15/5 Lecture Notes on Aging, Oxidative Stress, and Metabolic Regulation

Oxygen Radicals and Aging

  • Initial theory: aging is a balance between oxygen radical onslaught and defense.

  • Experimental evidence: overexpression of antioxidant enzymes in mice did not extend lifespan, challenging oxygen radicals as the sole aging mechanism.

Mitochondrial Theory of Aging

  • Related to oxygen radical theory but focuses on mitochondria.

  • Mutated proteins and oxygen radicals within mitochondria are key factors.

  • Mitochondrial DNA (mtDNA):

    • Small DNA piece coding for respiratory chain components.

    • Most mitochondrial genes are in the nucleus, proteins imported into mitochondria.

    • Mutations in mtDNA can disrupt the assembly of the respiratory chain.

  • Impact of disrupted electron transport chain:

    • Reduced ATP production, contributing to aging.

Experiment: Mouse with Defective Mitochondrial DNA Polymerase

  • Single mutation in mtDNA polymerase $\rightarrow$ higher error rate during replication.

  • Phenotype of mutated mice:

    • Hunchback posture.

    • Grey fur.

    • Reduced fat layer under the skin.

  • Lifespan reduction:

    • Normal mice: up to 60 weeks.

    • Mutated mice: died from 35 weeks onwards.

  • Other signs of deterioration:

    • Body weight initially increased, then decreased.

  • Mitochondria as a clock: introducing mutations which leads to mitochondrial deterioration causing organ failure.

Hallmarks of Aging

  • Multiple processes contributing to aging.

  • Criteria:

    • Increase with age.

    • Accelerating hallmark $\rightarrow$ accelerates aging.

    • Reducing hallmark $\rightarrow$ slows aging.

  • Key Hallmarks:

    • DNA damage and mutations.

    • Telomere shortening: caps on chromosomes shorten over lifetime, increasing vulnerability to mutations.

    • Accumulation of misfolded proteins: e.g., amyloids in Alzheimer's disease, AGEs (advanced glycation end products).

    • Epigenetic alterations: DNA methylation increases with age.

    • Accumulation of senescent cells: less functional cells accumulate, deteriorating tissue function.

    • Mitochondrial decline.

    • Resistance to signaling: e.g., inflammation, diabetes.

    • Changes to the microbiome.

Epigenetic Modifications and Biological Age

  • DNA methylation: Striking increase with age.

  • DNA methylation is measurable and can be used to estimate biological age.

Antioxidants and Nutrition

  • Can preventing oxidative stress reduce aging?

  • Vitamins:

    • Vitamin E (alpha-tocopherol): lipophilic, protects membranes against oxidative stress.

    • Vitamin C (ascorbate): water-soluble, protects DNA and proteins in the cytosol.

  • Mechanism:

    • Capture free radicals.

    • Ascorbate: captures one electron, generates intermediate, captures another electron $\rightarrow$ dehydroascorbate.

    • Vitamin E: ring system removes radical electron from oxidized lipids.

  • Vitamin E in blood plasma is inversely correlated with mortality from coronary heart disease.

  • You shouldn't be overdoing it.

French Paradox

  • Incidence of coronary heart disease compared to cholesterol intake in different countries.

  • France: high cholesterol intake, low incidence of coronary heart disease.

  • Finland: high cholesterol intake, high incidence of coronary heart disease.

  • Possible Explanations:

    • Antioxidants in meals, particularly red wine (resveratrol).

    • Mediterranean diet.

  • Resveratrol

    • Plant antioxidant in dark chocolate, red wine.

  • Studies:

    • Mice on high-calorie diet supplemented with resveratrol showed similar weight gain but lower mortality compared to those without resveratrol.

    • Doses are significantly higher than from occasional red wine and absorption is limited.

    • In Chianti study, total urinary resveratrol metabolite concentrations were measured and the proportion of participants who died from all causes was approximately the same across all quartiles of baseline total urinary respiratory metabolites.

Blood Glucose Regulation

  • Body tightly regulates blood glucose levels around 5 mM.

  • Above 8 mM: reabsorption in the kidney is overwhelmed, glucose appears in urine (diabetes).

  • 5.5 mM: insulin secretion increases.

  • 4.6 mM: insulin secretion decreases, glucagon increases, adrenaline and growth hormone increase blood glucose.

  • 3.2 millimolar: cortisol secretion kicks in as an emergency response.
    *

  • After a meal:

    • Plasma glucose increases, peaks, and then decreases.

    • Insulin increases rapidly.

    • Glucagon decreases.

Metabolism After a meal

*Getting glucose,amino acids,and fat.

  • Amino acids and fat poke insulin secretion from the pancreas.

  • Insulin promotes:

    • Glycogen production (liver, muscle).

    • Fat production (liver $\rightarrow$ adipose tissue, muscle).

    • Protein production (muscle, liver).

  • Glucose is converted to glycogen

  • Amino acids stimulates protein production.

  • Brain uses glucose.

  • Blood cells produce lactate, which is converted back to glucose in the liver.
    *The conversion is easy to remember because Insulin polymers are being put into a multimer for stroage.

Translocation of Glucose Transporters

*Translocation of glucose transporters into the plasma membrane.

  • Muscle cells in fasting state have few glucose transporters in their membrane.

  • Insulin:

    • Binds to insulin receptor.

    • Triggers signaling cascade through PI3 kinase.

    • Results in rearrangement of trafficking machinery.

    • Vesicles with glucose transporters are brought to membrane in muscle and adipose tissue.
      It stores the glucose as glycogen.

Metabolism Between Meals (Fasting State)

  • Glucagon is released.

  • No nutrients are coming from the gut.

  • Key Processes:

    • Glucose goes to the brain, remains constant.

    • Heart continues to use glucose.

    • Glucagon acts on the liver to convert glycogen back to glucose.

    • Fatty acids are mobilized from adipose tissue $\rightarrow$ muscle cells.

    • Glycerol goes back to the liver and is used for gluconeogenesis.

  • Glycogen stores last for a couple of hours

  • Muscle releases alanine for gluconeogenesis.

    • The glucose alanine cycle.

Metabolism During Exercise

  • Exercise acts more like a Fasting state.

  • Related to fasting state.

  • Adrenaline is released from adrenal glands.

  • Actions:

    • Increases fatty acid oxidation by muscle.

    • Breaks down glycogen (less in liver, more in muscle).

    • Lactate is released.

    • Lactate is reformed into glucose.
      Your metabolism can easily double or triple compared to resting state.

  • Releases fatty acids and glycerol from adipose tissue $\rightarrow$ the fatty acids go to muscle and heart because they are a very good fuel.

Preventing Energy Shortage During Exercise

  • ATP in muscle lasts only two seconds.

  • Creatine phosphate lasts about ten seconds.

  • Creatine

    • ATP storage device.

    • Creatine phosphate has similar energy content to ATP.

    • Reversible Reaction: ADP + Creatine-Phosphate <-> ATP + Creatine + En.

  • Creatine can diffuse quickly through muscles.

  • Aerobic glycolysis increases.

  • Anaerobic Glycolysis occurs from 10 seconds to 90 seconds (from Lactate).

  • 400-meter onwards Steady oxygen supply is needed.

Based on the note, here are some key takeaways for studying:

  1. Oxygen Radicals and Aging: Understand the initial theory and the experimental evidence that challenges it.

  2. Mitochondrial Theory of Aging: Focus on the role of mutated proteins, oxygen radicals within mitochondria, and the impact of mtDNA mutations on the electron transport chain. Understand the mouse experiment with defective mitochondrial DNA polymerase.

  3. Hallmarks of Aging: Know the criteria for hallmarks (increase with age, accelerating/reducing effects) and the key hallmarks listed (DNA damage, telomere shortening, etc.).

  4. Epigenetic Modifications: Understand how DNA methylation increases with age and can estimate biological age.

  5. Antioxidants and Nutrition: Understand the role of vitamins E and C, their mechanisms, and the importance of not overdoing it.

  6. French Paradox: Understand the possible explanations like antioxidants (resveratrol) and the Mediterranean diet. Note the conflicting study results regarding resveratrol.

  7. Blood Glucose Regulation: Know the normal blood glucose levels, the hormones involved (insulin, glucagon, adrenaline, growth hormone, cortisol), and their roles.

  8. Metabolism After a Meal: Understand the roles of insulin, glycogen production, fat production, and protein production.

  9. Translocation of Glucose Transporters: Understand how insulin causes glucose transporters to move to the cell membrane.

  10. Metabolism Between Meals (Fasting State): Understand the role of glucagon, and the processes that occur when no nutrients are coming from the gut, including glucose usage, fatty acid mobilization, and gluconeogenesis.

  11. Metabolism During Exercise: Understand how exercise is similar to a fasting state, the role of adrenaline, and the breakdown/reformation of glucose and fatty acids.

  12. Preventing Energy Shortage During Exercise: Understand the roles of ATP, creatine phosphate, aerobic glycolysis, and anaerobic glycolysis.