Autophagy Regulator MYTHOS Required for Some Life Extending Interventions in Nematode Worms
Researchers have shown that extension of life via calorie restriction requires functional autophagy, the collection of cell maintenance processes responsible for recycling damaged proteins and structures. Similarly, researchers here note a novel autophagy regulator gene called MYTHOS that is present in species as far distant as humans and nematode worms, and which is required for a number of life-extending genetic interventions to work in nematodes. Further, MYTHOS expression is upregulated with age, suggesting it is a compensatory adaptation that attempts to combat rising levels of cellular dysfunction with greater housekeeping. MYTHOS itself may or may not be a basis for intervention, but it is yet another piece of evidence to support continued efforts to develop therapies that can improve the operation of autophagy in order to slow aging.
A general cause of cellular senescence and organism aging is the progressive accumulation of dysfunctional organelles and cellular damage. Impairment of proteostasis alters the protein quality control systems, leading to the accumulation of aberrant and dysfunctional macromolecules and is considered among the primary hallmarks of aging. All cells take advantage of an array of mechanisms to preserve the stability and functionality of their proteins or to remove them when they are irreversibly damaged. One of the most important cellular housekeeping and prosurvival pathways is macroautophagy, hereafter named autophagy, whose main action is to remove damaged proteins/organelles and generate molecules that sustain cellular core metabolism.
To identify uncharacterized factors that control aging and proteostasis, we screened our published transcriptomic profiles. We discovered that the human DNA sequence C16ORF70 encodes a protein, named MYTHO (macroautophagy and youth optimizer), which controls life span and health span. MYTHO protein is conserved from Caenorhabditis elegans to humans and its mRNA was upregulated in aged mice and elderly people. Deletion of the orthologous myt-1 gene in C. elegans dramatically shortened life span and decreased animal survival upon exposure to oxidative stress. We tested the long-lived glp-1 (which shows reduced proliferation of germline cells) and eat-2 (a genetic dietary restriction model) mutants. The findings that the absence of myt-1 completely blunted the life extension of glp-1 mutants and partially affected the longevity of eat-2 mutants suggest that myt-1 is mediating the response to germline signals and dietary cues, respectively.
Mechanistically, MYTHO is required for autophagy likely because it acts as a scaffold that binds WIPI2 and BCAS3 to recruit and assemble the conjugation system at the phagophore, the nascent autophagosome. We conclude that MYTHO is a transcriptionally regulated initiator of autophagy that is central in promoting stress resistance and healthy aging.