The mechanisms of aging remain mysterious. The many findings arguing against the oxidative damage theory have led to doubts about the central premise that aging is a function of damage and maintenance. The recently proposed hyperfunction theory suggests that aging is caused not by damage but by deleterious run-on in late life of processes that promote fitness in early life. Such quasi-programmed hyperfunction [1] generates hypertrophy, atrophy and dysplasia, leading to age-related pathologies which cause death. We are testing this theory in C. elegans, in which many dysplastic pathologies do occur during aging [2], including atrophy and disintegration of the hermaphrodite distal gonad [3]. During normal hermaphrodite reproduction, germ cells undergo apoptosis, probably to provide cytoplasm for oocyte growth. We postulated that distal gonad atrophy is caused by quasi-programmed germline apoptosis, i.e. germline apoptosis is not switched off in post-reproductive worms, and so eats away the gonad. Consistent with this, blocking apoptosis by mutation of
ced-3 suppressed atrophy. Moreover, in males, where germline apoptosis does not occur, gonad atrophy does not occur either. A range of other genetic tests also supported our model, e.g.
gld-1(
op236), which increases germline apoptosis, accelerated gonad atrophy, and
ced-9(
n1950), which suppresses somatic but not germline apoptosis, did not suppress gonad atrophy. By contrast, treatments that increase damage levels (e.g. extra iron or mutation of
sod-2) did not accelerate gonad atrophy, nor did mutation of
spo-11, which blocks formation of DNA double-strand breaks during meiosis, have any effect on gonad atrophy. These findings provide a mechanistic explanation for a major pathology of aging in C. elegans, and its sex specificity: not molecular damage accumulation, but hyperfunction in the form of sex-limited quasi-programmed germline apoptosis. This supports a radical reinterpretation of the nature of aging in C. elegans. 1. Blagosklonny, Cell Cycle 7: 3344 (2008). 2. Gems, de la Guardia, Antiox. Redox Signal. Sep 24. [Epub ahead of print] (2012). 3. Garigan et al., Genetics 3: 1101 (2002).