Aging Lecture Flashcards

Slide 2: Life Span and Life Expectancy

Key Points:

• Life span represents the maximum duration an organism can live, while life expectancy is the average duration a person is expected to live based on current mortality rates.

• The graph shows survival rates across different time periods:

  • 1500: Lowest life expectancy.

  • 1890: Improvement due to better living conditions.

  • 1990 and 2040: Further increases in life expectancy predicted due to medical advancements and healthier lifestyles

  • Aging: is loss of viability

  • Senescence: loss of vitality

Explanation of Visuals:

• The survival curves indicate a shift towards longer life expectancy over time, suggesting advancements in healthcare, nutrition, and living conditions.

• Steeper declines in earlier periods highlight higher mortality rates.

Glossary:

• Life Span: The maximum age a species can theoretically reach.

• Life Expectancy: The average number of years a person is expected to live based on demographic factors.

Key Takeaway:
Advancements in healthcare and living standards have significantly extended life expectancy over centuries.

Slide 3: The “Ant” Case

Key Points:

• Worker ants (lifespan 1-5 years) and queen ants (lifespan 5-20 years) share the same genome.

• Differences in lifespan are influenced by the environment which include:

  • Hormones: Regulate growth and aging.

  • Stress: Affects longevity through oxidative damage.

  • Nutrition: Influences metabolism and lifespan.

Explanation of Visuals:

• Diagram highlights how identical genomes can result in different lifespans due to environmental and physiological factors.

Glossary:

• Genome: The complete set of genes in an organism.

• Hormones: Chemical messengers regulating body functions.

• Oxidative Damage: Cellular damage caused by free radicals.

Key Takeaway:
Environmental and physiological factors can significantly influence lifespan, even among genetically identical organisms.

Slide 4: Theories of Aging

Key Points:

• Programmed Aging Theory: Suggests aging is a genetically regulated process.

  • Hormones: Influence growth and aging.

  • Hayflick Limit: The number of times a normal cell can divide before stopping.

  • Genetic Diseases: Mutations accelerate aging.

• “Tear and Wear” Theory: Proposes aging is due to accumulated damage.

  • Oxidative Damage: Free radicals harm cells.

  • Mitochondria: Energy production leads to oxidative stress.

  • Toxin Accumulation: Environmental toxins build up in tissues.

  • Repair Systems: Decline over time, causing aging.

Explanation of Visuals:

• Comparison of two aging theories: one focusing on genetic programming and the other on accumulated damage.

Glossary:

• Hayflick Limit: The maximum number of cell divisions in a lifespan.

• Mitochondria: Organelles generating cellular energy.

• Oxidative Stress: Imbalance between free radicals and antioxidants.

Key Takeaway:
Aging can be explained by both genetic programming and accumulated damage mechanisms.

Slide 5: Theories of Aging (Simplified)

Key Points:

• Programmed Aging: Emphasizes hormonal regulation and genetic factors.

• Tear and Wear: Focuses on oxidative damage, mitochondrial stress, and toxin accumulation.

• Simplified comparison of the two theories, highlighting key aspects of each.

Explanation of Visuals:

• Side-by-side comparison reinforces the two main aging theories without overwhelming details.

Key Takeaway:
Aging is likely a combination of genetic programming and cumulative damage over time.

Slide 6: Aging and Organ Functions

Key Points:

• Organ functions decline with age, impacting various systems:

  • Nerve conductivity: Decreases, affecting reflexes and coordination.

  • Muscle strength: Gradually declines, reducing physical capabilities.

  • Cardiac output: Lowers with age, affecting circulation and endurance.

  • Vital capacity: Lung function reduces, limiting oxygen intake.

  • Renal plasma flow: Diminishes, impairing kidney filtration.

  • Max. O₂ uptake: Decreases, reducing aerobic capacity.

• The graph shows different rates of decline for each function, indicating organ-specific aging patterns.

Explanation of Visuals:

• Graph: Illustrates the decline in various organ functions as a percentage of their maximal capacity over time.

• Each curve represents a different function, highlighting variability in the aging process.

Glossary:

• Cardiac Output: The amount of blood the heart pumps per minute.

• Vital Capacity: Maximum air expelled from the lungs after maximum inhalation.

• Renal Plasma Flow: Blood flow to the kidneys available for filtration.

Key Takeaway:
Aging affects different organ systems at varying rates, leading to a progressive decline in overall function.

Slide 7: Stress Hormones and Aging

Key Points:

• Chronic stress accelerates aging through elevated glucocorticoids (stress hormones).

• Morbus Cushing: A disorder caused by excessive cortisol, leading to symptoms like weight gain and muscle weakness.

• Stress activates the hypothalamus-pituitary-adrenal (HPA) axis:

  • Hypothalamus: Releases CRH (corticotropin-releasing hormone).

  • Pituitary: Secretes ACTH (adrenocorticotropic hormone).

  • Adrenal glands: Produce cortisol, affecting metabolism and immune response.

• Overproduction of Cortisol.

• Can cause different metabolic changes

Cortisol (stress hormone)

• Chronic high cortisol damages tissues, promotes inflammation and insulin resistance

• Linked to aging and age-related diseases

Explanation of Visuals:

• Diagram: Shows the HPA axis and its role in stress response.

• Images: Illustrate the impact of chronic stress, such as fat distribution and muscle wasting.

Glossary:

• Glucocorticoids: Hormones involved in stress response and metabolism regulation.

• Cortisol: A glucocorticoid that increases blood sugar and suppresses the immune system.

• HPA Axis: A central stress response system.

Key Takeaway:
Chronic stress accelerates aging through the prolonged release of glucocorticoids, leading to metabolic disorders and immune suppression.

Slide 8: Glucocorticoids

Key Points:

• Elevated glucocorticoid levels cause various health problems (based on hormone stress):

  • ↑ Hepatic gluconeogenesis: Increases blood sugar, contributing to diabetes.

  • ↓ Glucose utilization in tissues: Leads to insulin resistance.

  • Proteolysis and lipolysis: Muscle and fat breakdown, causing muscle wasting and fat redistribution.

  • Sensitization for catecholamines: Raises blood pressure (hypertension).

  • Immune suppression: Reduces infection resistance.

  • ↓ Collagen synthesis: Delays wound healing.

  • ↑ CaHPO₄ resorption causing Osteoporosis: Increases bone breakdown, causing osteoporosis.

Explanation of Visuals:

• List format: Clearly presents the diverse effects of elevated glucocorticoids.

• Arrows indicate increased (↑) or decreased (↓) processes.

Glossary:

• Gluconeogenesis: Production of glucose from non-carbohydrate sources.

• Proteolysis: Breakdown of proteins into amino acids.

• Catecholamines: Hormones (like adrenaline) that prepare the body for stress.

• Collagen: A protein essential for skin and connective tissue integrity.

Key Takeaway:
Chronic elevation of glucocorticoids has wide-ranging negative effects, including metabolic disorders, immune suppression, and bone weakening.

Slide 9: Programmed Aging vs. “Tear and Wear”

Key Points:

• Reiterates the two main theories of aging:

  • Programmed Aging: Regulated by hormones and genetic programming.

  • Tear and Wear: Result of accumulated damage from oxidative stress and toxins.

• Focus on hormonal influence in programmed aging and cellular damage in the tear and wear model.

Explanation of Visuals:

• Side-by-side comparison highlights differences between the two theories.

• Simple layout reinforces the core ideas without overwhelming details.

Glossary:

• Oxidative Stress: Damage caused by free radicals exceeding antioxidant defenses.

• Toxin Accumulation: Build-up of harmful substances in tissues over time.

Key Takeaway:
Aging is influenced by both genetic programming and accumulated damage, requiring a combined approach for understanding longevity.

Slide 10: Hayflick Limit

Key Points:

• Hayflick Limit: Refers to the maximum number of times a normal cell can divide before it stops due to telomere shortening.

  • Example limits:

    • Mouse: 15 divisions (~3 years lifespan).

    • Chicken: 25 divisions (~12 years lifespan).

    • Human being: 50 divisions (~80 years lifespan).

    • Galapagos tortoise: 110 divisions (~175 years lifespan).

• Young fibroblasts: Actively divide.

• Old fibroblasts: Show signs of senescence, unable to divide further.

• Interesting on to question, why certain organisms (like shark don’t seem to show signs of aging)

Explanation of Visuals:

• Table: Compares the Hayflick limit and lifespan across species.

• Microscopic images: Show differences between young and old fibroblasts, emphasizing cellular aging.

Glossary:

• Hayflick Limit: The maximum number of cell divisions before growth stops.

• Fibroblasts: Cells that synthesize the extracellular matrix and collagen.

• Senescence: State where cells stop dividing but remain metabolically active.

Key Takeaway:
The Hayflick limit links the ability of cells to divide with lifespan, highlighting the role of telomere shortening in aging.

Slide 11: DNA Replication and Telomeres

Key Points:

• Telomeres: Repetitive DNA sequences (about 10,000 bp) at chromosome ends that protect against deterioration during replication.

• classic sequence looks like this: TTAGGGTTAGGGTTAGGGTTAGGGTTAGGG..

• Telomere shortening: Occurs with each cell division, limiting the number of divisions a cell can undergo.

• Telomerase: An enzyme that extends telomeres, preventing shortening and allowing more cell divisions.

• Research Insight:

  • Bodnar et al. (1998): Demonstrated lifespan extension by introducing telomerase into human cells.

Explanation of Visuals:

• Diagram: Shows telomeres at chromosome ends and how they shorten with each division.

• Nobel Prize: Recognizes the discovery of telomeres and telomerase by Blackburn, Greider, and Szostak.

Glossary:

• Telomeres: Protective caps at chromosome ends, preventing DNA loss during replication.

• Telomerase: Enzyme that adds DNA to telomeres, extending cell lifespan.

• Nobel Prize in Physiology or Medicine 2009: Awarded for telomere and telomerase research.

Key Takeaway:
Telomeres limit cell division, and telomerase can extend lifespan by preventing telomere shortening.

Slide 13 The Paradox of Cloned Animals

Key Points:

• Cloned animals can show signs of premature aging despite being genetically identical to the donor.

• Experiment:

  • Nuclear transfer from adult fibroblasts after many passages resulted in cloned calves.

  • Clones showed signs of aging due to shortened telomeres in the transferred nucleus.

• Study Reference:

  • Kubota et al. (2000): Demonstrated that telomere length impacts aging in cloned animals.

Explanation of Visuals:

• Diagram: Illustrates the nuclear transfer process for cloning.

• Calf images: Highlight the result of using old donor cells with shortened telomeres.

Glossary:

• Cloning: Creating a genetically identical copy of an organism.

• Nuclear Transfer: Technique where a nucleus from a donor cell is inserted into an enucleated egg.

• Telomere Shortening: Loss of DNA from telomere ends during cell division.

Key Takeaway:
Cloned animals age faster due to telomere shortening in donor cells, demonstrating the link between telomeres and aging.

Slide 14: Telomeres and Aging

Key Points:

• Ultra-long telomeres in mice:

  • Mice have longer telomeres compared to humans, suggesting that telomere length alone may not directly determine lifespan.

  • Reference: Kipling & Cooke, 1990.

• Short telomeres in wild-derived inbred mouse strains:

  • Wild-derived inbred mice show shorter telomeres than laboratory strains, which may influence lifespan.

  • Correlation: Shorter telomeres are linked to reduced lifespan in wild-derived strains.

  • Reference: Hemann & Greider, 2000.

Explanation of Visuals:

• Text boxes: Present summaries of studies on telomere lengths in different mouse strains and their impact on aging.

Glossary:

• Telomeres: Protective DNA sequences at chromosome ends that shorten with each cell division.

• Inbred Strains: Genetically similar animal populations used to study hereditary traits.

• Lifespan: The maximum length of time an organism can live.

Key Takeaway:
Telomere length varies significantly across species and strains, suggesting a complex relationship between telomeres and lifespan.

Slide 15: Telomeres and Aging in Humans

Key Points:

• Is telomere length a biomarker of aging?

  • Review of 10 studies: Found no consistent link between telomere length and aging in humans.

  • Key Insight: Chronological age may be a better predictor of survival than telomere length.

  • Reference: Mather et al. (2011).

Explanation of Visuals:

• Highlighted box: Summarizes the review findings, emphasizing the uncertainty of telomere length as an aging marker.

Glossary:

• Biomarker: A measurable indicator of a biological state, such as aging.

• Telomere Length: A potential marker for cellular aging due to its shortening during cell division.

Key Takeaway:
Telomere length is not a reliable biomarker for aging in humans, with chronological age being a stronger predictor of survival.

Slide 16: Dyskeratosis Congenita

Key Points:

• Cause: Mutations in the DKC1 gene affecting dyskerin, a subunit of the telomerase complex.

• Symptoms:

  • Hair loss, skin lesions, nail dystrophy.

  • Severe conditions: Lung fibrosis, intestinal diseases, thrombocytopenia (low platelet count), anemia.

• OMIM #305000: Catalogs the genetic mutation linked to the disease.

Explanation of Visuals:

• Images: Show symptoms of dyskeratosis congenita (e.g., nail abnormalities and histological findings).

• Pathway diagram: Illustrates the role of dyskerin in telomerase function.

Glossary:

• Dyskerin: A protein part of the telomerase complex involved in telomere maintenance.

• Thrombocytopenia: A condition with low platelet levels, leading to bleeding risks.

• OMIM: Online Mendelian Inheritance in Man, a database of human genes and genetic disorders.

Key Takeaway:
Dyskeratosis congenita highlights the importance of the telomerase complex in maintaining telomere integrity and preventing premature aging symptoms.

Slide 18: Genetic Diseases – Progeroid Syndromes

Key Points:

• Progeroid Syndromes: Group of rare genetic disorders causing premature aging symptoms.

• Key Examples:

  • Hutchinson-Gilford Syndrome: Characterized by rapid aging in children.

  • Werner Syndrome: Causes symptoms of aging in young adults.

  • Lipid and Carbohydrate Metabolism Disorders: Includes Seip-Berardinelli Syndrome.

  • Myotonic Dystrophy: Affects muscle function and causes aging-like symptoms.

Glossary:

• Progeroid Syndrome: Disorders that mimic aging symptoms prematurely.

• Myotonic Dystrophy: A genetic disorder causing muscle weakness and prolonged muscle contractions.

Key Takeaway:
Progeroid syndromes provide insight into the mechanisms of aging through mutations that accelerate aging symptoms.

Slide 19: Nuclear Membrane Defect – Hutchinson-Gilford Syndrome

Key Points:

• Hutchinson-Gilford Syndrome (OMIM #176670):

  • Caused by mutations in the LMNA gene affecting lamin A, a protein critical for nuclear structure.

  • Symptoms: Growth delay, hair loss, aged skin, and cardiovascular diseases.

  • Affected nuclei show abnormal shapes due to defective lamins.

Explanation of Visuals:

• Images: Show affected children and abnormal nuclear membrane structure.

• Diagrams: Illustrate how mutated lamin A disrupts nuclear stability.

Glossary:

• Lamin A: Protein providing structural support to the cell nucleus.

• OMIM: Online Mendelian Inheritance in Man, a database for genetic disorders.

Key Takeaway:
Hutchinson-Gilford Syndrome illustrates how nuclear membrane defects can accelerate aging processes.

Slide 20: DNA Replication Defect – Werner Syndrome

Key Points:

• Werner Syndrome (OMIM #277700):

  • Caused by mutations in the RECQL2 gene encoding a helicase essential for DNA repair and replication.

  • Symptoms: Early onset of cataracts, skin aging, cancer susceptibility, and cardiovascular diseases.

  • Defective DNA repair: Leads to genomic instability and premature aging.

  • Cause of death often via Myocarditis (inflammation of heart muscle)

When the WRN helicase is defective or missing:

1. DNA cannot be repaired properly
   → Mistakes build up

2. Telomeres shorten more quickly
   → Cells reach their “end” faster and stop dividing (cellular senescence)

3. Genomic instability
   → The genome becomes more fragile → contributes to aging and cancer risk

4. Abnormal DNA replication
   → Increases stress and damage to the cell’s DNA

Explanation of Visuals:

• Images: Show individuals with Werner Syndrome exhibiting premature aging features.

• Text box: Describes the mutation in the RECQL2 gene.

Glossary:

• Helicase: An enzyme that unwinds DNA strands during replication and repair.

• Genomic Instability: High frequency of mutations within the genome.

Key Takeaway:
Werner Syndrome demonstrates the role of DNA repair mechanisms in preventing premature aging.

Slide 21: DNA Replication

Key Points:

• Normal DNA Replication (Left side):

  • The WRN helicase (shown in yellow) unwinds the DNA structure to allow smooth replication.

  • This enables the replication fork to progress past complex DNA structures like G-quadruplexes (G4 structures).

  • DNA synthesis proceeds normally on both strands.

• Werner Syndrome (WS) – Impaired Replication (Right side):

  • WRN helicase is absent or defective, so G4 structures are not resolved.

  • This leads to fork stalling or incomplete replication.

  • Result: Unreplicated DNA, replication stress, and potential strand breaks.

• G-quadruplex (G4) Structures:

  • These are four-stranded DNA structures rich in guanine.

  • Normally, helicases like WRN unwind them to prevent blocking replication.

• Illustrated Mechanisms:

  • The chemical structure of a G-quartet and a G-quadruplex is shown.

  • A molecular rendering of a helicase on DNA demonstrates the unwinding mechanism.

  • The bottom right image shows the replication fork, with directionality of strand growth and key proteins (e.g., DnaB helicase, primase, sliding clamp).

Glossary:

• WRN (Werner helicase): An enzyme that unwinds complex DNA structures to support replication.

• G-quadruplex (G4): Stable, four-stranded DNA structures formed by guanine-rich sequences.

• Replication fork: The Y-shaped structure where DNA is split into two strands and copied.

Explanation of Visuals:

• Left panel: Compares normal DNA replication (with functional WRN) to defective replication in WS.

• Middle top: Shows molecular structure of G-quartet and how it stacks into a G-quadruplex.

• Middle bottom: 3D model of a helicase moving along DNA.

• Right panel: Detailed diagram of the replication fork, showing coordination of leading and lagging strand synthesis.

Key Takeaway:

Slide 22: Seip-Berardinelli Syndrome

Key Points:

• Seip-Berardinelli Syndrome: A rare genetic disorder causing a deficiency in adipose tissue.

  • Type 1: Caused by AGPAT2 mutation affecting lipid metabolism.

  • Type 2: Caused by BSCL2 mutation impacting adipocyte differentiation.

• Symptoms:

  • Lack of adipose tissue → insulin resistance, diabetes, hypertriglyceridemia.

  • High appetite and abnormal fat storage in liver and muscles.

• Pathway Impact: Affects the transformation of stem cells into adipocytes (fat cells).

Explanation of Visuals:

• Flowchart: Shows how mutations block the conversion of stem cells to healthy adipocytes, leading to metabolically active fat instead of mechanical adipose tissue.

Glossary:

• AGPAT2: Enzyme involved in lipid synthesis.

• BSCL2: Gene required for proper fat cell development.

• Adipocyte: Fat cell storing energy as lipids.

Key Takeaway:
Seip-Berardinelli Syndrome illustrates how genetic defects in lipid metabolism can lead to metabolic diseases and insulin resistance.

🧬 What is Myotonic Disease (Myotonic Dystrophy) → Slide missing here in the set

Myotonic disease, more precisely called Myotonic Dystrophy (DM), is a genetic, progressive muscle disorder. It belongs to a group of diseases called muscular dystrophies, which cause muscle weakness and wasting over time.

🧾 Why is it called "myotonic"?

The name comes from myotonia, a key symptom:

• Myotonia = Difficulty relaxing muscles after they contract
  → Example: You grip something and your hand stays stiff longer than normal before relaxing.

🧪 Types of Myotonic Dystrophy

There are two main types:

🧬 Cause: A Genetic Repeat Mutation

• It’s caused by a trinucleotide repeat expansion:

  • DM1: Expansion of CTG repeats in the DMPK gene

  • DM2: Expansion of CCTG repeats in the CNBP gene

• The longer the repeat, the more severe the disease, and it can worsen across generations (called anticipation).

Slide 23: Oxidative Damage

Key Points:

• Sources of Reactive Oxygen Species (ROS):

  • Endogenous: Mitochondria, NADPH oxidase.

  • Exogenous: UV light, radiation, pollutants.

• Antioxidants:

  • Enzymatic: SOD (superoxide dismutase), catalase, glutathione peroxidase.

  • Non-enzymatic: Vitamins E and C.

• Impact of ROS:

  • Low ROS: Immune deficiency.

  • High ROS: DNA damage, aging, and cell death.

Explanation of Visuals:

• Diagram: Illustrates the balance between ROS production and neutralization by antioxidants.

  • Left side: Low ROS → immune defects.

  • Right side: High ROS → oxidative damage.

• SHOWING THAT ROS NEEDS TO BE REGULATED TO BE KEPT IN BALANCE.

✅ Why do we need ROS?

1. Cell Signaling ("Redox Signaling")

• ROS act as molecular messengers in many signaling pathways.

• They help regulate:

  • Cell growth and division

  • Wound healing

  • Immune cell activation

  • Response to stress

2. Immune Defense

• ROS are used by immune cells (like neutrophils and macrophages) to:

  • Kill invading bacteria and viruses

  • Break down damaged cells and debris

Glossary:

• ROS (Reactive Oxygen Species): Reactive molecules derived from oxygen, causing cellular damage.

• Antioxidants: Compounds that neutralize ROS.

• SOD (Superoxide Dismutase): Enzyme converting superoxide radicals to hydrogen peroxide.

Key Takeaway:
Oxidative damage from ROS imbalance accelerates aging and disease, highlighting the importance of antioxidants.

Slide 24: Insufficient ROS…

Key Points:

• Chronic Granulomatous Disease (CGD):

  • Genetic disorder where neutrophils cannot kill bacteria due to insufficient ROS.

  • Defective NADPH oxidase: Prevents production of superoxide radicals required for bacterial killing.

• Affected Genes:

  • p22-CYBA, p91 CYBB, p47-phox, p67-phox: Components of NADPH oxidase complex.

Explanation of Visuals:

• Diagrams:

  • Show components of the NADPH oxidase complex and how their mutations impair ROS production.

  • Illustration: Depicts a neutrophil failing to kill bacteria due to insufficient ROS.

Glossary:

• NADPH Oxidase: Enzyme producing superoxide radicals for pathogen destruction in phagocytes.

• Neutrophils: White blood cells that kill bacteria using ROS.

• Phox Proteins: Components of the NADPH oxidase complex.

Key Takeaway:
Insufficient ROS production due to NADPH oxidase defects leads to immune deficiencies like chronic granulomatous disease.

Slide 26: …and too many ROS

Key Points:

• The slide shows how too many reactive oxygen species (ROS) can lead to β-cell destruction in the pancreas.

• This is a model for Type 1 Diabetes (IDDM), where β-cells are destroyed and insulin production fails.

• Alloxan, a toxic glucose analog, enters β-cells and triggers redox cycling with dialuric acid.

• This cycle generates multiple ROS:

  • Superoxide (O₂•⁻)

  • Hydrogen peroxide (H₂O₂)

  • Hydroxyl radical (OH•)

• Fe²⁺/Fe³⁺ ions participate in Fenton chemistry, further boosting ROS formation.

• ROS increase intracellular Ca²⁺, disrupting cell function and leading to β-cell destruction.

Explanation of Visuals:

• Left: Molecular structures of glucose and alloxan.

• Middle: Metabolic pathway showing the redox cycling between alloxan and dialuric acid.

  • Arrows show ROS generation at each step.

• Bottom: ROS causes increased calcium levels in β-cells.

• Right: Pathway leads to β-cell death, marked with arrows pointing to the final outcome.

Glossary:

• β-cell: Insulin-producing cells in the pancreas.

• IDDM: Insulin-dependent diabetes mellitus (Type 1 Diabetes).

• Alloxan: A toxic compound used in research to mimic β-cell destruction.

• ROS (Reactive Oxygen Species): Highly reactive molecules that can damage proteins, lipids, and DNA.

• Fenton reaction: A chemical reaction involving iron that generates the dangerous hydroxyl radical (OH•).

Slide 27: Mitochondrial damage

Key Points:

• Mitochondria: Major source of ROS due to electron transport chain.

• mtDNA (Mitochondrial DNA):

  • Repair is inefficient → mutation rate is 10-fold higher than nuclear DNA.

• Examples of Damage:

  • Doxorubicin: Increases mitochondrial Ca²⁺ flux → ROS production.

  • Cyclosporin: Impairs mitochondrial dehydrogenases in kidney cells.

Explanation of Visuals:

• Diagrams:

  • Show how ROS is generated during ATP production.

  • Fluorescence images: Highlight mitochondrial damage in cells.

Glossary:

• mtDNA: Circular DNA in mitochondria, inherited maternally.

• Doxorubicin: Chemotherapy drug causing mitochondrial toxicity.

• Cyclosporin: Immunosuppressant affecting mitochondrial function.

Key Takeaway:
Mitochondrial DNA is highly susceptible to ROS-induced damage, impacting cell function and aging.

Slide 28: Repair of mitochondrial DNA

Key Points:

• Inefficiency of mtDNA Repair:

  • High mutation rate leads to progressive dysfunction with aging.

• Experimental Evidence:

  • Mice studies: Defects in mtDNA repair accelerate aging symptoms.

• Key Findings:

  • Repair-deficient mice: Show early aging and reduced lifespan.

Explanation of Visuals:

• Graphs:

  • Compare lifespan and health span of normal vs. repair-deficient mice.

• Images:

  • Depict phenotypic aging in mice with mtDNA repair defects.

Glossary:

• mtDNA Repair: Mechanisms correcting mutations in mitochondrial DNA.

• Health span: Duration of life spent in good health.

Key Takeaway:
Inefficient mtDNA repair accelerates aging and highlights the importance of mitochondrial health.

Slide 31: Non-enzymatic glycation

Key Points:

• Glycation:

  • A non-enzymatic reaction between carbohydrates (e.g., glucose) and free amino groups in proteins.

  • Leads to the formation of Amadori products (intermediates).

• Advanced Glycation Endproducts (AGEs):

  • Formed by oxidation of Amadori products.

  • Associated with aging and chronic diseases (e.g., diabetes).

Explanation of Visuals:

• Reaction Pathway:

  • Illustrates the step-by-step process: carbohydrate → Amadori product → AGE.

• Key Terms Highlighted:

  • AGEs are shown in red, indicating their significance.

Glossary:

• Glycation: Non-enzymatic binding of sugars to proteins or lipids.

• Amadori Product: Intermediate formed during glycation.

• AGEs (Advanced Glycation Endproducts): Harmful compounds formed through glycation.

Key Takeaway:
AGEs result from non-enzymatic glycation and contribute to aging and disease.

Slide 32: Medical relevance of glycation

Key Points:

• Impact of Glycation:

  • Alters the structure and function of collagen, α-crystallin, and LDL.

• Consequences:

  • Collagen: Decreased elasticity → skin aging and vascular stiffness.

  • α-Crystallin: Contributes to cataract formation in the eyes.

  • LDL (Low-Density Lipoprotein): Promotes atherosclerosis (plaque buildup in arteries).

• Oxidants: Enhance glycation and AGE formation.

Explanation of Visuals:

• Flow Diagram:

  • Shows how different sugars and oxidants influence glycation and aging.

• Key Terms:

  • Aging highlighted as a central factor.

Glossary:

• Collagen: Structural protein in skin, tendons, and blood vessels.

• α-Crystallin: Protein preventing lens opacity in the eye.

• LDL: “Bad cholesterol” contributing to plaque formation in arteries.

Key Takeaway:
Glycation accelerates aging and contributes to diseases like cataracts and atherosclerosis.

Slide 33: Methylglyoxal and AGE

Key Points:

• Methylglyoxal:

  • A reactive dicarbonyl compound formed during glycolysis.

  • Major precursor of AGEs.

• Pathways Influenced by Methylglyoxal:

  • Protein cross-linking: Leads to stiffness and aging.

  • Gene transcription: Alters cellular functions.

  • DNA glycation: Promotes mutations and cancer.

• Conditions Increasing Methylglyoxal:

  • Hyperglycemia: Seen in diabetes.

  • Inflammation: Enhances glycation and AGE formation.

Explanation of Visuals:

• Pathway Diagram:

  • Highlights various effects of methylglyoxal on proteins, lipids, and DNA.

• Color-Coded Effects:

  • Different effects are color-coded for clarity (e.g., red for inflammation).

Glossary:

• Methylglyoxal: Toxic byproduct of glycolysis leading to AGEs.

• Glycation: Reaction of sugars with proteins or DNA causing dysfunction.

• Cross-linking: Bonding between molecules, causing rigidity.

Key Takeaway:
Methylglyoxal is a key driver of AGE formation, linking glycation to aging and chronic diseases.

Slide 34: The receptors of advanced glycation end products (RAGE) = key pathway in inflammatory complication and aging

Key Points:

• RAGE:

  • A receptor that binds to Advanced Glycation Endproducts (AGEs).

  • Activation leads to inflammation and oxidative stress.

• Signaling Pathways Activated:

  • NF-κB: Promotes expression of pro-inflammatory cytokines.

  • ROS (Reactive Oxygen Species): Increases cellular damage and aging.

  • MAPK and JNK: Pathways leading to cell death and inflammation.

• Sources of AGEs:

  • Exogenous: Diet (e.g., processed foods).

  • Endogenous: Formed during metabolism and hyperglycemia.

Explanation of Visuals:

• Central Role of RAGE:

  • Illustrated as a hub linking AGEs to various inflammatory pathways.

• Pathway Arrows:

  • Show the direction of signaling cascades leading to inflammation.

Glossary:

• RAGE: Receptor for AGEs that triggers inflammation.

• NF-κB: A transcription factor that activates genes for inflammation.

• MAPK (Mitogen-Activated Protein Kinase): Pathway involved in cell growth and apoptosis.

• ROS: Reactive molecules causing oxidative damage.

Key Takeaway:
RAGE activation by AGEs is a key driver of inflammation and aging-related complications.

Slide 35: Age pigments

Key Points:

• Lipofuscin:

  • An intracellular pigment containing lipids, proteins, and metals.

  • Formed by oxidative degradation of mitochondria and lysosomes.

  • Accumulates in aged cells, indicating oxidative stress.

• Amyloid-Plaques:

  • Insoluble protein aggregates found between neurons.

  • Comprised of amyloid-beta (Aβ), associated with Alzheimer’s disease.

• Oxidative Stress:

  • Key factor in the formation of age pigments.

Explanation of Visuals:

• Microscopic Images:

  • Show lipofuscin granules in cells and amyloid plaques between neurons.

• Comparison:

  • Contrasts normal neurons with those showing Alzheimer’s pathology.

Glossary:

• Lipofuscin: “Wear-and-tear” pigment indicating cellular aging.

• Amyloid-Plaques: Protein deposits linked to neurodegenerative diseases.

• Oxidative Stress: Damage caused by ROS to cellular components.

Key Takeaway:
Lipofuscin and amyloid plaques are markers of oxidative stress and aging.

Slide 36: The aging cells

Key Points:

• Young cells maintain protein homeostasis through:

  • Efficient protein folding by chaperones

  • Degradation of damaged proteins via the proteasome

  • Removal of damaged organelles and aggregates via autophagy

• As cells age, key protective systems decline:

  • DNA damage accumulates

  • Mitochondrial dysfunction increases oxidative stress

  • Protein quality control systems weaken

  • Endoplasmic reticulum (ER) stress rises

• In aged cells, this results in:

  • Increased misfolded proteins

  • Reduced chaperone activity

  • Impaired proteasomal degradation

  • Less efficient autophagy

  • Formation of harmful protein aggregates

Explanation of Visuals:

• Left (Young Cell):

  • Shows proper protein folding, functioning mitochondria, active proteasome, and autophagy removing damaged proteins.

• Right (Aged Cell):

  • Shows increased ER stress, misfolded proteins, and protein aggregates accumulating due to impaired degradation systems.

• Top section:

  • Illustrates the transition from young to aged cells and the associated molecular changes.

• A list highlights what is reduced in aged cells:

  • Protein quality control

  • Chaperones

  • Proteasomes

  • Lysosomes

Glossary:

• Chaperones: Proteins that help other proteins fold correctly.

• Proteasome: Cellular machinery that breaks down misfolded or damaged proteins.

• Autophagy: A recycling process where cells digest damaged components.

• ER stress: Stress in the endoplasmic reticulum due to misfolded proteins.

• Protein aggregates: Clumps of misfolded proteins that can be toxic to cells.

Key Takeaway:

Slide 38: Repair systems in aging

Key Points:

• DNA Repair Mechanisms:

  • Base excision repair (BER): Fixes small, non-helix-distorting base lesions.

  • Nucleotide excision repair (NER): Corrects bulky DNA lesions caused by UV radiation.

  • Mismatch repair (MMR): Fixes errors during DNA replication.

• Proteasomal Degradation:

  • Degrades misfolded and damaged proteins.

  • Efficiency declines with aging.

• Autophagy:

  • Degradation of damaged organelles and proteins via lysosomes.

  • Impairment contributes to cellular aging.

Explanation of Visuals:

• Repair Pathways:

  • Diagram highlights various DNA repair mechanisms.

• Arrows Indicate:

  • Flow of repair processes and their targets (e.g., DNA, proteins).

Glossary:

• Base Excision Repair (BER): Fixes oxidative DNA damage.

• Nucleotide Excision Repair (NER): Repairs UV-induced DNA lesions.

• Mismatch Repair (MMR): Corrects replication errors.

Key Takeaway:
Efficient repair systems are crucial to prevent aging, but their decline accelerates age-related damage.

Slide 38: Repair systems

Key Points:

• Antioxidants:

  • Include SOD (Superoxide Dismutase) and catalase which neutralize reactive oxygen species (ROS).

• DNA Repair Enzymes:

  • Helicases, polymerases, ligases repair damaged DNA.

• Scavenger Receptors:

  • CD36, CD163: Remove oxidized molecules like LDL and hemoglobin.

• Protein Chaperones:

  • Heat-shock proteins assist in proper protein folding.

• Detoxification Enzymes:

  • Cytochrome P-450: Helps in detoxifying xenobiotics and drugs.

Explanation of Visuals:

• Bullet Points:

  • Clearly outline different repair systems and their functions.

Glossary:

• SOD (Superoxide Dismutase): Enzyme neutralizing superoxide radicals.

• Scavenger Receptors: Remove oxidized lipids and proteins to prevent damage.

• Heat-shock Proteins: Assist in protein folding and prevent aggregation.

• Cytochrome P-450: Enzyme family involved in detoxification.

Key Takeaway:
Efficient repair systems are essential to prevent cellular damage and aging.

Slide 39: Aging and Antioxidants

Key Points:

• Antioxidant Activity vs. Lifespan:

  • Positive correlation between SOD activity and maximal lifespan across species.

• Species Comparison:

  • Humans exhibit the highest SOD activity relative to other primates and rodents.

• Implication:

  • Efficient antioxidant defenses may delay aging.

Explanation of Visuals:

• Graph:

  • X-axis: Maximal lifespan (years).

  • Y-axis: SOD units per mg protein.

  • Shows a positive trend between antioxidant activity and lifespan.

Glossary:

• Antioxidants: Molecules that neutralize ROS to prevent damage.

• SOD (Superoxide Dismutase): Key enzyme in antioxidant defense.

Key Takeaway:
Higher antioxidant activity is linked to increased lifespan.

Slide 40: “Scavenger” receptors

Key Points:

• Function:

  • Remove oxidized LDL, HDL, AGEs, phospholipids, and hemoglobin to prevent inflammation.

• Classes of Receptors:

  • Class A: Includes MSR1, MARCO.

  • Class B: Includes CD36, SR-B1.

  • Class C: Includes CD68, LOX-1.

• Hemoglobin Scavenging:

  • CD163: Specialized for clearing hemoglobin. → Free hemoglobin is toxic and needs to be eliminated by Scavenger receptors, as it is chemically active → it is oxidizing

    • Of course we have hemoglobin in red blood cells (erythrocytes), but there the hemoglobin is not free in the system but bound.

Explanation of Visuals:

• Receptor Classes:

  • Depicted with different colors for clarity.

  • Arrows indicate binding and removal of harmful molecules.

Glossary:

• Scavenger Receptors: Bind and remove oxidized molecules to prevent cell damage.

• Oxidized LDL: Damaged form of LDL contributing to atherosclerosis.

• CD163: Receptor for hemoglobin clearance.

• MSR Receptor (Macrophage Scavenger Receptor):
  A type of scavenger receptor mainly expressed on macrophages.
  It recognizes and binds to a wide range of ligands, including:

  • Clearing harmful substances

  • Bacterial components
    MSR receptors are important for:

  • Innate immunity (first line defense)

Key Takeaway:
Scavenger receptors play a vital role in preventing oxidative stress and inflammation.

Slide 41: Conclusion

Key Points:

• Dual Theories of Aging:

  • Programmed aging: Involves hormones, genetic factors, and the Hayflick limit.

  • Tear and wear→accumulation of stress molecules Involves oxidative damage, mitochondrial dysfunction, toxin accumulation, and impaired repair systems.

• Balance Concept:

  • Yin-Yang symbol: Represents the balance between programmed aging and wear-and-tear theories.

• Key Factors in Aging:

  • Oxidative damage: Leads to mitochondrial dysfunction.

  • Toxin accumulation: Involves AGEs and glycation products.

Explanation of Visuals:

• Yin-Yang Symbol:

  • Illustrates the balance between two aging theories.

  • Sections labeled to highlight distinct aging mechanisms.

Glossary:

• Hayflick Limit: Maximum times a cell can divide.

• Oxidative Damage: Harm caused by ROS to cells and DNA.

• Toxin Accumulation: Build-up of harmful molecules like AGEs.

Key Takeaway:
Aging is a result of the interplay between programmed mechanisms and cumulative damage.