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.