According to ideas of G.C. Williams and M.V. Blagosklonny, a major cause of senescent pathology (i.e. of aging) is harmful, late-life gene action, manifesting as deleterious run-on of developmental and reproductive functions (or hyper-function). In C. elegans hermaphrodites, open faucet-type run-on of reproductive processes is a cause of several major senescent pathologies, including gonad atrophy, uterine tumor formation, intestinal atrophy and yolk accumulation. The latter seems to occur because during hermaphrodite selfing, vitellogenin (yolk protein) is synthesized in the intestine and taken up by oocytes; after depletion of hermaphrodite sperm, oocyte ceases, but yolk production does not. This causes yolky lipid pools to accumulate to high levels in the body cavity, and ectopic yolk deposition, a form of senescent steatosis. We have formally tested this model, according to which yolk accumulation reflects failure to switch off its source (synthesis) and loss of a sink (egg laying). Consistent with this, after self-sperm exhaustion, yolk protein (YP) levels accumulate continuously up to day 14 of adulthood. This causes YP170 levels to increase up to 7-fold relative to day 1 levels, and an overall YP level that is 30-40% of total protein content. These changes are fully suppressed in long-lived
daf-2(
e1370) mutants. Moreover, provision of additional sperm by mating suppresses yolk accumulation, and spermless
fog-2 mutants exhibit accelerated yolk accumulation. Yolk synthesis is coupled to intestinal atrophy by autophagy-dependent conversion of gut biomass into yolk, and blocking YP synthesis by combined
vit-5,
vit-6 RNAi suppresses yolk steatosis and gut atrophy and extends lifespan. Notably,
vit-5 RNAi increased VIT-6 protein levels, and
vit-6 RNAi increased YP170 levels, but RNAi of
vit-5 and
vit-6, alone or combined, had no effect on overall protein content per worm. Moreover, RNAi of
vit-5 or
vit-6 alone does not prevent gut atrophy. This suggests a model in which vitellogenin synthesis monopolizes intestinal protein synthesis in a way that leads to organ atrophy. We are currently testing this model.