One of my first mentors was fond of pointing out that the risk of cancer skyrockets with chronological age, and that (therefore, in his estimation) anyone who lived long enough would eventually get cancer. The idea seems to make lifespan extension cruelly futile, as when mythic Eos secured eternal life for her mortal lover Tithonus but forgot to add an eternal youthfulness clause (short version: able to age but not die, he shriveled into an immortal cricket). Sure, anti-aging medicine might make us live longer, but that would just guarantee that we would eventually get cancer and die.
But maybe not.
Worms lacking a tumor suppressor gene develop tumors, which shorten the host’s already short life. This week, Pinkston et al. from the Kenyon lab at UCSF show that mutations in the DAF-2 IGF-like signaling pathway completely suppress the lethality of the tumors:
Mutations in gld-1 cause lethal germline tumors in the nematode Caenorhabditis elegans. We find that a wide variety of mutations that extend C. elegans’ life span confer resistance to these tumors. The long life spans of daf-2/insulin-receptor mutants were not shortened at all by gld-1 mutations; we attribute this finding to decreased cell division and increased DAF-16/p53–dependent apoptosis within the tumors. Mutations that increase life span by restricting food intake or inhibiting respiration did not affect apoptosis but reduced tumor cell division. Unexpectedly, none of these longevity mutations affected mitosis in normal germlines; this finding suggests that cellular changes that lead to longevity preferentially antagonize tumor cell growth.
This adds yet another accomplishment to the daf-2 mutation’s resumé: It extends life, increases stress resistance, regulates immunity to pathogens, prevents the accumulation of toxic protein aggregates … and (we now know) prevents tumors. Subject to all qualifications about this happening in a barely visible roundworm with a two-week lifespan, it’s still quite impressive.
Since DAF-2 is involved in a growth factor signaling pathway, it perhaps comes as no surprise that cells would grow more slowly in daf-2 mutants. Not so, however: only gld-1 daf-2 tumor cells are affected; the germ line of daf-2 animals with wildtype GLD-1 grow normally. (Worm biology review: adult C. elegans are post-mitotic except for the germline.)
Furthermore, there is also a higher rate of cell death in the tumor cells of gld-1 daf-2 animals, so it’s not just slower growth that accounts for the difference in survival. (To me, this is somewhat reminiscent of mammalian cells in culture undergoing apoptosis when they are deprived of serum growth factors, but once again, the germ line cells of daf-2 worms do not show increased cell death).
Take-home message: Downregulating IGF-like signaling in the worm not only extends life but extends the healthiest part of it, by multiple mechanisms. The next step in this story is to identify the downstream targets of DAF-2 that are responsible for the tumor suppression observed here, perhaps along the lines of the approach taken in the proteotoxicity paper we discussed last week.