Genetic and pharmacological factors that influence reproductive aging in nematodes

Abstract

Age-related degenerative changes in the reproductive system are an important aspect of aging, because reproductive success is the major determinant of evolutionary fitness. Caenorhabditis elegans is a prominent organism for studies of somatic aging, since many factors that extend adult lifespan have been identified. However, mechanisms that control reproductive aging in nematodes or other animals are not well characterized. To use C. elegans to measure reproductive aging, we analyzed mated hermaphrodites that do not become sperm depleted and monitored the duration and level of progeny production. Mated hermaphrodites display a decline of progeny production that culminates in reproductive cessation before the end of the lifespan, demonstrating that hermaphrodites undergo reproductive aging. To identify factors that influence reproductive aging, we analyzed genetic, environmental, and pharmacological factors that extend lifespan. Dietary restriction and reduced insulin/insulin-like growth factor signaling delayed reproductive aging, indicating that nutritional status and a signaling pathway that responds to environmental stress influence reproductive aging. Cold temperature delayed reproductive aging. The anticonvulsant medicine ethosuximide, which affects neural activity, delayed reproductive aging, indicating that neural activity can influence reproductive aging. Some of these factors decrease early progeny production, but there is no consistent relationship between early progeny production and reproductive aging in strains with an extended lifespan. To directly examine the effects of early progeny production on reproductive aging, we used sperm availability to modulate the level of early reproduction. Early progeny production neither accelerated nor delayed reproductive aging, indicating that reproductive aging is not controlled by use-dependent mechanisms. The implications of these findings for evolutionary theories of aging are discussed.

Figure 1. Reproductive Activity of C. elegans Hermaphrodites

(A), (C–E), (G), and (I) show average daily progeny production of live hermaphrodites. (B), (F), (H), and (J) show the percentage of live hermaphrodites producing progeny. The daf-2 plot (H) does not end at zero percent because no daf-2 hermaphrodites survived beyond day 12. Number of hermaphrodites at the start of the experiment is presented in Table 1. Hermaphrodites were mated for days 1 and 2 to three wild-type (WT) males, except data labeled Self. Studies were conducted at 20 °C, except data labeled 15 °C and 25 °C. The mutant alleles were isp-1(qm150), clk-1(qm30), eat-2(ad465), daf-2(e1370), and daf-16(mu86). Wild-type hermaphrodites were exposed to 2 mg/ml ethosuximide (+ETH) from conception until death (I and J).

Figure 2. Reproductive Aging Is Independent of Early Progeny Production

Wild-type (A), spe-8(hc50) (B), or fog-2(q71) (C) hermaphrodites were mated to wild-type (WT) males for 24–48 h starting with the day specified. Graphs show daily progeny production, and (D) shows the average total progeny production (+/−standard error) for days 1–7 and days 8–12. N, the number of animals examined. * and ** represent a p-value of 0.01−0.05 and <0.01, respectively, compared to the mated day 1 value of the same genotype. (E) A summary of the effects on early and late reproduction of an anticonvulsant drug, temperature, and mutations that affect mitochondrial function, caloric intake, and IGF signaling.

Figure 3. Reproductive Aging Contributes to the Ability of Animals to Generate the Optimal Progeny Number

Hypothetical progeny production curves illustrate three mechanisms for controlling progeny number: the timing of the onset of progeny production (labeled 1), the level of steady-state progeny production (labeled 2), and the timing of cessation of progeny production or reproductive aging (labeled 3). Reproductive aging might be sculpted during evolution by selection for animals that generate the optimal number of progeny.