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PMCOL 200 > 32 Anti-Aging Drugs > Flashcards

32 Anti-Aging Drugs Flashcards

1
Q

What are two ways to define aging?

A
  1. Increase in probability of death with increasing chronological age
  2. Characteristic changes in phenotype that occur over time due to limiting processes
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2
Q

What was the first longevity gene characterized?

A

DAF-2

DAF-2 knockout produced temperature-sensitive dauers (worm larva) - worms live twice as long at normal temp

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3
Q

What effects does caloric restriction have on DAF-2?

A

Caloric restriction decreases the DAF-2 pathway (increasing lifespan)

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4
Q

What is the human gene homolog to DAF-2?

A

Insulin/IGF receptor

  • inactivating mutations = increased lifespan
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5
Q

What is the human gene analog to DAF-16?

A

FOXO transcription factor

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6
Q

What is LY294002 and Wortmannin?

A

LY294002:

  • ATP competitive

Wortmannin

  • Non-competitive

Both are small-molecule drugs that inhibit the PI3K enzyme and block IIS signalling

(IIS signalling is activated in tx of type II diabetes so blocking IIS signalling is bad for diabetes)

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7
Q

What results from the knockout of SIR2?

A

Knockout of SIR2 shortens lifespan while overexpression extends lifespan

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8
Q

SIR2 regulates which post-translational process?

A

Acetylation - acetyl group added to lysine residues.

Can regulate protein stability and or structure (eg histones/chromatin structure)

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9
Q

How is SIR2 related to acetylation?

A

SIR2 is a nuclear deacetylase enzyme that removes acetylation from proteins

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10
Q

What cofactor does SIR2 use for the rxn that removes acetylation from proteins?

A

NAD (nicotinamide adenine dinucleotide)

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11
Q

NAD+ is a ___________ which plays a critical role in the __________ and the _________

A

NAD+ is a metabolic intermediate which plays a critical role in the glycolysis and the citric acid cycle

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12
Q

When energy is low, [NAD+] is ______

A

When energy is low, [NAD+] is high

Works to form NADH

THEREFORE SIR2 is activated by Caloric restriction

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13
Q

What is the mammalian homologue to SIR2?

A

SIRT1

SIRT1 deacetylates nearly 100 targets (histones, p53, NfkB, PGC1 alpha, FOXO) and regulates many pathways and diseases

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14
Q

In addition to extending lifespan, overexpression of ____ improves healthspan by preventing age-related diseases

A

In addition to extending lifespan, overexpression of SIRT1 improves healthspan by preventing age-related​ diseases

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15
Q

Provide an example for a synthetic and a natural allosteric Sir2/SIRT1 activator?

A

Synthetic: SRT1720

Natural: Resveratrol

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16
Q

Why would we want to increase base levels of NAD+?

A

NAD+ is a necessary cofactor for deacetylation by SIR2/SIRT1 (overexpression of SIRT1 increases lifespan)

  • Boosting levels of NAD+ can provide SIRT1 with more co-substrate and activate SIRT1 pathway
17
Q

NAD+ doesn’t easily cross the plasma membrane. How might we get NAD+ into the cell?

A

Precursors of NAD+ (NR and NMN) can be delivered across the membrane and then assemble to make NAD+

NR = Nicotinamide riboside

NMN = Nicotinamide mononucleotide

18
Q

What are mTORs?

A

TOR1 and TOR2 genes inhibit Sirtuins

TOR1/TOR2 -| SIRTs -> promote lifespan

So inhibition of mTORs increases lifespan

19
Q

What is the effect of caloric restriction on mTORs?

A

Caloric restriction suppresses mTORs (which inhibit SIRTs) therefore increases lifespan

20
Q

mTORs are ____/____ of the PI3K-related family that regulates cell growth and metabolism in response to nutrients/hormones

A

mTORs are serine/threonine-protein kinase of the PI3K-related family that regulates cell growth and metabolism in response to nutrients/hormones

  • Adds Phosphorylation PTM (post transcription mod)
21
Q

What is Rapamycin?

A

Antiaging drug that inhibits mTOR pathway through the formation of bridged ternary complex

  • shown to extend the lifespan of numerous organisms

mTOR -| SIRTs -| lifespan

22
Q

What results from overexpression of AAK-2?

A

Extends lifespan

  • AAK=2 is activated during Caloric restriction
  • integrated with many other pathways involved in aging
23
Q

AAK-2 = _________ in mammals

A

AAK-2 = AMPK in mammals

Adenosine monophosphate-activated protein kinase

24
Q

What does AMPK (adenosine monophosphate activated kinase) do?

A

Adds phosphorylation post translation to proteins

  • activated under low nutrient conditions (high AMP low ATP)
25
Q

What two drugs activate AMPK?

(Adenosine monophosphate activated kinase)

A

Metformin

AICAR

26
Q

How does metformin work?

A

Metformin activates AMPK through an indirect mechanism (still unknown but likely involves ETC complex 1)

  • increases lifespan in worms
  • medication for diabetes due to effects on insulin (increases insulin sensitivity)
27
Q

How does AICAR work to activate AMPK?

A

AICAR mimics AMP and acts as a direct activator

PMCOL 200 (30 decks)

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