Sci. Aging Knowl. Environ., 30 June 2004
Vol. 2004, Issue 26, p. pe28
[DOI: 10.1126/sageke.2004.26.pe28]

PERSPECTIVES

Epigenetic Regulation of Aging in Honeybee Workers

Stig W. Omholt, and Gro V. Amdam

Stig W. Omholt and Gro V. Amdam are in the Centre for Integrative Genetics and the Department of Animal Science, Agricultural University of Norway, 1432 Aas, Norway. Gro V. Amdam is also at the University of California, Department of Entomology, Davis, CA 95616, USA. E-mail: stig.omholt{at}cigene.no (S.W.O.)

http://sageke.sciencemag.org/cgi/content/full/2004/26/pe28

Key Words: evolution • honeybee • vitellogenin • hormones • epigenetic • worker bee

Introduction

The potential importance of social insects for biogerontology was recently discussed by Rueppell et al. at Science's SAGE KE (1). Research on aging in social insects is in its infancy, and it remains to be seen whether ants, wasps, bees, and termites ". . . will make important contributions to our overall understanding of aging in biological systems across all levels of biological organization" (1). However, in the case of the honeybee (Apis mellifera), we have at least begun to see the end of the beginning of a fascinating story about the reasons for senescence in the female worker bee.

The honeybee is one of the most socially advanced and by far the best-studied species in the order Hymenoptera [see (2) for a review on honeybee biology]. The honeybee worker is a beautiful gerontological model because (i) it is conditionally sterile (3); (ii) it possesses a flexible conditional age determination system (4-6); and (iii) it is represented in a wide range of habitats from tropical Africa to northern Europe. The conditional longevity patterns of honeybee workers cannot be understood unless one takes into account the fact that the workers live their entire life in a colony setting. Throughout periods of ample access to nectar and pollen, a honeybee colony consists of a queen, 10,000 to 30,000 workers, and a few hundred drones (males) (2). The worker population consists of a temporal hive-bee caste, which performs a multitude of tasks inside the nest; and a temporal forager caste, which specializes in collecting nectar, pollen, and water (2). The average duration of the hive-bee stage before the worker enters the forager stage is 9 to 40 days (2), but the most common range is 18 to 28 days (2). The forager then lives for 7 to 14 days (7-9) (Fig. 1).



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Fig. 1. Survival curves and corresponding longevity distributions for honeybee workers in temperate zones [guided by data in (11, 12, 48, 49)]. (A) Survival curves. The solid line indicates a worker population experiencing favorable conditions for foraging and brood rearing, where A and B represent the hive-bee phase and the forager phase, respectively. The dotted line indicates workers experiencing unfavorable foraging conditions, where C and D represent the buildup period of diutinus workers and the diutinus phase, respectively. The last section of this curve represents the post-diutinus period, where the foraging opportunities improve and the amount of brood increases. E and F denote the hive-bee phase and the forager phase, respectively. (B) Corresponding longevity distributions. The solid line refers to the population experiencing favorable conditions, whereas the dotted line refers to workers that experience unfavorable conditions. The vertical lines indicate the parts of the distributions that correspond to phase A and B (blue), C (green), and E and F (red).

 
When the sources of nectar and pollen diminish at the end of the productive season, a third, long-lived temporal caste emerges in temperate zones. These workers are called "winter bees" among apiculturists and are able to survive for up to 8 months on honey alone (10-12). The resulting bimodal longevity distribution of temperate honeybees is truly remarkable (Fig. 1). However, the emergence of this caste is not linked directly to a specific season. This is because the caste appears principally during periods of reduced brood rearing (6, 10, 13), a situation that may arise in connection with events such as swarming, replacement or loss of the reproductive queen, and whenever the foraging conditions remain unfavorable for prolonged periods (2). The Latin word diutinus means enduring or long-lived, and to avoid possible misconceptions associated with the "winter bee" term, we refer to the long-lived honeybee worker caste as diutinus bees in this article.

The occurrence of diutinus bees appears to be limited to temperate subspecies (for example, A. m. carnica and A. m. mellifera), because reduced brood rearing and unfavorable foraging conditions fail to trigger a similar increase in life span in subtropical honeybees such as A. m. scutellata (and A. m. scutellata hybrids) (12, 14, 15). The honeybee originated in tropical or subtropical Africa during the Tertiary period (66.4 to 1.6 million years ago) and then dispersed to northern Europe (16); the diutinus caste is probably a character that evolved during the migration toward more temperate climates. Here we outline how proximate (mechanistic: how) and ultimate (evolutionary: why) explanations can be combined into one coherent story about the origin of the observed longevity patterns of honeybee workers.

Proximate Mechanisms That Underlie the Aging Process in Honeybee Workers

Social exploitation of vitellogenin

Vitellogenin is a female-specific glycolipoprotein yolk precursor produced by all oviparous animals (17) (Fig. 2). Because honeybee workers do not normally lay eggs (2), it would make sense if they synthesized vitellogenin at very low rates or not at all. This is not the case [see (18) for review], and perhaps even more surprising, vitellogenin appears to be a major player in the regulatory machinery that controls the aging of workers.



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Fig. 2. A primer on vitellogenin. Vitellogenins are generally synthesized by the vertebrate liver and the invertebrate fat body, and constitute a multigene superfamily that includes insect apolipophorin I and II, human apolipoprotein B, and the large subunit of mammalian microsomal triglyceride transfer protein [see (4) for references]. In the honeybee queen (A) and worker, the fat body consists mainly of thin layers of cells spread against the body wall of the abdomen, where the cells are loosely organized in thin lobes of highly tracheated tissue (B). The fat body builds up during the first days of adult life and synthesizes vitellogenin. Vitellogenin is transported to the hemolymph, where it becomes the predominant protein in hive bees and diutinus workers. (C) An SDS-polyacrylamide gel electrophoresis electrophorogram of hemolymph proteins from a forager (left), a hive bee (middle), and a diutinus worker (right). An equal amount of hemolymph (1 µl) was loaded in each lane. A 180-kD monomer is currently the only known vitellogenin species in honeybees. Note the difference in vitellogenin concentrations between the three temporal castes. The two other major bands in the lanes represent an ~65-kD hexameric storage protein and an ~200-kD apolipoprotein (Apo1) [see (5) for more information on these proteins]. Vitellogenins are the main circulating zinc transporters in several species. (D) Relation between hemolymph titers of zinc (Zn) and vitellogenin in temperate honeybee workers [reprinted with permission from (31)]. AU, arbitrary units.

 
Underlying much of the following story is the realization that the honeybee has developed at least three elegant ways to exploit the ancient pathways for synthesis and metabolization of vitellogenin. First, in contrast to what is the norm in insects, nonreproducing honeybee workers synthesize vitellogenin in large amounts when their juvenile hormone (JH) titer is low. JH is one of the most versatile hormones in the animal kingdom, and it plays a role in many aspects of insect development, reproduction, and behavior. Hive bees and diutinus bees have a low JH titer, and in these workers, vitellogenin is the predominant protein (30 to 50% of total protein) in the hemolymph--the blood equivalent of insects (13, 19) (Fig. 2C). Second, and also in contrast to what is the norm in insects, a high JH titer represses vitellogenin synthesis in honeybee workers (20). Foragers have high JH titers (21); the worker, therefore, normally goes through a phase with a low JH titer and a high vitellogenin concentration before it enters a phase with a high JH titer and a low vitellogenin concentration (13, 21) (Fig. 2C). Third, during periods of brood rearing, the vitellogenin synthesized by hive bees is routed to their hypopharyngeal glands (brood food-producing glands) (5) for production of the proteinaceous "royal jelly" they use to feed larvae, the queen, workers, and drones (22). When nursing the brood, the daily rate of vitellogenin synthesis in hive bees can equal the amount needed to provision 30 to 100 eggs (18).

The hive bee-to-forager transition

One of the most pronounced transitions during the adult life of the honeybee worker is the shift from performing tasks within the nest to foraging, and it is characterized by substantial physiological as well as behavioral changes (21, 23, 24). The age at onset of foraging is normally much more variable than the length of the foraging period (7, 8, 25), which suggests that the duration of the hive-bee phase is a dynamic entity that is mainly determined by intracolonial conditions, whereas the duration of the forager phase is more dependent on extracolonial conditions. Clearly, the maximum life span of a hive bee is substantially greater than the time period that a worker normally belongs to this temporal caste (26). Thus, the timing of the switch is a major determiner of the overall life span of the worker (8, 25).

Vitellogenin appears to play a major role in the transition from hive bee to forager and in the subsequent determination of the potential life span of the forager. We recently developed the "double repressor hypothesis," which can account for the substantial amount of available data related to the hive bee-to-forager transition (27). The hypothesis suggests that the transition of a hive bee to a forager is regulated by an internal repressor (vitellogenin in the hive bee) and an external repressor [forager-secreted pheromone (FP)] of the hive bee's allatoregulatory central nervous system (ACNS). The ACNS is the part of the nervous system that serves an integrating and coordinating function concerning the induction of neurosecretory polypeptides that either inhibit (allatostatins) or stimulate (allatotropins) JH secretion by the corpora allata (two tiny glands behind the brain). The ACNS controls a positive regulatory feedback loop that involves JH and vitellogenin (Fig. 3). Our hypothesis implies that, independent of age, a hive bee is in a stable physiological and behavioral state as long as the internal repressor and/or external repressor is active (Fig. 4). As soon as the repression ends, either through a lack of inhibitory signals from foragers (28) or because of starvation conditions for the hive bees, which result in decreased vitellogenin production (29), the ACNS induces an increase in the production of JH in the corpora allata of the hive bee's brain (30). This further down-regulates the vitellogenin titer (20) (Fig. 4; see the high-titer JH pathway in yellow).



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Fig. 3. Outline of the double repressor hypothesis [see (3) for a detailed mathematical description and analysis]. A hive bee is physiologically competent to become a forager when it is 3 to 4 days old. By then, the expression of JH is under positive control by the ACNS. The part of the forager differentiation (FD) that is independent of JH is also under positive control by the neuroendocrine system. (A) The ACNS is under negative regulatory control by an internal repressor, vitellogenin (VG) (or a closely associated substance related to nutritional status), and an external repressor, FP. As long as the ACNS stays inhibited, the bee is physiologically and behaviorally locked in the hive-bee state. (B) Loss of sufficient internal and/or external repressor activates the ACNS pathway, causing an increase in JH production and induction of the JH-independent differentiation pathway. JH represses the synthesis of vitellogenin. The subsequent depletion of the worker's vitellogenin store triggers a positive feedback loop, causing the ACNS to be continuously activated. The bee now becomes behaviorally and physiologically locked into the forager state.

 


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Fig. 4. Conditional caste and age determination in temperate honeybee races. The JH titer of the competent worker is influenced by the demographic structure of the colony (numbers and relative proportions of foragers, hive bees, and open and sealed brood) through inhibitory and stimulatory signals and cues, the intracolonial food situation, and the foraging opportunities. The immune-competent diutinus workers, which can live for more than 8 months on honey alone, develop in colonies with adequate food stores and no (or little) brood, and when there is low foraging activity. The immune-competent hive-bee caste is associated with periods of brood rearing and foraging opportunities. An inhibitory signal from the foragers is likely to be instrumental for keeping a low JH titer in the hive bees (Fig. 3). A lack of this signal induces the transition from the hive-bee to the forager state. A lack of food in the colony may induce a precocious transition (Fig. 3). The forager represents a nutrient-deprived and immune-compromised state with a low potential life span of only a few weeks. Each state can be reached from the other two states, with the probable exception that if the worker has been in the forager state for several days, it is not capable of becoming a hive bee or a diutinus bee. The functional relations among the factors that influence the JH titer are more complex than what is outlined here, and they are far from being fully understood. Honeybee races in subtropical Africa do not seem to have a diutinus worker caste. See text for references and further details.

 
Moreover, it was recently shown that vitellogenin is the main zinc carrier in the hemolymph of honeybee workers (Fig. 2D) and that a lack of zinc induces pycnosis (death) of honeybee hemocytes (immune cells) in cell cultures (31). The total number of functional immunocytes in the hemolymph is a general assay of insect cellular immunity (32). Therefore, down-regulation of vitellogenin synthesis by JH in foragers may not only reduce the concentration of what is probably their main storage protein (6, 18), but also may compromise the integrity of their cellular immune system. Extensive hemocyte pycnosis has indeed been observed in foragers (21, 33). The putative causal chain JH -> vitellogenin -> zinc -> hemocyte pycnosis, therefore, represents a new regulatory pathway that controls somatic maintenance, and it establishes for the first time a causal link between JH and somatic maintenance in honeybees (31). It is tempting to suggest that the potential life span of the honeybee forager is endocrinologically tuned to the short actual life span caused by high extrinsic mortality.

The forager-to-hive bee reversion

Remarkably, the hive bee-to-forager transition can be reversed (34, 35). In these cases, experimental manipulation of the demographic structure of a colony induces foragers to return to hive duties, including brood rearing (nursing). At the same time, their JH titer decreases and their hypopharyngeal glands increase in size (35). This indicates that foragers are able to resume their vitellogenin synthesis and the use of vitellogenin for brood food production (5), and that the cellular immune system is restored. The honeybee thus seems to possess what quite a few gerontologists and pharmaceutical companies are seeking for humans these days--a simple means to revert a regulatory program that leads to a nutrient-deprived and immune-compromised stage to a nutrient-enriched and immune-competent stage.

Emergence of the diutinus worker state

Diutinus bees have considerably higher vitellogenin titers than hive bees (13).

A recent mathematical representation of vitellogenin dynamics in workers that experience various intracolonial conditions predicts that the observed accumulation of vitellogenin in diutinus workers is likely to be caused by continued synthesis of vitellogenin in the absence of brood (4) (Fig. 4). Furthermore, assuming that the biological pathways that lead to resumption of vitellogenin synthesis are activated, the model predicts that, except in the case where the workers have been foragers for several days, their previous life histories do not constrain them from becoming diutinus workers as long as they get ample food and time to build up their protein reserves.

The above "accumulation model" seeks to explain the observed differences in vitellogenin stores between hive bees and diutinus workers, and how vitellogenin as a storage protein and zinc carrier relates to the endurance of the diutinus stage (4). However, it does not try to account for other physiological and behavioral differences between hive bees and diutinus workers, and it is likely that comparison of high-resolution phenotypic data (such as mRNA and protein expression profiles and other metabolic and physiological signatures) will show that the two castes also differ in other traits.

Disappearance of the diutinus worker caste

In temperate zones, diutinus bees are the common worker caste that preserves the colony during the winter months (13, 19). In a normal wintering situation, the diutinus workers show negligible senescence (36), but their protein stores become gradually reduced with time (37). This supports the hypothesis that the diutinus worker metabolizes vitellogenin for various purposes and that the protein serves as a general storage protein [as suggested by Engels et al. (18)]. In the spring, when pollen and nectar become available, former diutinus bees start nursing and foraging (11, 12) (Fig. 1 and Fig. 4). Little is known about the regulatory mechanisms responsible for the initiation and regulation of these tasks among diutinus workers in early spring. However, it is likely that the majority of them finally die as nutrient-depleted and immune-compromised foragers (see Fig. 3 for a description of possible mechanisms).

Because the cessation (as well as the initiation) of the diutinus worker caste are largely determined by environmental factors, it is likely that the potential life span of the diutinus stage from the physiological point of view is substantially longer than what is normally observed. If diutinus bees were prevented from entering the production cycle as nurses and foragers, the mortality curve (Fig. 1) suggests a maximum life span of more than 2 years. In comparison, honeybee queens can live for several years [see (1) for review]. Interestingly, their vitellogenin concentrations also exceed those of diutinus workers (38). However, the regulatory circuitries that govern vitellogenin synthesis in queens and workers differ [see (4) for review], and it remains to be documented to what extent diutinus workers and honeybee queens share common mechanisms for somatic maintenance.

Ultimate Explanations for Honeybee Worker Aging

Down-regulation of vitellogenin in foragers

Pollen is a scarce commodity, and letting foragers contain as little as possible of the major storage protein when they perish in the field may contribute positively to the reproductive output of the colony by lowering the demand for pollen foraging. We think that this is the major reason for the capacity of JH to repress vitellogenin synthesis in honeybee workers (4).

This explanation is in accordance with the claim that age-based division of labor, with the performance of risky tasks delayed until late in life by workers with depleted nutrient stores, may have evolved as an energy-saving mechanism in insect colonies (39, 40). However, the explanation also extends this claim by showing that pathways connected to the regulation of aging can actively control this depletion of nutrient stores. Furthermore, the concerted down-regulation of the forager immune system fits very well into this explanatory picture, as it probably contributes to further nutrient deprivation as well as to a lowered nutrient demand as a result of reduced maintenance costs (32, 41). Therefore, it seems fair to conclude that aging in honeybees is not merely a collection of nonadaptive deleterious events that happen in the shadow of natural selection, but that natural selection has shaped the aging pattern to come under strict regulatory control that ensures improved allocation of resources at the colony level.

Creation of the diutinus worker caste

A non-oogenic use of vitellogenin for brood production, and the down- instead of up-regulation by JH, can be interpreted as the signature of group-level adaptation (5). This adaptation has probably been driven by habitat-independent, colony-level selection pressures for optimization of division of labor regimens as well as nectar and pollen collection and use (5). Therefore, one would expect that honeybees in both temperate and subtropical climates would share these traits. Available data on temporal vitellogenin concentrations in European and some African subspecies do indeed suggest that this is the case (6, 13, 19, 20, 42).

In contrast, A. m. scutellata workers, which inhabit tropical and subtropical climates, become only slightly more long-lived, if at all, during periods of unfavorable ambient conditions and reduced brood rearing (12, 14). This indicates that no strong selection pressure exists for developing a long-lived worker bee caste in major parts of Africa. On the basis of the hypothesis that vitellogenin functions as a life span-promoting storage protein in the honeybee (4), we would thus expect that African bees should have a substantially lower hemolymph vitellogenin titer than do European bees during periods when no broods are being produced. This appears to be the case (43). Taken together, these data strongly suggest that the emergence of a diutinus worker caste is an adaptive response to a more seasonal and homogeneous environment. It is difficult to envisage a more simple proximate solution than an enhanced capacity for synthesis and storage of vitellogenin.

Comparative Aspects

Because environmental differences may cause honeybee workers with the same genotype to acquire one of three different physiological states (Fig. 4) of relevance to somatic maintenance, the honeybee worker possesses what may be called strong epigenetic regulation of aging. Honeybees share this feature with Drosophila and several other insect species that are capable of entering adult diapause, a somatic state with arrested reproductive development and enhanced stress resistance (44). The same is true for Caenorhabditis elegans with its dauer larva, a nonfeeding, stress-resistant larval state that evolved for endurance under adverse conditions (45). This conditional aging system is, in some aspects, remarkably similar to that of the honeybee worker (4).

Given the fact that the orchestration of conditional regulatory pathways is a major occupation of hormones, it is not surprising that the above cases of strong epigenetic regulation have an endocrinological element in common (46). In terms of molecular details, the honeybee worker is also likely to share several evolutionarily conserved somatic maintenance mechanisms with other invertebrates. However, we think the differences deserve the most attention, because they are potential signatures of colony level-mediated natural selection on somatic maintenance patterns of an advanced worker caste. For example, the following features have, to the best of our knowledge, not yet been reported for any other organism: (i) The presence of an inverse relation between vitellogenin and JH and a causal relation between vitellogenin and immune function; (ii) the presence of a regulatory circuit (if the double repressor model is correct) in which a hormone that down-regulates somatic maintenance is under the influence of one of its downstream protein targets through a positive feedback loop; (iii) the presence of regulatory mechanisms that allow the reversal of a pathway that leads to a nutrient-deprived and immune-compromised state by a change in local demographic conditions; and (iv) the presence of regulatory machinery that can switch between the routing of vitellogenin to the ovaries for egg production and the hypopharyngeal glands for jelly production [because the honeybee worker is only conditionally sterile (2)].

Conclusion

Much research remains to be done before we will be able to see the beginning of the end of the honeybee aging story. However, considering what Mother Nature has revealed so far about somatic maintenance as a complex and epigenetically regulated life history trait in this species, the work seems well worth pursuing. It is thus encouraging that the honeybee genome is almost completely sequenced and that functional genomic tools for the honeybee are emerging (47, 48). The honeybee is likely to become the major gerontological model among social insects. However, in order to gain a comprehensive understanding of age determination under social conditions, the somatic maintenance patterns of several other social species need to be deciphered.


June 30, 2004
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Citation: S. W. Omholt, G. V. Amdam, Epigenetic Regulation of Aging in Honeybee Workers. Sci. Aging Knowl. Environ. 2004 (26), pe28 (2004).




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