The coexistence

What are social insects telling us about aging? Abstract
Research on aging in social insects has progressed much more than has been generally acknowledged. Here I review what I think are the four greatest contributions of social insect work to the field of aging research with the hope of high-lighting the truly exciting discoveries being made. These include the reversal of the fecundity / lifespan and size / lifespan trade-offs due to the evolution of sociality, that social environment can reverse the effects of aging, the contribution of social insect work to the overturning of the free radical theory of aging, and the discovery of vitellogenin as an im-portant protein for longevity. All of these discoveries have important ramifications for human and mammalian aging. Key words: Aging, ant, Formicidae, bee, free radical theory, longevity, social insects, vitellogenin, review.
Myrmecol. News 13: 103-110 (online xxx 2008) ISSN 1994-4136 (print), ISSN 1997-3500 (online) Received 13 November 2009; revision received 9 December 2009; accepted 10 December 2009 Dr. Joel D. Parker, School of Biological Sciences, University of Southampton, Southampton, SO16 7PX, UK. E-mail: [email protected] Introduction
Whenever I tell colleagues or others how the queen of one impact of social insects on biomedical aging research. The of the most common ants here in Britain (Lasius niger) four most biomedically relevant results for aging from re- can live nearly 30 years (KUTTER & STUMPER 1969), the re- search in social insects are: 1) social evolution can reverse sponse is always the same; they are amazed. Those who the assumed physiological trade-offs, 2) the social environ- have more than a passing interest in aging research imme- ment dictates and can reverse physiological changes asso- diately realize that such a small organism with such a long ciated with aging, 3) social insects' contribution to the over- lifespan must contain secrets about the evolution of aging. throw of the free radical theory of aging, and 4) the multi- Clearly, organisms such as eusocial queens must have some way of reversing the usual fecundity / lifespan and size / Social evolution is associated with the reversal of
lifespan trade-offs (see Box 1). Moreover, this reversal and fecundity / lifespan and size / lifespan trade-offs
extreme longevity correlates with the evolution of eusoci-ality in termites, bees and ants (KELLER & GENOUD 1997). The primary source for all research on social insect aging Despite this initial appeal, there are many impediments is the phylogenetic study of KELLER & GENOUD (1997). to the study of aging in social insects. First and foremost is The authors used a phylogenetic analysis to test the hypo- that aging research is directed at human health and wel- thesis that the evolution of eusociality correlates with evo- fare. This has created a hierarchy in funding and research lution of a long lifespan. The results were as statistically focus with humans and translational research on top, fol- significant as they are visually impressive (Fig. 1). That lowed by mouse, rat and other mammals as the main re- sociality can increase lifespan can be argued for other so- search systems, and the invertebrate models of Drosophila cial animals including humans (CAREY 2001). In general, so- melanogaster and Caenorhabditis elegans of academic in- ciality based on kin selection predicts a tendency to evolve terest. Compared to the collective power of these model longer lifespans (BOURKE 2007). In most cases of evolved systems, long lived and challenging non-model systems like increased lifespan, the evolutionary causes involved low- ants and bees might seem destined always to be several steps ered extrinsic mortality for the reproductives in the social behind. However, the reality is that the results coming out group. Social groups tend to protect the reproductives from of social insect work on aging are not just keeping up with predation while maintaining a more benign environment, the aging research field, but taking the lead as well. The thus reducing mortality from predators and stress. challenge for those of us working in social insects is to get Aging patterns and social structure are intimately con- the biomedical research enterprise to notice our most trans- nected in social organisms with social structure frequently determining the evolution of aging trajectories. This has There have been many comprehensive reviews of aging been modeled and demonstrated for worker age polyethism in social insects over the last several years (RUEPPELL & in social insects (BESHERS & al. 2001, TOFILSKI 2002, al. 2004, JEMIELITY & al. 2005, KELLER & JEMIELITY 2006, TRIPET & NONACS 2004, TSUJI & TSUJI 2005). However, BOURKE 2007, REMOLINA & al. 2007, HEINZE & SCHREMPF the evolution of extreme long life observed in ants and bees 2008, MUNCH & al. 2008). Instead of just recovering this occurs primarily with female reproductives. In ants this cre- area, I wish to take a practical perspective and highlight the ates an extreme difference in lifespan between queens (de- cades), workers (years) and males (months) (SEELEY 1978, HÖLLDOBLER & WILSON 1990, HARTMANN & HEINZE 2003). Sometimes overlooked is the exceptional long life Damage accumulation: the observed accumulation of
of workers (up to several years) (GODZINSKA & al. 1999) molecular and physical damage to an organism with which is short compared to queens but is extremely long lived for their size. Interestingly, workers would seem to Extrinsic mortality: mortality caused by predation, di-
be under the same evolutionary pressures to evolve long life sease, starvation, accidents or other environmental causes as queens, but only until they start to forage. This indi-cates that extrinsic mortality is once again the overriding Free radical theory of aging: the hypothesis that reac-
tive oxygen species cause molecular and cellular damage The reversals of trade-offs also extend to sexual con- flict but for different reasons. Mating in insects frequently Immunity / longevity trade-off: the hypothesis that ro-
reduces female lifespan (CHAPMAN & al. 1995, PROMISLOW bustness of the immune response trades off against life- 2003), but the reverse was found in the ant Cardiocondyla span. One can only be increased at a cost to the other. obscurior where mating increases queen lifespan (SCHREMPF Intrinsic aging: increase with time in fragility or pro-
& al. 2005). Kin selection and the structure of eusocial col- bability of dying due to internal causes onies can favor workers to replace the queen when the Intrinsic mortality: mortality caused by organ failure,
queen's fertility begins to decline (LEE 2003, BOURKE cancer or other causes internal to the animal's body 2007). This can happen when a queen's fecundity falls enough that the worker will pass on more of her own Fecundity / lifespan trade-off: the hypothesis that life-
genes to the next generation by replacing the queen. In- span and reproductive effort must trade-off. Increasing deed, through kin selection, the queen herself may favor one requires decreasing the other. Also called the long- colony turn-over to a related sister or daughter after the queen's own fecundity has fallen to some level. The timing Programmed aging: the idea that organisms are gene-
may also depend on how resources such as rank and terri- tically determined to grow old and die. Sometimes used tory may be inherited among kin. There may be a conflict in the timing of the colony turn-over if the worker's favored Rate-of-living theory of aging: the hypothesis that an
take-over time comes before the queen's favored hand-over organism's metabolic rate, sometimes scaled for size, de- time (BOURKE 2007). These sorts of intergenerational trans- termines the rate of aging. In the past, this was thought fer situations provide a rich set of conditions and examples to happen through controlling the rate of free radical pro- for studying senescence under varying social and kin selec- The observed reversal of the fecundity / lifespan trade- Size / lifespan trade-off: the hypothesis that size and
off seen in many reproductive social insects is an unex- lifespan trade-off. The original idea is that physics de- pected and completely revolutionary finding from a mo- termines the relationship between size and metabolism lecular and physiological point of view. Until such re- and larger animals with lower metabolic rate experience versals were documented and studied, the trade-offs were assumed more or less universal physiological constraints on longevity because they were observed across all of the regulator of cell metabolism controlling many aspects of short-lived model systems. Exceptions were noticed, but protein synthesis. The small workers and large queens were now they can be theoretically explained and it can be found to be associated with lower and higher TOR activity, proven that many of these trade-offs are physiologically respectively. This is the reverse of the expected TOR ac- malleable to ecological and evolutionary forces. tivities based on the lifespans (STANFEL & al. 2009). The These evolved intrinsic aging differences among castes free radical theory predicts that higher levels of TOR acti- offer an opportunity to test biochemical hypotheses and re- vity would lower lifespan by creating more metabolic ac- sults from the short-lived model systems. The results have tivity and more free radical damage accumulation. Thus been surprising, sometimes supporting and sometimes con- taken together, the biochemical nature of the difference tradicting the idea that aging will be correlated with the in intrinsic aging among castes is raising doubts about the accumulated damage from free radicals. Comparing Super- free radical theory just as model systems are. oxide Dismutase (SOD) across the sexes and castes found One under-exploited aspect of caste-specific lifespans that the longest-lived castes did not have the most anti- is the differences among polymorphic sterile worker castes oxidant protection contradicting the free radical theory of in ants. CHAPUISAT & KELLER (2002) showed that large aging (PARKER & al. 2004a). This work also led to the dis- workers were shorter-lived than small workers in a weaver covery that insects possessed the extra-cellular form of ant and argued that it was consistent with extrinsic mor- SOD (PARKER & al. 2004b). Other molecular work com- tality acting on the sterile individuals. In this case, there is paring queens and workers showed the same trend with reversal of the size / lifespan correlation for sterile wor- antioxidants in honey bees (CORONA & al. 2005, CORONA kers. This hypothesis would depend upon some connection & ROBINSON 2006). Characterizing telomeres across sex between the mortality rates of the large and small castes and castes in the ant Lasius niger found both supportive and the mortality rate of the colony which is the level se- and contradictory results for the free radical theory (JEMI- lection must be acting. The relationship of these various lev- ELITY & al. 2007). More fundamental differences in caste els acting across colony and different types of sterile wor- metabolism were found with the TOR pathway (PAGE & kers is one place where programmed aging could occur. AMDAM 2007, PATEL & al. 2007) which is a fundamental is potential for future work to examine the biochem- al. 2006, WOLSCHIN & AMDAM 2007a, b). Although con-firming fundamental differences between the subcastes in many basic pathways, these studies demonstrate the clas-sic limitation with proteomic and genomic aging studies. The typical experiment is to compare a long-lived and short-lived organism and the result is that the same basic meta-bolic pathways are usually affected. These include the in-sulin, TOR, and stress pathways. These are the three main biochemical processes that appear in many studies on aging (BROUGHTON & PARTRIDGE 2009, GREWAL 2009, PAPA-CONSTANTINOU 2009, STANFEL & al. 2009), but also so Fig. 1: The relative reproductive lifespan of various in- fundamental to regulating metabolism that any major change sect taxa showing the effect of eusociality. Details on the in the organism's metabolism will likely perturb them. The order Hymenoptera are given for several families because important result is that the subcastes are different at a eusociality evolved independently in the genus Apis and basic metabolic level. This is a key lesson for anyone doing in Formicidae (ants). Reprinted by permission from Mac- an "omics" experiment on aging. Thus far the results have millan Publishers Ltd: Nature (KELLER & GENOUD 1997), been too general to be interpreted by themselves and have proven most valuable as preliminary work for future re- ductionistic studies (WHITFIELD & al. 2006, GRAFF & al. istry of the size / lifespan trade-off in such eusocial sys- 2007). Most genomic studies require confirmatory work be- tems given that the ant with the most genomic resources fore meaningful results about specific genes and pathways available (Solenopsis invicta) also has an extreme size poly- morphism among its sterile workers (WANG & al. 2007, One particularly relevant result for biomedicine is the observed restoration of an age related decline in the im-mune system (AMDAM & al. 2004, 2005). It is well estab- Social environment can change intrinsic
lished that immune responses change over life time and are aging patterns in social insects
dependent on the behaviors (foraging or inside workers) Intrinsic aging rates can be dramatically altered by social of the worker bees and ants (DOUMS & al. 2002, BOCHER environment. Honey bees in particular have provided many & al. 2007, MORET & SCHMID-HEMPEL 2009). Immune insights into the physiology of the plastic responses of in- function declines with age in bumble bees (DOUMS & al. trinsic aging to social environment. For example, the size 2002) but stays the same or even increases in an ant (BO- of the colony affects individual aging rates (RUEPPELL & CHER & al. 2007). In honey bees, it drops when bees begin al. 2009). In the trade-off between colony and individual, to forage but can be restored when these bees are switched it is the individual situation that determines how the bees back to hive tasks (AMDAM & al. 2005). Thus, the decline age (RUEPPELL & al. 2008). Environment has been shown in immune function with age is reversible and not the re- to be more important in determining how honey bees age sult of permanent damage accumulation. Indeed, the pros- than the actual time the bee has been alive (RUEPPELL & pect of rejuvenating the human immune system is one seri- al. 2007b). The key seems to be when workers make the ous idea being considered to combat human aging (DORSH- transition to foraging and their mortality rates rise dramati- cally (RUEPPELL & al. 2007a, WOYCIECHOWSKI & MORON The idea that social interactions are important in aging has recently been tested in a Drosophila system which In honeybees, workers that develop in the autumn are produced a genuinely baffling result (RUAN & WU 2008). long-lived whereas workers developing in the spring are The authors cited the above honey bee work as the justifi- short-lived (MAURIZIO 1950, BECERRA-GUZMAN & al. cation and inspiration for these experiments. Short-lived fruit 2005). These subcastes can be determined by diet during flies with a cytoplasmic Cu-Zn SOD mutation were placed development and can live up to a year. These observations in an environment with long-lived flies and with younger combined with the ability to revert foragers back to brood short-lived flies. Living with younger flies caused the mu- care by altering their environment (ROBINSON & al. 1992) tant lines to recover a significant portion of the wild type provide manipulative tests for examining the changes as- fly lifespan compared to controls. The authors then went sociated with aging. This ability to revert aging pheno- through a series of carefully controlled experiments (con- types in this system has shown vitellogenin, Juvenile Hor- trolling food, decapitation, clipping wings, making the mone, and the insulin pathways as the regulators control- SOD mutants deaf, co-housing in the dark) to show that ling and responding to the two subcastes (AMDAM & OM- the effect was mediated by behavior. How this works is yet HOLT 2003, AMDAM & al. 2004, GUIDUGLI & al. 2005, to be explored, but the conclusion is that social environ- AMDAM & al. 2007, CORONA & al. 2007, NELSON & al. ment effects individual aging rates, even in what are usu- 2007, MUNCH & al. 2008). The link to the insulin path- way is particularly intriguing as it is one of the main path- This idea that organisms age depending on their social ways associated with aging in model systems. Even im- interactions has the potential to be one of the most clini- mune system function and the ability to learn could be re- cally relevant transferable findings to human aging. Hu- versed in these types of experiments (AMDAM & al. 2004, mans are social animals and almost certainly under similar AMDAM & PAGE 2005, BEHRENDS & al. 2007). selective pressures for increased longevity as social insects. Proteomic studies have been done with the winter/sum- Indeed social environment has been shown to have an ef- mer bee system comparing the subcastes (SCHIPPERS & fect on aging in humans although the effect is mediated by the type of interactions (ROHR & LANG 2009). Clinical re- ant nests as predicted by the old free radical theory. The search has tended to separate positive and negative social evidence does point in both directions, even in single stud- interactions with subsequent positive and negative effects ies as seen in ant telomeres where males have shorter te- on lifespan. While there are ethical barriers to the most ob- lomeres than workers and queens as predicted by the old vious replication of the honey bee results in humans, we free radical theory, but workers and queens have telomeres can test whether persons with child-care responsibilities of about the same length contradicting the theory (JEMIE- later in life are aging differently (mimicking the shift from LITY & al. 2007). The simple free radical theory and dam- forager to nurse bee). Early human studies suggest mixed age accumulation can not explain the contradicting cases results depending on various external stressors (BURNETTE 2000). It may be that honey bees are an ideal case where The idea that aging is not caused by accumulated damage there are no negative effects on lifespan by virtue of evo- can be very difficult to accept. There is a common every- lutionary pressures on the sterile castes. Coming from the day example that explains how an organism can age without human clinical direction, the effect of quality of the inter- accumulating physical damage. Consider how many actions in humans might be tested in less socially evolved computer failures you have had in your lifetime. By failure, insects like wasps. How does the rate of aging change with consider any time your machine locked up (needing a re- respect to position in a dominance hierarchy (TSUJI & TSUJI start) which would be the equivalent of death in a biolo- 2005), amount of violent interactions, and just as important- gical system. Now consider how many have been due to ly, what molecular mechanisms might underpin any change? hardware failures and how many due to software problems. In almost all cases computers are far more likely to lose Social insects and the death of the
function due to their internal state than due to the physical free radical theory of aging
breakdown of a component. Thus, computers and other The old free radical theory, that accumulation of oxidative complex systems like living organisms can fail globally be- damage causes aging (HARMAN 1956), is in the midst of be- cause they arrive in an inappropriate state, without any spe- ing overthrown. There is now overwhelming evidence that cific subsystem failure (all the parts can be functional, but aging is not caused by a simple accumulation of free rad- the whole is not). Such bad states in organisms and cells ical damage on macromolecules (BLAGOSKLONNY 2008, would involve changes to fundamental metabolic states or BRINK & al. 2009, GEMS & DOONAN 2009, PEREZ & al. developmental programs and might be expected to cause 2009). Instead, free radicals appear to be signaling mole- stress and damage leading to the observed correlations of cules related to stress as well as participants in fundamen- tal metabolic processes (BLAGOSKLONNY 2008, JUAREZ & How then can an organism age when the cause is not al. 2008, MAGLIARO & SALDANHA 2009). Part of this is accumulated damage? There are at least three recently pro- the regulation of damaged molecule turn-over (CHEN & al. posed and one older relatively unknown theory for how or- 2009). Hence, the accumulation of damage and the increased ganisms can age without accumulating damage being the mortality rate that defines aging appear to be caused by cause. Demetrius (DEMETRIUS 2004, BRINK & al. 2009) fundamental changes in regulatory and developmental path- proposes a metabolic instability hypothesis that the rate of ways (BUDOVSKAYA & al. 2008). These in turn are likely living coupled with demographic factors leads to metabolic effecting the accumulation of oxidative damage, autophagy instability causing aging. BLAGOSKLONNY (2008) describes and cellular repair mechanisms. What is happening to the what he calls "quasi-programmed aging" based on TOR-re- free radical theory of aging is a reversal of cause and ef- lated pathways being switched on by mistake over time. fect with damage looking more like the effect of aging pro- BUDOVSKAYA & al. (2008) suggest that aging is caused by cesses as opposed to the cause of aging (BLAGOSKLONNY developmental programs becoming inappropriately acti- vated with age and labels it the developmental drift theory Much support for the paradigm shift is coming from of aging. In 1978, Robert Rosen proposed the feedforward studies in social insects. The already stated reversal of the theory of aging arguing that all complex systems with feed- fecundity / lifespan trade-off in queens supports the new forward pathways (predictive models, not self-correcting) interpretation. Levels of the antioxidant Superoxide Dis- will inevitably fail at the global level without the need for mutase were higher in short-lived ant castes contrary to pre- any specific subsystem failure (ROSEN 1978). Basically, dictions of the old free radical theory (PARKER & al. 2004b) his idea is that every complex system will inevitably get while much more extensive genomic work found the same into a state incompatible with function as in the computer trends in honey bee (CORONA & al. 2005, CORONA & RO- example above. Although these theories have not been fully BINSON 2006). Additionally, free radical damage was found developed nor synthesized, they all share the characteris- not to be associated with age in honey bee (SEEHUUS & tics of being systems level explanations and can explain the al. 2006a) despite the antioxidant vitellogenin (SEEHUUS & results that the free radical theory and damage accumula- al. 2006b). Heatshock-gene expression does not agree with the simple free radical theory as some important heatshock- The important point is that the experimental evidence gene expression levels were observed to decline with age currently supports the notion that higher system level ef- in worker honey bees (AAMODT 2008). Finally, brain de- fects are more important drivers of aging than physical dam- velopment and complexity increase with age in both bees age accumulation. Social insect aging results are support- (FARRIS & al. 2001) and ants (SEID & al. 2005, SEID & ing this emerging paradigm. Social-insect researchers are al. 2008) while "wear and tear" would predict the opposite. already used to thinking in terms of emergent properties There are some correlations in the other direction such as and systems level phenomena. Hence, we should be in an the observed lifespan correlation with peroxidation-resis- intellectually strong position to contribute to this new emerg- tant lipids (HADDAD & al. 2007) and requeening of wood The role of vitellogenin in aging
mainstream biomedical aging-research community. As I see it, the key points of entry are 1) the evolution of reversals The significance of the discovery of vitellogenin as a major of physiological constraints on lifespan, 2) socially rever- player in aging (AMDAM & OMHOLT 2003, OMHOLT & AM- sible aging phenotypes, 3) the paradigm shift in the free DAM 2004, NELSON & al. 2007, AMDAM & al. 2009) has radical theory, and 4) the role of vitellogenin in aging. We yet to be recognized for its true potential significance. This have the advantage of natural and easily manipulated sys- is an excellent example of how a discovery in social in- tems that by definition far outstrip the capabilities of any sects is slow to penetrate into the more mainstream aging model system to explore these areas. Indeed the weaknes- field. Vitellogenin is thought to be related to mammalian ses of our social experimental systems can be overcome low density lipoproteins (LDL) (SAPPINGTON & RAIKHEL by testing in mainstream model systems through closer 1998, SMOLENAARS & al. 2007). LDL reactions in the vas- collaboration with biomedical researchers. Only when these cular endothelium of humans involve oxidative stress, in- results are replicated in established laboratory mammalian flammation, and programmed cell death and are thought to models will our results finally be transferable to human be major players in human cardiovascular disease (SIMA & al. 2009, WILENSKY & MACPHEE 2009). Understanding the Social behavior is the ultimate determinate of long- dynamics of vitellogenin might yield insights into human evity in humans, and social insects offer the only real op- tion for understanding the evolutionary forces underpinning Social insects appear unique in that the adult workers sociality and lifespan. Making this connection, and always can be expressing high amounts of vitellogenin in a com- looking towards the general principles at both the proxi- plex regulatory network with juvenile hormone (JH) (GUI- mate and ultimate level can not help but raise the profile of DUGLI & al. 2005, AMDAM & al. 2007). In sterile workers, JH can suppress vitellogenin and vitellogenin in turn can Acknowledgements
suppress JH in what is called the double repressor hypothe-sis (AMDAM & OMHOLT 2003, OMHOLT & AMDAM 2004). I thank Karen Parker for reading several versions of this The switch-over from nurse bee (high vitellogenin) to forag- manuscript. I also thank the patient editors at Myrmecolo- er (low vitellogenin) is then associated with a shift to more gical News and two anonymous reviewers whose comments rapid aging (FLURI & al. 1981, 1982). Vitellogenin acts as an antioxidant in honey bees by be- Zusammenfassung
coming irreversibly carbonylated (SEEHUUS & al. 2006b). Vitellogenin scavenges oxidants by essentially offering it- Die Erforschung der Alterung bei sozialen Insekten hat self as a noncatalytic target for the damage. On the sur- viel größere Fortschritte gemacht als landläufig bekannt. face, this seemed a perfect prediction for the damage accu- Hier biete ich einen Überblick über die vier meiner Ansicht mulation version of the free radical theory, but the meas- nach größten Beiträge der Forschung an sozialen Insekten ured accumulation of damage was better explained by so- zum Gebiet der Alterungsforschung, in der Hoffnung, die wahrlich fesselnden Entdeckungen, die gemacht wurden, The most novel finding is that vitellogenin is a zinc car- herauszustellen. Dies sind die Umkehr der Trade-offs von rier and this function might be associated with the immu- Fruchtbarkeit und Lebensspanne und von Größe und Le- nity / longevity trade-off (AMDAM & al. 2004). The signi- bensspanne in Folge der Evolution von Sozialität, die Er- ficance of this discovery urgently needs further exploration, kenntnis, dass die soziale Umwelt die Effekte des Alterns especially as it does not appear that zinc is associated with umkehren kann, der Beitrag der Forschung an sozialen In- the antioxidant effect of vitellogenin. The highly expressed sekten zum Kippen der Freie-Radikale-Theorie des Alte- zinc containing enzymes Cu-Zn SODs are major enzymes rungsprozesses sowie die Entdeckung von Vitellogenin als implicated in aging. Also, a well known age-related neuro- ein für die Langlebigkeit wichtiges Protein. Alle diese Ent- degenerative disease, familial amyotrophic lateral sclerosis deckungen sind ausgesprochen relevant in Hinblick auf das (or motor neuron disease) and other neurological damage Altern beim Menschen und bei anderen Säugetieren. can be caused by changes in Cu-Zn SOD that destabilize the zinc-binding ability of the enzyme (E References
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