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GENETICS AND LIFESPAN
Genetics of longevity
1. Heritability 0.23-0.26
2. Exceptional longevity (90+)
a. appears to be a real category
b. what is the basis?
-reduced incidence of cancer and heart disease
-slowed process of aging in general
GENETICS AND LIFESPAN
Centenarians: People 100 years old and older
Is there something special about them?
GENETICS AND LIFESPAN
Change in number centenarians in the Netherlands
GENETICS AND LIFESPAN
Age distribution of centenarians in the Netherlands
GENETICS AND LIFESPAN
Marital status of male and female Dutch centenarians
GENETICS AND LIFESPAN
GENETICS AND LIFESPAN
Longevity seems to be only moderately heritable.
The nature of genetic influences on longevity is
probably non-additive (ie. Single genes), suggested
by both statistical partitioning of heritability as well
as the class of “exceptional longevity”. As if
Exceptional longevity were like a discrete trait.
Is there evidence for particular genes?
GENETICS AND LIFESPAN
Cholesterol ester transfer protein (CETP)
Two functional variants produced by the
V and v alleles
VV higher % of larger lipoproteins (favorable)
vv
lower % of larger lipoproteins (unfavorable)
GENETICS AND LIFESPAN
VV 25% in patients 100 years or greater
vv
8 % in patients 70-73 years old
VV genotype significantly enriched in
those exhibiting the exceptional longevity phenotype.
Genetics and tissue transplantation
Why is it so hard to find a match?
Rejection of transplanted tisssue:
Graft versus Host reaction
Fever
Skin rashes
Inflammation surrounding
transplanted tissue
Genetics of successful tissue transplantation
Histocompatibility = tissue compatibility
Main factors in successful tissue transplanation?
ABO blood type for transfusions
MHC: Major Histocompatibility Complex
HLA: Human Leukocyte Antigen
HLA genes are tightly linked on chromosome 6
The frequency of each of these
alleles in a population is low
Which HLA loci are most important in
determining transplant success?
HLA - A
HLA - B
HLA - DR
Why, even among family members, a match
is difficult to obtain…..
What is the chance of
a match between
a parent and a child?
What is the chance of
a match between
two siblings ?
Need to match for ABO also when doing tissue
transplantation
HLA genotype and disease associations
DISEASE
HLA allele
Relative risk
Ankylosing spondylitis
B 27
87.4
Rheumatoid arthritis
DR 4
4.2
Systemic lupus
erythematosus
DR 3
5.8
Graves disease
DR 3
3.7
Celiac disease
DR 3
10.5
Myasthenia gravis
B8
3.4
Multiple sclerosis
DR 2
4.1
A3
8.2
Insulin dependent diabetes
Hemochromatosis
Ankylosing spondylitis
Autoimmune disease
1. Arthritis in spine
2. Other joints
3. 90% men
4. Onset between
16-40
Graves Disease: Immune
System sends signals to the thyroid
to make more hormone
Nervousness
Irritability
Anxiety
Muscle weakness
fatigue
Increased appetite,
Weight loss despite normal eating
Sweating,
Shaking, heart pounding
Hair loss or thinning
Bulging eyes
Vision disturbances
Skin rash
Dementia: Loss of cognitive function
Alzheimer's disease: neurodegenerative
Symptoms:
Loss of short term memory
Recognition problems
Language disorders
Motor skill decline
Progressive
Types of Alzheimer’s Disease (AD)
Types of Alzheimer’s Disease (AD)
All involves the accumulation of abnormally folded
amyloid beta protein
Age 65: 2-3% show symptoms
Age 85: 25%+ show symptoms
Heritability: 59 - 78 %
Early onset:
Symptoms appear in 30’s and 40’s
Highly familial, dominant?
Late onset:
APOE Apolipoprotein A
3 alleles ApoE 2, ApoE3 (dysfunctional), ApoE4
ApoE4 associated with late onset AD
Other senile dementias involve different steps in the
Pathway synthesizing the plaques:
“presenilins”
Proposed environmental factors:
Early head injury
Aluminum in the diet
Smoking