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What is the main source of ROS in the cell?
ROS can directly react with a wide range of biologic molecules.
True
What process may lead to the formation of adducts that compromise membrane fluidity and integrity in mitochondria?
Peroxidation of lipids
The chain reactions involving ROS will continue until the free radical intermediate pairs with its radical ______________.
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Match the following free radicals with their reactivity, from most reactive to least:
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What are the most physiologically important differences between mitochondrial and nuclear genomes?
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Which bonds are susceptible to hydrolysis in biological molecules?
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Water is a weak nucleophile that can react with susceptible targets inside cells.
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Aggressive physiochemical agents such as water, oxygen, and sunlight contribute to the _______________ of organic biomolecules over time.
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What are some agents that can contribute to the accumulation of damage in cells over time?
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What is the name of the first aging gene discovered in Caenorhabditis elegans?
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What is the impact of the mutation of the daf-2 gene in C. elegans?
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Why are telomeres hypothesized to serve as a molecular countdown clock?
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What is the Ku system responsible for repairing?
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Which theory suggests that aging is a preprogrammed process?
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The Telomerase enzyme is expressed in somatic cells.
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How many cell divisions can happen after the supply of telomere DNA is exhausted? __ cell divisions for humans.
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Match the theory of aging with its description:
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Study Notes
The Biochemistry of Aging
Stages of Human Life
- Infancy and childhood: continual growth, development of basic motor and intellect skills, period of vulnerability and dependency on adults
- Adolescence: final burst of growth, developmental changes transforming child into an independent and reproductively capable adult
- Adulthood: longest stage, period devoid of dramatic physical growth and development
- Old age: signaled by resurgence of physical and physiologic change, decline of essential bodily functions, and death
Wear and Tear Theories of Aging
- Human body succumbs to accumulation of damage over time resulting from injury and long-term exposure to environmental factors
- Damage inevitably leaks through and accumulates, particularly among cell populations that undergo turnover
- Agents that contribute to wear and tear include water, oxygen, and sunlight
Genetic Diseases and Aging
- Genetic diseases like Hutchinson-Gilford, Werner, and Down syndrome accelerate physiologic events associated with aging
- Slowing or preventing some degenerative processes accompanying aging can render later stages of life more vital, productive, and fulfilling
Lifespan vs. Longevity
- Life expectancy averages over all births and is influenced by infant mortality rates
- Longevity calculates expected lifespan only for those who survived infancy
Hydrolytic Reactions and Damage
- Hydrolytic reactions can damage proteins and nucleotides
- Water is a weak nucleophile that can react with susceptible targets inside cells
- Amino groups from heterocyclic aromatic rings of nucleotide bases are susceptible to hydrolytic attacks
Respiration and Reactive Oxygen Species (ROS)
- Biologic processes require enzyme-catalyzed oxidation of organic molecules by molecular oxygen
- ROS are generated during respiration and can react with and chemically alter virtually any organic compound
- ROS can form adducts with biologic compounds that contain multiple double bonds
- ROS react directly and indirectly with a wide range of biologic molecules
Mitochondrial Theory of Aging
- Mitochondria harbor the dominant source of ROS in the cell
- Oxidative damage to the electron transport chain (ETC) can lead to increased ROS yields
- Damage to mitochondria may also affect the rate of efficiency in generating ATP, leading to increased ROS production
Mitochondrial Genome
- The mitochondrial genome is a reduced, vestigial remnant of the genome of the ancient bacterium that gave rise to the mitochondria
- It encodes 2 rRNA, 22 tRNA, and polypeptide components of complexes I, III, IV of the ETC, and parts of F1, F0 ATPase
Chain Reactions and Destructiveness of ROS
- The destructiveness of ROS is exacerbated by their capacity to participate in chain reactions
- The chain of reaction will continue until the free radical intermediate pairs with its radical electron
Mitochondrial Theory and Free Radicals
- Denham Harmon (1956) observed that life span was inversely related to metabolic rate and postulated that free radicals played a role in aging
- Mitochondria are key participants in apoptosis, which is triggered by ROS, viral dsDNA, DNA damage, or heat shock
Advanced Glycation End Products (AGEs)
- AGEs are cross-linked aggregate products of glycation
- Impact of protein glycation is pronounced in long-lived proteins like collagen and beta-crystalline
- In vascular endothelial cells, cross-links can lead to progressive loss of elasticity and thickening of the basement membrane in blood vessels, potentiating plaque formation and increasing workload for the heart.### Apoptosome Assembly and Diabetic Susceptibility
- Apoptosome assembly initiates proteolytic activation events, and diabetics are particularly susceptible to the formation of AGEs (Advanced Glycation End-products).
Ultraviolet Radiation
- UV radiation has a wavelength below the blue end of the visible spectrum and is strongly absorbed by organic compounds possessing aromatic rings or multiple conjugated double bonds.
- UV radiation is highly mutagenic and can lead to the development of myelomas.
- UV radiation can cause:
- Rupture of covalent bonds in proteins, DNA, and RNA.
- Formation of thymine dimers in DNA.
- Cross-linking of proteins.
- Generation of free radicals.
Molecular Repair Mechanisms
- High efficiency of UV absorption leads to rapid accumulation of damage in the skin.
- Enzymatic and chemical mechanisms intercept damaging ROS (Reactive Oxygen Species).
- Glutathione plays a key role in combating ROS and aging:
- Reacts directly with ROS.
- Reacts directly with cysteine sulfenic acids and disulfides on proteins.
- Forms adducts with toxic xenobiotics.
Protein Glycation and Aging
- Glycation leads to the formation of AGEs, which can accumulate over time and contribute to aging.
- AGEs can cross-link with other proteins, leading to the formation of toxic aggregates.
DNA Integrity and Repair
- DNA integrity is maintained by proofreading and repair mechanisms, including:
- Mismatch repair enzymes.
- Nucleotide excision repair enzymes.
- Base excision repair enzymes.
- Ku system for repairing double-strand breaks.
- The last resort to repair is by apoptosis.
Aging Theories
- Somatic mutation theory of aging: mutations accumulated over time lead to compromised biological function.
- Metabolic theories of aging:
- "The brighter the candle, the quicker it burns": a higher metabolic rate leads to a shorter lifespan.
- Mitochondrial theory of aging: ROS accumulation leads to cellular damage and aging.
Protein Damage and Repair
- Some types of protein damage can be repaired through enzymatic mechanisms.
- Fibrous proteins in tendons, ligaments, bones, and matrix undergo little turnover, leading to accumulation of damage over time.
Telomeres and Aging
- Telomeres are repetitive DNA sequences (GT-rich hexanucleotide repeats) that cap the ends of eukaryotic chromosomes.
- Telomeres shorten with each cell division, leading to replicative senescence.
- Telomerase, a ribonucleoprotein enzyme, restores telomere caps to full length, enabling stem cells and some cancer cells to continue dividing.
Evolutionary Perspective on Aging
- Limited lifespans may be beneficial to the species as a whole, as they eliminate the drain on resources imposed by older, non-reproductive individuals.
- A genetically programmed limit on lifespan could provide time for newborns to develop, young adults to reproduce, and older adults to serve as a source of guidance.
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Description
This quiz covers the biochemistry of aging, including nonspecific and programmed processes, and determining whether aging and mortality are randomly determined.
