Telomeric autophagy in human health, aging, and diseases

Telomeres are repetitive DNA sequences that cap chromosome ends and protect genomic stability. The term "telomeric autophagy" has been applied to the relationship between telomere dysfunction and autophagy, but it has been used to describe two processes that are not equivalent, and much of the confusion in this literature follows from conflating them. The first is the induction of autophagy by dysfunctional telomeres. This is established: during replicative crisis, telomeric damage generates cytosolic chromatin fragments that activate cGAS-STING signalling and engage the autophagy machinery, an induction specific to telomeric damage and not produced by intrachromosomal breaks, and one that has been independently reproduced in cells maintaining telomeres through alternative lengthening. The second is the selective autophagic degradation of telomeric chromatin itself. For this we were unable to identify direct evidence: no receptor bridging telomeric chromatin to ATG8-family proteins has been described, telomeric cargo has not been recovered from autolysosomes, and no compound acts selectively on the process. This review therefore separates the two throughout, grades the evidence for each claim it makes, and applies the same grading to the disease literature, where cancer emerges as the only setting in which telomeric and autophagic endpoints have been measured in the same system. Its aim is to establish what is known with confidence, what rests on inference, and what would have to be shown for telomere-selective autophagy to be regarded as a pathway. Telomeric autophagy; telomere; aging; cellular senescence; autophagy; cancer; neurodegenerative diseases.