Cell Aging & Cell Death Lecture Notes PDF

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LuckyIntelligence7398

Uploaded by LuckyIntelligence7398

İstanbul Aydın Üniversitesi

2025

Meltem Ercan, PhD

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cell aging cell death biology medical biology

Summary

This lecture covers cell aging and different types of cell death, including apoptosis, autophagy, and necrosis. It details causes, mechanisms, and critical cellular responses.

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CELL AGING & CELL DEATH Assist. Prof. Meltem ERCAN, PhD. IAU Faculty of Medicine (Eng.) Medical Biology & Genetics 02/01/2025 [email protected] 1 OUTLINE ❑ CELL AGING ▪ Genetic Factors ▪ Environ...

CELL AGING & CELL DEATH Assist. Prof. Meltem ERCAN, PhD. IAU Faculty of Medicine (Eng.) Medical Biology & Genetics 02/01/2025 [email protected] 1 OUTLINE ❑ CELL AGING ▪ Genetic Factors ▪ Environmental Factors ▪ Relative Senescence ❑ CELL DEATH ▪ Apoptosis ▪ Autophagy ▪ Necrosis 2 CELL AGING ❑Cellular Aging is the result of a progressive decrease in cellular function and viability. 2 mechanisms: - genetic factors that influence ageing process - environmental factors that cause progressive accumulation metabolic and genetic damage o aging a balance between metabolic damage and repair mechanisms - Both genetic and environmental factors lead to replicative senescence (cells have limited capacity for replication) 3 4 GENETIC FACTORS Genetic influences on cellular aging primarily involve mutations, signaling abnormalities, and defects in repair systems. DNA Repair Defects: Impaired DNA repair mechanisms lead to the accumulation of mutations in the genome over time. This genomic instability reduces the cell’s ability to function and survive, eventually contributing to replicative senescence (the loss of a cell's ability to divide). Various Genetic Abnormalities (e.g., IGF-1 Pathway): Dysregulation of signaling pathways, such as the Insulin-like Growth Factor-1 (IGF-1) pathway, disrupts cellular homeostasis and growth regulation. This leads to abnormal cellular signaling, which promotes aging-related dysfunction. 5 DNA DAMAGE During the cell lifetime, the genomic DNA is continuously exposed to different hazards that undermine its integrity and functionality. DNA can be either challenged; o by exogenous environmental factors, such as oxidative stress, genotoxic drugs and ionizing radiation or o by endogenous chemicals, such as ROS, replication errors and spontaneous hydrolysis reactions. 6 If DNA lesions are not properly repaired, they DNA DAMAGE are converted into permanent mutations that significantly increase the risk of cancer. DNA damage could also cause replication arrest leading to cellular senescence or cell death, thus contributing to the onset of the aging process. Cancer and aging, both arising as the consequence of irreparable DNA damage. In aging the increase of DNA damage rate is the overall result of the imbalance between generation and disposal of by-products deriving from cellular metabolism, and the functional When cells experience DNA damage that is too decline of DNA repair efficiency. severe to be repaired, programmed cell death 7 occurs, most commonly by apoptosis. ENVIRONMENTAL FACTORS External influences accelerate cellular aging by damaging cellular components and reducing the cell's ability to maintain protein quality: Environmental Insults: Factors like radiation, toxins, and oxidative stress produce free radicals. These free radicals cause oxidative damage to DNA, proteins, and lipids, resulting in the accumulation of damaged cellular proteins and organelles. Reduced Proteasomal Activity: The proteasome is responsible for degrading damaged proteins. A decline in proteasomal activity with age leads to the buildup of damaged proteins and organelles, further impairing cellular function. 8 Free Radicals ❑A free radical can be defined as any molecular species capable of independent existence that contains an unpaired electron in an atomic orbital. 9 Sources of Free Radicals The body produces free radicals through natural processes, but they can be introduced through sun exposure, pollutants, toxins, tobacco smoke, alcohol, and other external sources. 10 Oxidative Stress ❑When there are excess free radicals in your system, it leads to oxidative stress. ❑Oxidation is when a free radical steals electrons from another molecule and damage parts of the cell, such as proteins, DNA, cell membranes and more. ❑The molecule that lost its electrons becomes Oxidized. ❑Oxidative stress is when the body has gone to more oxidation than it can combat. ❑Long-term oxidative stress contributes to the development of a range of chronic conditions including cancer, diabetes, and heart disease. 11 How Can Antioxidants Help Fight Free Radical Damage? ❑ The body combats oxidative stress with antioxidants. When the amount of free radicals exceeds the amount of antioxidants, oxidative stress happens. ❑ Antioxidant: Any synthetic or natural substance that delay or inhibits oxidative damage to a target molecule and capable to neutralize free radicals by donating electron or hydrogen molecule. ❑ They prevent cell damage and tissue damage and act as scavenger. They are thought of as “self-sacrificing soldiers” and help prevent oxidative stress. ❑ For example; As we age, the skin’s own antioxidant defense system weakens, losing its capacity to fight the oxidative stress caused by free radicals. An antioxidant-rich diet and a concentrated antioxidant skincare routine can help boost your antioxidant defense! 12 How Can Antioxidants Help Fight Free Radical Damage? Antioxidant enzymes’ functions are to convert free radicals to nontoxic and non radical forms. o SOD catalyze the rapid dismutation of superoxide radical to hydrogen peroxide. o Catalase reduces peroxide (H2O2) to water and oxygen. Antioxidant vitamins neutralize the free radicals by donating one electron to the radical in non-enzymatic reactions. o Vitamin E is a fat soluble vitamin and prevent peroxidation of lipid by donating of electrons to free radicals. o Vitamin C is a water soluble vitamin that reacts with several radical species. o Vitamin A Works as an antioxidant in form of carotenoids. Mainly beta carotenoids (CAR) react with free radicals and prevent lipid oxidation. 13 Glycation ❑Glycation (Maillard reaction) is another cause of aging. ❑Glycation, also called nonenzymatic glycosylation, is the result of a glucose or other monosaccharides covalently linked to a protein, lipid or nucleic acid molecule without a catalytic action of an enzyme. ❑ Advanced glycation end products (AGEs) are proteins or lipids that become glycated as a result of exposure to sugars. 14 ❑ AGEs are slowly formed and accumulate in long-lived structural proteins such as collagen and elastin, thereby leading to increased stiffness of blood vessels and joints, and impaired functions of the lung, kidney, heart, and retina. These are commonly seen as features of aging. AGEs and glycated proteins are more resistant to degradation by the proteasome. This creates a feedback loop: reduced proteasomal activity leads to more damaged proteins, which are glycated and become even harder to degrade. 15 REPLICATIVE SENESCENCE ❑ Replicative senescence is a natural process in which cells stop dividing after a finite number of cell divisions. ❑ It is primarily caused by the progressive shortening of telomeres, the protective caps at the ends of chromosomes, during DNA replication. ❑ This phenomenon acts as a natural limit to cell proliferation, known as the Hayflick limit. 16 Young cell vs Senescent Cell ❑Lipofuscin is regarded as a product of lysosomes containing hydrolytic enzymes to degrade proteins, lipids and damaged organelles. 17 Telomere Shortening ▪ A telomere is a region of repetitive DNA sequences at the end of a chromosome. ▪ Telomeres protect the ends of chromosomes from becoming frayed or tangled. ▪ Each time a cell divides, the telomeres become slightly shorter. ▪ Eventually, they become so short that the cell can no longer divide successfully, and the cell dies. 18 Telomere Shortening ❑With each cell replication, the telomeres get shorter. ❑Telomeres can be rebuilt by an enzyme called telomerase to restore cell division. ❑Telomerase is active in germ cells and stem cells but absent in somatic cells. ❑Telomerase may be reactivated in cancers 19 Cellular Senescence and the activation of telomerase ❑ In germ cells programmed for an eternal lifespan, the telomere maintenance results from the activity of the enzyme telomerase. ❑ Growth of somatic cells in culture results in progressive shortening of telomeres, until such time as cellular division ceases and senescence is reached. ❑ Cells driven to proliferate past that point by the expression of transforming genes continue to shrink their telomeres until they reach crisis, a point at which chromosomes become unstable and massive cell death results. ❑ In small numbers of cells, telomerase may be activated at the time of crisis, producing immortal cell lines capable of indefinite growth in vitro. ❑ The majority of human cancers express high levels of telomerase. 20 21 CELL DEATH CELL DEATH MECHANISMS ❑There are mainly 3 different cell death mechanisms: Type 1: Apoptosis Programmed Cell Death Type 2: Autophagy Type 3 : Necrosis 22 APOPTOSIS ❑If cells are no longer needed, they commit suicide by activating an intracellular death program. This process is called programmed cell death (apoptosis). What purposes does the massive cell death serve? ❑During embryonic development some structures are sculpted by cell death (mouse paws). ❑Cells die when the structure they form is no longer needed. ❑Cell death helps regulate cell numbers. 23 APOPTOSIS ❑A cell that undergoes apoptosis dies neatly, without damaging its neighbours. 1. The cell shrinks and condenses. 2. The cytoskeleton collapses, 3. The nuclear envelope disassembles, and the nuclear DNA breaks up into fragments. 4. The cell surface is altered, displaying properties that cause the dying cell to be rapidly phagocytosed. 24 Animation 19.1 from The Cell 8e, by Geoffrey Cooper https://learninglink.oup.com/access/content/cooper8e-student-resources/cooper8e-chapter- 19-animation-1?previousFilter=tag_animations 25 Phagocytosis of apoptotic cells. ‘Eat me’ signal In normal cells, phosphatidylserine is restricted to the inner leaflet of the plasma membrane. 26 Targets of Caspases ❑ Caspases are the ultimate executioners of programmed cell death. ❑ The intracellular machinery responsible for apoptosis depends on a family of proteases that have a cysteine at their active site and cleave their target proteins at specific aspartic acids. They are therefore called caspases. Caspases cleave 100 different cell target proteins in the event of apoptosis. 27 Caspase Cascade ❑ Caspases are synthesized in the cell as inactive precursors, or procaspases, which are usually activated by cleavage at aspartic acids by other caspases. ❑ The activation of an initiator caspase starts a chain reaction of caspase activation leading to death of the cell. 28 The Extrinsic Pathway of Apoptosis ❑ Extracellular signal proteins binding to cell-surface death receptors trigger the extrinsic pathway of apoptosis. ❑ Death receptors are transmembrane proteins containing an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular death domain , which is required for the receptors to activate the apoptotic program. ▪ DISC: death-inducing signaling complex ▪ FADD: Fas-associated death domain 29 The Intrinsic Pathway of Apoptosis ❑ Cells can also activate their apoptosis program from inside the cell, usually in response to injury or other stresses, such as DNA damage or lack of oxygen, nutrients, or extracellular survival signals. ❑ A crucial protein released from mitochondria in the intrinsic pathway is cytochrome c, a water-soluble component of the mitochondrial electron-transport chain. ❑ When it released into the cytosol, it binds to a procaspase-activating adaptor protein called Apaf1 (apoptotic protease activating factor-1), causing the Apaf1 to oligomerize into a wheel-like heptamer called an apoptosome. ❑ The Apaf1 proteins recruit initiator procaspase-9 proteins, which are activated by proximity in the apoptosome. ❑ The activated caspase-9 molecules then activate downstream executioner procaspases to induce apoptosis. 30 31 Animation 19.2 from The Cell 8e, by Geoffrey Cooper Animation 19.2 The Mitochondrial Pathway of Apoptosis - The Cell 8e Student Resources - Learning Link (oup.com) 32 Bcl-2 Family Proteins as the Main Intracellular Regulators of the Cell Death Program ❑ A major class of intracellular regulators of apoptosis is the Bcl2 family of proteins ❑ These proteins regulate the apoptosis by controlling the release of cytochrome c and other intermembrane mitochondrial proteins into the cytosol. ❑ Some Bcl2 proteins are pro-apoptotic and promote apoptosis by enhancing the release, whereas others are anti- apoptotic and inhibit apoptosis by blocking the release. The three classes of Bcl2 proteins. 33 The role of BH123 pro-apoptotic Bcl2 proteins (mainly Bax and Bak) Bax or Bak When activated by an apoptotic stimulus, the BH123 proteins aggregate on the outer mitochondrial membrane and release cytochrome c and other proteins from the intermembrane space into the cytosol by an unknown mechanism. 34 Bax or Bak ❑ In the absence of an apoptotic stimulus, anti- apoptotic Bcl2 proteins bind to and inhibit the Bax or Bak on the mitochondrial outer membrane ❑ In the presence of an apoptotic stimulus, BH3-only proteins are activated and bind to the anti-apoptotic Bcl2 proteins so that they can no longer inhibit the BH123 proteins, which now become activated and aggregate in the outer mitochondrial membrane and promote the Bid release of intermembrane mitochondrial proteins into the Bad cytosol. Noxa Puma Bim 35 IAP Proteins as the Main Intracellular Regulators of the Cell Death Program ❑ Another important family of intracellular apoptosis regulators is the IAPs (inhibitors of apoptosis) family. ❑ All IAPs have one or more BIR (baculovirus IAP repeat) domains, which enable them to bind to and inhibit activated caspases. ❑ Some IAPs also polyubiquitylate caspases, marking the caspases for destruction by proteasomes. ❑ The major mammalian IAP : XIAP ❑ These proteins are thought to inhibit apoptosis in two ways: 1. They bind to some procaspases to prevent their activation, 2. They bind to caspases to inhibit their activity. 36 anti-IAP proteins ❑ IAPs can be neutralized by anti-IAP proteins, which are produced in response to various apoptotic stimuli. ❑ Anti-IAPs are released from the mitochondrial intermembrane space when the intrinsic pathway of apoptosis is activated, blocking IAPs in the cytosol and thereby promoting apoptosis. ❑ The two known mammalian anti-IAPs: Smac/Diablo and Omi ❑ The intracellular cell death program is also regulated by extracellular signals, which can either activate apoptosis or inhibit it. ❑ These signal molecules mainly act by regulating the levels or activity of members of the Bcl-2 and IAP families. 37 IAP Proteins as the Main Intracellular Regulators of the Cell Death Program ❑ In the absence of an apoptotic stimulus, IAPs prevent accidental apoptosis caused by the spontaneous activation of procaspases. The IAPs are located in the cytosol and bind to and inhibit any spontaneously activated caspases. Bax or Bak ❑ When an apoptotic stimulus activates the intrinsic pathway, among the proteins released from the mitochondrial intermembrane space are anti-IAP proteins, which bind to and block the inhibitory activity of the IAPs. At the same time, the released cytochrome c triggers the assembly of apoptosomes, which can now activate a caspase cascade, leading to apoptosis. 38 Role of p53 in DNA damage-induced apoptosis ❑ p53 transcription factor (encoded by the human gene TP53) stands out as a key tumor suppressor. ❑ The many roles of p53 as a tumor suppressor include the ability to induce cell cycle arrest, DNA repair, senescence, and apoptosis. (the guardian of the genome) ❑ DNA damage leads to activation of the ATM and Chk2 protein kinases, which phosphorylate and stabilize p53, resulting in rapid increases in p53 levels. ❑ The p53 protein then activates transcription of genes encoding the proapoptotic regulatory proteins PUMA and Noxa, leading to cell death. 39 Apoptosis: Pathways “Extrinsic Pathway” Death Death Initiator Ligands Receptors Caspase 8 Effector “Intrinsic Pathway” Caspase 3 PCD (Apoptosis) DNA Initiator Mitochondria/ damage Caspase 9 Cytochrome C & p53 AUTOPHAGY ❑Programmed cell death can also occur by non-apoptotic mechanisms such as autophagy. ❑Autophagy is a process in which a cell eats in own contents. ❑In normal cells, autophagy provides a mechanism for gradual turnover of the cell’s components by uptake of proteins or organelles into vesicles that fuse with lysosomes. ❑Autophagy can also be an alternative to apoptosis as a pathway of cell death. ❑ Greek: Auto (self), phagy (eating) 41 AUTOPHAGY ❑Autophagic cell death does not require caspases. ❑It is activated by extracellular and intracellular factors ▪ Growt factors ▪ Nutrient deprivation/under starvation ▪ Stress-oxidative, salt, ER stress ▪ During pathogen invasion ▪ Protein aggregation/organalle aggregation 42 Types of Autophagy ❑ Macroautophagy:, An isolation membrane (known as the phagophore) encloses a portion of cytoplasm, forming a characteristic double-membraned organelle named autophagosome which then fuses with lysosome to form autophagolysosome and the cytoplasmic components are subsequently degraded by lysosomal enzymes. ❑ Microautophagy: The lysosome directly engulfs the cytoplasm via the inward invagination of the lysosomal membrane. ❑ Chaperone-mediated autophagy (CMA): With the help of chaperone proteins, selective proteins can be targeted and translocated to the lysosomal lumen, a process known as chaperone-mediated autophagy. 43 Types of Autophagy 44 NECROSIS ❑Cells that die as a result of various agents such as hypoxia, chemical and physical agents, microbial agents, acute injury etc. typically swell and burst. ❑Causes rupturing of cells and leakage of their contents into surrounding tissues ❑As a result, the non-specific immune response occurs and leads to inflammation 45 Nuclear changes Nuclear changes: ▪ pyknosis (degeneration and condensation of nuclear chromatin), ▪ karyorrhexis (nuclear fragmentation) ▪ karyolysis (dissolution of the nucleus) 46 NECROSIS VS APOPTOSIS NECROSIS APOPTOSIS ▪ Occurs less frequently, involves ▪ Occurs more frequently, many cells, may not be localised involves one cell at a time, and is pathological. localised and is on purpose. ▪ Abnormal and uncontrolled cell ▪ Controlled program of cell death that is associated with a death that is normal as it is a pathological condition. natural physiological process. ▪ Caused by external and internal ▪ Contains intrinsic and extrinsic injuries. pathways. ▪ Caspase independent pathway. ▪ Caspase dependent pathway. ▪ Inflammation present. ▪ Inflammation absent. ▪ Cells swells and burst, releasing ▪ Cell shrinks in size and the its content at once. condensation of chromatin ▪ Swelling of the mitochondria occur. and endoplasmic reticulum ▪ No leakage and no release of occurs. enzymes as small blebs are ▪ Leakage and enzymatic being released. Hence no digestion of neighbouring damage to surrounding tissues. cellular contents. ▪ Intact plasma membrane ▪ Disrupted plasma membrane structure. structure. ▪ Eosinophilia cell-like not ▪ Eosinophilia cell-like present present (cells presenting pink on a ▪ Nuclear changes: fragments histology slide) into nucleosome-size ▪ Nuclear changes: pyknosis, fragments or the nucleus karyorrhexis and karyolysis. usually dissolves into apoptotic bodies. Pyknosis and Karyorrhexis. 47 ❑ «Programmed Necrosis» or «Necroptosis» ❑ Some forms of necrosis can be a programmed cellular response to stimuli such as infection or DNA damage. ❑ Regulated necrosis may provide an alternative pathway of cell death if apoptosis does not occur. 48 SUMMARY 49 Thank you for your attention. [email protected] 50

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