The Importance of Lysosomes in Aging and Longevity

The lysosome is a type of cellular component that serves as a recycling unit, breaking down unwanted proteins and structures into their raw materials. As such they play an important role in cellular housekeeping, the removal of damaged structures, machinery, and waste that will, if left unchecked, harm cells and cellular processes. Unfortunately not all byproducts of metabolism can be broken down, either efficiently or at all, and in long-lived cell populations lysosomes become bloated and dysfunctional, filled with a mix of hardy waste products called lipofusin, and much less able to perform their recycling activities. This contributes to the progression of aging, leading to a sort of runaway garbage catastrophe.

Researchers have demonstrated that improving lysosomal function, even without addressing the issue of liposfusin, can greatly improve measures of organ function in older animals. The SENS rejuvenation research approach to this aspect of aging is to find ways to break down the important constituents of lipofuscin by mining the bacterial world for suitable enzymes capable of digesting it. We know they exist because lipofuscin doesn't build up in the soil of graveyards. At present this work has produced some candidates, and is slowly heading in the direction of initial commercial development - though as for near all lines of research relating to repair of the causes of aging, there is all too little interest and funding.

Lysosomes are found in all animal cell types (except erythrocytes) and represent the cell's main catabolic organelles. The variety of substrates degraded in the lysosomes is wide, ranging from intracellular macromolecules and organelles to surface receptors and pathogens, among others. However, lysosomes are not mere sites for disposal and processing of cellular waste but also act as pivotal regulators of cell homeostasis at different levels. For instance, they are involved in the regulation of cellular responses to nutrient availability and composition, stress resistance, programmed cell death, plasma membrane repair, development, and cell differentiation, among many others. Thus, lysosomes play a determining role in processes that control cellular and organismal life and death. Concurring with this pleiotropic importance, lysosomal dysfunction is associated to a plethora of disorders. Notably, lysosomal defects disturb the balance between damaged proteins and their proteolytic clearance, ultimately resulting in the accumulation of highly cross-linked aggregates. Accumulation of aggregates in post-mitotic cells appears to be particularly dramatic, since the material cannot be diluted via cell division. Many resulting aggregates of oxidized proteins may further react with cellular components like lipids and metals in different compositions, forming a fluorescent material termed lipofuscin. Indeed, the aging process itself may be fueled by a decrease in lysosomal function.

Mounting evidence suggests that a cell's lifespan is partly determined by lysosomal function. This implies that processes in which lysosomes are generally involved, but which have not been clearly associated to aging yet, might also directly or indirectly modulate longevity. Lysosomal exocytosis, for example, in which lysosomes dock to the cell surface, fuse with the plasma membrane and release their content into the extracellular space, has an important role in membrane repair and may contribute to intracellular regeneration upon cellular senescence. At the same time, lysosomal exocytosis is involved in secretion processes that could interact with aging-related intercellular signals at the tissue and organismal level and/or help alleviate intracellular stress conditions, possibly in cooperation with selective secretion through exosomes. Interestingly, lysosomal exocytosis is modulated by Ca2+ and TFEB, both of which have regulatory functions during aging.

On the other hand, molecular processes known to impact aging may at least partly do so because they affect lysosomal function. Such processes may engage single components of the cellular network that are involved in lifespan control, including mitochondria, the nucleus, or peroxisomes. Intriguingly, lysosomes not only communicate with other organelles in the frame of their autophagic removal. For example, the peroxisome-lysosome interaction does not seem to be restricted to pexophagy. The membranes of both organelles can come in close apposition (without fusion), creating lysosomal-peroxisome membrane contacts (LPMC), which are essential for the cellular trafficking of cholesterol. Interestingly, cholesterol oxide derivatives (oxysterols) are involved in different aging-relevant processes like redox equilibrium and inflammation. In addition, they have been associated to major age-related pathologies like neurodegenerative and cardiovascular diseases. Thus, organelles associated with the generation, transformation and transport of such molecules may strongly influence their impact on aging. The occurrence of membrane tethering sites (microdomains) like LPMCs allows an efficient interplay between organelles. Thus, the establishment of microdomains between lysosomes and other organelles may allow signal exchanges that contribute to a dynamic and orchestrated control of aging. Though some remain speculative in their causality, these lysosome-aging connections exemplify the multilayered mechanisms through which lysosomal function may crucially contribute to aging control. Recognizing this potential opens doors not only to further understand the process of aging but also to improve the ravages of time via lysosomal avenues.



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