Biochemistry Chapter 57: The Biochemistry of Aging

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.

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