The difference between a ‘clean’ drug and a ‘dirty’ drug

This clip is from episode #207 – AMA #35: “Anti-Aging” Drugs — NAD+, metformin, & rapamycin, originally released on May 16, 2022.

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Defining a “clean drug” and a “dirty drug” [1:38:00]

Dirty drugs 

• This means that, biochemically, the mechanism of action is unclear
• For instance, we know there are multiple targets that metformin hits biochemically in cells, and NAD, as we’ve already alluded to, hits hundreds, if not thousands of different targets
• A dirty drug is something that’s nonspecific, that has several potential ways that it might be acting
• People still don’t know how metformin is working, from a mechanistic perspective, as a drug for diabetes 
• There are several mechanisms that have been proposed, including 
  • activation of AMP kinase
  • at least at higher doses, is an electron transport chain inhibitor
  • It can affect folate metabolism by the microbiome
• In terms of effects on aging, it’s really unclear how effective metformin actually is in mice, but secondarily, what the mechanism of action would be.
• What Matt means by a “dirty drug” is it could be acting through any number of mechanisms and it’s hard to know whether you’ve got specificity in how it’s working

Clean drugs

A clean drug would be something, biochemically, that only hits one target.

Examples:

• Peter thinks in a “two by two” which is mechanism of action: known, unknown; Biomarker: present, absent
• One of the challenges of rapamycin is we don’t have a good biomarker, but at least we have a clear mechanism of action
• Conversely, metformin, we don’t really have a clear mechanism of action and we don’t have a good biomarker
• NR and NMN, we don’t have a good biomarker and we don’t have a clear mechanism of action
• The point here, on one level, is this gero-protective space is not that tidy
  • It’s not like statins where you know exactly which enzyme is inhibited and have a perfect biomarker
• Matt responds, “I think it depends on the biomarker you’re talking about.”
  • If you’re talking about a biomarker of efficacy for aging, he agrees that we don’t have that for anything because we don’t have any biomarkers of efficacy for aging
  • But we do have clear biochemical biomarkers, certainly for rapamycin
  • We know rapamycin is a very specific inhibitor of mTOR, and we have good biochemical ways to measure mTOR inhibition
  • The challenge is we don’t know what level of mTOR inhibition is optimal for aging, and that gets back to the aging biomarkers