Fight Aging!

Lysosomes are structures within cells packed full of enzymes capable of breaking down proteins and structures into raw materials; they serve as recycling centers. Lysosomes are the final destination of damaged or unwanted proteins and structures flagged for destruction by the cellular maintenance processes of autophagy. Lysosomes are known to become dysfunctional with age, for reasons that are not fully explored. Some of it is a matter of changes in the expression of relevant genes, some of it is a matter of the accumulation of persistent metabolic waste that lysosomes cannot effectively break down. Given enough of that waste, lysosomes become bloated and inefficient. If a cell cannot effectively recycle, it becomes dysfunctional, inflammatory, and eventually dies. The more that this happens, the more that it contributes to degenerative aging.

Lysosomal dysfunction didn't make it into the Hallmarks of Aging as a headline category of its own. Arguably it should have. The earlier Strategies for Engineered Negligible Senescence (SENS) proposals included lysosomal dysfunction as a part of the problem of the aggregation of persistent metabolic waste inside cells, and did not focus all that much on harmful epigenetic change, save as it exists as a maladaptive reaction to other forms of molecular damage.

In today's open access paper, researchers report on novel findings in lysosomal aging, and show that it is possible to build a sufficiently complex signature of lysosomal aging from these findings to enable the creation of an aging clock. That one can build a decent aging clock from this data doesn't definitively indicate that this is an important cause of degenerative aging, however. That has to be separately determined the old-fashioned way. As is usually the case, the fastest path to demonstrating relevance as a contributing cause of aging is to find a way to reverse the specific observed changes in isolation, and then observe the outcome. Unfortunately one has to establish a path to therapy, then see whether or not it is viable, and not the other way around.

The Lysosomal Clock: Are We Only as Old as Our Lysosomes?

Lysosomes are a major organelle involved in intracellular degradation, membrane traffic, and metabolic signaling, but how their biochemical composition changes during normal aging remains poorly defined. Researchers now combine lysosome purification with metabolomics and lipidomics across tissues, species and ages to reveal a conserved signature of lysosomal aging characterized by accumulation of glycerophosphodiesters (GPDs) and cystine, and remodeling of bis(monoacylglycero)phosphate (BMP). Strikingly, these changes are largely obscured in whole-tissue analyses and resemble metabolic abnormalities associated with lysosomal storage disorders, including CLN3 disease and cystinosis.

The signature develops progressively with age, can predict chronological age, and is attenuated by caloric restriction in peripheral tissues but not in the brain. Within the brain, age-dependent metabolite accumulation is particularly prominent in microglia and is also detected in neurons, linking lysosomal aging to cell populations central to neurodegenerative disease. These findings define an organelle-level metabolic clock, suggesting that one might be only as young as one's lysosomes. Establishing whether GPDs, cystine, and BMP remodeling merely mark lysosomal age or actively contribute to declining lysosomal degradation and membrane traffic may uncover a metabolic connection between physiological aging, lysosomal storage disorders, and vulnerability to late-onset neurodegeneration.