Aging: Biology and Pathology Flashcards
definition of aging
- the natural progressive decline in body function that leads to death
- aging begins once growth and development are completed, near the end of the third decade, but the effects of aging do not really become evident until the seventh, eighth, and ninth decades, and beyond.
1) the effects of aging are cumulative (and essentially irreversible), and 2) the overall decline in physiologic function accelerates with increasing age.
Aging adults in the US
- by 2030, expected that 64 million (20% of pop) will be over 65
- those greater than 85 will increase to 8.8 million
- in the past 30 years there has been a 26% decrease in mortality rate for those greater than 80
-Around 2024, Medicare commitments will begin to exceed revenues
Life expectancy in US
(average at at death)
81 y F
76 y M
Worldwide: women outlive men by 7-10 years
Men suffer more cancer and infectious disease
Life span
- the greatest possible life expectancy
- Widely held that humans cannot live beyond about 110 years under the most favorable conditions
Still unclear what fixes the life-span of human beings and other species
Limit not accounted for by evolutionary pressure
Changes seen in normal aging
1) Hair-graying, thinning and overt hair loss.
2) Skin-thinning, loss of elasticity, wrinkles, “age” spots
3) Eyes-farsightedness (presbyopia, difficulty seeing up close), later cataracts, sometimes macular degeneration.
4) Benign prostatic hypertrophy (BPH). Atrophy of ovaries and uterus in post-menopausal women.
5) Hearing-loss.
6) Skeleton-age-related osteoporosis and degenerative arthritis; decreased 1,25 Vit D production
7) Brain: significant loss of myelin and white matter; less loss of neurons than first thought, some loss of subcortical nuclei in the gray matter; brain shrinks
8) atherosclerosis; varicosities
9) Kidneys: loss of nephrons, kidney decreases in weight
10) Increased fat content of bone marrow; atrophy of thymus and spleen
11) Immune system: T and B cell functional defects; loss of naive T cells; ineffective vaccination; increased autoimmunity, cancer, acute/chronic infection
12) heart: atrophy of myocytes, accumulation of lipofuscin (“wear and tear” pigment– product of peroxidation of unsaturated FA– also in brain/liver
13) Lung: loss of elastic tissue; accumulation of anthracotic pigment
14) soft tissue: increase in body fat
15) decrease in ability to survive trauma, heal wounds, less immune system surveillance
Aging leads to an increased susceptibility to:
Cancer (incidence and mortality increase with increasing age; in CO cancer mortality is highest at age 70; it takes time for right set of 5-7 somatic mutations to accumulate in genes governing cell growth and differentiation in order for a stem cell to become malignant
Generalized atherosclerosis
Cerebrovascular accidents
Non-insulin-dependent diabetes mellitus
Alzheimer’s and Parkinson’s (20% of those over 80 are diagnosed with Alzheimers)
Thromboembolism
Theory of Aging #1: the Clock theory/telomere hypothesis
- the aging process and death are programmed/controlled by genes
- hundreds of mutations in model organisms have been identified that either increase the rate of aging or increase lifespan
- somatic cells have been shown to be “programmed” to die– mediated by shortening of the telomeric ends of chromosomes over time
- cells undergo a finite number of doublings; capacity to divide diminishes with age
- Senescent cells stop dividing and don’t respond to added growth factors (fresh serum FGF)
- Permanent arrest at the G1-S checkpoint
What happens to senescent cells that are no longer dividing?
- they don’t die, they live for extended periods
- contain granular cytoplasm
- often possess chromosome abnormalities
- contain high levels of beta-galactosidase
Correlation between capacity to undergo doublings and life span of a species. What may account for this?
- With each cell division, the ends of chromosomes (telomeres) shorten
- tandem repeats of TTAGGG
- somatic cells lack telomerase, the enzyme that produces the telomeric repeat
Telomeres are critical for long term survival.
- stabilization of chromosomal ends
- imp for attachment of chromosome to nuclear envelope and for proper chromosome segregation
HOWEVER ongoing studies contradict the idea that the telomeres act as the “clock” that defines the life span
Three components of telomerase complex
TERT: reverse transcriptase activity of telomerase
TERC: RNA component template for telomere repeat sequence
Protein component DSC1 (dyskerin)
*if mutated these individuals have problems, but don’t exhibit premature aging that you would expect if telomere length were the aging clock (so loss of telomere length may not be what defines life span)
Progeria
- individuals show signs of accelerated aging and a life span of no more than 10 years - death from cardiac or cerebrovascular disease.
- Occurs due to a dominant negative mutation in lamin A/C.
- This disrupts function of the nuclear lamina, needed for transcription, chromatin replication, and higher order chromatin structure, and results in a higher rate of cell loss through apoptosis.
Werner’s syndrome
- affected patients develop cataracts, aging changes in skin and hair while still in their twenties. Early onset of diabetes, osteoporosis, cancer and heart disease - death by age 50.
- Cells show a mutator phenotype (increased rate of somatic mutation) and rapid telomere shortening
- due to a DNA helicase on chromosome 8 (DNA helicases melt duplex DNA and are essential for repair and replication of DNA)
- Werner helicase has been shown to help reinitiate DNA synthesis from stalled replication forks that occur when replication encounters a site of DNA damage. When the helicase is absent, recombination occurs to overcome the block, and often this produces DNA deletions, and leads to “mutator” phenotype.
Down syndrome as it relates to aging
premature death (life span ~60 yrs - almost all patients develop Alzheimer’s disease, alopecia, thyroid dysfunction, neurodegeneration.
apoE4 isoform
associated with longevity
Theory #2: the Rust Theory
aging process results from the accumulation of somatic mutations and oxidative damage in membranes and macromolecules such as DNA
- aged individuals have elevated levels of LIPOFUSCIN, cross-linked collagen, and oxidized DNA and protein
- about 10% of total protein is oxidized in young individuals; 20-30% is oxidized in those over 80y
- may stem from lower levels of antioxidants (glutathione) and less ability to degrade oxidized protein in the aged.
- There is also an increase in non-enzymatic glycosylation of proteins with age, esp. in diabetics.
