Exercise, aging and disease Flashcards
What can obesity lead to?
Chronic diseases
- Diabetes type II
- CVD
- Cancer
Obesity is increasing in the last 40 years
Can also induce Osteoarthritis and Osteoporosis
What year will British people be the fattest in Europe?
2025
What number is physical inactivity to death worldwide?
Physical inactivity is the 4th major contributor to death worldwide
What are the figures for deaths from non-communicable diseases attributed to physical inactivity?
- 6-10% for all causes
- 30% for ischaemic heart disease (coronary artery atherosclerosis)
What is SeDS?
Sedentary death syndrome
Death due to lack of regular physical activity
How does the body maintain constant weight?
The body has an homoeostatic mechanism
An increase of food intake = increase of energy expenditure
What is adaptive thermogenesis?
Signals from blood nutrients and leptin from adipocytes controlled by hypothalamus
Activates the sympathetic NS and Brown adipose tissue (rodents/infants)
What is leptin?
Leptinis one of the hormones directly connected to body fat and obesity.
Leptin, a hormone released from the fat cells located in adipose tissues, sends signals to the hypothalamus in the brain
Produced by white adipose tissue
Activates the sympathetic nervous system
How is energy utilised in the body?
Obligatory energy expenditure (required for cellular and organ function) - 50%
Physical activity (variable) - 30%
Adaptive thermogenesis (variable, regulated by hypothalamus and responds to diet and temperature) - 20%
Where does leptin act upon in the hypothalamus?
Acts on Ob-Rb receptors
Hypothalamus will encourage the endocrine system
What occurs if there is a mutation in the gene encoding leptin (ob/ob mouse)?
Type 2 diabetes develops
Extremely obese (results in overeating) hyperphagia + decrease in energy expenditure
What is leptin resistance in obesity?
As people gain weight, they develop leptin resistance
How are carbohydrates, lipids and protein ABSORBED as?
Carbohydrate - Mainly glucose
Lipids - Mainly fatty acids + Cholesterol + Phospholipids
Protein - Amino acids
How are carbohydrates, lipids and protein STORED as?
Carbohydrates - Glycogen
Lipids - Mainly triglyercides
Protein - Protein
What are carbohydrates, lipids and protein STORAGE SITES?
Carbohydrates - Liver (100g), Muscle (400g)
Lipids - Liver (limited), Adipose tissue (large quantities), Other cells (limited)
Protein - Very limited in all cells
What is the FATE OF EXCESS of carbohydrates, lipids and protein?
Carbohydrates - Converted to lipid
Lipids - Stored in unlimited quantities as triglyceride
Proteins - Deaminated then converted to CHO (& fat)
What is the normal blood glucose before a meal?
4.0 - 5.9 mM
What is the blood glucose after a meal?
7.8 mM 90+ after a meal
What happens to the brain if glucose levels dip below normal levels?
It leads to a hypoglycemic condition and coma
Type 1 diabetics are at risk of this due to loss of main hormone that controls regulation of diabetes
Where does the body detect glucose?
In the pancreas
B-cells of islets of Langerhans
Glucose is taken up through these cells and promotes the generation of ATP
More glucose = More ATP, inhibits the potassium channel, depolarises the cell and depolaristion of the cell activates the voltage dependent calcium channel resulting in calcium influx and release of insulin
What is insulin?
It promotes glucose uptake
It does this by promoting the muscle to take up glucose
What is the % of glucose load stored after a meal?
70% of glucose load is stored in muscle
What does the liver do?
It converts glucose to glycogen
Inhibits gluconeogenesis
What does adipose tissue do to insulin?
Converts to triglyceride
What does the insulin receptor do?
- Particularly abundant in muscle and adipocytes
- Low insulin: most GLUT4 in vesicles
- Insulin binding causes rapid insertion of GLUT4 into surface membrane
What pathway leads to the insertion of GLUT4 into the Glucose plasma membrane?
PI-3K signalling pathway
Happens quickly
What does the increase of triglyceride storage do in insulin receptors?
It increases the circulating fatty acids (Non-esterified-fatty acids or free-fatty acids)
Reduces insulin sensitivity
There are several proposed targets:
- Glucose transporter
- Early signalling events
- Transfer of GLUT4 transporters from vesicles into the membrane
Is insulin resistance reversible?
Yes, for patients that are becoming insulin resistant, controlling their diet and doing exercise is an important intervention that can reverse pre-diabetic situation to full diabetes
What are the reasons for variations in physical activity?
Reasons for differences in sedimentary behaviour between individuals (same sex twin studies):
- 69% due to environmental factors
- 31% have genetic basis (polygenic basis/multiple genes)
What is pre-diabetes (impaired glucose tolerance)?
Elevated blood glucose but not as high as in Type 2 diabetes (eg before a meal of 5.6 to 7.0 mmol/L)
How much 150 minutes of exercise/week lowers risk?
- Coronary heart disease = 40%
- High blood pressure = 50%
- Stroke = 27%
- Type 2 diabetes = 50%
- Colon cancer = 60%
- Breast cancer = 20% - 50%
- Alzheimer’s disease = 33%
(Daniel Lieberman 2011)
What is the outcome of the reduced level of obesity?
Reduced obesity –> Reduced NEFA –> Reduced insulin resistance –> Improved glucose control –> Reduced stress of pancreatic beta cells and less chance of progressing to insulin dependent diabetes
How much energy is in the food we eat?
53 g mars bar for 70KG person
- 40 min jogging
- 50 min leisurely cycling
- 100 min leisurely walking
- 3 hours typing
Takes a long time to burn off the calories
What is the mechanism of the ability of regular exercise to reduce chronic disease?
- Trained muscle
INCREASED muscle mass, insulin sensitivity and ability to use lipid as energy source will lead to DECREASED conversion glucose to fat, circulating fats and storage of fat. - INCREASED physical fitness and brain health can lead to resisting effects of pathogens/disease/stress
- DECREASE of inflammation (anti-inflammatory cytokines released from muscle = myokines) as many chronic diseases have an inflammatory basis
- Specific anti-disease reduction by myokines
- Acute activation of body stress responses
How does atherosclerosis develop?
- Underlying cause of the majority of CVD
- A chronic inflammatory disease of medium-large arteries
- Deposition of lipids in blood vessel wall and will result in endothelial activation. As a result immune cell (lymphocutes, monocytes, macrocytes) will be recruited underneath the endothelium. The cells will activated themselves and they will generate pro-inflammatory cytokines. Foam cells form and will acquire lipid into the cytoplasm
END PRODUCT = IT WILL RUPTURE
What is important for the progression of atherosclerosis?
The balance between pro-inflammatory and anti-inflammatory cytokines
What are 2 anti-inflammatory cytokines?
- TGF-B
- Interleukin-5,10
What are 3 proinflamminatroy cytokines?
- Tumour necrosis factor-a
- Interferon-Y
- Interleukin-9
What do muscles secrete?
Myokines that include anti-inflammatory cytokines
What is epidural anaesthesia?
Blocks the nerves going down the spine making the legs useless
What does contracting skeletal muscle do?
It will release humoral factors known as myokines and it is now known to interact with various organs
- adipose tissue
- liver
- brain
- cardiovascular system
What are myokines?
- Cytokines or other peptides released from contracting skeletal muscle
- endocrine, paracrine and autocrine functions
- Many are produced upon contraction; thus can mediate effects of physical activity
- A key interaction is by the myokines going to adipose tissue limiting and releasing adipokines
- Has a general effect of reducing diabetes type 2, atherosclerosis, cancer etc.
Name 5 myokines?
Myostatin - Regulates skeletal muscle hypertrophy
Brain-derived neutrophic factor (BDNF) - Neural growth and activity
IL-6: (100 fold in circulation) - cross-talk with adipose tissue; releases cortisol from adrenal cortex and increases sensitivity
IGF-1 and FGF-2: osteogeneisis; muscle nerve innervation remodelling
Unidentified - anti-tumour, altered pancreatic function
WHat does BDNF do?
More exercise = More BDNF released
Through higher amounts of BDNF, we get;
- Increased serotonin
- Increased dopamine
BDNF increases brain plasticity (new connections between cells in a wide array of important cortical areas of the brain)
Suggested to be better than anti-depressants for overcoming mild-moderate depression
Proven therapy for neurodegenerative diseases
How do we improve multiple cognitive tasks?
By doing submaximal aerobic exercise performed of periods around 60 mins
What are the roles of the body’s physiological stress response systems?
- Stress responses (flight or fight)
- Co-ordination of cardiovascular, muscloskeletal and nervous systems
- To be able to meet the demands and restore body homoeostatis and restore the status quo
- Chronic activation (always on) which gives dysregulation of multiple body systems, weakened stress responses and immune suppression
- Autonomic nervous system + hypothalmus:pituary:adrenal axis + immune system
What is stress reduced activation of the sympathetic nervous system?
Stress gets picked up by the amygdala influenced the hypothalamus
The hypothalmus activates the sympathetic nerve output of the nervous system
This generates sympathetic nerves that go to the organs (heart)
Nervous output is supplemented by adrenaline by adrenal medulla and adds to direct nervous output
What happens when the sympathetic nervous system releases sympathetic nerve outputs to various organs?
- Increases heart rate
- Increases mobilise energy stores
- Increases breathing rate
- Increase the amount of blood available
- Sympathetic innovation to smooth muscle to divert blood from gut to skeletal muscle to brain to be more alert in fight or flight response
What is the hypothalamic:pituitary:adrenal axis?
Longer term than the sympathetic output
Slower than sympathetic output to various organs
Hypothalamus becomes alert to stress and releases corticotrophin (CRH) via hypophyseal stalk portal blood system
Anterior releases andrenocorticotrohic hormone (ACTH) via the blood
Adrenal cortex releases cortisol
What does the adrenal cortex do?
It mobilises energy stores and immune cells to fight infection
What are the consequences of chronic activation of the physiological stress response?
Long term stress
What are the problems with long term stress?
Constant cortisol will:
- increase appetite and that will increase fat storage
- Cortisol resistance
- Weakened immune system
Repeated adrenaline surges will:
- increase blood pressure which can lead to endothelial injury which can risk of development of atherosclerosis
What does the brain release as a “pleasure reward”?
- Endocannabinoids
- Endorphins
- Dopamine (INCREASED)
- Serotonin (INCREASED)
What is responsible for a runners high?
Endorphins
They are not very permeable across the blood brain barrier
In the brain, what does BDNF cause an increase in after exercise?
- Dopamine
- Serotonin
What can inhibit long term stress?
Relaxation that comes from the 4 pleasure reward systems
- Endocannabinoids
- Endorphins
- Dopamine (INCREASED by BDNF)
- Serotonin (INCREASED by BDNF)
When does loss of functional capacity occur?
After the age of 30
Where does loss of functional capacity normally occur?
Mostly in skeletal muscle mass
What is sarcopenia?
Age-associated loss of muscle mass
What happens in sarcopenia?
- Number of muscle fibres decrease (hypoplasia)
- Decrease in the area of each muscle fibre (atrophy)
What is accompanied by sarcopenia?
- Increase of fat and connective tissue infiltrating in the muscle
- Fat deposition is called Myosteatosis
How is sarcopenia and myosteatosis accelerated?
By doing too little exercise and allowing fat to increase
What is the mechanism responsible for sarcopenia?
- Neuropathic processes
- Axonal sprouting from remaining motorneurones
- Decrease in growth factors with age
- Nutritional changes
- Increase of infiltration myosteatosis and connective tissue with age
What are neuropathic processes?
a) loss of a-motorneuones which leads to muscle denervation and loss of motor
May result inability of nerves to recover from oxidative stress
Changes in mitochondrial capacity with age
b) loss of nerve innervation leads to denervation muscle atrophy: irreversible reduction in number of muscle fibres
What is axonal sprouting from remaining motorneuones?
Reinneravtion of some denervated muscles –> giant motor units
Leads to decrease of fine control of motor unit recruitment when regulating force
What are the principles of loss of growth factors with age?
- Insulin like growth factor decreases
- Decrease in pituitary function
- Shift from lowering anabolic to increasing catabolic influence
What are the nutritional changes as a result of sarcopenia?
- Loss of apetite as food intake goes down
What happens during the infiltration of fat and connective tissue?
- Fat cells and fat droplets will enter the cytoplasm
- Myosteatosis will increase a load on specific muscle
What does the introduction of myosteasosis do on the load of the specific muscle?
It increases the insert load which increases pro-inflammatory adipokines which promotes sarcopenia
Increases inflammation which increases insulin resistance
How do we limit sarcopenia?
- Exercise is the only known treatment for sarcopenia and myosteatosis
Primary treatment is resistance training using weights or resistance bands
Fast twitch type II fibres tend to atrophy more than type I with age
What can endurance training do?
Can limit normal loss of aerobic power & VO2 max
