Ex2 L9 - Nutrient Sensing Flashcards
What are the cellular macronutrients?
carbohydrates, lipids, and proteins
Cells sense the —— and respond to —— by ——-
sense the abundance of macronutrients and respond to scarcity by mobilizing nutrient stores
What are the four key pathways/groups of the nutrient sensing network?
IGF-1
mTOR
AMPK
Sirtuins
Why are the signals and regulation of metabolic pathways so important?
- byproducts cause damage over time (oxidative stress, ER stress, mitochondrial dysfunction, all lead to aging)
- careful nutrient sensing prevents overutilization of nutrients (not too much or too little)
- nutrient-sensing becomes dysregulated in aging and disease
What is mTOR?
mammalian target of rapamycin
- nutrient sensor that also responds to cellular stress
- regulates (increases) cell growth, proliferation, and survival
How is mTOR activated and inhibited?
- activated by nutrient abundance
- inhibited by nutrient depletion, exercise, and DNA damage/cellular stress
What happens to mTOR with age? What have studies shown?
- hypothalamic mTOR activity increases with age (associated with late-life obesity)
- lower mTOR activity correlates with longer lifespan in animal models, but acute inhibition also impairs healing and causes insulin resistance
What is Rapamycin?
- FDA approved mTOR inhibitor called Sirolimus
- derived from fermented soil
- immunosuppressive and anti-proliferative effects
- inhibiting mTOR mimics exercise
How does Rapamycin effect aging/what have the studies shown?
in mice:
- reduces age related disease and extends lifespan
- intermittent administration extends lifespan
What are the risks of long term use of Rapamycin?
- infection due to immunosuppression
- metabolic impairment (insulin secretion/sensitivity)
- low dose studies show limited side effects
What is AMPK?
AMP-Activated Protein Kinase
- energy sensor (measure of energy depletion) that regulates many cellular metabolic processes
How is AMPK activated?
- activated by increased AMP: ATP ratio (energy depletion) or exercise
What are the actions of AMPK?
stimulates:
catabolic pathways like…
- fatty acid oxidation
- glucose uptake via GLUT4 (insulin not required)
- autophagy (recycling things for resources)
inhibits:
anabolic pathways like…
- protein synthesis via inhibition of mTOR
- glycogen, cholesterol, and fatty acid synthesis
What happens to AMPK with age?
activity decreases with age
What is Metformin?
- antidiabetic drug that lowers blood glucose in part by activating AMPK
- mimics exercise (which also activates AMPK)
What did studies show about the effects of metformin?
- increase lifespan in rodents
- more studies underway
What are the risks of Metformin?
- risk for lactic acidosis (due to overproduction or underuse of lactic acid)
- overactivation of AMPK is linked to cardiac hypertrophy
What is the definition of caloric restriction?
10-40% reduction in calories without malnutrition or deprivation of essential nutrients
What is the effect of caloric restriction on aging? Why does it occur?
- shows delayed onset of age-related disease (especially cancer) and extended lifespan in some animal model, but not seen directly in humans
- results from increasing AMPK and decreasing mTOR (both of which mimic exercise) via nutrient depletion
Describe the monkey experiment that demonstrated caloric restriction?
monkeys were fed a 30% calorie restructed diet for 20 years
- reduced age-related disease like cancer, diabetes, heart disease
- one of two studies reported increased lifespan
- Canto and Owen were two of the famous monkey brothers on different diets
What was the CALERIE study?
- Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)
- 218 normal/moderately overweight adults
- goal was to follow a diet with 25% restriction for 2 years (low compliance)
- average 10% weight loss that was sustained for 2 years after
- reduced risk factors for age related disease (lower BP and cholesterol)
- improved sleep, mood, sexual function, life quality
- but also saw slight reduction in bone mass, brief anemic episodes
What is intermittent fasting and what are the important factors in performing it?
- pattern of eating involving restricted meal schedules
- the timing of the fast is important: meals are restricted to an 8-10 hour window related to circadian rhythms
What does fasting do to metabolism?
promotes lipolysis, which produces ketones
What are ketones helpful for?
- more efficient energy source than glucose
- may protect against age-related metabolic damage in the CNS
