Biology of Aging

  1. The Hallmarks of Aging: Molecular and Cellular Mechanisms
    1. Genomic Instability
      1. Sources of DNA Damage
        1. Exogenous sources
          1. Ultraviolet radiation
            1. Ionizing radiation
              1. Environmental toxins
                1. Chemical mutagens
                2. Endogenous sources
                  1. Replication errors
                    1. Reactive oxygen species
                      1. Spontaneous chemical changes
                        1. Hydrolytic reactions
                      2. DNA Repair Mechanisms and their Decline
                        1. Base excision repair
                          1. Glycosylases
                            1. AP endonucleases
                              1. DNA polymerases
                              2. Nucleotide excision repair
                                1. Global genome repair
                                  1. Transcription-coupled repair
                                  2. Mismatch repair
                                    1. Recognition proteins
                                      1. Excision and resynthesis
                                      2. Double-strand break repair
                                        1. Homologous recombination
                                          1. Non-homologous end joining
                                        2. Somatic Mutations and Chromosomal Aberrations
                                          1. Mutation accumulation
                                            1. Aneuploidy
                                              1. Chromosomal rearrangements
                                                1. Copy number variations
                                                  1. Clonal hematopoiesis
                                                2. Telomere Attrition
                                                  1. Structure and Function of Telomeres
                                                    1. Telomeric DNA repeats
                                                      1. Shelterin complex
                                                        1. TRF1 and TRF2
                                                          1. POT1
                                                            1. TIN2
                                                              1. TPP1
                                                                1. RAP1
                                                                2. T-loop formation
                                                                3. The End-Replication Problem
                                                                  1. DNA polymerase limitations
                                                                    1. Telomere shortening with cell division
                                                                      1. Leading vs lagging strand synthesis
                                                                      2. Role of Telomerase
                                                                        1. Telomerase structure and function
                                                                          1. TERT catalytic subunit
                                                                            1. TR RNA component
                                                                            2. Regulation of telomerase activity
                                                                              1. Transcriptional control
                                                                                1. Post-translational modifications
                                                                                2. Telomerase in stem cells and cancer
                                                                                3. Consequences of Telomere Shortening
                                                                                  1. Cellular senescence
                                                                                    1. Apoptosis
                                                                                      1. Genomic instability
                                                                                        1. Tissue dysfunction
                                                                                        2. Alternative Lengthening of Telomeres
                                                                                          1. ALT mechanism
                                                                                            1. Cancer cells without telomerase
                                                                                          2. Epigenetic Alterations
                                                                                            1. DNA Methylation Changes
                                                                                              1. Global hypomethylation
                                                                                                1. Promoter hypermethylation
                                                                                                  1. CpG island methylator phenotype
                                                                                                    1. DNA methyltransferases
                                                                                                    2. Histone Modifications
                                                                                                      1. Acetylation
                                                                                                        1. Histone acetyltransferases
                                                                                                          1. Histone deacetylases
                                                                                                          2. Methylation
                                                                                                            1. Histone methyltransferases
                                                                                                              1. Histone demethylases
                                                                                                              2. Phosphorylation
                                                                                                                1. Ubiquitination
                                                                                                                2. Chromatin Remodeling
                                                                                                                  1. Changes in chromatin structure
                                                                                                                    1. Impact on gene expression
                                                                                                                      1. Chromatin remodeling complexes
                                                                                                                        1. Heterochromatin formation
                                                                                                                        2. Epigenetic Drift
                                                                                                                          1. Stochastic epigenetic changes
                                                                                                                            1. Consequences for aging
                                                                                                                              1. Epigenetic noise
                                                                                                                                1. Loss of epigenetic maintenance
                                                                                                                                2. Non-coding RNAs
                                                                                                                                  1. MicroRNAs
                                                                                                                                    1. Long non-coding RNAs
                                                                                                                                  2. Loss of Proteostasis (Protein Homeostasis)
                                                                                                                                    1. Protein Synthesis and Folding
                                                                                                                                      1. Ribosomal function
                                                                                                                                        1. Ribosome biogenesis
                                                                                                                                          1. Translation efficiency
                                                                                                                                          2. Co-translational folding
                                                                                                                                            1. Endoplasmic reticulum stress
                                                                                                                                            2. Chaperone Systems
                                                                                                                                              1. Heat shock proteins
                                                                                                                                                1. HSP70 family
                                                                                                                                                  1. HSP90 family
                                                                                                                                                    1. Small heat shock proteins
                                                                                                                                                    2. Chaperonins
                                                                                                                                                      1. GroEL/GroES system
                                                                                                                                                        1. TRiC/CCT complex
                                                                                                                                                        2. Co-chaperones
                                                                                                                                                        3. Protein Degradation Pathways
                                                                                                                                                          1. Ubiquitin-Proteasome System
                                                                                                                                                            1. Ubiquitination process
                                                                                                                                                              1. E1 activating enzymes
                                                                                                                                                                1. E2 conjugating enzymes
                                                                                                                                                                  1. E3 ligases
                                                                                                                                                                  2. Proteasome function
                                                                                                                                                                    1. 26S proteasome structure
                                                                                                                                                                      1. Catalytic activities
                                                                                                                                                                      2. Proteasome assembly and regulation
                                                                                                                                                                      3. Autophagy
                                                                                                                                                                        1. Macroautophagy
                                                                                                                                                                          1. Autophagosome formation
                                                                                                                                                                            1. Autophagosome-lysosome fusion
                                                                                                                                                                            2. Microautophagy
                                                                                                                                                                              1. Chaperone-mediated autophagy
                                                                                                                                                                                1. LAMP-2A receptor
                                                                                                                                                                                  1. HSC70 recognition
                                                                                                                                                                                2. Lysosomal degradation
                                                                                                                                                                                3. Accumulation of Misfolded and Aggregated Proteins
                                                                                                                                                                                  1. Amyloid formation
                                                                                                                                                                                    1. Proteotoxic stress
                                                                                                                                                                                      1. Inclusion body formation
                                                                                                                                                                                        1. Prion-like propagation
                                                                                                                                                                                      2. Deregulated Nutrient-Sensing
                                                                                                                                                                                        1. Insulin and IGF-1 Signaling (IIS) Pathway
                                                                                                                                                                                          1. Components and regulation
                                                                                                                                                                                            1. Insulin receptor
                                                                                                                                                                                              1. IGF-1 receptor
                                                                                                                                                                                                1. IRS proteins
                                                                                                                                                                                                  1. PI3K/AKT pathway
                                                                                                                                                                                                  2. Role in lifespan determination
                                                                                                                                                                                                    1. FOXO transcription factors
                                                                                                                                                                                                      1. Downstream targets
                                                                                                                                                                                                      2. mTOR (Mechanistic Target of Rapamycin) Pathway
                                                                                                                                                                                                        1. mTORC1 and mTORC2 complexes
                                                                                                                                                                                                          1. mTORC1 components and functions
                                                                                                                                                                                                            1. mTORC2 components and functions
                                                                                                                                                                                                            2. Regulation of growth and metabolism
                                                                                                                                                                                                              1. Upstream regulators
                                                                                                                                                                                                                1. TSC1/TSC2 complex
                                                                                                                                                                                                                  1. Rheb GTPase
                                                                                                                                                                                                                    1. AMPK
                                                                                                                                                                                                                    2. Downstream effectors
                                                                                                                                                                                                                      1. S6K1
                                                                                                                                                                                                                        1. 4E-BP1
                                                                                                                                                                                                                      2. AMPK (AMP-activated protein kinase) Pathway
                                                                                                                                                                                                                        1. Energy sensing
                                                                                                                                                                                                                          1. Effects on metabolism and aging
                                                                                                                                                                                                                            1. Upstream kinases
                                                                                                                                                                                                                              1. Downstream targets
                                                                                                                                                                                                                                1. Metabolic reprogramming
                                                                                                                                                                                                                                2. Sirtuins
                                                                                                                                                                                                                                  1. NAD+-dependent deacetylases
                                                                                                                                                                                                                                    1. Role in stress resistance and metabolism
                                                                                                                                                                                                                                      1. SIRT1 functions
                                                                                                                                                                                                                                        1. SIRT3 mitochondrial functions
                                                                                                                                                                                                                                          1. Other sirtuin family members
                                                                                                                                                                                                                                          2. p53 Pathway
                                                                                                                                                                                                                                            1. DNA damage response
                                                                                                                                                                                                                                              1. Cell cycle regulation
                                                                                                                                                                                                                                                1. Senescence induction
                                                                                                                                                                                                                                              2. Mitochondrial Dysfunction
                                                                                                                                                                                                                                                1. Mitochondrial Theory of Aging
                                                                                                                                                                                                                                                  1. Historical background
                                                                                                                                                                                                                                                    1. Evidence and controversies
                                                                                                                                                                                                                                                      1. Vicious cycle hypothesis
                                                                                                                                                                                                                                                      2. Decline in Mitochondrial Biogenesis
                                                                                                                                                                                                                                                        1. Regulation by PGC-1α
                                                                                                                                                                                                                                                          1. Impact on energy production
                                                                                                                                                                                                                                                            1. Mitochondrial transcription factors
                                                                                                                                                                                                                                                              1. Nuclear respiratory factors
                                                                                                                                                                                                                                                              2. Increased Reactive Oxygen Species (ROS) Production
                                                                                                                                                                                                                                                                1. Sources of ROS
                                                                                                                                                                                                                                                                  1. Complex I
                                                                                                                                                                                                                                                                    1. Complex III
                                                                                                                                                                                                                                                                      1. Other sources
                                                                                                                                                                                                                                                                      2. Oxidative damage to macromolecules
                                                                                                                                                                                                                                                                        1. DNA damage
                                                                                                                                                                                                                                                                          1. Protein oxidation
                                                                                                                                                                                                                                                                            1. Lipid peroxidation
                                                                                                                                                                                                                                                                          2. Impaired Mitochondrial Dynamics (Fission and Fusion)
                                                                                                                                                                                                                                                                            1. Key proteins involved
                                                                                                                                                                                                                                                                              1. Fusion proteins (MFN1, MFN2, OPA1)
                                                                                                                                                                                                                                                                                1. Fission proteins (DRP1, FIS1)
                                                                                                                                                                                                                                                                                2. Consequences for mitochondrial function
                                                                                                                                                                                                                                                                                  1. Mitochondrial network organization
                                                                                                                                                                                                                                                                                  2. Mitophagy Decline
                                                                                                                                                                                                                                                                                    1. Mechanisms of mitophagy
                                                                                                                                                                                                                                                                                      1. PINK1/Parkin pathway
                                                                                                                                                                                                                                                                                        1. Receptor-mediated mitophagy
                                                                                                                                                                                                                                                                                        2. Accumulation of dysfunctional mitochondria
                                                                                                                                                                                                                                                                                          1. Quality control mechanisms
                                                                                                                                                                                                                                                                                          2. Mitochondrial DNA Mutations
                                                                                                                                                                                                                                                                                            1. mtDNA damage and repair
                                                                                                                                                                                                                                                                                              1. Clonal expansion
                                                                                                                                                                                                                                                                                                1. Heteroplasmy
                                                                                                                                                                                                                                                                                              2. Cellular Senescence
                                                                                                                                                                                                                                                                                                1. Definition and Characteristics
                                                                                                                                                                                                                                                                                                  1. Irreversible cell cycle arrest
                                                                                                                                                                                                                                                                                                    1. Morphological and functional changes
                                                                                                                                                                                                                                                                                                      1. Senescence-associated β-galactosidase
                                                                                                                                                                                                                                                                                                        1. Senescence-associated heterochromatin foci
                                                                                                                                                                                                                                                                                                        2. Triggers of Senescence
                                                                                                                                                                                                                                                                                                          1. Replicative Senescence
                                                                                                                                                                                                                                                                                                            1. Telomere shortening
                                                                                                                                                                                                                                                                                                              1. p53/p21 pathway
                                                                                                                                                                                                                                                                                                              2. Oncogene-Induced Senescence
                                                                                                                                                                                                                                                                                                                1. Activation of oncogenes
                                                                                                                                                                                                                                                                                                                  1. p16/Rb pathway
                                                                                                                                                                                                                                                                                                                  2. Stress-Induced Senescence
                                                                                                                                                                                                                                                                                                                    1. DNA damage
                                                                                                                                                                                                                                                                                                                      1. Oxidative stress
                                                                                                                                                                                                                                                                                                                        1. Mitochondrial dysfunction
                                                                                                                                                                                                                                                                                                                      2. Senescence-Associated Secretory Phenotype (SASP)
                                                                                                                                                                                                                                                                                                                        1. Pro-inflammatory cytokines
                                                                                                                                                                                                                                                                                                                          1. IL-1β
                                                                                                                                                                                                                                                                                                                            1. IL-6
                                                                                                                                                                                                                                                                                                                              1. TNF-α
                                                                                                                                                                                                                                                                                                                              2. Proteases and growth factors
                                                                                                                                                                                                                                                                                                                                1. Regulation of SASP
                                                                                                                                                                                                                                                                                                                                2. Role in Tumor Suppression and Wound Healing
                                                                                                                                                                                                                                                                                                                                  1. Protective effects
                                                                                                                                                                                                                                                                                                                                    1. Tissue remodeling
                                                                                                                                                                                                                                                                                                                                      1. Immune surveillance
                                                                                                                                                                                                                                                                                                                                      2. Pro-aging Effects of Senescent Cell Accumulation
                                                                                                                                                                                                                                                                                                                                        1. Chronic inflammation
                                                                                                                                                                                                                                                                                                                                          1. Tissue dysfunction
                                                                                                                                                                                                                                                                                                                                            1. Stem cell exhaustion
                                                                                                                                                                                                                                                                                                                                              1. Paracrine senescence
                                                                                                                                                                                                                                                                                                                                            2. Stem Cell Exhaustion
                                                                                                                                                                                                                                                                                                                                              1. Decline in Stem Cell Number and Function
                                                                                                                                                                                                                                                                                                                                                1. Hematopoietic stem cells
                                                                                                                                                                                                                                                                                                                                                  1. Bone marrow niche changes
                                                                                                                                                                                                                                                                                                                                                    1. Lineage bias
                                                                                                                                                                                                                                                                                                                                                    2. Mesenchymal stem cells
                                                                                                                                                                                                                                                                                                                                                      1. Adipogenic shift
                                                                                                                                                                                                                                                                                                                                                        1. Reduced osteogenic potential
                                                                                                                                                                                                                                                                                                                                                        2. Neural stem cells
                                                                                                                                                                                                                                                                                                                                                          1. Neurogenesis decline
                                                                                                                                                                                                                                                                                                                                                            1. Quiescence vs activation
                                                                                                                                                                                                                                                                                                                                                            2. Intestinal stem cells
                                                                                                                                                                                                                                                                                                                                                              1. Muscle satellite cells
                                                                                                                                                                                                                                                                                                                                                              2. Impaired Self-Renewal and Differentiation
                                                                                                                                                                                                                                                                                                                                                                1. Changes in signaling pathways
                                                                                                                                                                                                                                                                                                                                                                  1. Wnt signaling
                                                                                                                                                                                                                                                                                                                                                                    1. Notch signaling
                                                                                                                                                                                                                                                                                                                                                                      1. BMP signaling
                                                                                                                                                                                                                                                                                                                                                                      2. Loss of regenerative capacity
                                                                                                                                                                                                                                                                                                                                                                        1. Epigenetic changes in stem cells
                                                                                                                                                                                                                                                                                                                                                                        2. Niche Deterioration
                                                                                                                                                                                                                                                                                                                                                                          1. Alterations in stem cell microenvironment
                                                                                                                                                                                                                                                                                                                                                                            1. Impact on stem cell maintenance
                                                                                                                                                                                                                                                                                                                                                                              1. Extracellular matrix changes
                                                                                                                                                                                                                                                                                                                                                                                1. Vascular changes
                                                                                                                                                                                                                                                                                                                                                                                2. Impact on Tissue Regeneration
                                                                                                                                                                                                                                                                                                                                                                                  1. Delayed wound healing
                                                                                                                                                                                                                                                                                                                                                                                    1. Organ atrophy
                                                                                                                                                                                                                                                                                                                                                                                      1. Functional decline
                                                                                                                                                                                                                                                                                                                                                                                    2. Altered Intercellular Communication
                                                                                                                                                                                                                                                                                                                                                                                      1. Neuroendocrine Dysregulation
                                                                                                                                                                                                                                                                                                                                                                                        1. Hormonal imbalances
                                                                                                                                                                                                                                                                                                                                                                                          1. Impact on homeostasis
                                                                                                                                                                                                                                                                                                                                                                                            1. Hypothalamic-pituitary axis
                                                                                                                                                                                                                                                                                                                                                                                              1. Circadian rhythm disruption
                                                                                                                                                                                                                                                                                                                                                                                              2. Immunosenescence (Inflammaging)
                                                                                                                                                                                                                                                                                                                                                                                                1. Chronic low-grade inflammation
                                                                                                                                                                                                                                                                                                                                                                                                  1. Altered cytokine profiles
                                                                                                                                                                                                                                                                                                                                                                                                    1. NF-κB activation
                                                                                                                                                                                                                                                                                                                                                                                                      1. Inflammasome activation
                                                                                                                                                                                                                                                                                                                                                                                                      2. Changes in Gap Junctions and Cell Adhesion
                                                                                                                                                                                                                                                                                                                                                                                                        1. Connexin expression
                                                                                                                                                                                                                                                                                                                                                                                                          1. Tissue integrity
                                                                                                                                                                                                                                                                                                                                                                                                            1. Cell-cell communication
                                                                                                                                                                                                                                                                                                                                                                                                            2. Extracellular Vesicles and Signaling
                                                                                                                                                                                                                                                                                                                                                                                                              1. Exosomes and microvesicles
                                                                                                                                                                                                                                                                                                                                                                                                                1. Role in cell-to-cell communication
                                                                                                                                                                                                                                                                                                                                                                                                                  1. Cargo transfer

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                                                                                                                                                                                                                                                                                                                                                                                                              Go to top

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                                                                                                                                                                                                                                                                                                                                                                                                              4. Systemic and Organismal Aging