Ageing is driven by the progressive, lifelong accumulation of cellular damage. Autophagy (cellular self-eating) functions as a major cell clearance mechanism to degrade such damages, and its capacity declines with age. 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. Here we show that age-associated defects in autophagic degradation occur at both the early and late stages of the process. 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. The age-related increase in EDTP activity is associated with a growing DNA N6-adenine methylation at EDTP locus. MTMR14, the human counterpart of EDTP, also tends to accumulate with age in brain neurons. Thus, EDTP, and presumably MTMR14, promotes brain ageing by increasingly suppressing autophagy throughout adulthood. 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 N6-methyladenine levels in insects.

Autophagy is a highly conserved self-degradation process of eukaryotic cells which is required for the effective elimination of damaged and unnecessary cytosolic constituents. Defects in the process can cause the intracellular accumulation of such damages, thereby leading to the senescence and subsequent loss of the affected cell. Defective autophagy hence is implicated in the development of various degenerative processes, including cancer, neurodegenerative diseases, diabetes, tissue atrophy and fibrosis, and immune deficiency, as well as in accelerated aging. The autophagic process is mediated by numerous autophagy-related (ATG) proteins, among which the ATG8/LC3/GABARAP (Microtubule-associated protein 1A/1B-light chain 3/Gammaaminobutyric acid receptor-associated protein) superfamily has a pivotal role in the formation and maturation of autophagosome, a key (macro) autophagic structure (the autophagosome sequesters parts of the cytoplasm which are destined for breakdown). While in the unicellular yeast there is only a single ATG8 protein, metazoan systems usually contain more ATG8 paralogs. ATG8 paralogs generally display tissue-specific expression patterns and their functions are not strictly restricted to autophagy. For example, GABARAP proteins also play a role in intracellular vesicle transport, and, in addition to autophagosome formation, ATG8 also functions in selective autophagy. In this review, we summarize the functional diversity of ATG8/LC3/GABARAP proteins, using tractable genetic models applied in autophagy research.

Autophagy is a conserved, lysosome-dependent catabolic process of eukaryotic cells which is involved in cellular differentiation. Here, we studied its specific role in the differentiation of spermatogonial cells in the Drosophila testis. In the apical part of the Drosophila testis, there is a niche of germline stem cells (GSCs), which are connected to hub cells. Hub cells emit a ligand for bone morhphogenetic protein (BMP)-mediated signalling that represses Bam (bag of marbles) expression in GSCs to maintain them in an undifferentiated state. GSCs divide asymmetrically, and one of the daughter cells differentiates into a gonialblast, which eventually generates a cluster of spermatogonia (SG) by mitoses. Bam is active in SG, and defects in Bam function arrest these cells at mitosis. We show that BMP signalling represses autophagy in GSCs, but upregulates the process in SG. Inhibiting autophagy in SG results in an overproliferating phenotype similar to that caused by bam mutations. Furthermore, Bam deficiency leads to a failure in downstream mechanisms of the autophagic breakdown. These results suggest that the BMP-Bam signalling axis regulates developmental autophagy in the Drosophila testis, and that acidic breakdown of cellular materials is required for spermatogonial differentiation.

Cellular regeneration, which relies on extensive restructuring of cytoplasmic materials, is an essential process to restore tissues and organs lost during aging, degenerative diseases and injury. At early stages of Drosophila spermatogenesis, when cellular constituents are intensely remodeled, there are two different populations of stem cells, the somatic stem cells and the germline stem cells (GSCs). GSCs divide by asymmetric division to give rise two distinct daughter cells. One of them will leave the stem cells’ niche and differentiate into spermatogonial cells (SCs). Both aging and cellular stress can lead to the loss of GSCs. Lost GSCs can be restored by dedifferentiation of SCs into functional GSCs. In other tissues, macrophages provide specific conditions for cellular transformation. Here we examined the potential role of immune surveillance cells called hemocytes during dedifferentiation of SGs into GSCs. We found an elevated number of hemocytes during this dedifferentiation process. Immune depletion of hemocytes decreased the regeneration capacity of germline. We also show that autophagy, which plays a pivotal role in cellular differentiation by eliminating unwanted, superfluous parts of the cytoplasm, becomes upregulated in dedifferentiating SCs upon JAK-STAT signaling emitted by hemocytes. Furthermore, these immune cells regulate expression of Omi/HtrA2, a key regulator of apoptosis in early spermatogenesis. Together, we suggest that hemocytes have important functions in the dedifferentiation process of GSCs.

Aging is driven by the progressive, lifelong accumulation of cellular damage. Autophagy (cellular self-eating) functions as a major cell clearance mechanism to degrade such damages, and its capacity declines with age. Despite its physiological and medical significance, it remains largely unknown why autophagy becomes incapable of effectively eliminating harmful cellular materials at advanced ages. Here we show that age-associated defects in autophagic degradation occur at both early and late stages of the process. Furthermore, in the fruit fly Drosophila melanogaster, the myotubularin-related (MTMR) lipid phosphatase EDTP (egg-derived tyrosine phosphatase) known as an autophagy repressor gradually accumulates in brain neurons during the adult life span. The age-related increase in EDTP activity is associated with a growing DNA N6-adenine methylation at EDTP locus. MTMR14, the human counterpart of EDTP, also tends to accumulate with age in brain neurons. Thus, EDTP, and presumably MTMR14, promotes brain aging by increasingly suppressing autophagy throughout adulthood. We propose that EDTP and MTMR14 phosphatases operate as endogenous pro-aging factors setting the rate at which neurons age largely independently of environmental factors, and that autophagy is influenced by DNA N6-methyladenine levels.