An evolving AI research projectBackground · goals · methodsUpdated 12 Oct 2026

Study register

Connect the literature. Challenge assumptions. Understand function.

Cumulative update · 12 Oct 2026 One further TIMP2 sample is verified. Missing control and pool details still limit statistical analysis; a shared batch label does not establish biological independence. AG-T01 remains 🔵 Level 2. Daily report 12 Oct 2026 →

Data structure · 12 Oct 2026

AG-R01 (12 August 2026; DOI 10.1038/s41467-026-74906-z), metadata update 12 October 2026: GSM9001954 additionally checked; GSM9001955/61 only partly accessible. Sample manifest separates read fields, prior-day evidence and unknowns. No raw-data analysis or new study. Twenty-eight distinct studies; sources and exact limits in today’s report.

Data structure · 11 Oct 2026

AG-R01 (article 12 August 2026; DOI 10.1038/s41467-026-74906-z): GEO metadata audit on 11 October 2026. GSE297916: snRNA, old WT mice, TIMP2/PBS, four libraries. GSE297917: bulk, neonatal microglia, WT/KO, 14 pooled samples. Both series public since 1 June 2026, last updated 2 September 2026; no additional studies. Pooling directly checked in three example GSM records; no raw-data analysis. Sources in the daily report; 28 distinct studies unchanged.

Source dependencies · 10 Oct 2026

AG-R05 (19 April 2017), AG-R08 (publisher date 15 June 2023; first-online date still unresolved) and AG-R01 (12 August 2026) were audited on 10 October 2026 for authors, institutions, material/data statements, acknowledgements and interests. Three distinct DOIs remain three registry studies, not three confirmed independent reproductions. Do not pool different protein constructs and experiments without verification. Details and sources in today’s report; still 28 distinct studies.

Methods audit · 9 Oct 2026

AG-R05 (Castellano et al., DOI 10.1038/nature22067): first published 19 April 2017, issue date 27 April 2017; retrieved 9 October 2026. Indexed original text/legends extend the previous abstract entry. Do not pool recombinant TIMP2 with cord plasma. Exact group statistics, effect size, longer follow-up and slice/mouse hierarchy remain open; no raw-data analysis. No new registry entry: still 28 distinct studies. Publisher · Author manuscript

Methods audit · 8 Oct 2026

AG-D06 · First online23Oct2025, issueJanuary2026, DOI10.1016/j.neurobiolaging.2025.10.003. Follow-up8Oct2026: supplement/code not verified, current PMC request returns reCAPTCHA. Previous main-text evidence retained. Our APOE score decision plan is not a performed reanalysis; no upgrade, still28studies. Original source

AG-D06 · Anastasi et al.

Proteomic polygenic risk scores of age-related plasma protein levels reveal a role for Metalloproteinase inhibitor 2 (TIMP2) in cognitive performance

First online 23 Oct 2025; issue January 2026 · DOI 10.1016/j.neurobiolaging.2025.10.003 · Retrieved 7 Oct 2026. Human cross-sectional genetic/proteomic association, no MR or intervention. Cognition only ALFA+; Knight-ADRC validates protein prediction.119 variants,118trans/1cis including APOE. Measured TIMP2 not significantly associated with PACC/memory. Supplement effect intervals unverified here. Limited association evidence, ⚪ Level1; no human efficacy. Final main text/metadata assessed, no successful pixel or raw-data audit. Two preprints belong to the same study family. Now28 selected studies, including one preprint. Original source

Methods audit · 6 Oct 2026

AG-R08 · DOI 10.1523/ENEURO.0031-23.2023. Indexed publisher heading15 June2023, PMC heading12 June2023; date assignment unresolved. Retrieved6 Oct2026. Fig.1D/6A: tests against chance, no direct cognitive contrast in these analyses. Nesting/synapses separate. Indexed original methods and legends assessed, no pixels or raw data. Still27 DOI-unique studies. Original source

Methods audit · 5 Oct 2026

AG-S03 · original article 21 May 2025, DOI 10.1038/s41586-025-09036-5; review file retrieved 5 Oct 2026, separate publication date not established. Cell selection and unresolved linkage of an authors’ abnormal-digit observation examined. No additional study: still 27 DOI-unique studies. No independent replication. Public review file

AG-D05 · Nacu et al.

FGF8 and SHH substitute for anterior–posterior tissue interactions to induce limb regeneration

2016-04-27 · DOI 10.1038/nature17972 · Retrieved 4 Oct 2026

⚪ Level 1 · preclinical countercomparison, no human efficacy. Access: publisher preview, supplement and author upload; limits in daily report. Original source

AG-D04 · Jiang et al.

Autophagosome-targeting single-domain antibody clears tau in patient-derived neurons and improves motor function in tauopathy mice

2026-04-15 · DOI 10.1126/scitranslmed.aea4205

Provisional preclinical comparator, ⚪ Level 1. P301L neurons/JNPL3 mice; authors report tau degradation and motor function. Abstract and metadata inspected; final methods, effect size, controls and duration open. Probable predecessor DOI 10.1101/2025.06.30.662446 is not counted as another study. Original abstract

AG-S03: targeted appraisal of spatial mispatterning, cell state and positional memory; publication 21 May 2025, retrieval 3 Oct 2026. AG-D03: reporting form visually inspected 2 Oct, reported allocation/blinding partly resolved; complete units/time horizons remain open.

AG-D03 · Guo et al.

Engineered autophagy receptors administered with extracellular vesicles eliminate pathological Tau and TDP-43

2026-08-26 · DOI 10.1038/s41551-026-01774-9

Engineered autophagy receptors; preclinical, methodological appraisal provisional. ⚪ Level 1. TDP-43/AAV motor outcome separate from Tau/sEV pathology; no human efficacy. Publisher preview, figures and numerical source data inspected; complete methods remain open. Primary source

AG-D02 · Added to the register on 30 Sep 2026

Extracellular tau clearance is governed by its aggregation state and independent of microglial activation by LPS and IFN-γ

Shultz et al. · Neurobiology of Disease · 2025-08-18 · DOI 10.1016/j.nbd.2025.107058

Cell models and Tau-HiBiT; moderate evidence for lysosomal involvement in reporter processing. ⚪ Level 1. No TIMP2 or human efficacy test. Indexed primary methods and figure legends assessed; direct full-text access limited. Preprint and peer-reviewed version are the same study. Primary record

AG-D01 · Added to the register on 29 Sep 2026

Tracking tau and cellular responses in human iPSC-microglia: from uptake to seedable secretion, including in extracellular vesicles

Karabova MK et al. · Alzheimer’s & Dementia · 2026-04-06 · DOI 10.1002/alz.71337

Cell model, not a clinical trial; moderate evidence for export/seeding in the studied system. ⚪ Level 1. No TIMP2 intervention. Full text and relevant methods assessed; no raw-data reanalysis. Primary study

AG-R01

Youth-associated protein TIMP2 regulates microglial state and function in healthy and aged mice

Hemmer BM; Philippi SM et al. · Nature Communications · 2026-08-12 · DOI 10.1038/s41467-026-74906-z

Model / design: Mouse; genetic loss of function and supplementation; original research.

Evidence: mechanistic intervention; moderate, preclinical.

Access / limitations: publisher full text · Opposing substrate directions in Results; see bilingual dossier. Not silently corrected.

Primary study

AG-R02

Ageing promotes microglial accumulation of slow-degrading synaptic proteins

Guldner IH et al. · Nature · 2026-01-21 · DOI 10.1038/s41586-025-09987-9

Model / design: Mouse; neuron-specific protein tracing; original research.

Evidence: mechanistic tracing; moderate, preclinical.

Access / limitations: publisher full text

Primary study

AG-R03

Early mitophagy activation by Urolithin A prevents, but late activation does not reverse, age-related cognitive impairment

Jara C et al. · npj Aging · 2026-03-05 · DOI 10.1038/s41514-026-00351-3

Model / design: C57BL/6 and SAMP8 mice; original research.

Evidence: intervention; moderate within model, timing comparison confounded.

Access / limitations: publisher full text

Primary study

AG-R04

The mitochondrial unfolded protein response in human microglia disrupts neuronal–glial communication and promotes senescence

Perez J MJ et al. · Nature Neuroscience · 2026-06-26 · DOI 10.1038/s41593-026-02320-1

Model / design: Human cellular models; induced mitochondrial stress; original research.

Evidence: mechanistic intervention; moderate in vitro, low aging translation.

Access / limitations: publisher full text

Primary study

AG-R05

Human umbilical cord plasma proteins revitalize hippocampal function in aged mice

Castellano JM et al. · Nature · 2017-04-19 · DOI 10.1038/nature22067

Model / design: Aged mouse; original research.

Evidence: preclinical intervention; access-limited appraisal here.

Access / limitations: 9 Oct 2026: indexed original text/legends, no complete direct access; exact statistics and durability unverified.

Primary study

AG-R06

Oxidative stress causes a reversible decrease of deubiquitylases activity in old vertebrate brains

Sahu AK et al. · Nature Communications · 2026-04-21 · DOI 10.1038/s41467-026-71921-y

Model / design: Vertebrate brain and cellular models; original research.

Evidence: mechanistic intervention; moderate, preclinical.

Access / limitations: publisher full text

Primary study

AG-R07

Targeting iron-associated protein Ftl1 in the brain of old mice improves age-related cognitive impairment

Remesal L et al. · Nature Aging · 2025-08-19 · DOI 10.1038/s43587-025-00940-z

Model / design: Mouse and cellular models; original research.

Evidence: mechanistic intervention; moderate, preclinical.

Access / limitations: publisher full text

Primary study

AG-R08

Noncanonical Activity of Tissue Inhibitor of Metalloproteinases 2 (TIMP2) Improves Cognition and Synapse Density in Aging

Britton R et al. · eNeuro · Publisher heading 15 June 2023; PMC heading 12 June 2023; first online date unresolved · DOI 10.1523/ENEURO.0031-23.2023

Model / design: Aged male C57BL/6J mice; original research.

Evidence: preclinical intervention; partial-access appraisal.

Access / limitations: 6 Oct 2026: indexed original methods and legends assessed, no figure pixels or raw data. Earlier access limits (403/CAPTCHA) remain documented; no bypass of restrictions. Cognitive Fig. 1D/6A test against chance, not directly between treatments.

Primary study

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Study register

DOI, date, model, design, evidence and peer review.

Publication date means first online publication, or the stated preprint version. Strength refers to the specified claim scope; all literature findings are ⚪ project level 1. “Not assessed” means neither confirmation nor refutation.

AG-S01

Cellular senescence promotes progenitor cell expansion during axolotl limb regeneration

Yu Q et al. · Developmental Cell · 2023-10-24 · DOI 10.1016/j.devcel.2023.09.009

Model / design: Axolotl limb; Gain/loss of function.

Evidence: moderate, preclinical mechanism. Peer reviewed: yes.

Independent replication: not assessed. Access: Primary abstract and article metadata.

Original source

AG-S02

Single-cell Stereo-seq reveals induced progenitor cells involved in axolotl brain regeneration

Wei X et al. · Science · 2022-09-02 · DOI 10.1126/science.abp9444

Model / design: Axolotl telencephalon; Spatial single-cell transcriptomics.

Evidence: moderate, descriptive animal atlas. Peer reviewed: yes.

Independent replication: not assessed. Access: Primary abstract and article metadata.

Original source

AG-S03

Molecular basis of positional memory in limb regeneration

Otsuki L et al. · Nature · 2025-05-21 · DOI 10.1038/s41586-025-09036-5

Model / design: Axolotl limb; Lineage analysis and signalling perturbation.

Evidence: moderate, preclinical mechanism. Peer reviewed: yes.

Independent replication: not assessed. Access: Publisher full text and primary abstract.

Original source

AG-S04

Adrenergic signaling coordinates distant and local responses to amputation in axolotl

Payzin-Dogru D et al. · Cell · 2025-10-24 · DOI 10.1016/j.cell.2025.09.025

Model / design: Axolotl amputation; Systemic and local signalling perturbation.

Evidence: moderate, preclinical mechanism. Peer reviewed: yes.

Independent replication: not assessed. Access: Publisher summary; PMC publication metadata.

Original source

AG-S05

Neuronal activation in the axolotl brain promotes tail regeneration

Walker SE et al. · npj Regenerative Medicine · 2025-05-08 · DOI 10.1038/s41536-025-00413-2

Model / design: Axolotl brain and tail; Neural mapping and pharmacological perturbation.

Evidence: moderate, preclinical mechanism. Peer reviewed: yes.

Independent replication: not assessed. Access: Publisher full text.

Original source

AG-S06

Metabolic changes during cardiac regeneration in the axolotl

Dittrich A et al. · Developmental Dynamics · 2025-03-22 · DOI 10.1002/dvdy.70020

Model / design: Axolotl cardiac cryoinjury; Metabolic profiling and oxygen intervention.

Evidence: limited-to-moderate, exploratory animal study. Peer reviewed: yes.

Independent replication: not assessed. Access: Publisher metadata and PMC indexed full text.

Original source

AG-S07

A characterization of axolotl digit regeneration: conserved mechanisms, divergent patterning, and a critical role for hedgehog signaling

Griffiths JR et al. · npj Regenerative Medicine · 2026-03-25 · DOI 10.1038/s41536-026-00461-2

Model / design: Juvenile axolotl digits; Anatomical comparison and hedgehog perturbation.

Evidence: moderate, endpoint- and anatomy-specific animal evidence. Peer reviewed: yes.

Independent replication: not assessed. Access: Publisher full text.

Original source

AG-S08

Oxidative stress causes a reversible decrease of deubiquitylases activity in old vertebrate brains

Sahu AK et al. · Nature Communications · 2026-04-21 · DOI 10.1038/s41467-026-71921-y

Model / design: Mouse, killifish, human iPSC-derived neurons; Activity-based proteomics and perturbation.

Evidence: moderate, multi-model preclinical mechanism. Peer reviewed: yes.

Independent replication: Multiple cohorts/models within one paper; external replication not assessed. Access: Publisher full text.

Original source

AG-S09

Targeting iron-associated protein Ftl1 in the brain of old mice improves age-related cognitive impairment

Remesal L et al. · Nature Aging · 2025-08-19 · DOI 10.1038/s43587-025-00940-z

Model / design: Mouse hippocampus and primary neurons; Viral/genetic manipulation and behavioural readouts.

Evidence: moderate, preclinical intervention. Peer reviewed: yes.

Independent replication: not assessed. Access: Publisher full text.

Original source

AG-S10

Ageing promotes microglial accumulation of slow-degrading synaptic proteins

Guldner IH et al. · Nature · 2026-01-21 · DOI 10.1038/s41586-025-09987-9

Model / design: Mouse neuronal proteome; complementary human material; Cell-specific pulse-chase proteomics and microglial analysis.

Evidence: moderate, descriptive/longitudinal protein-tracing animal evidence. Peer reviewed: yes.

Independent replication: not assessed. Access: Publisher full text.

Original source

AG-S11

Single-cell transcriptomic and genomic changes in the ageing human brain

Jeffries AM et al. · Nature · 2025-09-03 · DOI 10.1038/s41586-025-09435-8

Model / design: Human post-mortem prefrontal cortex; snRNA-seq, single-cell genome sequencing, spatial validation.

Evidence: moderate, cross-sectional human observation. Peer reviewed: yes.

Independent replication: Within-paper orthogonal validation; external replication not assessed. Access: Publisher full text.

Original source

AG-S12

Organ-specific proteomic aging clocks predict disease and longevity across diverse populations

Wang Y et al. · Nature Aging · 2025-11-26 · DOI 10.1038/s43587-025-01016-8

Model / design: UK, Chinese and US human cohorts; Observational plasma proteomics with external cohort validation.

Evidence: moderate-to-strong for prediction; not causal or interventional. Peer reviewed: yes.

Independent replication: External cohorts within one publication; distinct external team not established. Access: Publisher full text.

Original source

AG-S13

Shifts in protein aggregate stability define proteostasis decline in the aging human brain

Anderton E et al. · bioRxiv · 2026-04-18 · DOI 10.64898/2026.03.27.714902

Model / design: Human post-mortem hippocampus; Detergent-fractionation proteomics.

Evidence: low, unreviewed human observation. Peer reviewed: NO – preprint.

Independent replication: not established. Access: Version-2 indexed abstract; version-1 primary full text; version-2 metadata.

Original source

AG-S14

Temperature-Dependent Modulation of Cardiac Metabolism, Post-Injury Survival and Regenerative Rate in Axolotls

Dittrich A et al. · Metabolites · 2026-06-13 · DOI 10.3390/metabo16060414

Model / design: Adult axolotl cardiac cryoinjury; Temperature intervention; imaging, physiology and histology.

Evidence: limited-to-moderate, small preclinical groups. Peer reviewed: yes.

Independent replication: Not assessed; author overlap with AG-S06. Access: PMC primary full text and PubMed publication metadata.

Original source

Current report with sources and evidence · Status rules

New human benchmarks

Full evidence assessment and sources AG-J01 to AG-J03

AG-J01 · Effect of Structured Physical Activity on Prevention of Major Mobility Disability in Older Adults: The LIFE Study Randomized Clinical Trial · 2014-05-27 · Original study
AG-J02 · A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial · 2015-03-12 · Original study
AG-J03 · Structured vs Self-Guided Multidomain Lifestyle Interventions for Global Cognitive Function: The US POINTER Randomized Clinical Trial · 2025-07-28 · Original study

28 DOI-unique studies have 31 source IDs. Alias pairs: AG-R02 = AG-S10; AG-R06 = AG-S08; AG-R07 = AG-S09. These duplicate references do not count as additional studies or replications.