One view of aging is as the set of endogenously-generated pathologies that increase in late life, some of which contribute to age-related mortality. This implies that to understand aging in C. elegans one needs to characterize age-related pathologies and their development, identify the processes that promote pathology development, and establish which pathologies cause death. To this end we have established methodologies for simultaneous assessment of a range of late-life pathologies of aging C. elegans. Using these we have identified a burst of rapid pathogenesis involving gross anatomical changes, which occurs mainly between day 4 and 10 of adulthood in N2 hermaphrodites. One such pathology results from the continuation of yolk production after reproduction has ceased, causing accumulation of yolk and in detrimental effects on the worm in later life. Yolk is a lipoprotein complex of yolk proteins (vitellogenins) and lipids, including phospholipids and triglycerides. Continued yolk synthesis leads to an eventual ~8–fold increase in the major yolk protein component YP170. Yolk proteins eventually constitute ~75% of total worm protein content, and there is an ~10-fold age increase in total protein content per worm. In old animals, up to 50% of the body cavity can be filled up with yolk pools, which stain with the lipophilic dye Bodipy, and there is a ~5-fold increase in overall triglyceride content. Thus, elderly hermaphrodites experience severe hyperproteinemia and steatosis. Knock down of vitellogenins using vit-5 + vit-6 RNAi suppressed yolk accumulation and the development of other age-related pathologies, and increased lifespan. Conversely, suppressing yolk uptake by oocytes by rme-2 RNAi increased yolk pool accumulation, altered other pathologies and decreased lifespan, suggesting that ectopic yolk deposition has toxic effects. In long-lived daf-2 insulin/IGF-1 receptor mutants this yolk hypertrophy is suppressed. Together, these data suggest that aging C. elegans hermaphrodites undergo an overgrowth phase during early adulthood, characterized by vigorous biological activity rather than loss of function. This overgrowth phase results in, among other things, excess biosynthesis and the accumulation of large pools containing vitellogenic proteins and lipids in the body cavity, which have toxic effects and result in the acceleration of age-related pathologies and shortening of lifespan.
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