Chapter 70: Aging Flashcards
Aging definition
- Progressive deterioration of biological systems
- Leads to increase in age-related mortality
- Dependent on intrinsic and extrinsic factors
Average life expectancy in the U.S.
- 81 years
Decrease in human physiological function with age shows
- Linear decline in organ function with age
The Hayflick Phenomenon
- Normal cells in fact have a finite replicative capacity which contributes to the aging process at the cellular level
In the Hayflick Phenomenon, at least one chromosome
- Has lost a substantial part of its telomeres
- Cell stops dividing and dies
Only cells capable of overcoming the Hayflick Limit
- Mutated cancer cells
- Cells expressing viral oncogenes
“Programmed” intrinsic cellular aging theories
- Biological clock/ predetermined, sequential genetic “program” which governs the aging process
- Follows a biological timetable
The somatic mutation hypothesis
- Errors in DNA structure-aggressive environmental factors
- Not accurately repaired and accumulate over a lifetime
The umber of errors in the DNA of an aging cell is dependent on
- The rate at which these errors occur and ability of the cell to repair them
Change in nucleotide structure involves
- Methylation of cytosine moieties/residues
- Methylation has been shown to decrease with cell age
Changes in chromatin structure
- Limit enzyme access to the DNA
- Causes problems with replication/repair
Telomere theory
- In DNA synthesis after primer removal, the freshly replicated strand is sequentially shortened at the 5’-end
- During differentiation telomerase becomes repressed
- While dividing, the telomeres shorten until most chromosomes reach a critical minimum length of about 1.5 kbp, ‘‘crisis’’, death
- Only a few cells escape “crisis” by mutations evoking telomerase activity
DNA damaging agents
- Oxygen radicals
- Advanced glycation end products (AGEs)
- Mutagens
- Ultraviolet light
Free radical theory of aging
- Chemical species with a single unpaired electron
- Implicated in degenerative disorders, including cancer, atherosclerosis, cataracts, and neurodegeneration
“Biochemical bad boys” (free radicals)
- Hydrogen peroxide
- Superoxide
Free radical damage can occur by
- Repeated environmental exposure to ionizing radiation
- Progressive reduction of antioxidant defence mechanisms (superoxide dismutase/SOD)
Free radicals can induce thousands of
- Base modifications in mitochondrial and nuclear DNA per cell per day
SOD findings (gerbil study)
- SOD levels are directly related to life span in 20 different species
- Longer-lived animals having higher levels of SOD
SOD supplementation does not work because
- It is broken down in digestion
Other antioxidants correlated with extended life span
- Vitamin C
- Vitamin E
- Beta-carotene
SOD findings (fruit fly study)
- Inserting extra copies of the SOD gene into fruit flies extends their average life span
- Transgenic fruit flies, carrying extra copies of the gene for SOD, live 5-10% percent longer than average
Mitochondria
- The principal sites of energy production
- Known to accumulate changes with age
- Lysosomal pathway for removal may operate at reduced effectiveness with age
Mitochondrial DNA
- Damaged at a much greater rate than nuclear DNA during aging
- Damage increases exponentially with age
- Type II diabetes associated with defects in mitochondria
Cellular changes with age
- Irregular nuclei
- Changes in mitochondrial shape
- Decreased endoplasmic reticulum
- Distorted Golgi apparatus
- Accumulation of lipofuscin
Advanced glycation end producs (AGEs)
- Post-translational glycation of intracellular and extracellular proteins by glycation associated with aging
- Production initially slow and non-enzymatic
AGEs toughen tissues
- May cause some of the deterioration associated with aging
AGEs appear at younger ages in
- People with diabetes, who have hyperglycemia
Various biological activities of AGEs
- Increase endothelial cell permeability
- Bind to receptors stimulating secretion of cytokines
- Quench of nitric oxide (inhibits vasodilation)
- Enhance oxidative stress
- Modify renal function
- Oxidation of low-density lipoproteins
Diabetic model of aging
- Diabetic complications mimic the physiologic changes that can accompany old age
- Diabetics have shorter life expectancies
The body is able to defend itself against AGEs since
- Macrophages bind, engulf, and digest them
Degraded AGEs are
- Ejected into the blood stream
- Filtered by the kidneys and
- Eliminated in urine
AGE defense system is incomplete in the elderly, so
- Level of AGEs increases
- Macrophages of the immune system become less active with advancing age
Modification of hemoglobin by glycosylation
- Provides an invaluable tool in the management of diabetic patients
Three leading causes of death in people 75 to 84 years of age
- Heart disease
- Cancer
- Cerebrovascular disease
