Age-Related Lysosomal Dysfunctions

Abstract

Organismal aging is normally accompanied by an increase in the number of senescent cells, growth-arrested metabolic active cells that affect normal tissue function. These cells present a series of characteristics that have been studied over the last few decades. The damage in cellular organelles disbalances the cellular homeostatic processes, altering the behavior of these cells. Lysosomal dysfunction is emerging as an important factor that could regulate the production of inflammatory molecules, metabolic cellular state, or mitochondrial function.

Keywords: aging; lysosome; senescence.

Figure 1

An overview of TFEB regulation through mTORC1 and calcineurin activity. Under nutrient rich conditions, mTORC1 phosphorylates TFEB, which is sequestered in the cytosol by 14-3-3 proteins. Under nutrient deficiency, mTORC1 is inactive, and calcineurin eliminates TFEB phosphates, allowing nuclear translocation, where TFEB induces the expression of genes related to autophagy, endocytosis, lysosome exocytosis, and lysosome biogenesis.

Figure 2

An overview of the lysosomal dysfunctions associated with aging or senescence. v-ATPase dysfunctions and membrane disruption impair the lysosomal acidification process, which shows increased alkalinization. Protons escaping the lysosome provoke cytosolic acidification, which alters cellular metabolism, and the presence of cathepsin B has been linked to NLRP3 inflammasome activation. Impaired hydrolysis inside the lysosome results in protein aggregation and lipofuscin storage. Incorrect amino acid storage is linked to mitochondrial dysfunction, and mTORC1 activation in the lysosome surface correlates with the synthesis of SASP molecules and geroconversion.

Figure 3

An overview of mTORC1 and mTORC2 on senescence control by the regulation of the p53/p21 and p16/pRb pathways. p21 is stabilized through mTORC1 dependent 4EBP phosphorylation, and through mTORC1 via S6K1 dependent mTORC2 inhibition, which has repercussions on p53 stabilization. p16 is activated downstream of mTORC1 by S6K1 phosphorylation, inhibiting the CDK–Cyclin complexes and impeding pRb phosphorylation. This results in the sequestration of E2F and the prevention of cell cycle progression, eventually leading to senescence.