Defective recruitment of motor proteins to autophagic compartments contributes to autophagic failure in aging

Abstract

SummaryInability to preserve proteostasis with age contributes to the gradual loss of function that characterizes old organisms. Defective autophagy, a component of the proteostasis network for delivery and degradation of intracellular materials in lysosomes, has been described in multiple old organisms, while a robust autophagy response has been linked to longevity. The molecular mechanisms responsible for defective autophagic function with age remain, for the most part, poorly characterized. In this work, we have identified differences between young and old cells in the intracellular trafficking of the vesicular compartments that participate in autophagy. Failure to reposition autophagosomes and lysosomes toward the perinuclear region with age reduces the efficiency of their fusion and the subsequent degradation of the sequestered cargo. Hepatocytes from old mice display lower association of two microtubule‐based minus‐end‐directed motor proteins, the well‐characterized dynein, and the less‐studied KIFC3, with autophagosomes and lysosomes, respectively. Using genetic approaches to mimic the lower levels of KIFC3 observed in old cells, we confirmed that reduced content of this motor protein in fibroblasts leads to failed lysosomal repositioning and diminished autophagic flux. Our study connects defects in intracellular trafficking with insufficient autophagy in old organisms and identifies motor proteins as a novel target for future interventions aiming at correcting autophagic activity with anti‐aging purposes.

Age-Related Intraneuronal Aggregation of Amyloid-β in Endosomes, Mitochondria, Autophagosomes, and Lysosomes

“…These results support ageand AD-related deficits in the mTOR pathway [50] and deficits in pAkt modulation of this pathway [58]. Further work is needed to discriminate between the fusion process, aspects of energized motor proteins for vesicle trafficking [59], processing of the A␤-CTF motif [11,60], processing of cytoplasmic A␤ by chaperone mediated autophagy [61] in age-related effects on iA␤ accumulation. These results confirm and extend histology and immunoblot results of agerelated changes in late-endosome regulation in the A␤PP/PS1 mouse brain [39].…”

Autophagy and cardiac aging

“…It would be critical to determine how autophagy flux is altered with aging. A recent study pointed out the significance of defects in intracellular trafficking of the autophagosome in aging-induced insufficient autophagy [137]. Lysosomal function also declines with age in which altered v-ATPase activity and lysosomal pH dysregulation are implicated as causes [138].…”

Expression of WIPI2B counteracts age-related decline in autophagosome biogenesis in neurons

“…For example, lysosomal integrity has been shown to decrease with age in neurons (Nixon, 2017). In non-neuronal cells, retrograde transport of autophagosomes appears to decrease with age in primary mouse fibroblasts (Bejarano et al, 2018). It will be interesting to investigate how the later stages of autophagy are altered with age in neurons.…”