Loss of proteostasis is a central hallmark of ageing and a key driver of neurodegeneration. Lysosomes are primary effectors of proteostasis, and their functional decline during ageing is well established, yet the molecular mechanisms remain incompletely understood. Posttranslational modifications (PTMs) — phosphorylation, ubiquitination, and others — represent a powerful but unexplored regulatory layer of lysosomal biology, acting as reversible switches modulating protein activity independently of abundance. Which PTMs on lysosomal proteins are functionally relevant and how they drive lysosomal dysfunction and neurodegeneration remains unknown.The LPM-AGE project exploits a unique quantitative dataset of lysosomal PTMs available at project start — the first compartment-specific, pan-PTM resource generated under pro-longevity and pro-ageing conditions. PTMs changing in opposite directions under these contrasting conditions are hypothesised to represent functional regulators of ageing-relevant lysosomal processes, distinguishable from non-specific stress responses or abundance-driven effects.The project moves through four objectives: bioinformatic prioritisation of PTM candidates integrating effect size, directionality, and pathway context; experimental validation in cellular ageing models using compartment-specific proteomics and targeted mass spectrometry (PRM/SRM), with functional readouts assessed by automated high-content imaging; mechanistic dissection to distinguish causal from correlative modifications; and targeted in vivo validation in mouse brain under ageing, neurodegeneration, and neuroinflammation, combining targeted and spatial proteomics.Expected outputs include a validated set of lysosomal PTM regulators with defined mechanistic roles, publicly deposited datasets, and candidates with assessed biomarker potential. Beyond lysosomal biology, the project establishes a reusable framework for PTM-level dissection of organelle function in various diseases.