INTRODUCTION TO AGING IN C. ELEGANS
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1 Overview

C. elegans offers several advantages for studying the basic biology of aging. First, the lifespan is relatively short (just 2-3 weeks under standard laboratory conditions), rendering whole-life survival analyses feasible. Second, large numbers of genetically identical animals can be easily grown under controlled environmental conditions.  Third, the transparent body enables an in vivo view of how cells and tissues change with age. Fourth, a wealth of in-depth knowledge of cell orgins (Sulston and Horvitz, 1977; Sulston et al., 1983), neuronal connections (White et al., 1986; Jarrell et al., 2012; Cook et al., 2019), and genome content (C. elegans Sequencing Consortium) support mechanistic investigations. A major advantage of the C. elegans model is the ease with which genetic approaches can be exploited to inform on biology, such that a large number of genetic mutations that can alter longevity have been identified. Finally, the C. elegans lifespan exhibits tremendous plasticity, and can be affected by environmental conditions and nutrition, as well as genetic mutations (Antebi, 2007; Collins et al., 2008). It is interesting that, even under controlled conditions, individual lifespans can vary significantly, revealing a stochastic component to aging (Herndon et al., 2002).

Under laboratory conditions, C. elegans are provided with ample food, a controlled environment and protection from competition and hazards. Therefore, laboratory conditions create an environment in which older, frail nematodes most likely survive longer than they would in nature (Félix and Duveau, 2012; Samuel et al., 2016). Life history will most certainly also differ between laboratory-raised C. elegans and C. elegans in nature, where food can be quickly depleted leading to the dauer developmental diapause (Schulenburg and Félix, 2017). While researchers acknowledge the artificial nature of measuring C. elegans lifespan under laboratory conditions, the range of phenotypes observed in laboratory-housed nematodes and their recapitulation of many features of metazoan aging coupled with the powerful experimental tools applicable to argue for the value of C. elegans in deciphering the basic biology of aging.



2 C. elegans Life History

With abundant food, optimal temperature (20°C), and sparse population, C. elegans larvae complete development from embryo to adult in about 3 days. After hatching, C. elegans larvae proceed through four larval stages, L1 to L4, before becoming fertile adults. Between each larval stage, larvae undergo molting, during which pharynx pumping ceases and the stage-specific cuticle is shed and replaced by a newly synthesized one. Most adult C. elegans are self-fertile hermaphrodites (males can arise spontaneously as the result of rare sex-chromosome non-disjunction; for more details of hermaphrodite development see Hermaphrodite Introduction). C. elegans adult hermaphrodites produce ~300 progeny by self fertilization before they enter a post-reproductive stage, during which they undergo behavioral and physiological declines leading up to death (AIntroFIG 1; see also IntroFIG 6).

C. elegans rate of development is affected by temperature such that animals raised at higher temperatures develop more rapidly and die more quickly than animals raised at lower temperatures (IntroTABLE 2). Similarly, aging-related declines in adults occur faster at higher temperatures (Klass 1977; Lee and Kenyon, 2009).

Under harsh environmental conditions, with limited food, high temperature, or overcrowding, larvae may reversibly arrest development in an alternative third larval stage named the dauer (“enduring”) larvae (DIntroFIG 1) (Klass and Hirsh, 1976; Hu, 2007; Félix and Braendle, 2010). Dauer larvae possess distinct adaptations for long-term survival in harsh environments (DIntroFIG 3). Dauers have a thickened cuticle that seals the buccal cavity for protection from environmental threats. With the buccal cavity sealed closed, dauers are unable to feed and shift to fat-based metabolism, utilizing lipid stored during dauer development (for detailed description see Dauer Handbook). The dauer has been called “non-aging” since it can survive for many months in this state. Exposure to food or more favorable environment triggers recovery from dauer into the fourth larval (L4) stage and subsequent development into normal adults, indistinguishable from adults which did not pass through dauer. While time spent in the dauer stage does not affect adult lifespan (Klass and Hirsh, 1976), recent studies have shown that long-term dauer diapause can affect the reproductive success of recovered animals and that there this extended period of time spent in dauer can result in adaptive transgenerational effects such as starvation resistance and increased lifespan (Webster et al., 2018).

Adult hermaphrodites are self-fertile for approximately 3-4 days and produce about 300 progeny, reproduction that is limited by the number of sperm the hermaphrodite carries, although she can produce extra progeny when fertilized by a male partner (Hughes et al., 2007). After reproduction ceases, animals enter a post-reproductive period lasting up to 2 to 3 weeks before death (Klass and Hirsh, 1976; Johnson and Wood, 1982). During the post-reproductive period, feeding, defecation and locomotory rates decline, tissues deteriorate, and animals become more sensitive to microbial infection (Johnson, 1987; Herndon et al., 2002; Glenn et al., 2004; Huang et al., 2004; Garigan et al., 2002; Johnston, 2008). Given that different laboratory conditions and methodologies significantly impact aging rates and lifespan results (Lithgow et al., 2017), experiments performed across laboratories often show a variability in the timing and magnitude of aging-related phenotypes and as such cannot be directly compared.

AIntroFIG 1: Life Cycle of C. elegans. C. elegans larval development proceeds through 4 larval stages (L1 through L4). L4 larvae molt into adults that survive for approximately 3 weeks under normal laboratory conditions; age-associated declines can be meansured as various aging "phenotypes" over adult life. L1 larvae may proceed through the alternate dauer pathway under harsh environmental conditions. Dauer larvae are adapted for long-term survival and dispersal to new environments. Once in a more favorable environment, dauer larvae reenter reproductive development by molting into the L4 larval stage and progressing through the rest of the life cycle normally. (Adapted from WormAtlas IntroFIG 6 and DIntroFIG 1.)

3 Hallmarks of Aging

3.1 Gut Granules

During aging, C. elegans adults undergo physical changes that reflect waste accumulation and molecular alterations in the body’s cells and tissues. One of the most easily observed aging-related changes is the accumulation of fluorescent compounds in the intestine, referred to as “gut granules”. The “gut granules” are hypothesized to consist of lipofuscin, also known as advanced glycation end products (Klass, 1977; Garigan et al., 2002; Herndon et al., 2002; Gerstbrein et al. 2005). Other studies indicate the presence of anthranilic acid in gut granules (Coburn and Gems, 2013). Studies by Pincus et al. (2016) indicate that the autofluorescense seen in C. elegans is the product of a complex mixture of materials that reflect distinct aspects of organismal physiology and aging. Their results suggest that autofluoresence in the red wavelengths best correlates with aging related processes and lifespan of individual animals.

3.2 Reproductive Senescence

Production of progeny slows after the first 3-5 days of adulthood, and ceases altogether when the hermaphrodite’s sperm stores have been exhausted, a process called reproductive senescence. However, mated hermaphrodites can continue to produce progeny for a few more days indicating that hermaphrodites continue to produce good oocytes for a few days even after using up their own sperm supply. Theseoocytes, however, decline in their quality with age (Hughes et al., 2007; Luo et al., 2010; Luo et al., 2011; Templeman et al., 2018). In older individuals, these unfertilized oocytes continue to flow through the gonad, undergo various subcellular changes, and can create a large tumor-like body filling the hermaphrodite uterus (McGee et al., 2012; Kryiakakis et al., 2015; de la Guaria et al., 2016; Herndon et al., 2017).

During reproductive senescence, the intestine continues to produce and secrete large amounts of yolk protein for uptake by developing oocytes, even as oocyte production dwindles (Garigan et al., 2002Herndon et al., 2002McGee et al., 2011) (see Aging Intestine Handbook and AIntFIG 4). Several different cell types display nuclear dysregulation, with a loss of regulatory control over transcription and translation. In some cell types, nuclei seem to fade and then disappear altogether, which may well confer detrimental downstream effects on transcription, translation and the structure and function of other cellular components (McGee et al., 2011; AIntFIG 8).

3.3 Locomotory Decline

Like many animals, older C. elegans adults tend to move more slowly and with less vigor as compared to their younger selves. Both hermaphrodites and males exhibit peak activity in behaviors during the first few days of adulthood. For hermaphrodites, the first 3 days of adulthood mark the time of maximum body length, movement rate and egg laying rate (Hosono, et al., 1980; Herndon, et al., 2002; Huang et al., 2004; Pickett and Kornfeld., 2013; Hahm, 2015). Males display the most energetic mating behaviors during the first 3 days as adults (Koo et al., 2011; Guo et al., 2012; Chatterjee, 2013). After the young adult period, movement gradually declines. Body motions become sporadic during days 6-10, and eventually animals stop spontaneous motion altogether, though they may still be aroused by strong mechanical stimuli for a few days longer (AIntroVID 1, AIntroVID 2, AIntroVID 3 & AIntroVID 5) (Herndon et al., 2002; Glenn et al., 2006; Pincus and Slack, 2010; Stroustrup et al., 2016). Pumping of the pharynx gradually slows after the first few days of adulthood, and the function of the grinder in breaking down bacterial food becomes less and less successful (Bolanowski et al., 1981; Huang et al., 2004; Chow et al., 2006; Zhao et al, 2017).

The rate of locomotory decline is variable from animal to animal, and some animals continue active and coordinated locomotion for many days. The adults displaying the most accelerated locomotory declines are also the most likely to die earlier (Hosono et al., 1980; Herndon et al., 2002; Glenn et al., 2004; Huang et al., 2004; Johnston, 2008; Hahm, 2015). Muscle tone is gradually lost due to decline in muscle structures (Herndon et al., 2002). Changes in neurons may predate muscular decline (Toth et al., 2012; Liu et al., 2013). Male behavioral declines during aging remain to be thoroughly characterized.


AIntroVID 1. C. elegans movement declines during aging. Videos of swimming wildtype C. elegans (A.) young adults (day 4) (B.) middle-aged adults (day 11) and (C.) old adults (day 15). The swimming movement is termed “thrashing” and can be manually counted or computationally analyzed in detail. Thrashing rates decline as the animals age. (Video Source: C.I. Ventoso and M. Driscoll, Rutgers University; Restif et al., 2014; Ibáñez-Ventoso et al., 2016)

AIntroVID 2: Worms of 3 ages crawling on agar. Video shows 3-day worm in center, 8-day worm on left, and 12 day worm on right. With increasing age, C. elegans show decreased spontaneous movement and locomotion. (Video Source: J. Durieux, Dillin Lab.)

AIntroVID 3: Plate of worms from hatching to death. Time-lapse video covering 3 weeks of automatic image captures by the Lifespan Machine (Stroustrup et al., 2013) of a single plate with wild-type animals grown at 25°C , overlaid with metadata from image analysis. Animals are colored according to their movement class. Animals that manifest locomotion are colored purple. Stationary animals that manifest posture changes are colored yellow. Completely motionless (dead) animals are colored red. Blue objects have been excluded as nonworm objects during the validation step. The survival curve of the plate population is shown on the bottom right. Note that all the wild type worms are dead by 12 days (8 seconds). (Video source with permission Stroustrup et al., 2013.)

3.4 Morphological Changes

Generally, the body deteriorates in appearance as C. elegans adults age (Garigan et al., 2002; Herndon et al., 2002; Collins et al., 2017; Herndon et al., 2017). Older adults can become locally shrunken and take on a swollen appearance at the midbody. The cuticle becomes wrinkled along its length (AIntroFIG 2 & AIntro FIG 5; see also Aging Cuticle). The pharynx can become weakened and bent with large vacuoles appearing in the bulbs and isthmus (AIntroFIG 4; APhaFIG 8; see also Aging Pharynx). The gonad deteriorates and takes on a disorganized appearance (AIntroFIG 3 & AIntroFIG 4). The intestine atrophies (AIntFIG 2) but the lumen may also swell in places where bacterial growth has begun (AIntFIG 3; see also Aging Intestine). Overall, old adults become frail and flaccid-appearing (AIntroFIG 3, AIntroFIG 4 & AIntroVID 4). Importantly, many of these changes are stochastic, and the rates of decline vary among cells within an animal, as well as among individual animals within a synchronized population (AIntroVID 5) (Herndon et al., 2002; Herndon et al., 2017).


AIntroFIG 2: Scanning electron micrographs (SEMs) of young and old C. elegans. Panels show nemtodes at different ages of adulthood with anterior on left and posterior on right. A. In a young adult (2-day), the external cuticle appears mostly smooth. B. 7-day-old nematode features more distinctive annuli in head and tail with some deeper wrinkles in these areas. Vulval extrusion is visible in this example. C. 13-day-old nematode has extensive wrinkling along entire body with deep grooves and cuticular folds that deform the shape of the body structure with a large vulval extrusion in this specimen. (Image source: Arjumand Ghazi, University of Pittsburgh School of Medicine.)
AIntroFIG 3: Nomarski images of young and older C. elegans. Panels show nemtodes of different ages of adulthood with anterior on left and posterior on right. A. 1-day-old worm is smooth, with well organized internal organs. Proximal and distal gonad are pronounced with embryos lined up at various stages of development in the proximal arm. Intestine runs in a even line from the pharynx to the anus (see IntroFIG 1 for labeled diagram). B. 4-day-old worm is still smooth and the organs are distinct. More late stage embryos inside the gonad. C. 7-day-old worm is post-reproductive with no viable looking embryos or germline. Intestine looks full and there are areas of clearing throughout the body. D. 15-day old worm features a kinked intestine that is pushed against the hypodermis by other internal components and a gonad that is swollen and filled with tumor-like masses. Extensive areas of clearing throughout the body. (Image source: M. Hess, Ewald Lab.)
AIntroFIG 4: A single worm imaged at time points throughout lifespan. Brightfield images are shown of a single individual for each day of life from the L4-adult molt (top image) until death (bottom image). Images were acquired at 10× magnification, using a custom culture apparatus maintained at 25°C. The position of the individual in each image was manually annotated and the images were computationally straightened into the "worm frame of reference" with anterior on the right and posterior on the left. Shrinking of the animal with age is particularly striking in this series. (Image source: Z. Pincus, Washington University; Zhang et al., 2016.)
AIntroFIG 5: TEM showing wrinkling and changes in body structure with age. A. TEM of young adult exhibiting thin cuticle with annuli appearing in regular, evenly spaced patterns. Note organized muscle structure and gonad (gonad is seen obliquely so that the rachis is not in frame of thin section). (Image source: [Hall] N533 F1_Z731.) B. Lengthwise electron microscopy image of 7-day-old adult (class B) with thickened cuticle that has deep wrinkles with annuli that are less even and distinct in appearance. Electron dense yolk protein fills the body cavity (pseudocoelom) and there is extensive vacuolization of the intestinal cell cytoplasm while the lumen is filled with live bacteria. (Image source: {Hall] N824 5073.)

4. Death

Anatomical changes during aging may constitute proximal causes of death in C. elegans, as for many other organisms. Weakened mechanical defenses along the alimentary tract may allow bacterial cells to invade the body and once internalized, could proliferate unchecked due to coelomocyte aging and inactivity. Indeed, environments supplemented with antimicrobial compounds can extend C. elegans lifespan (Garigan et al., 2002). However, the fact that antimicrobial protection does not confer immortality demonstrates that C. elegans adults also succumb to other causes of death. Generalized physical deterioration may disrupt bodily functions to a lethal extent (Zhao et al., 2017). Clearance of detritus and toxins appears to be impaired in older C. elegans, as evidenced by accumulation of debris in the pseudocoelomic space. Declining neuronal signaling, combined with muscle cell breakdown as aging progresses, interfere with foraging and escape from environmental threats. In some hermaphrodites, gonad dysfunction leads to internal hatching of embryos, which is a lethal event for the mother.



AIntroVID 4: Time-lapse video of individual from hatching to death. Brightfield images are shown of a single individual, from hatching until death. Images were acquired at 5× magnification, using a custom culture apparatus maintained at 25°C. Specific life stages (L1-L4 and adulthood) are noted, as are the time of hatching, the times of the first and last egg laid, and the time of death. This individual is of genotype spe-9(hc88), and at the restrictive temperature of 25°C lays unfertilized oocytes. (Video source: Z. Pincus, Washington University; Zhang et al., 2016.)

AIntroVID 5: Time-lapse video of group from adulthood to death. Brightfield images of 20 individuals are shown in a grid from young adulthood until death (see IntroMOVIE 2 for video of same animals from hatching to adulthood). Images were acquired at 5× magnification, using a custom culture apparatus maintained at 25°C. Specific life stages (reproductive [egg] and post-reproductive [post] adulthood) are denoted by the colored bars; dead individuals fade to gray. These individuals are of genotype spe-9(hc88), and at the restrictive temperature of 25°C lay unfertilized oocytes. (Video source: Z. Pincus, Washington University; Zhang et al., 2016.)

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* Description of Behavioral Classes (A, B, C) as described in Herndon et al., 2002

To characterize aging phenotypes, age-synchronized individual worms were scored both for spontaneous movement and for response to prodding with a wire over the course of their lifespan. Three distinct classes representing behavioral phenotypes were established. Animals that move constantly and make sinusoidal tracks were designated as class A. Class B animals mainly move when prodded. When they move it is with uncoordinated motion, leaving non-sinusoidal tracks. Class C animals do not move forward or backward, even upon prodding, but do show head and/or tail movement and twitch in response to touch.  All animals begin adulthood in class A. Class B animals appear around days 6-7 of adulthood  and class C around day 9-10 (at 20oC). At later ages, animals representing all classes can be found within the same population and it was found that the behavioral class type was the better predictor of life expectancy than chronological age (Herndon et al., 2002). Due to the stochastic nature of aging in an individual nematode, these classifications only reflect ongoing changes in nerve and muscle, while other tissues can show very different age-related effects within one behavioral class, declining faster or remaining healthy much longer.



This chapter should be cited as: Herndon, L.A., Wolkow, C.A., Driscoll, M. and Hall, D.H. 2018. Introduction to Aging in C. elegans. In WormAtlas.
Edited for the web by Laura A. Herndon. Last revision: December 1, 2018.
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