Exam 3 study guide- Aging Flashcards Preview

Biochem 6200 > Exam 3 study guide- Aging > Flashcards

Flashcards in Exam 3 study guide- Aging Deck (14):

hallmarks of aging

Genetic instability, Deregulated Nutrient Sensing, Loss of proteostasis, Stem cell exhaustion and altered intracellular communication- Telomere attrition-The Hayflick limit – cellular senescence


two forms of Alzheimers disease

Rare early onset familial form (fAD)
Much more common, later sporadic form (sAD) (>65 years)


Hayflick limit

cellular senescence - when you grow cells in culture, they have a limited ability to grow and will plateau off. This is due to telomere attrition.


What are the major pathways that are known and what genes/proteins are involved?

Amyloid plaques, Beta-amyloid, tau proteins.
Amyloid precursor protein (APP)
Presenilin 1 & 2 (PSEN1, 2) γ-secretase - fAD

Insulin and IGF-1 and other signalling pathways relationship to dietary restriction and aging


Alzheimers - What genes and proteins have been found, and what does that say about the mechanisms of disease?

Amyloid plaques
-Beta-amyloid peptide
Neurofibrillary tangles
-Tau protein
Brain shrinkage


• Understand what the Hayflick limit (cellular senescence) is and how it can be explained by telomere attrition. Understand what telomeres are, how they solve the end replication problem, and the mechanism of telomerase

End replication problem - no DNA for another priming event. Telomerase adds DNA, removing this issue. Telomerase has RNA with a protein w/reverse transcriptase.


• Know about pathways that are proposed for nutrient sensing and how they are thought to explain the anti-aging effects of caloric restriction.

Insulin and IGF-1 and other signalling pathways relationship to dietary restriction and aging

Caloric restriction: First shown 1935 in rats.
Also found in mice, flies, worms, etc.
Also reported in rhesus monkeys although evidence not incontrovertible (p = 0.03 and excluded some deaths)
Effects age-related diseases (i.e. cancer) as well as lifespan

Sirtuins – family of NAD+ dependent deacetylase proteins related to SIR2 (Silent information regulator) in yeast
Initial reports:
Sirtuin over expression increases longevity in yeast, flies, worms, mice on high fat diet
Resveratrol (from red wine) binds to SIRT1 and activates
Boosting NAD+ may also stimulate (nicotinamide riboside, nicotinamide mononucleotide)
Other contradictory reports
There were other genes that were different in the initial fly and worm models
The activation effect was only seen with a specific fluorescent substrate
Despite controversy, companies making supplements available (Basis, Niagen)


progerias/progeroid syndrome: what genes cause them and how they relate to genomic instability.

Progerias cause accelerated aging and affect DNA gyrases for repair and nuclear lamin


free radical theory of aging and the evidence against it

ROS lead to aging. Cons: Anti-oxidants are essential (vits. C, E) but don’t extend life
Genetics on mice, worms
some cases increased oxidation/damage increases lifespan
Can oxidative damage signal repairs?


Rare early onset familial form (fAD)

Amyloid precursor protein (APP)
Presenilin 1 & 2 (PSEN1, 2) γ-secretase


Much more common, later sporadic form (sAD) (>65 years)

Caused by ??
Increased risk (4-fold): Apolipoprotein E (APOE) APOE4 allele
Other genes, less risk


Amyloid hypothesis

The hypothesis is that Aβ production/aggregation is the driving force for AD
Backed by genetics of fAD and evidence from mouse models
Contrary evidence:
Humans can have plaques w/o disease (PET scan method)
Can reverse plaques w/o curing
Mice in models don’t get tangles or irreversible neurodegeneration
Amyloid plaque brain locations do not correlate well with effects, tau tangles are better correlated
So far, drug trials targeting Aβ have not been effective


Alzheimers may be

Alzheimer’s disease may be a disorder of proteostasis
Amyloid plaques – Neurofibrallary tangles
Amyloid beta makes plaques
Comes from APP
Mutations in familial AD in APP and secretase gamma
Other evidence suggests there is more than amyloid going on


Nutrient Sensing

Nutrient sensing is a cell's ability to recognize and respond to fuel substrates such as glucose. Each type of fuel used by the cell requires an alternate pathway of utilization and accessory molecules. In order to conserve resources a cell will only produce molecules that it needs at the time. The level and type of fuel that is available to a cell will determine the type of enzymes it needs to express from its genome for utilization.