Cellular Aging | Chapter 2 | ROBBINS PATHOLOGY Based Audio Podcast

ROBBINS PATHOLOGY CHAPTER 2 - Cell Injury, Cell Death, and Adaptations Cellular Aging - Cellular aging involves the differentiation and maturation of an organism, leading ultimately to the progressive loss of functional capacity characteristic of senescence and culminating in death. Aging is not merely a passive process but is regulated by evolutionarily conserved genes. It is one of the strongest independent risk factors for many chronic diseases, including cancer, ischemic heart disease, and Alzheimer disease. Cellular aging is fundamentally the result of a progressive decline in cellular function and viability caused by genetic abnormalities and the accumulation of cellular and molecular damage resulting from exposure to exogenous influences. The mechanisms contributing to cellular aging are defined as a combination of reduced capacity to divide (replicative senescence), accumulating cellular damage (e.g., from free radicals/ROS), defective protein homeostasis, and a reduced ability to repair damaged DNA. Key Mechanisms of Cellular Aging 1. DNA Damage and Repair The integrity of nuclear and mitochondrial DNA is constantly threatened by both exogenous agents (physical, chemical, and biologic) and endogenous factors like Reactive Oxygen Species (ROS). While most DNA damage is repaired, some damage persists and accumulates as cells age. Defective DNA repair mechanisms contribute significantly to the aging process. Accelerated accumulation of chromosomal damage that mimics normal aging occurs in genetic disorders like Werner syndrome, which involves a defective DNA helicase, or in Bloom syndrome and ataxia-telangiectasia, where mutated genes encode proteins involved in repairing double-strand breaks in DNA. 2. Cellular Senescence (Replicative Senescence) All normal cells have a limited capacity for replication. After a fixed number of divisions, cells become arrested in a terminally nondividing state known as replicative senescence. This mechanism underlies aging. Two main processes are believed to drive cellular senescence: • Telomere Attrition: Telomeres are short, repeated DNA sequences at the ends of chromosomes. In most somatic cells, telomerase (the enzyme that maintains telomere length) is absent or present at low levels. Because a small section of the telomere is not duplicated during cell replication, telomeres progressively shorten. Once they become critically short, the chromosome ends are seen as broken DNA, signaling cell cycle arrest. • Activation of Tumor Suppressor Genes: The activation of specific tumor suppressor genes, particularly the p16 (INK4a) protein encoded by the CDKN2A locus, is correlated with chronological age. p16 protects cells from uncontrolled mitogenic signals and promotes the senescence pathway by controlling G1- to S-phase progression. 3. Defective Protein Homeostasis Protein homeostasis relies on two systems: chaperones that ensure correct protein folding, and the autophagy-lysosome/ubiquitin-proteasome systems that degrade damaged or misfolded proteins. Evidence suggests that the folding and degradation of misfolded proteins are impaired with aging. This defect can lead to the accumulation of misfolded proteins, which may trigger apoptosis. Counteracting Aging (Nutrient Sensing) Paradoxically, caloric restriction increases longevity in all eukaryotic species tested. This effect is regulated by nutrient sensing systems. Caloric restriction is thought to work by: • Reducing Insulin and IGF-1 Signaling: Attenuating the intensity of the Insulin/Insulin-like Growth Factor 1 (IGF-1) signaling pathway leads to lower rates of cell growth and metabolism, potentially reducing cellular damage. The drug rapamycin, which inhibits the downstream mTOR pathway, also increases the life span of middle-aged mice. • Increasing Sirtuins: Caloric restriction increases sirtuins, which are NAD-dependent protein deacetylases. Sirtuins are believed to promote longevity by inhibiting metabolic activity, reducing apoptosis, stimulating protein folding, and counteracting free radicals. Sirtuins also promote genomic integrity by activating DNA repair enzymes.