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
Caloric restriction and intermittent fasting both…
alter the activity of nutrient sensing networks
What is hormesis?
a process that exhibits a biphasic dose response
What is the hormetic zone? Give an example.
the zone in which there is a favorable response to a stressor or toxin
- there is an amount of ROS that is good and has benefits, but when you are below or above that amount, there are damaging effects
What are Sirtuins?
nutrient sensors that allow pathways to be mediated within the hormetic zone
- family of histone deacetylases that “pack” DNA during cell division and regulate gene expression
What activates sirtuins?
- increase NAD+ (energy depletion)
Sirtuins can contribute to…
increased lifespan in rodent models, but there is a greater impact on healthspan
The FDA does not classify —— as a ——-
does not classify aging as a disease
Byproducts of nutrient metabolism can cause ——– ——– over time via:
cellular aging
via: oxidative stress, ER stress, mitochondrial dysfunction
Nutrient sensing ——– in aging and disease
becomes dysregulated
