Lecture 19. Ageing 4. The Hallmarks of Ageing and Dietary Intervention Flashcards
What are the primary hallmarks of ageing?
The causes of cellular damage associated with ageing: specific alterations to DNA and proteins in the cell
What are examples of the primary hallmarks of ageing?
Genomic instability
Loss of telomeres
Epigenetic alterations
Loss of proteostasis
What causes DNA damage?
Exogenous threats (chemical and biological agents), and by endogenous threats (DNA replication errors, spontaneous hydrolytic reactions, and reactive oxygen species (ROS)
What are examples of DNA repair mechanisms?
Those that repair damages inflicted to nuclear DNA
Mechanisms for maintaining the appropriate length and functionality of telomeres. Defects in the nuclear architecture, known as laminopathies, link these: they can cause genome instability and result in premature ageing syndromes
The integrity of mitochondrial DNA (mtDNA)
What is telomere attrition?
Accompanied with normal ageing
Pathological telomere dysfunction accelerates ageing in mice and humans, whereas experimental stimulation of telomerase can delay ageing in mice
What are telomeres?
Repetitive DNA sequences at the ends of metazoan chromosomes
What are epigenetic changes?
Heritable changes in gene expression that are not caused by changes in DNA sequence
What are examples of heritable changes?
DNA and histone methylation patterns
Acetylation of histones
Chromatin remodelling
What does methylation of DNA and histones do?
Causes nucleosomes to pack together, hindering access of transcription factors: the genes are not expressed
What does acetylation of histones lead to?
Loose packing of nucleosomes
Transcription factors have easy access, and the genes are expressed
How are the epigenetic marks of the female passes?
To the ova
What replaces the protamines associated with the sperm DNA?
Acetylated histones from the ovum’s cytoplasm and male DNA is then systematically demethylated
But some male epigenetic marks remain
What are the antagonistic hallmarks of ageing?
Deregulated nutrient sensing
Mitochondrial dysfunction
What is the somatotrophic axis in mammals comprised of?
Growth hormone (GH), which is produced by the anterior pituitary
And insulin-like growth factor 1 (IGF-1), produced in response to GH by many cell types, most notably hepatocytes.
What signalling pathway does IGF-1 share?
The signalling pathway of IGF-1 is the same as that of insulin, which informs cells of the presence of glucose Nutrient sensing
What is the name of the highly conserved ageing-controlled pathway in evolution?
The “insulin and IGF-1 signalling” (IIS) pathway
What is the proposed model to explain the deregulation of the IIS pathway with age?
It is a defensive response to ageing, and not a cause of ageing
It minimises cell growth and metabolism and thus limits damage
An advantage to ageing organisms
An advantage when nutrient availability is low
What are the integrative hallmarks of ageing?
The end result of the primary and antagonistic hallmarks and are ultimately responsible for the functional decline associated with ageing
What are examples of the integrative hallmarks of ageing?
Cellular senescence
Stem cell exhaustion
Altered intracellular communication
What is cellular senescence?
The processes by which the capacity for cell division, growth, and function is lost over time
What does stem cell exhaustion cause?
HSCs (haematopoietic stem cells) which cause anaemia myelodysplasia
MSCs (mesenchymal stem cells) which cause osteoporosis and poor fracture repair
IESCs (intestinal epithelial stem cells) which cause reduced intestinal function
Satellite cells which cause poor muscle fibre repair
What does altered intracellular communication cause?
Neuroendocrine dysfunction
Inflammation
Immunosenescence
Bystander effects
What is the ‘Westernised’ lifestyle?
Low physical activity
High calorific activity
Low fruit, fibre and vegetable intake
What are the pros of white adipose tissue (WAT)?
WAT stores energy
People with greater WAT mass have increased chances of survival in famine conditions
WAT regulates immune responses, gives mechanical protection, has endocrine functions, and regulates thermoregulation
What are the cons of white adipose tissue?
A high-fat diet (HFD) induces obesity
What is the effect of reducing the size of the stomach on relative telomere length?
~2% increase in the lengths of the leucocyte telomeres
What is the Mediterranean diet?
A high intake of olive oil, fresh fruits, legumes and vegetables
A low intake of animal fat, meat, processed meat products and salty foods
What does olive oil contain?
High levels of phenolic compounds, which possess strong antioxidant, and anti-inflammatory activities
What does broccoli contain?
Glucosinolates and their degradation products which have health promoting benefits
What is the mode of action of Nrf2?
Nrf2 is normally held inactive by Keap1, ubiquitylated and destroyed, keeping its concentration low. Under oxidative stress, Keap1 releases Nrf2, which then enters the nucleus and stimulates expression of catalase and superoxide dismutase
What is the mode of action of sulforaphane?
Sulforaphane binds Keap1 and inhibits proteasome targeting. Result, increased anti-oxidant activity
What is curcumin?
A polyphenolic bioactive compound from Curcuma longa, usually in the form of turmeric. Anti-ageing in most model organisms tested. It upregulates NRF2, so suppresses oxidative stress
What is spermidine?
A polyamine that induces autophagy both in cultured cells and in vivo and has exceptional anti-ageing activity
It increases lifespan in both C. elegans and Drosophila, and reduces oxidative damage in mice
It may be a universal anti-ageing compound
What are key sources of spermidine?
Vegetables (dried soybeans) and cheese (mature cheddar)
