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Longevity: Measuring autophagy in the body #21

Open jdhodgkins opened 2 years ago

jdhodgkins commented 2 years ago

Bounties for Foresight Technical Groups

Each of these will run for 6 weeks, the objective is to stimulate conversation and get people thinking about interesting and relevant future science. Submissions will be in the form of project proposals for solving these issues, and several winners will be chosen for each category. A short overview on the problem, a description of a solution, and your plan to implement it are required in the submission.

Measuring autophagy in the body

Autophagy is the cornerstone of many current therapies targeting longevity, but it cannot be measured in vivo (in the body while alive). What new methods might help us to get autophagy diagnostic data?

Submit your bounty-response below for your chance to be rewarded 0.15 ETH.

gitcoinbot commented 2 years ago

Issue Status: 1. Open 2. Started 3. Submitted 4. Done

This issue now has a funding of 0.15 ETH (458.7 USD @ $3057.98/ETH) attached to it as part of the https://github.com/foresight-org fund.

gitcoinbot commented 2 years ago

Issue Status: 1. Open 2. Started 3. Submitted 4. Done

Work has been started.

These users each claimed they can complete the work by 5 hours from now. Please review their action plans below:

1) darom1998 has started work.

I'am going to study musulmans cases while fasting and evaluate all the parametres related with human body to see how it change over time , with gathering this type of data , we can build some models based on interpolation to know really how this phenomen evolve. 2) ify01 has started work.

i will give my best project proposal on this issue. 3) aukb has started work.

'll start by giving a definition of autophagy, mentioning the different types of autophagy, then describing the state-of-the-art methods to visualise and/or measure autophagy and making suggestions of how methods could be developed further. Regarding your in vivo measurements, are you aiming to measure in human or in mouse? How invasive can the methods be? Is it allowed to genetically modify the human? 4) andydlee has started work.

Vincere Bio is working with the creators of MitoQC/AutoQC, and MtKeima to measure mitophagy and autophagy in mice. We have small molecules engaging multiple mitophagy/autophagy targets and have demonstrated increase of mitophagy in the rodent brain and human cells using these florescent reporters.

I'd like to propose a parallel project to measure substrates that may be clinically relevant biomarkers that we can correlate with autophagy in rodents so that we may accurately measure mitophagy/autophagy in humans to detect system deficits and verify target engagement/efficacy of interventions.

This may involve targeted measures (e.g. western blot, etc) or unbiased analyses (e.g. proteomics, etc) 5) zauberkugel2 has started work.

Hey, I have an idea: So, the state of the art are autophagy reporter mice. That's where they tag an autophagosomal marker (LC3) with a pH-sensitive GFP variant. It's bright when you have autophagosomes, but once they acidify and become lysosomes, the GFP is destabilized and goes dark. You image only active autophagosomes, and stop getting signal once the job is complete. (e.g. PMID 24179166)

It’s neat, and mostly works in vivo for a mouse. But if you make it any bigger than a mouse, then the serious limitation of the GFP is that the fluorescence doesn’t reach all the way out of the animal’s deep tissues anymore. That’s why we can’t just take this same tech and scale it to say a non-human primate that might provide a whole lot more meaningful aging readout than a mouse does.

Here’s how we’re going to fix it: We’re going to replace the GFP with an MRI reporter gene. These are enzymes that synthesize biocompatible iron-oxide crystals, which you can pick up on MRI scans that have essentially no tissue depth limit (e.g. PMID 27213309). The trick is, these crystals too are by nature pH sensitive (like rust dissolves in acid) and are completely catabolized by lysosomes. With luck, the timing might work out: In an active autophagosome you see them, and in the lysosome you don’t.

What do you think? 6) idonai has started work.

This paper used bio markes from whole blood to examine autophagic flux in humans: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8525931/ Although testing of this method would be required in other settings (during water fasting or specific drugs), slight modifications to this protocol might make it work as a reliable autophagic diagnostic tool.

Other possibility would be measuring mRNA levels of autophagy specific proteins including: LC3, p62, Beclin-1, ULK1. For this it would be needed to examine interpersonal differences or atleast work from a baseline. 7) sepandhaghighi has started work.

Autophagy Estimation in Vivo by Using a Black-Box Model

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gitcoinbot commented 2 years ago

Issue Status: 1. Open 2. Started 3. Submitted 4. Done

Work for 0.15 ETH (288.73 USD @ $1924.84/ETH) has been submitted by:

  1. @sepandhaghighi

@jdhodgkins please take a look at the submitted work:

gitcoinbot commented 2 years ago

Issue Status: 1. Open 2. Started 3. Submitted 4. Done

The funding of 0.15 ETH (271.25 USD @ $1808.33/ETH) attached to this issue has been approved & issued to @sepandhaghighi.