Biochemistry Chapter 57: The Biochemistry of Aging

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Questions and Answers

What is the main source of ROS in the cell?

Polyunsaturated fatty acids

Endoplasmic reticulum

Nucleotide bases

Mitochondria (correct)

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 ______________.

electron Signup and view all the answers

Match the following free radicals with their reactivity, from most reactive to least:

Hydroxyl radical (OH) = Most reactive Superoxide = Moderately reactive H2O2 = Least reactive Signup and view all the answers

What are the most physiologically important differences between mitochondrial and nuclear genomes?

Mitochondrial genomes are circular with their own transcription and translation systems, while nuclear genomes are linear and complex with chromosomal packing. Signup and view all the answers

Which bonds are susceptible to hydrolysis in biological molecules?

All of the above Signup and view all the answers

Water is a weak nucleophile that can react with susceptible targets inside cells.

True Signup and view all the answers

Aggressive physiochemical agents such as water, oxygen, and sunlight contribute to the _______________ of organic biomolecules over time.

degradation Signup and view all the answers

What are some agents that can contribute to the accumulation of damage in cells over time?

Water, oxygen, and sunlight Signup and view all the answers

What is the name of the first aging gene discovered in Caenorhabditis elegans?

Daf-2 Signup and view all the answers

What is the impact of the mutation of the daf-2 gene in C. elegans?

It extends the lifespan of the worms Signup and view all the answers

Why are telomeres hypothesized to serve as a molecular countdown clock?

Because they progressively shorten with each division of a somatic cell Signup and view all the answers

What is the Ku system responsible for repairing?

double strand breaks Signup and view all the answers

Which theory suggests that aging is a preprogrammed process?

Multilayered Repair System Signup and view all the answers

The Telomerase enzyme is expressed in somatic cells.

False Signup and view all the answers

How many cell divisions can happen after the supply of telomere DNA is exhausted? __ cell divisions for humans.

100 Signup and view all the answers

Match the theory of aging with its description:

Somatic Mutation Theory = Mutations serve as drivers of the aging process Metabolic Theories of Aging = Aging is related to the rate of metabolism Mitochondrial Theory of Aging = Focuses on the role of ROS in aging Signup and view all the answers

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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This quiz covers the biochemistry of aging, including nonspecific and programmed processes, and determining whether aging and mortality are randomly determined.