Lysosomes are a vital component in the recycling systems of the cell, organelles that break down harmful or unwanted molecules in order to provide raw materials for manufacture of new molecules. As is the case for all cell components, lysosomes become dysfunctional with age. The buildup of persistent metabolic waste, such as lipofuscin, that cells struggle to break down is implicated in age-related lysosomal dysfunction in long-lived cells, such as neurons. Sweeping epigenetic and transcriptomic changes that alter the production of proteins occur with age in all cells, and it is likely that a subset of these changes contributes meaningfully to impaired lysosomal function.
Today's open access paper is interesting not just for the connection between specific forms of lysosomal dysfunction and hematopoietic stem cell aging, and thus the aging of the immune system, but also because the researchers involved found that a vacuolar ATPase inhibitor can reverse this dysfunction. Vacuolar ATPases are responsible for acidifying lysosomes, among other activities, and the specific issue identified in aged hematopoietic stem cells is that their lysosomes are overly acidic. When lysosomes cease to function efficiently, as appears to happen in this circumstance, the whole cell suffers because harmful molecules are not cleared and recycled in good time. As the researchers point out, this includes mislocalized DNA from mitochondria that can trigger inflammatory pathways. Restoring lysosomal function in aged cells reduces inflammatory signaling and improves cell health.
Scientists Reverse Aging in Blood Stem Cells by Targeting Lysosomal Dysfunction
Lysosomes are specialized structures that act as the cell's recycling system, breaking down proteins, nucleic acids, carbohydrates, and lipids. Lysosomes accumulate and degrade waste, and eventually recycle it to be reused in biosynthetic processes. Lysosomes can also store nutrients to be released when needed. Lysosomes are recognized as pivotal for regulating metabolism in the cell, both catabolism (breaking down complex molecules to simple ones) and anabolism (building complex molecules from simpler ones).
As people age, hematopoietic stem cells (HSCs) become defective and lose their ability to renew and repair the blood system, decreasing the body's ability to fight infections as seen in older adults. Another example is a condition called clonal hematopoiesis; this asymptomatic condition is considered a premalignant state that increases the risk of developing blood cancers and other inflammatory disorders. Its prevalence increases significantly with age.
Researchers discovered that lysosomes in aged HSCs become hyper-acidic, depleted, damaged, and abnormally activated, disrupting the cells' metabolic and epigenetic stability. Using single-cell transcriptomics and stringent functional assays, the researchers found that suppressing this hyperactivation with a specific vacuolar ATPase inhibitor restored lysosomal integrity and blood-forming stem cell function. The old stem cells started acting young and healthy once more. Old stem cells regained their regenerative potential and ability to be transplanted and to produce more healthy stem cells and blood that is balanced in immune cells; they renewed their metabolism and mitochondrial function, improved their epigenome, reduced their inflammation, and stopped sending out "inflammation" signals that can cause damage in the body.
Reversing lysosomal dysfunction restores youthful state in aged hematopoietic stem cells
Aging impairs hematopoietic stem cells (HSCs), driving clonal hematopoiesis, myeloid malignancies, and immune decline. The role of lysosomes in HSC aging - beyond their passive mediation of autophagy - is unclear. We show that lysosomes in aged HSCs are hyperacidic, depleted, damaged, and aberrantly activated. Single-cell transcriptomics and functional analyses reveal that suppression of hyperactivated lysosomes using a vacuolar ATPase (v-ATPase) inhibitor restores lysosomal integrity and metabolic and epigenetic homeostasis in old HSCs. This intervention reduces inflammatory and interferon-driven programs by improving lysosomal processing of mitochondrial DNA and attenuating cyclic GMP-AMP synthase-stimulator of interferon gene (cGAS-STING) signaling. Strikingly, ex vivo lysosomal inhibition boosts old HSCs' in vivo repopulation capacity by over eightfold and improves their self-renewal. Thus, lysosomal dysfunction emerges as a key driver of HSC aging. Targeting hyperactivated lysosomes reinstates a youthful state in old HSCs, offering a promising strategy to restore hematopoietic function in the elderly.
View the full article at FightAging
