In the nematode Caenorhabditis elegans and fruit fly Drosophila melanogaster, autophagy was indeed found to operate at significantly lower levels in aged animals than in young adults 15, 16, 17. This raises the possibility that autophagy works less effectively in neurons at advanced ages as compared to early adult stages. Defects in the autophagic process are implicated in the development of diverse neurodegenerative pathologies 9, 13, 14.

The autophagosome then fuses with a lysosome to form an autolysosome, in which the enzymatic breakdown eventually takes place (Fig. Macroautophagy (hereafter referred to as autophagy) involves the formation of a double membrane-bound vesicle called autophagosome to sequester the cytoplasmic materials destined for degradation. Depending on the mechanism by which autophagic cargo is delivered into the lysosomal compartment, three major types of autophagy can be distinguished: microautophagy, chaperone-mediated autophagy and macroautophagy. During autophagy, parts of the cytoplasm are delivered into lysosomes for degradation by acidic hydrolases. Thus, the effective elimination of damaged cytosolic materials is crucial for the long-term operation and survival of cells, primarily for those that are terminally differentiated and lost their capacity to proliferate, like neurons.Īutophagy acts as a major catabolic process of eukaryotic cells by which cellular damage can be effectively eliminated 8, 9, 10, 11, 12. Massive levels of cell death can then lead to the development of various age-associated degenerative pathologies, particularly neurodegenerative diseases. Such damages mainly include oxidized, aggregated and misfolded (i.e., non-functional) proteins, which interfere with cellular processes and homeostasis, thereby leading to the senescence and subsequent loss of the affected cells. The accumulation of cellular damage is a characteristic hallmark of essentially all ageing cells 1, 2, 3, 4, 5, 6, 7. We propose that EDTP and MTMR14 phosphatases operate as endogenous pro-ageing factors setting the rate at which neurons age largely independently of environmental factors, and that autophagy is influenced by DNA N 6-methyladenine levels in insects. Thus, EDTP, and presumably MTMR14, promotes brain ageing by increasingly suppressing autophagy throughout adulthood.

MTMR14, the human counterpart of EDTP, also tends to accumulate with age in brain neurons. The age-related increase in EDTP activity is associated with a growing DNA N 6-adenine methylation at EDTP locus. Furthermore, in the fruit fly Drosophila melanogaster, the myotubularin-related (MTMR) lipid phosphatase egg-derived tyrosine phosphatase (EDTP) known as an autophagy repressor gradually accumulates in brain neurons during the adult lifespan. Here we show that age-associated defects in autophagic degradation occur at both the early and late stages of the process. Despite its physiological and medical significance, it remains largely unknown why autophagy becomes incapable of effectively eliminating harmful cellular materials in many cells at advanced ages.

Autophagy (cellular self-eating) functions as a major cell clearance mechanism to degrade such damages, and its capacity declines with age. Ageing is driven by the progressive, lifelong accumulation of cellular damage.

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