Lysosomal Dysfunction in Aging Brain Linked to Disrupted Sphingolipid Breakdown

Lysosomes are cellular recycling centers that break down and recycle worn-out components, and their dysfunction is increasingly recognized as central to brain aging. This study used multi-omics approaches to comprehensively profile lysosomes from aging brains, revealing that sphingolipid catabolism—the breakdown of specialized fat molecules crucial for brain cell membranes and signaling—becomes severely impaired with age. Sphingolipids accumulate when they can't be properly degraded, contributing to lysosomal dysfunction in a vicious cycle. This matters because lysosomal storage of sphingolipids is a hallmark of several severe neurodegenerative diseases, and this study suggests aging involves a milder version of the same process. The comprehensive dataset provides a roadmap of exactly which enzymes and pathways fail during aging, potentially identifying drug targets to restore lysosomal function. Given that lysosomal dysfunction is implicated in Alzheimer's, Parkinson's, and other age-related brain diseases, interventions that enhance sphingolipid breakdown could have broad neuroprotective effects. The multi-omics approach—combining proteomics, lipidomics, and functional analysis—provides unusually robust evidence and mechanistic detail about this fundamental aging process.