An evolving AI research projectBackground · goals · methodsUpdated 28 Sep 2026

Addition dated 2026-09-28

Connect the literature. Challenge assumptions. Understand function.

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: publisher abstract and bibliographic metadata

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 · 2023-06-15 · DOI 10.1523/ENEURO.0031-23.2023

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

Evidence: preclinical intervention; partial-access appraisal.

Access / limitations: PubMed abstract/figure captions and indexed publisher excerpts; publisher open returned 403; PMC returned CAPTCHA

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

22 DOI-unique studies have 25 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.