinal Cord
Modest decrease in
number of cells in the
spinal cord
Other changes represent
disease processes, such as
degenerative disease of the
spine and intervertebral
disks with compression of
the spinal cord and
entrapment of the nerve
roots.
58
EFFECTS OF AGING ON THE
DIFFERENT ORGANS
Reduction in the absolute
numbers of motor
neurons
Distance between the
junctional axon and the
motor end-plate is
increased
Folds of the motor end-
plate are flattened
The concentration of Ach
receptors at the motor
end-plate is decreased
The amount and released
of Ach in the junctional
vesicles is decreased
59
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Cardiac Output and Age
No change at rest in :
Cardiac output
End-diastolic
End-systolic
Volumes
ejection
fraction
60
Summary of Cardiac Morphological Changes
Consequences :
Higher systolic BP more common
Trend towards diastolic
dysfunction
Reduced ability to increase heart
rate
Increased postural hypotension
61
1
4
3
2
Age-related Respiratory Changes
Decreased chest expansion :
Kyphoscoliosis
Calcification of intercostal
cartilage
Arthritis of the costovertebral
joints
Decreased elastic recoil of the
lungs
Reduced diaphragm function
Increased airways obstruction
Reduced vital capacity
Increased residual capacity
62
Consequences of Age-related Changes
Increased energy of
breathing
Increased airways
resistance
Increased in dead-space
Reduced V/Q ratio
resulting in a decrease
in the partial pressure of
oxygen in blood when
breathing room air.
63
Oropharyngeal
Modest change in taste
Modest reductions in sub-
mandibular and sublingual
gland secretions
Swallowing intact in normal
elderly
64
Gastric Function and Aging
Modest
reduction in
fluid emptying
from stomach
Decline in gastric
secretions
Atrophic gastritis
more common
Prone to
increased pH
65
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Small Intestine
and Aging
Modest changes in
motility
Normal transit
time and
absorption in
absence of disease
Pancreas shows
decrease in overall
weight, duct
hyper-plasia, and
lobular fibrosis
66
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Liver Function and Aging
Standard LFTs
unchanged
Microsomal
oxidation, has been
found to be slowed
with aging
Metabolism through
Cytochrome P450
system delayed
67
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Large Intestine Function and Aging
Changes in motility
Increase in
retropropulsion
Increased transit time
Tendency to
constipation
68
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Glomerular Function and Aging
Decline in renal blood flow from 1200mL/minute at age
30 to 40 years to 600mL/minute at age 80
69
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Tubular Function and Aging
Decline in ability to excrete concentrated urine
Delayed or slowed response to sodium deprivation or a
sodium load
Delayed or sluggish response to an acid load
70
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Urogenital Changes In Men and
Women
The urethra is more likely to
be colonized by gram
negative organisms
Alterations in mucosa lead
to increased bacterial
adherence
Decreased blood flow may
lead to longer time to
orgasm
71
Male Specific Changes
Decreased blood
flow may lead to a
decrease in erectile
function
Sperm count tends
to decline and
chromosomal
abnormalities tend
to increase
The prostate
increases in size
and prostatic fluid
reduced.
72
Female Specific Changes
Reproductive
capacity is lost at the
time of menopause
Ovary, uterus, and
vagina tend to
atrophy following
menopause
Tendency to urgency
and stress
incontinence
73
Sarcopenia
Between ages 30 and 75:
Lean body mass decreases
due to loss of skeletal muscle
mass
Number and size of muscle
fibers progressively decrease.
74
Successful Aging
Recent research:
Elderly individuals with weak muscles are at greater
risk for mortality than age-matched individuals
Increase in amount and rate of loss of muscle
increases risk of premature death
Physical inactivity is 3rd leading cause of death in
US and plays role in chronic illnesses of aging
Muscle Fibres and Aging - Impact
Type I (slow twitch, aerobic) muscle fibers are resistant to age-associated
atrophy, at least until the ages of 60 to 70 years
Type II (fast-twitch, anaerobic) muscle fibers appear to decline with
increased
76
CHARACTERISTIC FAST FIBRES SLOW FIBRES
TYPE IIb TYPE IIa TYPE I
Number of mitochondria Low High/Moderate High
Resistance of Fatique Low High/Moderate High
Predominant Energy
System
Anaerobic Combination Aerobic
ATPase Activity Highest High Low
Velocity:Speed of
Shortening
Highest Intermediate Low
Efficiency Low Moderate High
Specific tension High High Moderate
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Muscle Strength and Aging
Decrease in the ability to maintain force
production is not so much a function of age
as it is related to muscle group location
The muscles of the lower extremity are
better able to maintain force output when
compared to the muscles of the upper
extremity
Research indicates that elderly muslce can
adapt positively, just like young muscle, to
resistance exercise
77
EFFECTS OF AGING ON THE DIFFERENT ORGANS
Vulnerability to Falls
Reduced sensory input including
propioceptive information
Delayed nerve conduction
Reduced numbers of motor
neurons
Reduced fast twitch fibres
Reduced muscle mass
Environment always important!
78
Endocrine Changes with Aging
Change in GTT Insulin
resistance increase
Increased incidence
DM
Decrease in
ADH/vasopressin response
to osmotic stimuli
Risk of dehydration or
hyperosmolar state
Tendency to thyroid
dysfunction
Abnormal TFTs
Growth hormone,
melatonin and DHEA,
decline with aging
?
79
Hormone Deficiencies many if not most of the
signs, complaints, causes of Senescence
80
Age-related
physiology :
- Intestinal transit
- cardiac output
- kidney function
- liver function
Age-related signs :
- wrinkles
- skin & hair
thinning
- hair loss
- muscle atrophy
- abdominal obesity
Age-related symptoms :
- fatique
- cognition
- depression
Age-related
diseases :
- cardiovascular
- cancer
- obesity
- diabetes
- osteoporosis
- dementia
81
82
83
84
85
Melatonin Deficiency : onset
86
Changes with thyroid treatment
87
Thierry Hertoghe,MD, Atlas of Endrocrinology for Hormone Therapy, HIS,pg 109
Osteoporosis and Fractures
Low dietary intake of
calcium
Loss of endocrine
protection
Reduced endogenous
production of vitamin D
Disuse
Disease Chronic Renal
Disease, Rheumatoid
Arthritis, Thyroid Disease
Medications Steroids,
Thyroxin.
88
Osteoporosis
89
Age related disorder,
aging disease major morbidity/mortality
atherosclerosis CV diseases
metabolic syndrome
tumors
neurodegenerative diseases
Osteoporosis
90
Asymptomatic bone fracture & complication
bone mineral density
Loss of architectural integrity
Should understand physiology
pathophysiology
Immuno senescence & inflammatory of aging
Immuno senescence lifelong antigenic load
chronic immune system activation
proinflammatory
till
Fragility fracture
risk
hyper
production
91
Proinflammatory cytokines - IL-1, IL-6,
TNF inverse CRP
Immuno senescence shape the same
immunological cell & cytokine
TNF, IL-1, Rank-L, M-CSF expression
osteoclast precursor
Why not build the osteoblast
aging & estrogen deficiency : most
important risk - osteoporosis
92
Immune Mechanism of Osteoporosis
The skeleton is physiologically in a state of dynamic
equilibrin between
formation vs reabsorption
osteoblasts vs osteoclasts
tuning by cytokins
growth factors
93
accumulation
Age immune profile
memory/effector cells expressing
Rank L resident in bone
secreting
osteoclastogenic
proinflammatory cytokins
94
Natural Bone
Building Plan
1. Hormones
2. Minerals
3. Vitamins
4. Diet
5. Digestion
6. Exercise
95
96
Hormones
Vit D is a steroid hormones
Determinat for bone
health & all ages
determinant
Summary of Hormones to treat bone loss (1)
1. Estrogen to prevent bone loss : estradiol
transdermal titrated area 1 mg/ml
2. Progesterone
To build bone & balance estrogen
50-300mg oral / transdermally
97
Summary of Hormones to treat bone loss (2)
3. DHEA/testosterone
Start DHEA (5-25 mg/day)
Testosterone 1-5 mg/night
4. Melatonin (0.5 3 mg/night)
5. GH if IgF -1 low or below mid range
98
Summary of Vitamins to treat Bone Loss
1. Vitamin D
3
2000-5000 u/d
2. Vitamin K
2
50-150 mcg/d
3. Vitamin C 1000mg 4000mg/d
4. Vitamin B 100mg/d, if
homocysteine not
improving use
Methyl B12/ folic
acid
5. Vitamin E 200-800 U
99
1. Magnesium
100
Summary of Mineral to treat Bone Loss
Oxide, glycinate, aspartate 200-
600 mg/d
Magnesium
Orotate, citrate, aspartate 800-
1500 mg/d
Calcium
20mg/d or 6mg/d for
maintenance
Silicon
Citrate in trialkali powder or
alone in capsule
Potassium
Boron 2-3 mg/d, manganese 15-20 mg/d,
copper 1-2 mg/d, zinc 20-50 mg/d
Trace Mineral
170-680 mg/d
Strontium
Diet & Bone Health
Enzyme function optimally at P
H
neutral
Acidic by products accelerate bone loss
High protein & diary (western diet) chronic metabolic
acidosis
Bones ability to neutralize acid load -- depend on K
T
stores
K
+
intertitial fluid
K
+
Ca
++
from bone to buffer in a place of K
T
chronic high steroids
diuretics
Eating alkaline diet
Rich fresh fruit vegetables
Limited protein & diary
Artificial sweetness
Preservatives
101
K
T

Acidifying Foods
Sugar
Yeast, wheat breads
Soft drinks, alcohol, tea, coffee
Cranberries
Sweet potato
Salt
HOPS
Corn oil
White balsamic vinegar
Saccharine, aspartame
benzoate
102
Alkalinizing Foods
Honey, maple syrup, stevia
Goats milk
Soy milk
Umeboshi plums
Sea salt
Most herbal teas
Lemon, limes, grapefruit,
onion
Olive oil
Miso
Most fruits & vegetables
NAD
+
dependent
deacetylase
Diverse physiological
process
Longevity
103
Implicated in
SIRT1
Audrey Hepburn
is
a
SIRT 1
A key mediator of beneficial effects of :
Caloric restriction
Regulates lipid
Regulates glucose
Regulates metabolism
By deacetylating metabolic regulators
SIRT1 levels are regulated by microRNAs
(miRs)
104
Nuclear receptor FxR / SHP cascade
pathway expression of MiR-34A

SIRT 1
This cascade is useful for age related
disease including metabolic disorders
105
control
targets
106
107
SIRT 1
SIRT 1
SIRT 1
SIRT 1
Effects of a urinary factor from women in early
pregnancy on HIV-1, SIV and associated disease
Yanto Lunardi-Iskandar
1
, Joseph L. Bryant
1
, William A. Blattner
1
, Chia
Ling Hung
2
, Louis Flamand
1, 3
, Parkash Gill
4
, Phillipe Hermans
5
, Steven
Birken
6
& Robert C. Gallo
1
1
Institute of Human Virology, University of Maryland, 725 West Lombard Street,
Baltimore, Maryland 21201-1192 USA
2
Advanced BioScience Laboratories Inc., 5510 Nicholson Lane, Kensington, Maryland
20895 USA
3
Presently at Laboratory of Virology, Rheumatology and Immunology Research Center,
Pavillen CHUL and Laval University, Quebec, Canada
4
University of Southern California, School of Medicine, 1441 Eastlake Avenue, Los
Angeles, California 90033 USA
5
University Libre de Bruxelles, CHU St-Pierre Hospital, Dept. des Maladies Infectious,
322 rue Haute, 1000 Bruxelles, Belgium
6,
College of Physicians and Surgeons of Columbia University,
630 W. 168
th
Street, New York, New York 10032 USA
HAF [hCG associated factors :Maternin & Maxima peptides]
Nature Medicine 4, 428 - 434 (1998)
doi:10.1038/nm0498-428
108
UnRx
YU1563
Maxima
MATERNIN
UnRX
MATERNIN/MAX GLP AS ANTI-HIV, DIABETES ANTI AGING
Homozygotes transgenic HIV-1 mice
Rx synthetic GLP Maternin peptide
109
Some age gracefully
some not