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:

 

• The Hallmarks of Aging, Carlos López-Otín, Maria A. Blasco, Linda Partridge, Manuel Serrano, and Guido Kroemer, Cell. 2013 Jun 6; 153(6): 1194–1217.
• Wikipedia.