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BIOL 355 Final: BIOL 355 Notes for FINAL EXAM - University of Waterloo

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BIOL 355
Cheryl Duxbury

Cellular Aging • 7. Telomere Theory of Aging o “Cellular timing”  another possible mechanism for internal clock o Another piece of evidence for finite L.S. in cultured cells o Linked directly to cell replication o What is a telomere? ▪ Region on ends of chromosomes; composed of repeating units of 6 nucleotides ▪ Humans = TTAGGG (repeating 2,000 times) ▪ Somatic cells have a finite # of telomeres ▪ “Junk” DNA, no apparent genetic value (currently) ▪ Stabilize ends of chromosomes (protects coding sequences) o What do telomeres do? ▪ Protect the chromosomes ▪ Separate one chromosome from another in the DNA sequence (help cell recognize chromosomes from damaged DNA) ▪ Without telomeres, the ends of the chromosomes would be "frayed”, leading to chromosome fusion and massive genomic instability • The body would have no way to know where the chromosomes end. • It would treat them as broken pieces of DNA and attempt to repair them by joining them with other chromosomes o Telomeres are lost after each round of cell division ▪ When cells divide, parental strand is replicated into a daughter strand ▪ DNA poly always needs a free 3’ OH to add bases on the new daughter strand ▪ Since DNA is linear there is no base to prime the daughter strand • So a short piece of RNA (primer) is added to the end of the daughter strand ▪ Need to remove the RNA primer from the daughter strand • Removal of primer results in a gap at the end  telomeres lost • Each cycle of daughter strands will have a gap  therefore telomeres are lost with every round of replication • Each time replication happens, the length of chromosome gets shorter • Loss of telomeres from actively dividing cells is typically 50-150 bp/cell doubling in vitro and 15-50 bp/cell in vivo o What’s the problem with staggered ends? ▪ Cell will think it’s broken or frayed b/c of the overhang ▪ If there are 2 single stranded areas of chromosomes, then it will fuse the two together ▪ ssDNA could fold on itself and form a hairpin ▪ ssDNA could also be degraded (attacked by nucleases) o How to combat staggered ends ▪ Telomeres are recognized by specific proteins called telomere binding proteins ▪ These staggered ends are curled up around the ends of chromosomes and bound by proteins  to protect them Loop formed is called a T-loop ▪ When teleomeres are lost, T-loops can’t be formed o Telomere Protective Function ▪ Telomeres serve to protect eukaryotic chromosomal ends from being recognized as damaged DNA ▪ By forming T-loops, they hide the ends from DDR (damaged DNA response pathway) ▪ DDR pathway  will try to repair ends by fusing chromosomes together! • Won’t recognize chromosome with T-loop • Will recognize chromosome with exposed staggered ends (not able to adequately form T-loop) o Consequences of shortened/dysfunctional telomeres ▪ Evidence suggests that critically shortened (dysfunctional) telomeres may help initiate the onset of cancer ▪ Note: P53 is a checkpoint protein that stops replication or results in apoptosis of the cell ▪ As cells age, telomeres get shorter  can’t form T-loops  become dysfunctional ▪ Cells with dysfunctional telomeres will either: • A) Undergo apoptosis or stop replicating when p53 is functional  good • B) In absence of p53 (mutated cell), dysfunctional telomeres can initiate cancer by promoting genomic instability  bad o Recognized as strand breaks and tries to repair o p53 not around to look at chromosome lengths o Cell is still allowed to replicate o Results in chromosome instability, fusion, and cancer o Consequences of complete telomere loss ▪ 1) Once the protective ends on the chromosomes are gone, important genetic information WILL be lost with each cell replication • Results: altered proteins, abnormal cell function and potential cell death! ▪ 2) Systems will compensate for low telomeres for a bit (limited telomerase activity or recombination), but if replication continues then will switch into p53 pathways: • 1) Cell senescence where cells are held up in cell cycle (discussed before) or • 2) Apoptosis which is cell suicide o How do cells become immortal? ▪ Have enzyme capable of adding telomeres back onto end of chromosome called telomerase • If telomerase is inhibited in tumor cells (in vitro) the telomeres become shorter and cells die! ▪ Somatic cells have telomerase potential  but gene has been turned off in all cells ▪ Function telomerase gene only found in two cell types: • Precursor cells that give rise to germ cells  sperm, eggs, ovaries • Most cancer cells ▪ Study showed: • Telomerase active in 90 out of 101 immortal cell lines representing 12 tumour types, in normal testes and ovaries • In contrast, telomerase activity was not detected in 22 out of 22 normal somatic cell line cultures and in 50 out of 50 normal or benign biopsies of 18 different tissues. o Evidence for Telomere Theory of Aging ▪ 1) The length of telomeres is inversely proportional to age of cells in tissue culture • Older cells in culture have shorter telomere ▪ 2) Telomeres lost faster from individuals with progerias! ▪ 3) Immortal cells such as cancerous cells have a constant telomere length ▪ 4) Blood vessels under turbulent blood flow show shorter telomeres than long straight sections (no turbulence) • Areas with turbulence have more erosion  more cell turnover  more replication  shorter telomeres ▪ 5) Oxidative stress (free radicals) speed up telomere shortening ▪ 6) Centenarians and their offspring maintain longer telomeres compared with controls with advancing age; longer telomeres are associated with protection from age-related diseases, better cognitive function, and lipid profiles of healthy aging ▪ Study showed: • Adding telomerase to human cells in tissue culture resulted in: • Increase the maximum life span for tissue cultured cells (past the Hayflick’s limit of 50) • When they re-lengthening the telomeres in the cells that are already in Phase 3 (cells scenescing or dying)  o They were able to change the morphology to move back towards Phase 2 cells  i.e. reversing of aging process!! Telomeres, Hayflick’s Limit and the Cell Cycle • Comparison of cell line telomere length o Germ line: telomere length remains constant with age o Somatic cell line: telomere length decreases with age o Premature aging: telomere length decreases very quickly with age  early death Telomere Length Vs. Population Doubling (Hayflick’s Limit) *KNOW THIS* o Telomerase is active in germline cells, maintaining long stable telomeres o Telomerase is repressed in most normal somatic cells  telomere loss (60 bp/cycle) o At mortality phase 1 (M1 or Hayflick limit) there are presumed critical telomere loss on one or more chromosomes ▪ This will signal irreversible cell cycle arrest (senescent cells) ▪ Chromosome will reach critical state at different times depending on turnover, heterogeneity o Events may allow somatic cells to bypass M1 WITHOUT activating telomerase ▪ Continue replicating  more shortening of telomeres  enter crisis state o When telomeres become critically short on a LARGE number of chromosomes cells enter crisis (M2) o During crisis, cells depend on p53 ▪ 1) If p53 positive  Cell cycle arrest and apoptosis of cell ▪ 2) If p53 negative  May result in transformation to telomerase + cells  cell become immortal  cancer; frayed edges  genomic instability  also leads to cancer • Is Telomere Length Linked to Hayflick’s Limit? o Cultured cells double  50 times because their telomere length has  to a point where the cell undergoes suicide (cell death) o Studies with cultured cells to which telomerase had been added show that these cells had an  number of replications beyond the normal 50 doublings o Problems with Telomere length and cell senescence ▪ Only applicable to continuously mitotic cells (what about post mitotic) ▪ Does not correlate with lifespan of organism. • i.e. mice have very long telomeres (longer than humans) and lifespan is only 3 years • Mice bred with shorter telomeres (same length as humans) showed some traits of aging –skin ulceration, infertility, GI lesions, cancer o They don’t resemble normal aged mice in most respects ▪ Conclusion: Life span doesn’t equate to number of serial passages that someone has • Seems like there are more serial passages than the maximum LE • Aging and the Cell Cycle  Linked to Hayflick’s Limit o G 1hase: period growth of cell (protein synthesis, increase in organelle size) ▪ G1  S: checkpoint o S phase: period of DNA synthesis (when telomeres are lost) ▪ S  G2: checkpoint o G 2hase: cells prepare for mitosis ▪ G2  M: checkpoint o M phase: mitosis ▪ After M: checkpoint o G ohase: post-mitotic cells  Very important cyclic part of the cell cycle ▪ Where post mitotic cells go once they're differentiated ▪ Where non-dividing cells go ▪ If a mitotic cell is shunted into G0 and it's not meant to be there  bad • If held up too long  might inactivate p53, activate telomerase • Progression in Cell Cycle o Progression to next phase in life cycle is highly regulated using many checkpoints o If cell checkpoints are NOT met, cells will not proceed to next phase of cell cycle (even if you add growth factors or mitogens) o Hayflick’s findings: Dividing cultures contain a percentage of senescent (growth-arrested cells); this percentage progressively increases until all cells in the population are quiescent, (stopped dividing –around 63 passages) ▪ Senescent cells are growth arrested in transition from phase G1 to phase S of the cell cycle ▪ Growth arrest is irreversible  growth factors cannot stimulate the cells to divide even though senescent cells are metabolically active • P53 Role in Cell Cycle o P53 pathway prevents DNA replication at G1/S border o Prevents damaged DNA from being duplicated in S (shortened telomeres!) o If damage exists, p53 is activated  halts cell cycle before it can proceed to S ▪ If damage is repaired then cell cycle proceeds, ▪ If not repaired, cell cycle cells won’t enter S phase  shunted to Go until they die or undergo apoptosis • Chronometer o Hypothalamus is the master clock that regulates longevity and controls the production of hormones by the pituitary gland ▪ Regulates reproduction, energy, metabolism, adaptation and other organs to produce other hormones ▪ Information is carried throughout the body from the hypothalamus via neurons and hormones, o As one ages: signal gets weaker, less hormones produced, less neurons activated, less receptors on cells and less neurotransmitters ▪ Function of target organs depending on the hypothalamus and pituitary will suffer  leads to changes typical of aging ▪ Could results in positive feedback loop: Signal weakens  hypothalamus tries to correct it, by working harder (producing more hormones)  leads to systemic imbalances and makes hypothalamus even weaker o Above theory may support that aging is extrinsic to the cell in vivo o Factors limiting with age ▪ Gene expression decrease with age ▪ Hormones, neurons and neurotransmitters decrease with age ▪ Functional capacity decrease with age • Apoptosis o Deliberate programmed death of cells that occurs naturally o Purpose of apoptosis: ▪ To remove unwanted cells • Extra cells during development • Damaged cells • Cells without proper destination/cell-cell communications ▪ Balances cell removal with cell replication o Steps to apoptosis: ▪ 1) Signal to received apoptosis is activated intrinsically or extrinsically ▪ 2) Cell shrinks, chromatin condenses, gene expression stops ▪ 3) Membrane starts blebbing, organelles stop functioning  specifically mitochonidia ▪ 4) Membrane continues blebbing, cell collapses  breaks off into smaller bodies (blebs) ▪ 5) Cell wrinkles and dies while blebs are scavenged by immune system o Example of gene involved in apoptosis: Fos Apo-1 gene (CD95): ▪ Suicide gene that codes for a protein which becomes a transmembrane receptor • Once proper ligand binds to receptor, apoptosis begins ▪ Some ligands can be in the family of tumour necrosis factors • Tumour necrosis factor is a protein produced by several cell types (WBCs) • Promotes the destruction of some types of cancer cells • Used in the immune reactions against harmful cells ▪ Apo-1 like genes can arrive in two ways: • Intrinsically via signal from inside cell • Extrinsically via ligand binding to a Apo-1 receptor (only in old cells) o Malfunctioning of Apoptosis ▪ Results from mutation in of gene involved in any step of apoptosis such as initiation, mediation or execution ▪ Insufficient apoptosis can lead to: • Cancer (cell accumulation due to lack of apoptosis and clean up by immune system) • Autoimmunity (failure to eliminate cells that attack their own body) • Persistent infections (failure to eradicate infected cells) ▪ Excessive apoptosis can lead to: • Neurodegenerative diseases (Alzheimer’s, Parkinson’s, Huntington’s) • Autoimmunity (uncontrolled apoptosis in specific organs) • Ischaemia (stroke or myocardial infarction due to death of heart cells) Random (Error) Theories of Aging • 1. Gene (Somatic) Mutation Theory o Premise: Accumulation of mutations occur in DNA (genes) of cells as you age ▪ Mutations may be irreversible and deleterious to cells  leads to malfunctions and changes in function ▪ Altered proteins lead to altered function of organelles + cells  leads to aging and cell death o Cause of mutations: ▪ Ionizing radiation ▪ Free radicals (oxidative phosphorylation) ▪ Toxins and chemicals ▪ Decrease repair system ▪ Replication errors o Types of mutations: ▪ Point: deletion or insertion of bases ▪ DS breaks: fragmented chromosomes (prone to fusion with other chromosomes) ▪ Substitutions: change of bases ▪ Translocation: segment of DNA from one chromosome to another ▪ Remember: Changes in DNA bases of gene may alter primary structure of protein  changing how its folds and functions o Support for theory: ▪ 1) Radiation exposure increases mutation of DNA and decreases life span ▪ 2) In humans, an increase in radiation leads to increase in cancer • 3-fold increase in leukemia for women given pelvic X-radiation for non- malignant gynaecological problems • Survivors of Hiroshima and Nagasaki show increase leukemia but their children don’t ▪ 3) Calorie restriction results in lower mutation frequency in some tissue ▪ 4) Liver and heart cells in old mice have more DNA mutations (3-fold) than same cells in young mice ▪ 5) Non-smoking young adults have 6-fold less mutations in DNA than 60 y/o ▪ 6) Cancers as evidence of mutations (increase levels of mutation and rates as animals age) o Process of mutations: ▪ Intrinsic and extrinsic sources causes DNA damage which causes  ▪ Mutations and changes within the protein (cell cycle arrest, transcription impairment, gene expression, deregulation, apoptosis)  ▪ Cell loses functional capacity and loss of homeostasis  • When cells are contiguously damaged and apoptosed, they must draw on stem cells to replace them o Result: Less stem cells when individual is older o Less capacity to replace cells that are damaged  contributes to having lower L.E ▪ Leads to biological aging o Examples for theory: ▪ SCA, cystic fibrosis, haemophilia ▪ Single bp changes in DNA have led to many disease ▪ Note: mutations in somatic cell line will not be passed on to progeny but mutations in germ cell line will be! • 2. DNA Repair Theory o Premise: ▪ DNA accumulates errors increasing with age ▪ But there’s also a decrease in repair mechanism as age increases ▪ Thus: accumulation of errors results from a decrease in repair mechanism ▪ Ability to repair DNA damage correlates with increased life span o Example/Support ▪ Thymine dimers results from UV radiation damage; very damaging to cells ▪ Normal repair: Dimer is excised and replaced with new bases that are sealed with ligase ▪ However, this repair decreases with age and results in increased risk of: • Xeroderma Pigmentosum: Pre-mature aging disease o Inability to repair UV radiation induced thymine dimers; causes ▪ Dry skin, increased moles ▪ Skin cancer at age 13, death around age 25 ▪ Skin cancer represents major morbidity in Xeroderma Pigmentosum patients • Incidence of malingnant melanoma in patients with XP who are younger than 20 is 2000-fold greater than age-matched controls • 3. Accumulation of Waste Theory (Cellular Garbage Theory) o Premise ▪ Accumulation of by-products of normal cellular metabolism causes aging ▪ These accumulations are found in the cell cytoplasm and are more common in post- mitotic cells such as neurons, muscles, and brain cells o Types ▪ Inert: lipofuscins are yellow-brown pigments (age pigments) ▪ Reactive: free radicals and reactive molecules that alter other molecules o Process/Role in Aging: ▪ Strongly cross-linked molecules that cannot be broken down by lysosomes  accumulate as cellular garbage in cytoplasm • Cross linked by AGE products and free radicals • Lysosome becomes less efficient with age and becomes overwhelmed with amount of garbage that accumulates • Over accumulation  garbage is shunted out to cytoplasm and accumulates there ▪ Interfere with normal functioning by causing: • Loss of transcription • Loss of cytoplasm mass • Loss of mitochondria (other organelles) • Loss of RER (protein synthesis) • 4. Cross-Linkage Theory: o Premise ▪ With increased age, new cross-links form between or within macromolecules such as macromolecules which leads: • Altered structure and function • Dysfunction of cells, tissues, and organs ▪ Cross-links are normal to a protein  allows them to fold • After protein is already folding, new cross-links will mess up the structure • AGE  breaks existing cross-links and/or creates new ones • If catalytic or active site gets messed up, substrate binding will be interrupted • May result in a decrease in functional capacity enzymatically o Cross-linked Proteins: ▪ Collagen: most susceptible to cross-links • Long-lived; longer its out in body  more x-links develop • Predominant tissue in body  more of it means more susceptible to x-links • Makes up part of the connective tissue of body • Connective Tissue o Most abundant tissue by weight and has multiple functions such as support, protection, and tissue repair o Functions: binding, supporting framework ▪ Protection against infection ▪ Repairs tissue damage o Elements of Connective Tissues ▪ Living Cells • Macrophages: immune cells that engulf and destroy foreign cells with lysosomes • Fibroblasts: Most common cell type; star-shaped; produce fibres and matrix materials • Mast cells: mainly used in immune allergic reactions; release histamine • Adipose cells: store energy in the form of fat; also provides insulation ▪ Fibres • Elastic: Composed of elastin o Less strength than collagen; more elasticity o Offers elasticity to structure: blood vessels, heart, lungs, and skin (ability to stretch and recoil) • Collagen: composed of collagen o Holds structures together; can be torn o Offers strong, tough, flexible, highly tensile strength that resists stretching (tendons, ligaments, dermins of skin) ▪ Matrix o Classifications of Connective Tissues ▪ Adipose: specialized connective tissue in form of fat • Found beneath the skin and around organs • Provides protective cushioning and a source of energy for tissues ▪ Loose Connective Tissue: thin membranes throughout the body • Found beneath skin and around blood vessels • Provides support and elasticity ▪ Dense Connective Tissue: dense collagen fibres • Provide strong resistance and support • Have poor blood supply means  slow healing process o Age-Related Changes in Connective Tissues: As age increase: ▪ Turnover of collagen decreases (breakdown is slower  lasts longer in the body) ▪ Solubility decreases (harder to break down) ▪ Elasticity decreases (loss of elastin and x-links of elastin and collagen changes properties of tissue elasticity and tensile strength) ▪ Deposition of collagen increases (replaces elastin with collagen and loses elasticity  fibrosis) ▪ Fibrosis: Loss of elasticity due to formation of excess fibrous CT • Ends up with more collagen than there should be and more x-links • x-links reduce elastic properties  elastin becomes resistance to stretch, less flexable, more rigid with age • x-links reinforce collagen properties  collagen becomes even more resistant to stretch, less flexable, more rigid with age Effects of Advanced Glycation End-products (AGE) • Advanced Glycation End-products (AGE) o Formation: KNOW THIS ▪ 1) Glucose binds to amino acid to form a Schiff base that is unstable ▪ 2) Schiff base quickly forms an Amadori product which is stable and lasts for years (10-20 years) ▪ 3) Amadori product rearranges very slowly over 10-20 years to become  ▪ 4) Glucose derived structure which in turn forms (irreversible)  ▪ 5) Advanced Glycosylation End-product (AGE) ▪ 6) AGE increases deposition of collagen and decreases elasticity by cross-linking collagen fibrils together to form a clump (CML, HI, Pentosidine) o Two Main Sources: ▪ Exogenous (ingested in foods) • Western diets are rich in AGEs • AGEs formed when food is processed at elevated temperatures (deepfrying, broiling, roasting, grilling) • Examples: cheese, sausage, hamburgers, tobacco smokes ▪ Endogenous (formed in the body) • AGE’s formed during aging and in diabetics o Risks: High in elderly ▪ Cataract formation, Alzheimer’s, Osteoarthritis, ▪ Arterial stiffness, cardiovascualar disease ▪ Diabetes, kidney disease, anemia, poor skeletal muscle strength o Process ▪ Forms cross-links between connective tissues such as elastin and collagen ▪ Increase oxidative stress (free radicals) ▪ Up-regulate inflammation (swelling of tissue) ▪ Stiffen tissues with matrix that are rich in these proteins • Examples: skeletal muscle, tendons, joints, bone, heart, arteries, lung, skin and lens of eye • Biological Mechanisms for Harmful Effects of AGE Crosslinks o AGEs affect virtually every tissue in the body o Blood Vessels ▪ Cross-link of collagen increases stiffness and decrease elasticity of blood vessels ▪ Increase in blood pressure makes the heart work harder o Brain ▪ AGE’s accumulate in human brain with age in dead neurons and senile plaques (AZ) ▪ Elevated levels of CML causes cognitive impairment and cerebrovascular disease in elderly o Skin ▪ Decrease in flexibility and elasticity in skin due to lack of elastin ▪ Increase in collagen cross-links (skin wrinkles and sags) o Kidney ▪ Loss of kidney function and filtration (renal failure) with age ▪ Up-regulate synthesis of more collagen in kidneys causes cross-links and decrease permeability of kidney capillaries via fibrosis  leads to sclerosis ▪ Slows down exchange of gases, nutrients and waste (reduced filtration) • Build-up of creatine, pH and fluid ▪ Note: Serum CML (AGE) levels were 3-5-fold higher in patients with end-stage renal disease compared to controls o Eyes  Cataracts ▪ AGE’s accumulate in lens and retina of the eye as x-linked crystalline protein ▪ Cloudy vision caused by cross-linked collagen in the eye ▪ AGE also found in high concentrations in lesions of age-related macular degeneration compared to controls o Bones ▪ Collagen in bone have very long lifetime  more susceptible to AGE changes ▪ Deterioration of bone tissue quality ▪ Negative impact on bone density ▪ Increase stiffness and fragility ▪ AGEs are very high in patients with osteoporosis  associated with fractures o Muscles and Tendons ▪ Increased muscle stiffness ▪ Reduced muscle function ▪ Loss of muscle mass (low grip strength and walking speed) o Lungs ▪ Decreased elasticity due to cross links in elastin of the lungs ▪ Harder to breath (requires more effort) o DNA ▪ If x-linked, dsDNA cannot be opened, replicated or repaired ▪ Decrease in transcription and loss of repair system • AGE Immunostaining o Kidney cells were exposed to control, AA, high glucose, and AA/high glucose conditions ▪ Green: accumulation of antibodies to identify AGEs ▪ Red: nucleus of cell o Results: ▪ Added AGE inhibitor to A-D: no AGE products formed ▪ No addition of inhibitor to E-H: a lot of AGE products formed in G and H ▪ Addition of vitamin E (antioxidant to free radicals) to I-L: no AGE products formed • Prevention of AGE Intake o Reduce dietary AGE intake: cooking food at lower temperature and not charring o it; avoiding processed food as they contain high AGE content; using water to cook o such as braising; using acid such as lemon juice or vinegar to marinade ▪ Low calorie intake of mice increases lifespan; likely due to decrease intake of AGE o Exercise: exercise slightly correlates to decrease levels of AGE in mice and rats o Pharmacological interventions: blockers of AGE include metformin (diabetes), aminoguanidine (reduced lipofuscin and prevents age disease), and aspirin • Diabetes and AGE Products o At risk of cross-links due to high levels of glucose in blood o Type 1: Insulin-dependent; develops at age before 20 ▪ Normally insulin is released by the pancreas when blood glucose levels are high so that cells take in glucose ▪ Pancreas can’t make insulin  high plasma glucose o Type 2: Non-insulin dependent; mature onset; makes insulin but uptake of glucose altered ▪ Aging thought to cause type 2 diabetes due: • Decreased receptors for insulin on the cell  no signal for glucose uptake • Decreased receptors for glucose on the cell  no glucose uptake by cell o Studies show that diabetics: ▪ Have increased glucose levels react with hemoglobin; Red blood cells form amadori products (AGE); Hemoglobin turns into HbA1c  3x more of this in diabetics • Non-diabetics: 3-5% HbA 1c • Diabetics: 5-20% HbA1c ▪ Develop age related symptoms earlier (cataracts, kidney failure, etc) o Diabetes Testing ▪ Testing of HbA1c is a diagnostic test for high glucose readings ▪ RBC’s turn over every ~120 days • If glucose level is still high in subsequent tests (after RBC turnover) then it may be an indication of diabetes ▪ Graph measurement of HbA1c over 9 weeks • Graph A: Glucose (green line) changes between 7-12 o Results in an HbA1c level of 10% at the end of the 9 weeks (red line)  Poorly controlled • Graph B: Glucose changes between 5-9 o Results in an HbA1c level of 7% at the end of the 9 weeks  Well controlled Aweeks. The glucose (green line)ere the glucose changes changes between 7-12. This between 5-9. This results in results in an HbA1c level of 10%HbA1c level of 7% at the at the end of the 9 weeks (rednd of the 9 weeks. Well line). Poorly controlled. controlled. o Diabetics have age-related symptoms that are more severe and earlier ▪ Cataracts, heart attacks, strokes, gangrene of feet and legs, stiff joints, kidney failure Effects of Free Radicals • Free Radicals o Free radicals are molecules with one or more unpaired electrons ▪ Highly reactive and unstable (very short lived, reacts fast); ▪ Want to gain or lose an electron o Damaging because: ▪ All macromolecules of cell at risk of damage ▪ Produce other free radicals in the process of stabilizing itself ▪ Cause mutations of DNA and altering cross-links in proteins and DNA o Formed by: ▪ Oxidation from mitochondrial metabolism (oxidative phosphorylation in ETC) ▪ Final step in ETC: oxygen is the final electron acceptor  only accepts one at a time • This step can form oxygen free radicals • Points along the ETC are more susceptible to loss of electrons that will react with oxygen (site I and III) ▪ With age, control of these electrons species becomes weaker • They may leave ETC and combine with oxygen before the final water molecule is formed! (or form ROS during the terminal stage with Cyto C) • Most common ROS: superoxide  hydrogen peroxide  hydroxyl radical ▪ Note: 1- 4% of O2 at end of mitochondria ETC becomes free radicals when young and increase with age! ▪ ROS also formed by: • Radiation from external environment (UV, X-rays, Gamma rays) • Toxins (carcinogens in food, air, and products such as cigarettes) • Effect of ROS on Biological Molecules o DNA ▪ Causes dsDNA breaks, base substitutions, x-links and mutations within genome • Could be responsible for damage and mutation to DNA with  age! ▪ Free radicals attack DNA  gene damage leads  cancer • Evidence of free radical damage to DNA in human breast cancer cells • Indicates that some breast cancers may be due to  free radicals with  age o Proteins ▪ Proteins get oxidized and form different bonds and conformations • AAs with thiol groups (SH) are easily oxidized  • Free radical steal e- and H+ from AA from SH group of S-shaped protein • Free sulphides make disulphide bridge  C-shaped protein • Loses functionality and/or changes the function ▪ With increased age: • Increased number of cross-links in proteins • 2-3-fold increase in oxidized proteins o Proteins that are oxidized with age usually become inactive o Lipids ▪ Lipid surface becomes oxidized or form carbonyl groups that alter membrane fluidity ▪ Primary targets are unsaturated lipids  leads to increase in lipid peroxidation • Forms double bonds between FA tails  FAs become rigid/less flexible ▪ Harmful because leads to chain reaction in lipid membranes • Alters selective permeability of membrane, makes it less selective • Alters membrane protein properties: channels, gates, etc. • Evidence for Free Radical Damage and Aging o Animals show oxidative damage to DNA, proteins and lipids with age o Species that live longer are less susceptible to oxidative damage & have better repair mechs. o Organisms with antioxidant defenses boosted artificially live longer o More free radicals are generated by a high metabolic rate, and a high metabolic rate is associated with shorter lifespan o Caloric restriction of organisms increased their maximal lifespan  increases antioxidant defences and reduces oxidative damage • Examples of Free Radical Damage o Oxidized lipids in blood promotes thickening of arteries leading to increased blood pressure and cardiovascular disease o Oxidized cholesterol carried in LDL can cause plaques o Evidence that HDL may act as an anti-oxidant to prevent free radical damage to arterial walls o Repair rate of damage from ROS is ~99% but with age, increased number of radical my overwhelm repair mechanisms • Endogenous Antioxidants o Superoxide Dismutase (SOD) ▪ Found in all cells  scavenges superoxide radicals ▪ Increased SOD increases life span ▪ Studies in drosophila showed: •  SOD expression (mutation),  L.S. to 10 days from 60 days (normal) •  SOD expression (10-20%),  L.S to 90 days o Catalase ▪ Breaks down hydrogen peroxide into water and oxygen ▪ Works in conjunction with SOD o Vitamin E ▪ Lipid soluble vitamin that protects membrane lipids from free radical damage ▪ Makes organs use oxygen more efficiently and increases immune system ▪ Vitamin E inserts itself into the membrane and stops the cycle • Accepts electron and stops them from repeatedly damaging large strips • After accepting electron, it must be recycled so it can be active again ▪ Studies show that Vitamin E: • Makes O 2se more efficient in brain, heart, organs • Increases stimulation of immune system • Protects against cancers ( esp. dietary tract) • May prevent atherosclerosis ▪ European study showed: • Men who had low Vit. E in serum showed  mortality to C.V. disease • Whereas men with high levels showed significantly less mortality! o Vitamin C (Ascorbic acid) ▪ Water soluble vitamin that acts as a reducing agent  reduces the risk of cancer, disease and cataracts (1000mg/day) o B-carotene (Carotenoid) ▪ Precursor of vitamin A and acts as chemoprevention of cancer ▪ Low levels of B-carotene associated with increased risk of cancer & chronic disease ▪ However, 1996 study showed that there was an increased incidence of lung cancer among smokers taking B-carotene • But it was not from natural sources o Selenium ▪ Offers protection against cancer, stimulates immune system and has anti- inflammatory properties ▪ Low selenium levels are linked to cancer and CV disease o Note: People who have longer LE, live to be centenarians: likely have a suite of longevity genes that allow for high levels of vitamin E, selenium and b-carotene Organelle Cellular Changes with Increasing Age • Cell Membranes o  free radicals,  lipid peroxidation, o Membranes become less fluid and more viscous (thickened); this will  selective permeability o Membranes become “leaky” with age and affects function of cell o Protein composition changes, receptors  cell surface,  autoimmune diseases • Nuclear Membrane: o Chromatin clumps (free radicals, AGE?), more difficult for enzymes to repair o  Function (gene expression?),  DNA repair,  protein synthesis,  mutations o In-folding of the nuclear membrane  blebbing  leads to chromosomal instability, decreased dna repair, replication, telomeres) o Decreased rate of DNA synthesis • Cytoplasm: o Cell size  with age; water comes in and cell swells o  lipofuscin • Ribosomes: o  rRNA content o  number of free and attached ribosomes o  rate of protein synthesis • Mitochondria: o Becomes abnormal in size and shape o  number of mitochondria, especially in post-mitotic cells o Membranes change shape (esp. inner) and become less ordered o Accumulation of lipofuscin • Lysosomes: o  efficiency and numbers o  “leakiness,  size o Leaky membrane releases active digestive enzyme in cytoplasm  anything is fair game to be attacked an digested ▪ Can damage many internal organs Integumentary System • Skin (Epithelial Tissue) o Largest organ; covers most of body’s surfaces ▪ Covers organs and lines body cavities ▪ Anchored to connective tissue by basement membrane ▪ Injuries to epithelium heal rapidly (highly vascularized) ▪ In direct contact with the external environment ▪ Influenced by both internal and external factors: ▪ Classified according to the shape and arrangement of the cells o Composed of: skin, hair, nail, and glands o Major roles: ▪ Maintaining homeostasis ▪ Protection against external environment (UV radiation, wind, temperature) ▪ Indicator of aging process (texture changes, wrinkles, pale skin, infections) • Functions of the Skin o 1) Protection from external damaging agents via chemical, physical and biological barriers ▪ Keratin (water insoluble protein) prevents excessive water loss (dehydration) ▪ Pigments like melanin protect against UV radiation from the sun ▪ Langerhans cells protect against infection from foreign particles, bacteria, microbes, viruses, and abrasion ▪ Oily secretions form an acidic protective film that waterproofs the body and retards the growth of microorganisms ▪ Thickness of skin and presence of keratin help withstand abrasion o 2) Regulation of body temperature ▪ Maintains homeostasis body temperature of 37 degrees using blood vessels(constriction or dilation) and sweat glands (releasing sweat cools body temperature) o 3) Sensory reception ▪ Conveys external sensations (pain, temperature, touch, pressure) to the brain and spinal cord o 4) Skin cells ▪ Synthesizes components such as melanin, keratin, pre-cursors to vitamin D o 5) Absorption ▪ Absorbs harmful chemicals, drugs and toxins that can cause harm to the body and processes it in a safe manner (depending on concentration) • Structure of the Skin (3 layers) o 1) Epidermis ▪ Made up of flat cells (squamous epithelium) ▪ Lack blood vessels but have nerve fibres ▪ Cells contained • Keratinocytes (make keratin for outer layer) • Melanocytes (makes melanin for UV protection) • Langerhans (immune function) ▪ Whole epidermis is called stratified squamous epithelium ▪ Balances between cell production and cell loss ▪ Formation of epidermal layer • All cells originate from the bottom basal layer and actively undergo mitosis to generate cells • New daughter cells moves upward and cells fill with keratin from keratinocytes • Move farther away from blood supply  causes them to stop dividing and die off  • Forms a layer of dead cells at the top which gets lopped off every 28 days  • Good defense mechanism because any harmful substances that bind to that layer will eventually be lopped off due to cell turn over ▪ All keratinocytes linked via tight junctions and communicate via desmosomes o 2) Dermis ▪ Deeper and thicker than epidermis ▪ Binds epidermis to underlying tissues; provides support to skin ▪ Connective tissue lies here (collagen fibres, elastin) and is highly vascularized with blood vessels and nerve endings, sweat glands, oil glands and hair follicles ▪ Regulates body temperature with blood vessels and sweat glands o 3) Hypodermis ▪ Deeper than the dermis and attaches the skin to the underlying structure of muscle and bone ▪ Loose connective tissue lies here such as adipose which insulates the body and cushions the inner organs o Basement Membrane ▪ Forms adhesion and diffusion barrier between epidermis/dermis • Dermis is vascularized, epidermis is a-vascular, ▪ Basal layer relies on nutrients, growth facto2s,O passed through the basement membrane for growth ▪ Thus, it regulates cell growth of the epidermal layer • Age-Related Changes to Skin o Epidermis ▪  Thinning of the layers causes the skin to be more fragile • Decrease in basal layer cell division effects turnover rate of epithelial cells resulting in: o  ability to repair the skin when damaged o  irritation to chemicals ▪  Permeability leads  spacing between keratinocytes  dysfunctional barrier • Disorganized cell arrangement (shape and size change) • Allows harmful chemical through to the dermis and into the blood vessels ▪ Loss of sebaceous glands in the dermis makes the skin, hair dry (less oil production) • Epidermis becomes rough, scaly, dry ▪ Loss of melanocyte leads to reduced skin pigment (pale) • Can’t produce much melanin (Brown pigment) which protects from UV-light • Melanocytes die out as you age and the ones that remain have less function; remaining cells group together and are called lentingo • Decrease in melanin in hair bulb causes greying of hair • Note: Everyone has same # of melanocytes, different amount melanin gives us different skin tones ▪  Langerhans’ Cells:  risk of skin cancers,  risk of infections ▪ Basement membrane thickens due to x-links in collagen •  diffusion of nutrients and waste between dermis/epidermis • Could contribute to  mitotic division of basal layer • Flattening of membrane and decreased surface area o Dermis ▪ Major cells are fibroblasts •  in # of fibroblasts and collagen fibers, and collagen becomes thicker • cross-links of collagen, leads to  stiffness, thickness, rigidity dermis •  in # of elastin fibers (cross-links and possible calcification) • Changes to both elastin and collagen contribute significantly to loss of elasticity and wrinkling of skin • Loss of dermis makes skin transparent, translucent ( UV damage) •  # of sweat glands ( risk of heat exhaustion) ▪  Blood flow to dermis ( number of blood vessels, 1/3 lost with age); leads to: •  in pallor (whiteness) of skin •  clearance of foreign material (irritations develop on skin) •  wound healing ability (less immune cells at site) •  inflammatory response (mast cells) • Skin cooler to touch (less peripheral blood) • Atroph
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