In an important new perspective, Dr. Sheng-Cai Lin of Xiamen University unifies three distinct longevity interventions—caloric restriction (CR), Metformin, and bile acids—into a single, convergent molecular pathway. The central discovery is that glucose itself is a signaling molecule, not just a fuel. Lin’s team has mapped a precise “lysosomal glucose-sensing pathway” that acts as the master switch for aging.
The narrative overturns the textbook view that AMPK (the cell’s energy sensor) is activated solely by low ATP (energy deficit). Instead, Lin reveals that Aldolase, a glycolytic enzyme, physically senses the absence of glucose-derived metabolites (specifically Fructose-1,6-bisphosphate or FBP). When FBP drops, Aldolase triggers a domino effect on the lysosome surface, inhibiting the proton pump (v-ATPase) and recruiting the “AXIN” protein scaffold to activate AMPK.
Crucially, this paper demonstrates that Metformin (via the PEN2 protein) and Lithocholic Acid (a bile acid elevated during fasting, via TULP3) hijack this exact same lysosomal machinery to trigger longevity signals. The team believes they have effectively cracked the code of how fasting works and translated it into a novel drug candidate, Aldometanib, which mimics glucose starvation without actual starvation, extending lifespan and mobilizing immune cells to fight cancer.
Source
- Open Access Paper: Pioneers: Glucose Sensing and Control of Health-span and Lifespan
- Institution: School of Life Sciences, Xiamen University, Fujian, China.
- Journal: Journal of Molecular Biology.
- Impact Evaluation The impact score of this journal is ~4.7 (Impact Factor) / 10.2 (CiteScore). Therefore, this is a Medium-High impact journal.
Part 2: The Biohacker Analysis
Study Design Specifications
- Type: Perspective & Review of Primary Research. (Note: This document summarizes a body of work spanning ~2013–2025, rather than presenting a single new dataset).
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Subjects (in referenced key experiments):
- Mice: C57BL/6J (referenced in underlying studies for Aldometanib and Metformin work).
- C. elegans: Used for initial lifespan screening of Metformin and Aldometanib.
- Cell Lines: HEK293T, MEFs (Mouse Embryonic Fibroblasts), and Hepatocellular Carcinoma (HCC) models.
Lifespan Analysis
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Control Group Audit: The specific survival curves required to audit the control group against the Harrison et al. benchmark (expected median ~800-900 days for C57BL/6J) are not present in this summary text. The author cites their 2022 Nature Metabolism paper for the raw data.
- Warning: Without the raw Kaplan-Meier curves, we cannot confirm if the “extension” was due to robust drug effects or short-lived controls.
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Claimed Extension:
- Aldometanib (Synthetic Aldolase Inhibitor): Reported ~7.5% extension in murine lifespan.
- Metformin: Cited as extending lifespan in C. elegans and mice via the PEN2-lysosomal pathway, though specific % stats for mice are generalized in this text.
- Lithocholic Acid (LCA): Described as a “CR mimetic” that phenocopies anti-aging effects of calorie restriction.