A sensor/autophagy biomarker panel as a surrogate endpoint for human trials
No human trial endpoint yet · confidence 70% · Atlas ID H5
The gap
So far, every human clinical trial aimed at an ageing or healthspan outcome has either missed its main goal or only checked safety — not one has directly proven a health or lifespan benefit in people. The wins that do exist are for specific diseases (like certain cancers), not for ageing itself. Testing ageing directly takes decades, so researchers want a faster stand-in measurement, and a tool that can track mTOR activity live inside human cells now exists — making that stand-in more realistic to build, even though it hasn't been done yet.
Technical framing: QUANTIFIED human-endpoint desert: every completed human trial in this corpus with an aging/healthspan PRIMARY endpoint missed it or was safety-only. PEARL (MOE2025): visceral fat NOT met (secondary bone density OR 0.24, 95% CI 0.06-0.93, p=0.04). RTB101 phase 3 (MAN2021): symptomatic-RTI primary NOT met. Resveratrol (POU2013): fully negative. CALERIE (ROM2016): the paper held here is the SAFETY analysis of the two-year randomised caloric-restriction trial in 218 non-obese adults - CR was safe and well tolerated overall, but bone density fell significantly more than in controls, so 'no significant differences' would be wrong. Scope note: CALERIE is a caloric-restriction trial, not an mTOR-inhibitor trial; it belongs here as a geroscience comparator, not as direct evidence on an mTOR intervention. The human 'wins' are disease indications (BOLERO-2: PFS roughly doubled with exemestane, overall survival not significantly improved; RADIANT-3: median PFS 11.0 vs 4.6 months, HR 0.35, p<0.001) or surrogate biomarkers (topical rapamycin epidermal p16 reduced, p=0.008). Not 'few trials' but none with a hard aging endpoint. CORRECTION (2026-08-30): this block previously cited 'RADIANT-3 PFS 5% vs 2%'. Those figures are the grade 3/4 hyperglycaemia rates from that trial's adverse-event table, not a progression-free-survival result - a safety number had migrated into an efficacy claim. UPDATE (2026-07-09): a candidate real-time readout tool for the mTORC1-vs-mTORC2 arm of the panel now exists -- AIMTOR (BOU2020), a genetically encoded BRET biosensor validated in human and mouse cells that reads mTOR activity live, including subcellular resolution (lysosome/cytosol/nucleus/mitochondria). This does not fill the human-endpoint desert itself, but it derisks the panel's feasibility: the biosensor arm is no longer a proposed capability, it is a published, working assay.
The hypothesis
Educated guess: a panel of measurements — how the nutrient sensors are behaving, how much cleanup (autophagy) is happening, and the balance between mTORC1 and mTORC2 — could serve as a faster stand-in for “is this drug slowing ageing,” making much shorter human trials possible.
Technical framing: A pathway-activity panel (SAMTOR/GATOR readout + LC3-II/p62 autophagic flux + mTORC1-vs-mTORC2 substrate phosphorylation) tracks lifespan-extending interventions and can serve as a validated surrogate, enabling short human geroprotection trials.
How it could be tested
Back-test the panel across the animal longevity studies in the corpus (does it separate lifespan-extending from null interventions?), then validate prospectively against EVERLAST's daily-vs-weekly arms. The mTORC1-vs-mTORC2 substrate-phosphorylation arm can now build directly on AIMTOR (BOU2020) rather than needing de novo assay development.