Download Age - xenia.sote.hu!

Document related concepts

Oncogenomics wikipedia , lookup

Behavioral epigenetics wikipedia , lookup

History of genetic engineering wikipedia , lookup

Gene therapy of the human retina wikipedia , lookup

Site-specific recombinase technology wikipedia , lookup

Designer baby wikipedia , lookup

Mutagen wikipedia , lookup

Therapeutic gene modulation wikipedia , lookup

Artificial gene synthesis wikipedia , lookup

Mutation wikipedia , lookup

Polycomb Group Proteins and Cancer wikipedia , lookup

Epigenetics of neurodegenerative diseases wikipedia , lookup

Microevolution wikipedia , lookup

Nutriepigenomics wikipedia , lookup

Vectors in gene therapy wikipedia , lookup

Point mutation wikipedia , lookup

NEDD9 wikipedia , lookup

Epigenetic clock wikipedia , lookup

DNA damage theory of aging wikipedia , lookup

Transcript
Pathophysiology of Ageing
Miklós Molnár
6357
Semmelweis University Inst. of Pathophysiology
Aging as a global phenomenom
600
Cumulatív % of Increase
500
400
55-64 years old
65-74 years old
75-84 years old
85+
300
200
100
0
1920 1940
1960 1980
2000 2020
Years
2040 2060
Introduction to Human Aging

Number and percentage of the elderly

In the US, more persons over 65 than under 25
years of age

Median age was ~32 in 1995; was 36 in 2000,
and will be ~42 by 2040
Estimates/projections of total U.S. population
and percentage of elderly
year
pop.
1900
1940
1960
1980
1990
2000*
2030*
75.6 mil
132.3 mil
181.0 mil
228.0 mil
250.0 mil
268.5 mil
304.7 mil
number > 65
3.1 mil
9.0 mil
16.6 mil
25.6 mil
31.2 mil
34.9 mil
64.6 mil
%
4.1
6.8
9.2
11.2
12.5
13.0
21.2
Percentage of elderly by age group
Problems for the younger members of
our society

30% of health care resources used by persons
>65 years (will increase to 50% by 2030)

Older persons require more social services and
specialized recreational facilities; these require
money (increased taxes)

The burden of support falls now and will fall
more heavily on the younger generations.
Ages
 Chronologic age
 Biologic age
–
–
–
–
–
–
–
mitochondrial DNA damage
β-galactosidase (fro skin biopsy)
Glycolysation products
presbyopia
Rate of DNA unrounding
vitalcapacity
etc.
WHO Classification of age groups
 Middle-aged (45-59 years)
 Elderly (60-74 years)
 Old (75-90 years)
 Very old (90- )
Introduction to Human Aging

General effects of aging




Aging is a continuing, normal process.
Begins at maturity, ends with death
Effects of aging increase at age 40.
Aging is influenced by interactions of genetics
and environmental factors.
Biologic Changes Occuring by Age
 Universal, in every species
 Progressively on going process
 Internal causes
 Viability of the body is decreasing
So what is normal biological ageing?
Ageing is characterised primarily by a reduction in the capability to adapt to changes in
the environment.
This adaptation includes an ability to recognise the
abnormal substances which we come into contact with
in daily life. Hence if this capacity is reduced then the
organism becomes ever greatly prone to disease and
damage.
Estimated declines in some human
functions with age (age 30 = 100%)
% at 60
nerve conduction velocity
basal metabolic rate
cardiac index
kidney function
renal plasma flow
vital capacity
maximal breathing capacity
96
96
82
96
89
80
80
% at 80
88
84
70
61
51
58
42
The Deficits of Aging
Basic physiologic changes:
 less water, more fat
 decreased circulation
 Immune system failure
 neuronal loss, myofibril loss,cartilage loss
 Limited fibroblast replication
lifetime limit = 50 replications
Deficits of Aging: Sensory
Hearing
– Tinnitus (ringing): blocking frequencies
– Presbycusis: limited ability to pick out speech in a
noisy environment
Visual
– Macular degeneration, cataracts
Deficits of Aging: Sensory
 Taste
> Loss of most taste buds except sugar and salt
 Smell
> Loss of olfactory stimulation
> Stimulation helps preserve what’s lost
Deficits of Aging: Anatomic
 Bones
> 1-2% mineral loss of bone matrix after age 65
> Exercise
> Medication
 Muscles
> 1-2% loss of myofibrils per year after 65
> If you can increase strength by 25% through exercise, you
can add a decade of function, compensated by increasing
myofibril size
Deficits of Aging: Functional
 Reflexes
> Slowed with age
 Balance
> Loss of proprioceptive neurons from feet and neck
receptors
Result = FALLS (40% of >70y will fall)
> Compensate with exercise and balance drills
Deficits of Aging: Functional
 Cognition
> Decrease in short term memory
> Can recall, but need more time for recall
> Affected by diabetes, HTN
 Learning
> Visuospatial is diminished but auditory is well
preserved
> Learn slowly, but better able to put it to wider use
Deficits of Aging: Psychiatric
 Depression
 Dementia
> Often with depression, frequently medication related
> Incidence rises with survival
- Age 65-74, 2-3%
- Age 75-84, 22%
- Age >85, 50%
Pathology
of elderly
Normal Brain surface:
Atrophy – Senile / Alzheimer's
Ageing:
“Progressive time related loss of structural and
functional capacity of cells leading to death”
 Senescence, Senility, Senile changes.
 Ageing of a person is intimately related to cellular
ageing.
 Blood vessel damage precedes ageing.
Plasma Membrane:
Structural Changes lead to
Changes in permeability
Less Fluid due to increase in saturated fatty acids
Nuclear Changes
Chromatin becomes more condensed
(increase cross-links)
(disulfide bonds between histones)
Implication: Damage to DNA less likely repaired
Lymphocytes in culture, add reducing agents to medium
(break disulfide bonds)
senescent cells divide again
Cytoplasmaic Changes
Increase volume with age
Lipofuscin- (age pigment)
found in non-dividing cells
e.g. nerve and muscle
Lipofuscin granules
Ribosomal Changes
rRNA decreases with age
general decline in protein synthesis
Mitochondrial Changes
Decrease number of folds (cristae)
Decrease in number of mitochondria
Lysosomal Changes
Decrease in activity leads to
accumulation of cellular garbage
e.g. lipofuscins
Release of enzymes leads to cell death
Pre-programmed Cell Death (apoptosis)
Apoptosis vs. Necrosis
Necrosis - external cause (trauma)
random breaks in DNA
Apoptosis- internal cause (cellular suicide)
non-random 180 base fragments
Apoptosis - natural developmental process
e.g. interdigital tissue (webbing)
neurons
Factors affecting Ageing:
 Genetic 60% & Environmental 40%
 Clock genes, (fibroblast culture)
 Werner’s syndrome.
 Age gene on Chromosome 1.
 “Age” is a character from female parent.
 Mammalian mitochondria come from ovum.
Progeria
Factors affecting Ageing:
 Environmental factors (40%)
 Trauma
 Diseases – Atherosclerosis, diabetes
 Diet – malnutrition, obesity etc.
 Psychological & Social health – stress.
Theories of Aging
Possible Mechanisms
(How ?)
3 Criteria of Aging Theories
1. Must occur in all individuals of the population
2. Produce Changes in function/ structure
3. Changes increase with age (progressive)
3 Catagories of Theories
1. Wear and Tear (Damage) Theory
2. Physical/ Chemical Changes
3. Genetically Programmed
Why Do We Age?
Why do not we die aerlier?
Wear and Tear Theories
Weismann (1891)
Ordinary insults and injuries of daily living accumulate
and decrease function to some sub-vital level
e.g.
loss of teeth  starvation
molecular level: enzymes
accumulation of harmful metabolites
(cell garbage theory)
e.g. aldehydes, free radicals, lipofuscins
interfere with cell function
Wear and Tear Theories (cont.)
finite energy theories
 animals with high metabolic rates have shorter life
spans
 rats on calorie restrictive diets live longer
Wear and Tear Theories Refuted
 Animals in protected environments have no
change in maximum life span.
 Time-dependent changes cannot initiate aging
 Cellular/ Genetic evidence
Reformulated as Failure to Repair Theories
Physical/ Chemical Changes

Cross Linkage Theory (Post-translational
modification)
–
macromolecules cross linked (denatured) leading to a decline
in function e.g. proteins- collagen, elastin
How ?
Disulfide bonds Advanced Glycation
End-Products (AGEs) accelerated in diabetics
DNA cross-linkage occurs also
Physical/ Chemical Changes

Altered Protein Theory
– protein folding no change in primary structure
decline in catalytic activity with age e.g. enolase in
nematodes denature/renature experiments

increased carbonyl content (ketones, aldehydes)
of proteins (oxidative)
Physical/ Chemical Changes


Free Radical Theory (Oxidative Damage)
– Free Radicals: contain unpaired electrons making
them highly reactive therefore only exist for a short
time. e.g. Super oxide, hydroxyl , peroxide
Lipid peroxidation- damage to cell membranes
Protein cross linkage DNA damage
Antioxidants - Vitamins A, C, E, Cellular
Defenses- Catalase, Superoxide Dismutase
Free Radical
Theory
Aging By Program
Assumptions:
Biological Clock
Molecular Clock- the Telomere ?
Life Span Inheritable
Twin Studies
Biological Clock:
Hypothalamus
Decline in Signal
Decreased Sensitivity to Feedback
Programmed senescence does not require central
control
- cell culture evidence
Species
Lifespan
(year)
Cellular
divisions
Turtle
175 év
90-125
Human
110 év
40-60
Dog
30 év
15-35
Mouse
3,5 év
18-28
Telomerase in ageing:
Germ
Cells
Somatic
Cells
A telomer hypothesis
Replication Error of the 5’. End
Telomer: 5-15 kb TTAGGGRepeated sequences, shortened during
the replications progressively
Function of Telomerase
Aging By Program
 Gene Mutation Theory- accumulation of somatic
cell mutations leads to a decline in function
 Liver cells of older mice have more mutations than
young
 Short life span strains have more mutations at
same age
DNA repair mechanisms decrease in repair function??
Aging By Program
Gene Theory
One or more harmful genes active only later
in life
Evidence? Microarray analysis
For practitioners, based on the biology of
ageing
 New diseases could have different signs
 Clinical manifestations of diseases are more serious,



because decreases in reserve capacity
– hyperthyreodism  heart failure etc.
Easier to cure, better respond to therapies
Drug induced side effects are more frequent
Because a reduction in the capability to adapt occurs the side
effects of the diseases worsening the status of the patient more,
however any treatment directed again the side effect can
improve the life of the patients
For practitioners, based on the biology of
ageing
 What ever is abnormal in young may be has no
clinical meaning in elderly, eg. bacteriuria,
decreased glucose tolerance, incontinentia etc.
– Bacteruria may not be the cause of the fever from
unknown origin.
 Difficult to find the right diagnosis because the
clinical signs are more complex
 Because elderly patients suffer more from the side
effects of the diseases, they improve better by the
treatment or prevention