Ageing

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Summary

  • Introduction.
  • Ageing and disease.
  • Nine Hallmarks of Ageing.
    • Genomic Instability.
    • Telomere Attrition.
    • Epigenetic Alterations.
    • Cellular Senescence.
    • Deregulated Nutrient Sensing
    • Mitochondrial Dysfunction.
    • Stem Cell Exhaustion.
    • Loss of Proteostasis.
    • Altered Intercellular Communication.
  • Ageing and Cognitive Diseases.
  • Ageing and Dietary Restriction (DR).
  • Alternative to DR: Low Protein or Low Methionine.
  • Sources.

Introduction

  • Progressive loss of physiological integrity.
    • Leading to impaired function.
    • Increased vulnerability to death.
  • Time-dependent accumulation of cellular damage.
  • Primary risk factor for major human pathologies:
    • Cancer.
    • Diabetes.
    • Cardiovascular disorders.
    • Neurodegenerative diseases.
  • Rate of aging controlled by pathways and processes conserved in evolution:
    • Genetic pathways.
    • Biochemical processes.
  • Nine hallmarks of ageing identified.
    • Interconnected.
    • Different relative contributions to ageing.

Ageing and Disease

  • Aging and disease may seem opposite:
    • Cancer: consequence of a gain of fitness gone wild.
    • Aging: consequence of a loss of fitness.
  • Fundamentally the same underlying process:
    • The accumulation of cellular damage.
    • In certain diseases, the cell damage may have (temporary) advantages.
  • Therefore, need to understand:
    • Type of cell damage.
    • Potential compensatory response.
    • Inter-connection of various damage and response processes.
    • Ability to intervene.

Nine Hallmarks of Ageing

  • Genomic instability.
  • Telomere attrition.
  • Epigenetic alterations.
  • Cellular senescence.
  • Deregulated nutrient sensing
    • IGF-1
    • mTOR
    • Sirtuins
    • AMPK
  • Mitochondrial dysfunction.
  • Stem cell exhaustion.
  • Loss of proteostasis.
  • Altered intercellular communication.

Genomic Instability

  • DNA damage.
  • Common denominator of aging.
  • Challenge to integrity and stability of DNA by:
    • Exogenous physical, chemical, and biological agents.
    • Endogenous threats (DNA replication errors, reactive oxygen species (ROS), etc.)
  • Resulting damage highly diverse:
    • Mutations, telomere shortening, gene disruption, etc.
  • Organisms have evolved a complex network of DNA repair mechanisms.
  • Takes place in cell nucleus, as well as mitochondria.
  • Deficiencies in DNA repair mechanisms cause accelerated aging.
    • Senescent cells, replicating mutant cells.
  • Fix: no drugs known to repair DNA.

Telomere Attrition

  • DNA damage in general is somewhat random.
  • However, one DNA section, telomeres, is particularly susceptible to age-related deterioration.
  • Telomeres:
    • The DNA sequence repeated thousands of times at the end of a chromosome.
    • Provide chromosome protection during DNA binding / copying.
    • Not completely copied during cell division.
    • Need specific protein for full replication – not many cells have it (telomerase).
  • Telomere exhaustion is one of the reasons cells stop dividing.
    • At a certain length, signals start of cell senescence or apoptosis.
  • Telomeres are bound by a protein that inhibits DNA repair.
    • Damage to telomeres is persistent.
  • Poor diet, lifestyle may increase rate of telomere loss.
  • Some evidence for delay in aging under stimulation of telomerase.
  • May make more sense to remove senescent cells than to restore telomere loss in aging cells.

Epigenetic Alterations.

  • DNA modification that changes the pattern of gene expression in a cell.
  • Alterations in:
    • DNA methylation patterns.
    • Posttranslational modification of histones.
    • Chromatin remodeling.
  • Alterations to the epigenome may compromise cell function (turning on pro-aging genes, turning off beneficial genes).
  • Inflammation, mutation, transcription errors lead to increased epigenetic alterations.
  • Caloric restriction may slow the rate of epigenetic changes.
  • Fix: reset epigenetic factors – long way to go.

Cellular senescence

  • See Cellular Senescence write-up.
  • Cells that no longer divide or support the tissues of which they are part.
  • Emit a range of potentially harmful chemical signals (pro-inflammatory).
  • Normally destroyed through apoptosis or removed by immune system.
  • Build up causes chronic inflammation and surrounding cell damage.
    • Senescence-associated secretory phenotype (SASP).
  • Senescent cells that survive express higher level of pro-survival genes (resisting apoptosis).
  • Function of senescence is to limit cell life to avoid replicating mutated cells.
  • Fix: senolytics – targets removal of death-resistant senescent cells.

Deregulated Nutrient Sensing

  • Nutrient levels influence activity.
  • Deterioration of the cell’s nutrient level response
  • Leading to impairments in energy production, cell growth, and other essential functions.
  • Four pathways / protein groups that regulate metabolism.
    • IGF-1
    • mTOR
    • Sirtuins
    • AMPK
  • IGF-1:
    • Glucose sensing.
    • Inhibits secretion of growth hormone by binding to a receptor on the cell surface.
    • Reduced expression may increase health / lifespan.
    • Increased expression may increase risk of some types of cancer (increased cell production).
    • Expression may be good in early life, not good later.
    • Importance of cycling.
    • Inhibited by fasting, exercise.
  • mTOR:
    • See mTOR write-up.
    • Amino acids sensing.
    • Key regulator of anabolic metabolism (building new proteins and tissues).
    • Function similar to IGF-1 pathway (both anabolic).
    • Inhibited by rapamycin.
    • As with IGF-1, lower expression may not always be beneficial.
  • Sirtuins:
    • See Sirtuins write-up.
    • NAD+ sensing.
    • Control gene expression by removing acetyl groups (depending on presence of NAD+).
    • NAD+ production lowers with age, obesity, inflammation.
    • Catabolic pathway.
    • Loss of the mitochondrial sirtuins can induce a senescence response.
    • Low NAD+/NADH ratios promote cellular senescence at least in part by limiting glycolysis and ATP production.
    • Activated by fasting, NAD+ precursors, resveratrol.
    • Upregulating sirtuins may increase health or lifespan (weakly).
  • AMPK:
    • AMP and ADP sensing.
    • AMP and ADP go up when ATP / nutrients are scarce.
    • Master regulator of cellular responses to energy stress.
    • Catabolic pathway to create more ATP.
    • Works by activating a compensatory series of responses:
      • Fatty acid oxidation.
      • Inhibition of fatty acid synthesis.
      • Increased mitochondrial biogenesis.
      • Stimulation of glucose uptake.
    • AMPK activation can induce cell cycle arrest and, ultimately, senescence.
    • Activated by fasting, exercise, metformin.
    • Upregulating AMPK may increase health or lifespan (weakly).

 Mitochondrial Dysfunction.

  • Energy provision to the cell.
  • DNA stored in the mitochondria may be damaged.
  • Resulting in reduced efficiency in energy (ATP) production, increase in oxidative stress, and the contamination of other mitochondria in a chain reaction.
  • Damaged mitochondria build up (as mithophagy becomes less efficient with age).
  • Oxidative stress (ROS) may have an important signaling function (see The Vital Question).
  • But ROS mostly thought to be harmful (DNA mutation, background inflammation, etc.).
  • Fix: NAD+ supplementation.

Stem Cell Exhaustion.

  • Undifferentiated cells that maintain and repair tissue.
  • Reduced stem cell activity can lead to weaker immune system and loss of tissue repair / regeneration.
  • Decreased activity due to variety of reasons including inflammaging (more senescent cells), direct damage (telomere shortening).
  • Fix: removal of inflammatory sources (senescent cells), stem cell therapy, NAD+.

Loss of Proteostasis.

  • Mechanism to maintain stable and defect-free protein production.
  • Too few, too many, mis-folded proteins.
  • Defective proteins aggregate and clump together – harmful by-products.
  • Damage due to environmental stress, DNA mutation, transcription errors.
  • Fix: DNA repair, drugs (including rapamycin)

Altered Intercellular Communication.

  • Deregulation of communication channels between cells
  • Causing chronic inflammation and tissue damage.

Ageing and Cognitive Diseases

  • Many cognitive diseases share characteristics with the mechanisms of aging:
    • Abnormal intracellular protein metabolism.
    • Leading to protein accumulation.
    • Oxidative stress.
    • Mitochondrial dysfunction.
    • Deregulated nutrient sensing.
  • Three specific  pathways affect aging and neurodegenerative processes:
    • mTOR.
    • SIRTs.
    • IGF-1.

Ageing and Dietary Restriction (DR)

  • Evolutionarily conserved strategy reported to extend lifespan in a broad range of organisms.
  • Reduced food intake / calorie restriction is the basis for the effect on lifespan.
  • Difficulties:
    • Contrasting effects in studies.
    • Difficult to implement.
    • May have undesirable side-effects.
    • Difficult to separate different effects (reduced diet toxicity, etc.).
  • Alternative regimen:
    • Decrease proteins and/or individual essential amino acids, such as methionine and tryptophan.

Alternative to DR: Low Protein or Low Methionine

  • Among the three major nutritional components (proteins, carbohydrates, lipids), proteins may be most effective in regulating lifespan and mimic the effect of DR on aging.
  • Low protein:
    • In certain studies has led to a reduction in IGF-1.
    • Associated with reduced cancer incidence and overall reduced mortality.
    • May be an effective regimen to delay aging by influencing the insulin/IGF-1 pathway.
    • Balance with carb consumption is important:
      • Increased carb consumption may dilute effect.
  • Low methionine:
    • Similarly input to mTOR signaling pathway.
    • May work as well as DR.
    • Lifespan extension has been observed similar to interventions that reduce calorie intake.
    • Further studies are required.
    • Sources of methionine: eggs, fish, meat, sesame seeds.
  • Intermittent dosing important, allowing for cycle of cell death and rebuild.

Sources:

 

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