On the caffeine/longevity question => would ought be able to factorize variables used in causal modeling? (eg figure out that caffeine is a mTOR+phosphodiesterase inhibitor and then factorize caffeine's effects on longevity through mTOR/phosphodiesterase)? This could be used to make estimates for drugs even if there are no direct studies on the relationship between {drug, longevity}

[aka inverse-compositionality]

Also would ought be able to compare the dose/response curves used on animals and then "translate" them to humans? (eg effects of a study on rats/mice fed 10 mg/kg of X => automatically transfer this to estimated equivalent dose for a 45kg human). The literature I care most about is amphetamine neurotoxicity, where the doses used in rats/mice/rhesus macaques are WAY above the doses used in humans, and where there's huge uncertainty regarding whether 10mg of Adderall in a 45kg human is neurotoxic.

Or also "translate 10mg Adderall in 45kg human to uM/nM equivalent in human brain tissue => compare this with uM/nM equivalent observed in all animal experients". There are differences between how sensitive rat/mice/rhesus macaque neurons are wrt excess dopamine neurotoxicity.

Other questions I'm interested in:

• What are all the things that Sphingosines/ceramides do in the cell? How do they affect the rigidity/fluidity of the cell membrane?
• What are effects of H3K9me3 and HeK27me3 on longevity? (along with chromodomain proteins which act on them)
• "How much exogenous melatonin would increase intracellular melatonin to 20 μM?" [1] Doris Loh has many posts about the antioxidant/neuroprotective potential of melatonin (+has listed papers) and I want to figure out the optimal dose for melatonin for brain health (BOTH under normal conditions and for minimizing amphetamine neurotoxicity).
• what are levels of intracellular glucose seen in yeast (both calorie-restricted and ad lib), and how do they compare to levels of intracellular glucose seen in human tissue? 
• how does changing uM/nM concentration of intracellular glucose affect amount of cAMP/ATP produced in all papers studied?
• What is the dose-response curve of intracellular ATP with lifespan?
• What are effects of increased citrate concentration on longevity conditioned on changes in histone acetylation marks at all histone acetylation sites?
• what are $AverageChemicalProperties (such as hydrophilicity and lipophilicity moieties) of all antioxidants with the highest ORAC values? 
• How does amphetamine neurotoxicity change with age? Look at all papers that show changes in cellular antioxidant/redox/H2O2/catalase status + VMAT2/DAT/dopamine levels with age (+ changes in concentration of "repair proteins + lysosomal function" + ATP to power repair proteins + intrinsic reduction in dopamine with age) and then roughly assess if the damage is more irreversible for older brains than younger brains. Subcompartmentalize for effects on cytoskeleton+genome+epigenome+synaptosome+spiny dendrites+neurons+lipid composition+cardiolipin+mitochondria in PFC vs striatum vs VTA
• (Michael Levin question): Is there an estimate of what % of any metazoan genome is structural genes (enzymes, "load-bearing" proteins, etc.) vs. regulatory/computational machinery (transcription factors, ion channels, etc.) weighted by frequency of expression? Ofc these are not sharp categories, but anyone estimated a version of this?
• what is the optimal total modafinil/caffeine/amphetamine dose used for maximizing the amount of FLOPs computed in the lifetime of the human brain? (lol this is WAY out there but I'm throwing it out b/c important)
• what is the maximum grey matter/white matter mass seen in super-ager/old brains (eg https://twitter.com/jakob_seidlitz/status/1511779834187374597 ), and extract all demographic/genomic/proteomic data from superager brains
• https://twitter.com/constable_todd/status/1512749834968748032

My favorite lit-review papers, BTW, are from Doris Loh (eg https://www.mdpi.com/2076-3921/10/9/1483/htm ). Would be wonderful to make creation of similar lit reviews MUCH easier. appendix to https://scholar.google.com/citations?view_op=view_citation&hl=en&user=fINW1HkAAAAJ&citation_for_view=fINW1HkAAAAJ:hC7cP41nSMkC as well

[1] 

there may yet be another compelling reason that could explain how melatonin at pharmacological doses (10 mg/kg in vivo) [700] exerts neuroprotective effects in tauopathy.

An in vitro study on Neuro2A cells reported that melatonin at 10 μM concentration reduced intracellular ROS levels induced by tau aggregate treatment, and at 50 μM, melatonin reduced phospho-tau as well as GSK3β mRNA and subsequent protein levels. Melatonin increased cell viability in tau-exposed neurons in a dose-dependent manner, with 80% viability observed at 20 μM melatonin and a complete reversal at 200 μM, compared to only a 60% viability in controls without melatonin [704]. In an earlier study, the same group had reported that melatonin at strengths between 200 and 5000 μM failed to deter the aggregation of full-length tau. However, distinct morphology of small, broken tau fibrils were seen in the presence of either 1000 [705] or 5000 μM [352] melatonin. Furthermore, 5000 μM melatonin disaggregated tau fibrils by 54%, whereas 100 μM achieved only a ~14% effect [352]. It is possible that melatonin interacts with histidine residues to destabilize the assembly of aggregates [352] in a manner similar to how it disrupts salt bridges in Aβ, because tau phosphorylation alters side chain conformations through the formation of a network of salt bridges [706]. Salt bridge interactions were also observed in Aβ-mutated tau complexes assembled from Aβ peptides and mutated tau [707]. Earlier studies have reported that 300 μM melatonin interacted with hydrophobic segments in Aβ_1–40 and Aβ_1–42 to inhibit the formation of β-sheet and/or amyloid fibrils [708], and the inhibition of β-sheet and amyloid fibrils in samples containing 250 μM of Aβ_1–40 and Aβ_1–42 with only 100 μM of melatonin could not be replicated in control experiments using a potent free radical scavenger N-t-butyl-a-phenylnitrone (PBN), or a melatonin analog 5-hydroxy-N-acetyl-tryptamine (NAT) [337]. Even though melatonin could dissolve fibrils [709] by disrupting inter-peptide salt bridges between side chains Asp23 and ly28 [710,711] critical to β-sheet formation [712], the concentrations of 1000 [705] or 5000 μM [352] required to disassemble tau fibrils are significantly higher than the 100–300 μM melatonin used to inhibit β-sheet and amyloid fibrils [337,708], or the complete reversal of cell viability in tau-exposed neurons achieved with only 200 μM melatonin [704].