extension of life well beyond the period of reproduction and childbearing
constellation of deleterious functional and structural changes that are inevitable consequences of longevity
Maximal life span:
is not sigificantly different from protected and wild animals
Maximum human life span
Life expectancy (2007)
80 for females and 75 for men
Women live longer than men because
1. greater female longevity is universal in the animal kingdom 2. male to female ratio is 106:100 at birth but after, at age 75 its 2:3 ....greater male mortality from violent causes and susceptibility to CV diseease, cancer, resp illness, cirrhosis. `
Aging is characterized by :
functional and structural deterioration
Beginning in what decade is there a rapid decline in physiologic function (muscular strength, cardiac reserve, nerve conduction time, pulmonary vital capacity, glomerular filtration, vasc elasticity)?
these deteriorations are accompanied by structural changes like:
lean body mass, and constituents of connective tissue matrix progressively cross linked
What is the wear and tear pigment?
lipfuscin....accumulates in organs like brain, heart, kidney, liver...finely yellow and brown pigment composed of LIPID CONTAINING RESIDUES OF LYSOSOMAL DIGESTION
normal cultured human fibroblasts undergo how many population doublings?
50...at this point they stop dividing and irreversibly arrest in the G1 phase of cell cycle..REPLICATIVE SENSESCENCE
Children with progeria:
obvious reduced number of populatin doublings in vitro
oncogenic virus or a chemical carcinogen=
continue to replicate indeinitely (immortalized)
What are telomeres?
genetic elements (specialized DNA sequences) at the tips of the chromosomes....they keep track of and limit the # of cell divisions a cell can undergo. shoren until it interferes...too short and it will enter senesence stage. *normal procesS: end of chromosome is not copied exactly leaving a unreplicated gap
Telomere shortening is a molecular clock..produces a senesecen also called
End Replication Problem
RNA enzyme fills gap by attaching bases to end of chromosome and extending chromosomal ends
When telomerase levels decrease, telomeres will
shorten and activate the p-53 dependent system in the cell cycle
p53 activated mutant mice show
early onset aging with shortened life span.....correlate as a marker for several age related dz like atherosclerosis and Alzheimer as well as conditions associated with tumor development
tumor suppressing mechanism....stops tumorigenesis (without it= IMMORTAL CANCER CELLS)
Caloric restriction in rodents and lower species:
How do they increase longevity?
1. atteuation of age related increases in mito generation of ROS 2. slower accrual of oxidative damage
by - increasing the expression or sirtuins - lowering serum levels of insulin/IGF-1 (these tend to decrese level of cell activation)
What are sirtuins
promote cell survival by inhibiting apoptosis
Aging is caused by progressive and irreversible accrual of molecular oxidative damage
Manifestations of oxidative damagE:
1. peroxidation of membrane lipids 2 DNA modification (strand breaks, etc) 3. protein oxidation (loss of sulfhydrl groups)
O2 and H2O2
100,000 attacks on DNA per day by ROS...10% of protein molecules are modified by carbonyl adducts (antioxidant defenses dont do shit)
Deterioration of functuonality of organs whose main activiteies are performed by non dividing cells cause most of the physiological changes.
Cardiac myocytes are replaced by
resident progenitor cell populatins...but aging causes the ability to replenish to go down via:
1. impaired DNA repair mechanisms 2. accumulation of mitotic inhibitors suchas p16, p14, p53
Agiging is influenced by genetic factors:
1. correlation in longevity between related people 2. identical twins excellent concordance 3. existance of hertibale diseases with accelerated aging
What is Hutchinson Guilford Progeria?
entire process of aging is compressed into a span of <10 years.....male bald, cataracts, coronary artery dz.
**cause: LNMA gene mutation: abnormal gene product progerin accumulates in nuclei and damages nuclear heterochromatin that regulates numerous genes.....laminopathies
What is Werner Syndrome?
"adult progeria" autosomal recessive disease with early cataracts, atherosclerosis, osteoporosis, hair loss and skin atrphy. die in their 50s...
**cause: los of function of WRN gene (chromosomal stability and telomere maintenance).....increase apoptosis and telomere dysfunction resulting in accelerated aging
What is Cockayne syndrome type A and B?
stop growing early in life (12 year life expectancy)....afflicted with: 1. abnormal sensitivity to light 2. hearling loss/eye abnormalities (pigmentary retinopathy) 3. demyelinating disorders (cerebro-oclo0facio-skeletal syndrome)
**caused by defects in either pair of genes that participate in transcription coupled DNA repair (ERCC8 ERCC6).....lead to cells that accumulate DNA damage and cause defects in transcription