Biology of Aging

3.

The Hallmarks of Aging: Molecular and Cellular Mechanisms

3.1.

Genomic Instability

3.1.1.

Sources of DNA Damage

3.1.1.1.

Exogenous sources

3.1.1.1.1.

Ultraviolet radiation

3.1.1.1.2.

Ionizing radiation

3.1.1.1.3.

Environmental toxins

3.1.1.1.4.

Chemical mutagens

3.1.1.2.

Endogenous sources

3.1.1.2.1.

Replication errors

3.1.1.2.2.

Reactive oxygen species

3.1.1.2.3.

Spontaneous chemical changes

3.1.1.2.4.

Hydrolytic reactions

3.1.2.

DNA Repair Mechanisms and their Decline

3.1.2.1.

Base excision repair

3.1.2.1.1.

3.1.2.1.2.

AP endonucleases

3.1.2.1.3.

DNA polymerases

3.1.2.2.

Nucleotide excision repair

3.1.2.2.1.

Global genome repair

3.1.2.2.2.

Transcription-coupled repair

3.1.2.3.

Mismatch repair

3.1.2.3.1.

Recognition proteins

3.1.2.3.2.

Excision and resynthesis

3.1.2.4.

Double-strand break repair

3.1.2.4.1.

Homologous recombination

3.1.2.4.2.

Non-homologous end joining

3.1.2.5.

Age-related decline in repair efficiency

3.1.2.5.1.

Reduced protein expression

3.1.2.5.2.

Impaired coordination

3.1.3.

Somatic Mutations and Chromosomal Aberrations

3.1.3.1.

Mutation accumulation

3.1.3.2.

3.1.3.3.

Chromosomal rearrangements

3.1.3.4.

Copy number variations

3.1.3.5.

Clonal hematopoiesis

3.2.

Telomere Attrition

3.2.1.

Structure and Function of Telomeres

3.2.1.1.

Telomeric DNA repeats

3.2.1.2.

Shelterin complex

3.2.1.2.1.

3.2.1.2.2.

3.2.1.2.3.

3.2.1.2.4.

3.2.1.2.5.

3.2.1.3.

T-loop formation

3.2.2.

The End-Replication Problem

3.2.2.1.

DNA polymerase limitations

3.2.2.2.

Telomere shortening with cell division

3.2.2.3.

Leading vs lagging strand synthesis

3.2.3.

Role of Telomerase

3.2.3.1.

Telomerase structure and function

3.2.3.1.1.

TERT catalytic subunit

3.2.3.1.2.

TR RNA component

3.2.3.2.

Regulation of telomerase activity

3.2.3.2.1.

Transcriptional control

3.2.3.2.2.

Post-translational modifications

3.2.3.3.

Telomerase in stem cells and cancer

3.2.4.

Consequences of Telomere Shortening

3.2.4.1.

Cellular senescence

3.2.4.2.

3.2.4.3.

Genomic instability

3.2.4.4.

Tissue dysfunction

3.2.5.

Alternative Lengthening of Telomeres

3.2.5.1.

3.2.5.2.

Cancer cells without telomerase

3.3.

Epigenetic Alterations

3.3.1.

DNA Methylation Changes

3.3.1.1.

Global hypomethylation

3.3.1.2.

Promoter hypermethylation

3.3.1.3.

CpG island methylator phenotype

3.3.1.4.

DNA methyltransferases

3.3.2.

Histone Modifications

3.3.2.1.

3.3.2.1.1.

Histone acetyltransferases

3.3.2.1.2.

Histone deacetylases

3.3.2.2.

3.3.2.2.1.

Histone methyltransferases

3.3.2.2.2.

Histone demethylases

3.3.2.3.

Phosphorylation

3.3.2.4.

3.3.3.

Chromatin Remodeling

3.3.3.1.

Changes in chromatin structure

3.3.3.2.

Impact on gene expression

3.3.3.3.

Chromatin remodeling complexes

3.3.3.4.

Heterochromatin formation

3.3.4.

Epigenetic Drift

3.3.4.1.

Stochastic epigenetic changes

3.3.4.2.

Consequences for aging

3.3.4.3.

Epigenetic noise

3.3.4.4.

Loss of epigenetic maintenance

3.3.5.

Non-coding RNAs

3.3.5.1.

3.3.5.2.

Long non-coding RNAs

3.3.5.3.

Age-related expression changes

3.4.

Loss of Proteostasis (Protein Homeostasis)

3.4.1.

Protein Synthesis and Folding

3.4.1.1.

Ribosomal function

3.4.1.1.1.

Ribosome biogenesis

3.4.1.1.2.

Translation efficiency

3.4.1.2.

Co-translational folding

3.4.1.3.

Endoplasmic reticulum stress

3.4.2.

Chaperone Systems

3.4.2.1.

Heat shock proteins

3.4.2.1.1.

3.4.2.1.2.

3.4.2.1.3.

Small heat shock proteins

3.4.2.2.

3.4.2.2.1.

GroEL/GroES system

3.4.2.2.2.

TRiC/CCT complex

3.4.2.3.

3.4.3.

Protein Degradation Pathways

3.4.3.1.

Ubiquitin-Proteasome System

3.4.3.1.1.

Ubiquitination process

3.4.3.1.1.1.

E1 activating enzymes

3.4.3.1.1.2.

E2 conjugating enzymes

3.4.3.1.1.3.

3.4.3.1.2.

Proteasome function

3.4.3.1.2.1.

26S proteasome structure

3.4.3.1.2.2.

Catalytic activities

3.4.3.1.3.

Proteasome assembly and regulation

3.4.3.2.

3.4.3.2.1.

3.4.3.2.1.1.

Autophagosome formation

3.4.3.2.1.2.

Autophagosome-lysosome fusion

3.4.3.2.2.

3.4.3.2.3.

Chaperone-mediated autophagy

3.4.3.2.3.1.

LAMP-2A receptor

3.4.3.2.3.2.

HSC70 recognition

3.4.3.3.

Lysosomal degradation

3.4.4.

Accumulation of Misfolded and Aggregated Proteins

3.4.4.1.

Amyloid formation

3.4.4.2.

Proteotoxic stress

3.4.4.3.

Inclusion body formation

3.4.4.4.

Prion-like propagation

3.5.

Deregulated Nutrient-Sensing

3.5.1.

Insulin and IGF-1 Signaling (IIS) Pathway

3.5.1.1.

Components and regulation

3.5.1.1.1.

Insulin receptor

3.5.1.1.2.

3.5.1.1.3.

3.5.1.1.4.

PI3K/AKT pathway

3.5.1.2.

Role in lifespan determination

3.5.1.3.

FOXO transcription factors

3.5.1.4.

Downstream targets

3.5.2.

mTOR (Mechanistic Target of Rapamycin) Pathway

3.5.2.1.

mTORC1 and mTORC2 complexes

3.5.2.1.1.

mTORC1 components and functions

3.5.2.1.2.

mTORC2 components and functions

3.5.2.2.

Regulation of growth and metabolism

3.5.2.3.

Upstream regulators

3.5.2.3.1.

TSC1/TSC2 complex

3.5.2.3.2.

3.5.2.3.3.

3.5.2.4.

Downstream effectors

3.5.2.4.1.

3.5.2.4.2.

3.5.3.

AMPK (AMP-activated protein kinase) Pathway

3.5.3.1.

3.5.3.2.

Effects on metabolism and aging

3.5.3.3.

Upstream kinases

3.5.3.4.

Downstream targets

3.5.3.5.

Metabolic reprogramming

3.5.4.

3.5.4.1.

NAD+-dependent deacetylases

3.5.4.2.

Role in stress resistance and metabolism

3.5.4.3.

SIRT1 functions

3.5.4.4.

SIRT3 mitochondrial functions

3.5.4.5.

Other sirtuin family members

3.5.5.

3.5.5.1.

DNA damage response

3.5.5.2.

Cell cycle regulation

3.5.5.3.

Senescence induction

3.6.

Mitochondrial Dysfunction

3.6.1.

Mitochondrial Theory of Aging

3.6.1.1.

Historical background

3.6.1.2.

Evidence and controversies

3.6.1.3.

Vicious cycle hypothesis

3.6.2.

Decline in Mitochondrial Biogenesis

3.6.2.1.

Regulation by PGC-1α

3.6.2.2.

Impact on energy production

3.6.2.3.

Mitochondrial transcription factors

3.6.2.4.

Nuclear respiratory factors

3.6.3.

Increased Reactive Oxygen Species (ROS) Production

3.6.3.1.

3.6.3.1.1.

3.6.3.1.2.

3.6.3.1.3.

3.6.3.2.

Oxidative damage to macromolecules

3.6.3.2.1.

3.6.3.2.2.

Protein oxidation

3.6.3.2.3.

Lipid peroxidation

3.6.4.

Impaired Mitochondrial Dynamics (Fission and Fusion)

3.6.4.1.

Key proteins involved

3.6.4.1.1.

Fusion proteins (MFN1, MFN2, OPA1)

3.6.4.1.2.

Fission proteins (DRP1, FIS1)

3.6.4.2.

Consequences for mitochondrial function

3.6.4.3.

Mitochondrial network organization

3.6.5.

Mitophagy Decline

3.6.5.1.

Mechanisms of mitophagy

3.6.5.1.1.

PINK1/Parkin pathway

3.6.5.1.2.

Receptor-mediated mitophagy

3.6.5.2.

Accumulation of dysfunctional mitochondria

3.6.5.3.

Quality control mechanisms

3.6.6.

Mitochondrial DNA Mutations

3.6.6.1.

mtDNA damage and repair

3.6.6.2.

Clonal expansion

3.6.6.3.

3.7.

Cellular Senescence

3.7.1.

Definition and Characteristics

3.7.1.1.

Irreversible cell cycle arrest

3.7.1.2.

Morphological and functional changes

3.7.1.3.

Senescence-associated β-galactosidase

3.7.1.4.

Senescence-associated heterochromatin foci

3.7.2.

Triggers of Senescence

3.7.2.1.

Replicative Senescence

3.7.2.1.1.

Telomere shortening

3.7.2.1.2.

p53/p21 pathway

3.7.2.2.

Oncogene-Induced Senescence

3.7.2.2.1.

Activation of oncogenes

3.7.2.2.2.

3.7.2.3.

Stress-Induced Senescence

3.7.2.3.1.

3.7.2.3.2.

Oxidative stress

3.7.2.3.3.

Mitochondrial dysfunction

3.7.3.

Senescence-Associated Secretory Phenotype (SASP)

3.7.3.1.

Pro-inflammatory cytokines

3.7.3.1.1.

3.7.3.1.2.

3.7.3.1.3.

3.7.3.2.

Proteases and growth factors

3.7.3.3.

Regulation of SASP

3.7.4.

Role in Tumor Suppression and Wound Healing

3.7.4.1.

Protective effects

3.7.4.2.

Tissue remodeling

3.7.4.3.

Immune surveillance

3.7.5.

Pro-aging Effects of Senescent Cell Accumulation

3.7.5.1.

Chronic inflammation

3.7.5.2.

Tissue dysfunction

3.7.5.3.

Stem cell exhaustion

3.7.5.4.

Paracrine senescence

3.8.

Stem Cell Exhaustion

3.8.1.

Decline in Stem Cell Number and Function

3.8.1.1.

Hematopoietic stem cells

3.8.1.1.1.

Bone marrow niche changes

3.8.1.1.2.

3.8.1.2.

Mesenchymal stem cells

3.8.1.2.1.

Adipogenic shift

3.8.1.2.2.

Reduced osteogenic potential

3.8.1.3.

Neural stem cells

3.8.1.3.1.

Neurogenesis decline

3.8.1.3.2.

Quiescence vs activation

3.8.1.4.

Intestinal stem cells

3.8.1.5.

Muscle satellite cells

3.8.2.

Impaired Self-Renewal and Differentiation

3.8.2.1.

Changes in signaling pathways

3.8.2.1.1.

3.8.2.1.2.

Notch signaling

3.8.2.1.3.

3.8.2.2.

Loss of regenerative capacity

3.8.2.3.

Epigenetic changes in stem cells

3.8.3.

Niche Deterioration

3.8.3.1.

Alterations in stem cell microenvironment

3.8.3.2.

Impact on stem cell maintenance

3.8.3.3.

Extracellular matrix changes

3.8.3.4.

Vascular changes

3.8.4.

Impact on Tissue Regeneration

3.8.4.1.

Delayed wound healing

3.8.4.2.

3.8.4.3.

Functional decline

3.9.

Altered Intercellular Communication

3.9.1.

Neuroendocrine Dysregulation

3.9.1.1.

Hormonal imbalances

3.9.1.2.

Impact on homeostasis

3.9.1.3.

Hypothalamic-pituitary axis

3.9.1.4.

Circadian rhythm disruption

3.9.2.

Immunosenescence (Inflammaging)

3.9.2.1.

Chronic low-grade inflammation

3.9.2.2.

Altered cytokine profiles

3.9.2.3.

NF-κB activation

3.9.2.4.

Inflammasome activation

3.9.3.

Changes in Gap Junctions and Cell Adhesion

3.9.3.1.

Connexin expression

3.9.3.2.

Tissue integrity

3.9.3.3.

Cell-cell communication

3.9.4.

Extracellular Vesicles and Signaling

3.9.4.1.

Exosomes and microvesicles

3.9.4.2.

Role in cell-to-cell communication

3.9.4.3.

3.9.4.4.

Age-related changes in EV composition

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4. Systemic and Organismal Aging