In nematode worms, SKN-1 is a known longevity-related gene, and researchers here explore its role in the lysosomal enlargement that occurs with aging. Lysosomes are necessary for the cellular maintenance processes of autophagy to function. Lysosomes carry out the last step in the recycling of damaged and excess proteins machinery and structures in the cell, which is to break down those materials into components that can be reused. It has been observed that lysosomes become larger in cells in aged tissues, but this is apparently a compensatory behavior rather than a form of dysfunction. It is an attempt to maintain lysosomal function and thus the health of the cell in the face of the damage of aging.
Lysosomes are critical hubs for both cellular degradation and signal transduction, yet their function declines with age. Aging is also associated with significant changes in lysosomal morphology, but the physiological significance of these alterations remains poorly understood. Here, we find that a subset of aged lysosomes undergo enlargement resulting from lysosomal dysfunction in C. elegans. Importantly, this enlargement is not merely a passive consequence of functional decline but represents an active adaptive response to preserve lysosomal degradation capacity. Blocking lysosomal enlargement exacerbates the impaired degradation of dysfunctional lysosomes.
Mechanistically, lysosomal enlargement is a transcriptionally regulated process governed by the longevity transcription factor SKN-1, which responds to lysosomal dysfunction by restricting fission and thereby induces lysosomal enlargement. Furthermore, in long-lived germline-deficient animals, SKN-1 activation induces lysosomal enlargement, thereby promoting lysosomal degradation and contributing to longevity. These findings unveil a morphological adaptation that safeguards lysosomal homeostasis, with potential relevance for lysosomal aging and life span.
