Biochemistry of Aging PDF

# Biochemistry of Aging **By Dr. Rasha Ghazala** **Associate Professor of Medical Biochemistry** ## Definitions - **Lifespan:** The maximum age human beings could reach under optimum conditions. - **Longevity:** The capability to survive beyond the species-specific average age of death. - **Life...

# Biochemistry of Aging **By Dr. Rasha Ghazala** **Associate Professor of Medical Biochemistry** ## Definitions - **Lifespan:** The maximum age human beings could reach under optimum conditions. - **Longevity:** The capability to survive beyond the species-specific average age of death. - **Life span:** The number of years that one person lives. - **Life expectancy:** The number of years that someone is expected to live from a specific starting point. It changes as you grow older and face different risks. ## What is aging? - Aging is characterized by a gradual functional decline. - It occurs heterogeneously across multiple organ systems, causing a progressive deterioration that eventually results in tissue dysfunction. - It is a risk factor for many diseases, such as cardiovascular disease, dementia, and osteoporosis. ## Senescence - **Senescence** is a cellular response that limits the proliferation of aged or damaged cells. - It induces a stable growth arrest accompanied by certain alterations, including: - Chromatin remodeling - Metabolic reprogramming - Increased autophagy - The implementation of proinflammatory status. ## What causes senescence? - **Accumulation of senescent cells** has been described as a hallmark of aging. However, whether they are a causative factor or a consequence of tissue and organismal aging is still unknown. - **Aging and senescence** mutually influence each other through positive feedback. This leads to accelerated tissue damage and aging. - **Clearance of senescent or aging cells** might constitute putative targets for interventional approaches to reduce or reverse the impact of aging and improve cell and tissue homeostasis. ## Theories of Aging Modern biological theories of aging in humans fall into two main categories: - **Programmed and damage or error theories.** ### Programmed Theories These theories imply that aging follows a biological timetable: - **Programmed Longevity:** Aging is the result of a sequential switching on and off of certain genes. Senescence being defined as the time when age-associated deficits are manifested. - **Endocrine Theory:** Biological clocks act through hormones to control the pace of aging, with insulin/IGF-1 signaling pathway playing a key role in the hormonal regulation of aging. - **Immunological Theory:** The immune system is programmed to decline over time, which leads to an increased vulnerability to infectious diseases and thus aging and death. ### Damage or Error Theories These theories emphasize environmental assaults that induce cumulative damage at various levels. - **Wear and Tear theory:** Cells and tissues have vital parts that wear out resulting in aging. - **Rate of living theory:** The greater an organism's rate of oxygen basal metabolism, the shorter its lifespan. - **Cross-linking theory:** Accumulation of cross-linked proteins damages cells and tissues, slowing down bodily processes resulting in aging. - **Free radicals theory:** Free radicals cause damage to macromolecules, such as nucleic acids, lipids, sugars, and proteins giving rise to accumulated damage, causing cells to stop functioning. - **Somatic DNA damage theory:** DNA polymerases and other repair mechanisms cannot correct defects as fast as they occur. Genetic mutations occur and accumulate with increasing age, causing cells to deteriorate and malfunction. In particular, damage to mitochondrial DNA might lead to mitochondrial dysfunction. ## Wear and Tear Theories of Aging - Human body eventually ages due to the accumulation of damage over time as a result of long-term exposure to a variety of environmental factors. - Many of these agents that are most damaging to proteins, DNA, and other biomolecules are also essential for life, such as water, oxygen, and sunlight. ## Hydrolytic Reactions Can Damage Proteins and Nucleotides - Water is ubiquitous and high concentration, even this weak nucleophile will react with susceptible targets inside the cell. - Hydrolysis of peptide bonds can lead to cleavage of the peptide chain. A potential biological consequence is the reactions of the nucleotide bases in DNA with water. ## Ultraviolet Radiation Can Be Extremely Damaging It is strongly absorbed by compounds containing aromatic rings or multiple, conjugated double bonds: - Nucleotide bases of DNA and RNA - Aromatic side chains of the amino acids phenylalanine, tyrosine, and tryptophan - Polyunsaturated fatty acids - Heme groups - Cofactors such as flavins, cyanocobalamine Absorption of this short wavelength, high-energy light can cause the rupture of covalent bonds in proteins, DNA, and RNA. It can also cause the formation of thymine dimers in DNA and cross-linking of proteins. ## Respiration Generates Reactive Oxygen Species Numerous biological processes require enzyme-catalyzed oxidation of organic molecules by molecular oxygen (O2): - Hydroxylation of proline and lysine side chains in collagen - Amino acid oxidases - The generation of the chemiosmotic gradient in mitochondria by the electron transport chain ## Reactive Oxygen Species (ROS) in Humans - Electron transport chain employs specialized carriers such as ubiquinone and cytochromes to safely transport individual, unpaired electrons. Leakage from the electron transport chain is the major source of ROS. - Cells synthesize the second messenger nitric oxide (NO), which contains an unpaired electron that is important for vasodilation. **Reactive Oxygen Species Summary:** | Source | Reactive Oxygen Species | | :------------- | :-------------------------------------------------- | | Electron Transport Chain | Superoxide (O2-), Hydrogen Peroxide (H2O2) | | Nitric Oxide Synthase | Nitric Oxide (NO) | | Fenton Reaction | Hydroxyl Radical (OH.) | | Haber-Weiss Reaction | Hydroxyl Radical (OH), Hydroxide (OH-) | ## Oxidative Theory of Aging - ROS can react with and chemically alter virtually any organic compound, including proteins, nucleic acids, and lipids. - They can lead to the cleavage of covalent bonds. - They can form adducts, a product formed when two compounds combine together (e.g., nucleotide bases, polyunsaturated fatty acids, and other biological compounds possessing multiple double bonds). ## Oxidative Damage Targets - **DNA:** Breaking of strand, depurination and depyrimidination, mutation of bases, protein DNA crosslinks. - **Lipids:** Enhanced membrane fluidity and permeability, breaking of lipid chains. - **Protein:** Modified amino acids, breakage of the peptide chain, increased proteolytic degradation, inactivation of enzyme. ## Molecular Mechanisms That Combat Oxidative Damage - **Enzymes** such as superoxide dismutase and catalase protect the cell by converting superoxide and hydrogen peroxide, respectively, to less reactive products. - **Glutathione** (cysteine-containing tripeptide) acts as a chemical redox protectant by reacting directly with ROS to generate less reactive compounds such as water. - **Ascorbic acid and vitamin E** also possess antioxidant properties, which accounts for the fact that many "popular" diets improve the body's ability to neutralize ROS and slow aging. ## Exogenous Antioxidants | Antioxidant | Dietary Sources | | :----------------------------- | :------------------------------------------------------------------ | | Vitamin C (ascorbic acid/ascorbate) | Bell peppers, strawberries, kiwi, Brussels sprouts, broccoli | | Vitamin E (tocopherols, tocotrienols) | Vegetable oil and its derivatives (margarine, salad dressing), nuts, seeds | | Carotenoids (a-carotene, B-carotene, zeaxanthin, lutein, lycopene, B-cryptoxanthin, etc.) | Orange and red vegetables and fruits (carrots, tomatoes, apricots, plums) and green leafy vegetables (spinach, kale) | | Polyphenols (flavonols, flavanols, anthocyanins, isoflavones, phenolic acid) | Fruits (apples, berries, grapes), vegetables (celery, kale, onions), legumes (beans, soybeans), nuts, wine, tea, coffee, cocoa | | Trace elements (selenium, zinc) | Seafood, meat, whole grains | ## Metabolic Theories of Aging - **Heartbeat hypothesis:** Every living creature is capable of performing only a finite number of heartbeats and/or breaths (Raymond Pearl, 1920s). - **Pearl proposed:** An individual's lifespan was reciprocally linked to their basal metabolic rate. - **The Brighter the Candle, the Quicker It Burns.** ## Mitochondrial Role as a Central Player in Aging - **Mutant mitochondrial proteins:** - **Damaged mitochondrial proteins:** - **Error-prone DNA polymerase:** - **Decreased DNA repair:** - **Nuclear DNA damage:** - **ROS:** - **Apoptosis:** - **Aging:** ## Role of Aggregated Proteins in Aging - **Modifications to a protein's composition or conformation** can cause it to adhere to other protein molecules. This can lead to the formation of toxic aggregates. - **Such aggregates** are the hallmark of several neurodegenerative diseases, including Parkinson's, Alzheimer's, and Huntington's disease. - **The toxic effects** of these insoluble aggregates are due to their refractory nature to degradation or repair. ## Hutchinson-Gilford Progeria Syndrome (Progeria or HGPS) - **Rare, fatal genetic condition** characterized by an appearance of accelerated aging in children. Its name is derived from the Greek and means "prematurely old". - **Mutation in the gene called LMNA**, which produces the Lamin A protein, which is the structural scaffolding that holds the nucleus. - **Although they are born looking healthy**, children with Progeria begin to display many characteristics of accelerated aging within the first two years of life. - **Children with Progeria** die of atherosclerosis (heart disease) at an average age of fourteen years. - **Progeroid syndromes** include Werner's syndrome, also known as "adult progeria," which does not have an onset until the late teen years, with a life span into the 40's and 50's. ## HGPS Patient Features **Alopecia:** Absence of eyebrows & eyelashes, beak-shaped nose, shrunken chin, premature cardiac disease, narrow chest, swollen and stiff joints, age spots, dry, scaly & thin skin. **Macrocephaly:** Swollen veins **Micrognathia (small jaw):** Growth Retardation **Shared phenotypes with normal aging:** Abnormal gait, altered hearing, atherosclerosis, CVD and stroke, hypertension, limited range of motion, low bone mineral density, loss of subcutaneous fat, narrowing of coronary arteries, osteolysis, skin changes, vascular calcification. **Aging phenotypes absent in HGPS:** Cancer, cataract, increased abdominal fat, neurodegeneration.