Ageing Flashcards
Outline ageing - what does it affect?
Gradual decline in normal physiological functions in a time-dependent manner, affecting all biological systems: molecular interactions, cellular function, tissue structure, systemic physiology
What does ageing lead to?
Impaired function
Decreased ability to cope with environmental stressors
Increased incidence of age-related diseases
Increased vulnerability to death
How do you define a hallmark of ageing?
It should manifest during normal ageing
It’s experimental aggravation should accelerate ageing
It’s experimental improvement should slow down ageing and increase rate of healthy ageing
What are the 3 hallmarks (groups) of ageing?
Primary hallmarks - causes of damage
Antagonistic hallmarks - response to damage
Integrative hallmarks - linked to phenotype of ageing
What are the 4 primary hallmarks of ageing?
Genomic instability (increased damage/no repair) Telomere attrition (no replication) Epigenetic alteration (loss of translation/transcription) Loss of proteostasis (misfolding/structural changes)
What are the 3 antagonistic hallmarks of ageing?
Mitochondrial dysfunction Cellular senescence (frozen in time) Deregulated nutrient sensing
What are the 2 integrative hallmarks of ageing?
Stem cell exhaustion (no new cells)
Altered communication
How can healthy ageing be promoted?
Stem cell based therapies Anti-inflammatory drugs Elimination of damaged cells Telomerase reactivation Epigenetic drugs Clearance of senescent cells Activation of chaperones and proteolytic systems
What are some broad functional physiological changes with age?
CNS and PNS: slowed central processing/speech/cognition and reduced nerve conduction
GI: impaired drug metabolism, insulin secretion, Ca2+ Vit D absorption
Cardio: L ventricular hypertrophy, AF, chronic heart failure, raised systolic bp
Renal: increased excretion of proteins and reduced creatinine clearance
Bones/Joints: osteoporosis, reduced bone density, thickened cartilage, stiffness of cartilage matrix
Muscles: sarcopenia, increased type 1 % muscle fibres
What’s the terminology of ageing - the 3 categories of age
Young old: 60s and early 70s who are active and healthy
Old: 70s and 80s with chronic illnesses who are slowing down due to symptoms
Old-old: those who are often sick or disabled or perhaps nearing death
What’s the difference between lifespan and healthspan?
Lifespan = maximum length of time an organism is expected, or known to survive
Healthspan = the % of individuals life during which they are generally in good health
Life expectancy = average length of time an organism is expected to survive
Define health
State of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity (WHO)
What are some processes of ageing
Inflammation Oxidative stress Mitochondrial dysfunction Cellular senescence Stem cell exhaustion Epigenetic alterations Genomic instability
Outline genomic instability
Changes in the genetic code due to exogenous damage (UV/chemicals) or endogenous damage (ROS/replication errors)
Genome becomes unstable by structural changes (in lamins - proteins that provide structural function and transcriptional regulation in the cell nucleus)
What are telomeres? Outline telomere wearing?
Telomeres = repetitive nucleotide sequences at the end of chromosomes - protect end of chromosome from decay and fusion with other chromosomes
Telomere wearing obviously removes this protective effect leading to a theory of ageing
Outline epigenetic alterations in ageing
Epigenetic factors are those causing a heritable change in gene expression in the absence of change in DNA
DNA methylation at CpG dinucleotides
Histone modifications (acetylation)
Non coding RNAs (ncRNA)
What’s the Hovarth clock of ageing?
Biochemical test based on DNA methylation at CPG dinucleotides to measure biological (vs chronological) age
It’s the only available method that measures biological age in different tissues
What is proteostasis? Outline how a loss of it leads to ageing
Process by which cells control the abundance and folding of the proteome
In young/healthy tissues misfolded protein is disposed of by protein quality control systems
In ageing cells the protein quality control systems are overloaded = accumulation of misfolded proteins and loss of proteostasis
Which diseases show loss of proteostasis?
Alzheimer’s and Parkinson’s
Appearance of non-native protein aggregates is a common feature of degenerative diseases
What’s cellular senescence? What’s its primary purpose in healthy tissues?
A process that imposes permanent proliferative arrest on cells in response to various stressors, leading to formation of senescent cells with specific phenotypic characteristics
Purpose to prevent progress of damaged cells and trigger their removal
How does cellular senescence link to other hallmarks of ageing and cancer?
Senescent cell accumulation = ageing
Cellular connection, progenitor exhaustion, intercellular communication, immune system
Outline the stem cell theory of ageing
Stem cell exhaustion = inability of stem cells (or progenitor cells) to replenish the tissue of an organism
Exhaustion can be caused by decline in ability of stem cells to proliferate (senescence) or due to excessive proliferation leading to stem cell exhaustion and premature ageing
Why does systolic blood pressure increase with age?
Collagen and calcium deposition and loss of elastic fibres in the medial layer of larger arteries = vessel diameter narrows and loss of stretchability means resistance increases
Why can ageing increase the risk of left ventricular hypertrophy, chronic heart failure and atrial fibrillation?
VO2max declines with age - reduction in peak heart rate and pulmonary function
Cardiovascular performance during exercise is reduced - reduced cardiac B-adrenergic density and efficiency of B-adrenergic signalling
= reduction in physiological functional capacity
What are some changes in GI structure with ageing?
Reduced liver size and blood flow
Reduced saliva production and impaired response to gastric mucosal injury
Reduced pancreatic mass and enzyme reserve
Decrease in effective colonic contractions
Decrease in gut associated lymphoid tissue
What are some changes in GI function with ageing?
Reduced stomach acid production Impaired acid clearance Slowing of gastric emptying Reduced absorption of vitamin D/Ca2+ Delay in colonic transit Reduced insulin secretion Reduced tensile strength of rectal and colonic walls
What are some renal structural and functional changes with ageing?
Kidney size decreases, nephrons decrease
Glomerular basement membrane thickens
Increase in glomerular basement membrane permeability
Increase in glomerular basement membrane permeability = increased excretion of proteins (albumin)
GFR declines after 4th decade
Reduced kidney mass = reduced creatinine clearance
Outline changes to bones with ageing
Reduced bone density -> osteoporosis
Reduced osteoclast formation -> reduced bone remodelling
Increased adipocyte formation in bone marrow
Slower healing of fractures
Decreased vitamin D absorption
How do muscles change with age?
Muscle mass and strength declines with age
Distribution of muscle fibre type changes with age
Increased % of type I fibres in aged
Type I fibres = small, slow contracting, low tension output fibres
Sarcopenia = degenerative loss of skeletal muscle mass, quality and strength associated with age
