Knoll’s command didn’t abandoned researches of selegilin. And BPAP (a derivative of selegiline, which is not MAO-B inhibitor at all, but 160 times more potent catecholamin enhanser, which is very interesting).
The idea of Knoll was that amphetamine-like catecholamin action is to release a lot of products of neuromediators even without signal. But CAE, catecholamin enhancer effect is to enlarge the release when we have signal, but do nothing if there is no signal at all. So, stimulation only when we have a stimul.
There are several recent studies of deprenyl, and BPAP. And Rasagiline, which is MAO-B inhibitor, but not CAE. So only deprenyl is MAO-Bi AND CAE.
Analysis of my AI follows:
User question
MAO-B itself may also affect longevity. It seems to reduce inflammation, and maybe there are other mechanisms too. In that case, BPAP may be better as an enhancer, but worse than deprenyl, because the MAO-inhibition logic is absent. That could explain why its longevity effect drops off. So deprenyl may turn out to be the best of both worlds.
Assistant answer
Yes, I would formulate it exactly like that: your model is very plausible.
BPAP may be “better” as a pure enhancer, but worse as a geroprotector, because the MAO-B component is cut off. And deprenyl/selegiline is a hybrid that has both layers:
- MAO-B inhibition / PEA-dopamine metabolism / anti-inflammatory-neuroprotective axis
- CAE / TAAR1 / impulse-dependent monoamine release enhancer axis
And this is precisely why it may win on lifespan, even if BPAP is pharmacologically more “elegant” in the enhancer sense.
1. Two different logics
Logic A: MAO-B inhibition
This is not just “less dopamine breakdown.”
With aging, MAO-B is connected to several things:
- age-related increase in MAO-B activity;
- more oxidative monoamine metabolism;
- Hâ‚‚Oâ‚‚/aldehyde byproducts;
- astrocyte/glial axis;
- neuroinflammation;
- dopamine/PEA tone;
- possible effects on mood, motivation, and cognitive energy.
In Bene’s meta-analysis, the mechanistic hypotheses for deprenyl include: MAO-B inhibition opposing the age-related rise in MAO-B, SOD/catalase, and immunomodulation through interferons, TNF-α, interleukins, BDNF, and NK cells. So this is not only “dopamine stimulation.”
There is also a newer independent line: deprenyl reduced the inflammatory profile in an acute SIV infection model, and the authors explicitly described broad anti-inflammatory effects of deprenyl. This is not longevity evidence, but it supports the idea that the MAO-B/MAOI axis may be immunometabolic, not merely psychopharmacological.
Logic B: CAE/enhancer
This is the Knoll line:
the compound does not crudely dump monoamines, but enhances impulse-propagation-mediated release — meaning release during a normal nerve impulse.
BPAP is stronger in this logic: in older structure-activity work, BPAP enhanced impulse-mediated catecholamine/serotonin release, and in the shuttle-box model it was roughly 130 times more potent than deprenyl.
But that does not mean “better for longevity.” It means: better as a probe/tool of enhancer regulation.
2. Why BPAP may have underperformed in longevity
Because it probably has only one layer:
BPAP = enhancer without MAO-B inhibition.
Whereas deprenyl is:
deprenyl = enhancer + MAO-B inhibition + metabolite/PEA/dopamine axis + possible anti-inflammatory/antioxidant/immunomodulatory effects.
So “the best of both worlds” is a good formulation.
If deprenyl’s lifespan effect is composed of several components, then BPAP, even if stronger as a CAE, may fail to reproduce the whole phenotype.
The recent picture supports this:
- BPAP is mechanistically strong as an enhancer;
- but in aged Long-Evans rats in 2023, it did not significantly improve survival or cognition;
- deprenyl, meanwhile, shows an overall rodent lifespan signal in meta-analysis.
So mechanistic purity does not guarantee a lifespan effect.
3. Why rasagiline also loses here
Rasagiline is the reverse situation.
It preserves:
MAO-B inhibition
but, according to the Harsing/Miklya school, it loses:
the enhancer / TAAR1 / impulse-dependent release component.
The 2023 paper directly concludes: selegiline acts as a MAO-B inhibitor and dopaminergic enhancer drug, whereas rasagiline is devoid of enhancer activity and may act as a TAAR1 antagonist.
So we get a very clean matrix:
| Drug |
MAO-B |
CAE/enhancer |
Longevity meaning |
| BPAP |
no |
strong |
pure enhancer, but may lack the MAO-B/anti-inflammatory layer |
| Rasagiline |
yes |
no / possibly TAAR1 antagonism |
pure MAO-B, but not a Knoll-style enhancer |
| Selegiline / deprenyl |
yes |
yes |
hybrid: potentially the complete geroprotective package |
4. What may be the “magic” of deprenyl
I would break it down like this:
1. MAO-B/PEA axis
MAO-B destroys β-phenylethylamine very quickly. Deprenyl sharply increases PEA availability. And PEA itself is linked to trace amine / TAAR1 / motivational tone.
So MAO-B inhibition may enhance endogenous enhancer tone, not merely slow dopamine breakdown.
2. Dopamine preservation
With aging, the dopaminergic system deteriorates. Deprenyl may:
- reduce dopamine catabolism;
- reduce toxic byproducts;
- support nigrostriatal function;
- improve drive/movement/exploration.
In animals, this may translate into lifespan through activity, feeding, stress response, behavior, and thermoregulation.
3. Glia/neuroinflammation
MAO-B is especially interesting in the glial/astrocytic aging axis. If part of brain aging is astrocytic MAO-B / GABA / inflammation / oxidative metabolism, then a pure enhancer like BPAP is not necessarily expected to fix that.
4. Immune modulation
The Kitani line explicitly discusses interferons, TNF-α, interleukins, BDNF, and NK cells. This may be a peripheral lifespan component that BPAP does not cover.
5. CAE as a “functional amplifier”
And the enhancer component adds on top:
- better impulse-dependent dopamine/noradrenaline/serotonin release;
- without crude amphetamine-like flooding;
- possibly supporting youthful monoaminergic responsiveness.
5. But there is an important trap
One cannot conclude from this:
therefore, the more MAO-B inhibition + the more CAE, the better.
Rather:
there is a window.
In the meta-analysis, two negative studies were not included in the quantitative pooling, and the author specifically notes that they may have been negative because of early initiation and/or high systemic dose: Gallagher used 0.5 mg/kg SC starting at 3 months; Carrillo used 1 mg/kg SC.
So deprenyl as “the best of both worlds” only works in a narrow sense:
low/moderate dose, no crude stimulation, not lifelong high-dose exposure from youth, and no serotonergic/MAOI interaction risks.
6. My current hierarchy after all these data
For the longevity/brain-aging hypothesis:
1st place: selegiline/deprenyl
Because:
- it has MAO-B inhibition;
- it has CAE/enhancer activity;
- it has a rodent lifespan meta-analysis;
- it is a clinical drug;
- it has human safety history.
2nd place: rasagiline
Because:
- clinically clean;
- has MAO-B inhibition;
- has a Parkinson’s delayed-start story;
- but lacks the Knoll-style enhancer layer.
3rd place: BPAP
Because:
- the enhancer mechanism is elegant;
- potency is high;
- but it lacks MAO-B inhibition;
- has no clinical pathway;
- the recent aged-rat result is sobering;
- human safety is unclear.
Bottom line
Yes: deprenyl may be better than BPAP precisely because it is not “pure.”
BPAP is a beautiful tool for CAE.
Rasagiline is a clean MAO-B inhibitor.
But deprenyl is a mixed drug that simultaneously:
- inhibits MAO-B;
- supports PEA/dopamine;
- provides an enhancer effect;
- may reduce neuroinflammatory/oxidative/immunosenescence burden.
And if the lifespan effect is the sum of these axes, then deprenyl really does look like “the best of both worlds,” not like an outdated compromise.
