Ageing Flashcards
Define ageing
the gradual decline in the normal physiological functions and physiological integrity in a time-dependent manner, affecting all biological systems, such as molecular interactions, cellular function, tissue structure and systemic physiological homeostasis
What can ageing lead to?
impaired function, increased incidence of age-related diseases and conditions and increased vulnerability to death.
Define lifespan
the maximum length of time an organism is expected or know to survive (potential: 125 years in humans)
Define life expectancy
the average length of time an organism is expected to live (~80 years for UK)
Define healthspan
the percentage of an individuals life during which they are generally in good health
Define health
a state of complete physical, mental and social wellbeing and not merely the absence of disease or infirmity (World Health Organisation, 1948)
What are the ways to improve health span (relating to ageing)?
- Target molecular changes that occur at a cellular level with normal ageing
- Physiological changes associated with the normal ageing
What are the 9 cellular hallmarks of ageing?
Primary:
1) Genomic instability
2) Telomere attrition
3) Epigenetic alterations
4) Loss of proteostasis
Antagonistic:
5) Deregulated nutrient sensing
6) Mitochondrial dysfunction
7) Cellular senescence
Integrative:
8) Stem cell exhaustion
9) Altered intercellular communication
What are primary hallmarks?
Causes of damage (neg)
What are antagonistic hallmarks?
Response to damage (pos & neg)
What are integrative hallmarks?
Link to phenotype of ageing
What is the free radical theory?
Links to the genomic instability cellular hallmark
ageing is caused by accumulation of damage inflicted by reactive oxygen species (ROS)
Evidence against: anti-oxidants gene knockout in mice has no impact on lifespan
What is the telomere theory?
ageing is caused as a result of replication dependent shortening of telomeres that protect the ends of chromosomes. This leads to genome instability
Evidence against: neurons and lack of good correlation with age
What is cellular senescence?
a process that imposes permanent proliferative arrest (cell cycle arrest) on cells in response to various stressors, leading to formation of senescent cells with specific phenotypic characteristics.
What is the purpose of cellular senescence?
Primary purpose: prevention of progress of damaged cells and to trigger their removal (beneficial)
Age: Accumulation of senescent cells with ageing can reflect increase in rate of production to clearance (e.g. weakened immune response and reduced replacement by progenitor* cells referred to as exhausted regenerative capacity)
What is a SASP?
Senescence-associated secretory phenotype (SASP): proinflammatory cytokines and matrix metalloproteinases (MMPs**)
What is stem cell exhaustion?
Stem or progenitor cells exhaustion inability of stem cells or progenitor cells to replenish the tissue of an organisms (stem cell theory of ageing)
Stem cell exhaustion can be caused due to decline in the ability of stem cells to proliferate (e.g. due to stem cell senescence) or due to excessive proliferation, leading to stem cell exhaustion and premature ageing
How do the bones change with ageing?
Bone (trabecular and cortical bones) density, thickness and strength reduces (osteoporosis* & falls)
Reduced bone remodelling as a result of imbalanced in the activity of osteoclasts (responsible for bone resorption) and osteoblasts (responsible for bone formation) as number of osteoblasts reduces with age
Increased adipocyte formation in bone marrow
Decreased Vit absorption (Vit D is required for osteoblastic bone formation) leading to slower healing of fractions
How do the joints change with ageing?
Cartilage thickness is reduced.
Excessive collagen (most abundant matrix protein) cross-linking, leading to increased stiffness and brittleness of collagen and disordering the cartilage matrix
Impaired ability of chondrocytes to maintain the surrounding extracellular matrix
How do the muscles change with ageing?
Fat free muscle mass is reduced with age (atrophy)
Muscle strength is reduced with age (increase in falls, disabilities and immobility)
Distribution of muscle fiber type changes with age: loss of type II fibers as well as decrease in type II fiber size
Advancing age results in a redistribution of fat depots and infiltration into muscle bundles
Outcome: sarcopenia
How does the CNS change with ageing?
Decline in brain mass and weight
Fewer synaptic contacts and nerve cells
Reduce cerebral blood flow (CBF: blood supply to the brain in a given period of time)
Altered neurotransmitters (e.g. ↓: neurotransmitters dopamine, acetylcholine, serotonin; ↑ : enzyme activity choline acetyltransferase)
How does the peripheral nervous system change with ageing?
Decrease spinal motor neurons
Axon atrophy (wasting or shrinkage)
Nerve conduction slows
Reduced vibratory sensation (especially in feet due to e.g. damage to peripheral sensory nerves: large myelinated fibers)
Reduced thermal sensitivity (pain and temp: small unmyelinated fibers)
Loss of myelinated and unmyelinated nerve fibers (due to a decrease in the expression of the major myelin proteins)
How does the cardiovascular system change with ageing?
Thickening and stiffening of the large arteries (due to collagen and calcium deposition and loss of elastic fibers in the medial layer)
Consequence: Increase systolic blood pressure with age and diastolic blood pressure generally declines after the sixth decade
left ventricle undergoes a modest concentric wall thickening due to cellular hypertrophy (concentric/eccentric hypertrophic phenotype)
Reduced sensitivity to sympathetic stimuli that compromises myocardial contractility and pumping ability in older people
Maximal oxygen uptake (maximal oxygen consumption (VO2max) declines with age
Due to reductions in peak heart rate and peripheral oxygen utilisation
Cardiovascular performance during exercise in older adults is reduced
Due to deficits in both cardiac b-adrenergic receptor density and in the efficiency of postsynaptic b-adrenergic signalling
Consequence: Reduction in physiological functional capacity observed with advancing age, which eventually can result in a loss of independence in older adults
Overall: Ageing can increase the risk of left ventricular hypertrophy, chronic heart failure, and atrial fibrillation
What criteria do the hallmarks of ageing need to meet?
1) Should manifest during normal ageing
2) If agitated should accelerate ageing
3) If improved should slow down ageing rate and enhance healthy ageing
What are some changes in the GI system with ageing?
Decreased liver size and blood flow (drug metabolism)
Impaired response to gastric mucosal injury and reduced saliva production
Reduced pancreatic mass and enzyme reserve
Decrease in effective colonic contractions
Decrease in gut-associated lymphoid tissue
Reduced stomach acid production
Impaired acid clearance
Slowing of gastric emptying
Nutrition absorption decreases (Ca, vit D)
Delay in colonic transit
Reduced rectal wall sensitivity
Reduced tensile strength in muscle of colonic wall
Reduced insulin secretion
How does the renal system change with ageing?
Kidney size (weight and length) decreases
Nephron size and number decreases
Glomerular number and shape changes with age (glomerular simplification: reduced number of glomerular capillary loops)
Glomerular basement membrane thickening
Increase in glomerular basement membrane (GBM) permeability
Increase in glomerular basement membrane (GBM) leads to an increase in urinary excretion of proteins, including albumin
Glomerular filtration rate (GFR) is maintained in adults at ~140 ml/min/1.73 m2 until the fourth decade. GFR declines by about 8 ml/min/1.73 m2 per decade thereafter
Reduced kidney muscle mass results in reduction in creatinine clearance (CrCl) leading to reduction in the daily urinary creatinine excretion
Renal blood flow (RBF) is maintained at about 600 ml/min until approximately the fourth decade, and then declines by about 10 percent per decade
