Diapause, a stage-specific developmental arrest, is widely exploited by insects to bridge unfavorable seasons. Considerable progress has been made in understanding the ecology, physiology and evolutionary implications of insect diapause, yet intriguing questions remain. A more complete understanding of diapause processes on Earth requires a better geographic spread of investigations, including more work in the tropics and at high latitudes. Questions surrounding energy management and trade-offs between diapause and non-diapause remain understudied. We know little about how maternal effects direct the diapause response, and regulators of prolonged diapause are also poorly understood. Numerous factors that were recently linked to diapause are still waiting to be placed in the regulatory network leading from photoreception to engagement of the diapause program. These factors include epigenetic processes and small noncoding RNAs, and emerging data also suggest a role for the microbiome in diapause regulation. Another intriguing feature of diapause is the complexity of the response, resulting in a diverse suite of responses that comprise the diapause syndrome. Select transcription factors likely serve as master switches turning on these diverse responses, but we are far from understanding the full complexity. The richness of species displaying diapause offers a platform for seeking common components of a ‘diapause toolbox’. Across latitudes, during invasion events and in a changing climate, diapause offers grand opportunities to probe evolutionary change and speciation. At a practical level, diapause responses can be manipulated for insect control and long-term storage. Diapausing insects also contain a treasure trove of pharmacological compounds and offer promising models for human health.

The capacity for diapause, a dormant state encompassing months of suppressed metabolism, enables insects to survive highly seasonal environments and is thus a major contributor to the evolutionary success of insects. Much early work on insect diapause was descriptive and appeared in agricultural journals, but by the 1950s, researchers were beginning to probe more physiological and mechanistic approaches. Many of these early papers with a physiological perspective (e.g. Way and Hopkins, 1950; Cragg and Cole, 1952; Browning, 1953) appeared in the Journal of Experimental Biology, and the journal has featured prominently as an outlet for excellent diapause research ever since. As the journal approaches its centennial, it is thus appropriate to pay tribute to diapause and explore what I consider to be its exciting future.

Glossary

Allochronic speciation

A form of speciation arising from a temporal isolation of two populations.

Axenic

Sterile conditions not contaminated by other living organisms.

Circadian rhythm

An endogenous cycle with a periodicity of approximately 24 h.

Dauer stage

Term used for the period of arrested development, equivalent to diapause, in nematodes.

Diapause

A stage-specific, programmed developmental arrest commonly engaged to circumvent an adverse season.

Gnotobiotic

Culturing in which all microorganisms are either known or excluded.

Hourglass timer

A timekeeping mechanism that does not rely on a circadian clock but instead relies on a simple daily accumulation of a chemical during the day or night.

Mitophagy

Selective degradation of mitochondria.

Obligate diapause

A genetically programmed diapause that occurs in a specific developmental stage regardless of environmental input. This is in contrast to a facultative diapause that is programmed in response to specific environmental cues.

Ovarian arrest

The halt in egg maturation common to diapause in adult females.

Pharate

Developmental state in which the exoskeleton for the next stage is already formed but the insect is still encased within the exoskeleton of the previous stage.

Post-diapause quiescence

Refers to the interval after diapause is completed and the insect is developmentally competent to reinitiate development but fails to do so because favorable conditions have not yet returned.

Prolonged diapause

A diapause that persists for more than 1 year.

Quiescence

A developmental arrest that, unlike diapause, can occur at any developmental stage within a single species and is entered and exited in direct response to prevailing environmental conditions.

Voltinism

Refers to the number of generations produced in a single year.

An understanding of diapause is essential for predicting seasonal patterns of insect development and for examining the mechanisms that insects use to survive harsh seasons unfavorable for continuous growth. But, beyond these obvious attributes, the stops and starts of development that characterize diapause have offered a fertile field for identifying the hormonal regulatory mechanisms that govern metamorphosis. For example, pupal diapause in the silk moth Hyalophora cecropia offered a perfect model to allow Carroll Williams to identify the central role of the brain–prothoracic gland axis in shutting down and then later restarting development (Williams, 1952), a discovery that was foundational for understanding the hormonal basis for metamorphosis. In a similar fashion, the central role of juvenile hormone (JH) in regulating reproduction was clarified by Jan de Wilde in his experiments on adult diapause in the Colorado potato beetle, Leptinotarsa decemlineata (de Wilde and de Boer, 1961). How embryonic development can be started and stopped was defined in the silk moth Bombyx mori by the discovery of a unique diapause-inducing hormone, the neuropeptide we know as diapause hormone (Fukuda, 1951; Hasegawa, 1951). Diapause also featured prominently in the early literature focusing on metabolic suppression. The low metabolic rates observed during cecropia diapause (Schneiderman and Williams, 1953), along with mechanisms used to open and close the spiracles to prevent water loss in these large silk moths (Levy and Schneiderman, 1966), drew attention to the merits of exploring diapause as a subject of physiological interest. Diapause also offered a powerful tool for early experiments probing clock function (Lees, 1955). And, the latitudinal variation of the response in diverse populations (Danilevskii, 1965) led to recognition that the response is subject to selection and is thus a driver of evolutionary change.

Non-model insects have featured prominently in the diapause literature, simply because they have a more robust and more impressive diapause than the best model insect, Drosophila melanogaster. Indeed, the ovarian arrest (see Glossary) in D. melanogaster seen at low temperatures is more akin to quiescence (see Glossary), an arrest that lacks the photoperiodic-programming aspect that is characteristic of most other insect dormancies (Lirakis et al., 2018). That being said, we can still learn much from the dormancy of D. melanogaster, which, at the molecular level, shares many common attributes with diapause in other insect species.

Diapause is not just for insects. Though insects account for most of the diapause literature, a broader comparative approach benefits from exploring a similar state in other invertebrates as well as some vertebrates. Diapause in mites, brine shrimp, marine copepods and the dauer stage (see Glossary) in nematodes are among well-studied examples in other invertebrates, and experiments on diapause in the vertebrate killifish offer robust comparisons with the insect literature. On a broader scale, studies of insect diapause have much to offer in terms of understanding molecular mechanisms for arresting development, and new insights can be gleaned from comparisons with mammalian hibernation and plant dormancy. Certain parallels also exist between the delayed implantation of mammalian blastocysts (known as embryonic diapause) and the diapause observed in insects (Renfree and Fenelon, 2017). A recent paper by Wilsterman et al. (2021) offers an interesting framework for unifying our thinking about various forms of animal dormancy.

In my recent book, Insect Diapause (Denlinger, 2022a), I attempt to provide an overview of what we know about diapause, and I will not dwell further on our basic understanding of diapause here, but I will seize the opportunity in this Commentary to outline some of the remaining questions that I find particularly interesting. I also highlight a few papers that have appeared since the book's publication, especially those shedding new insight on the themes listed below.

What regulates diapause outside of temperate latitudes?

Most scientists live at temperate latitudes, thus it is not surprising that most work on diapause examines species from these regions. But, it is clear that tropical species, as well as those living at high latitudes, also engage in forms of dormancy, yet we have a much poorer understanding of the environmental factors that regulate diapause in these regions. Unlike temperate region diapause, in which low winter temperatures reinforce metabolic suppression, insects in the tropics face the challenge of maintaining metabolic suppression at high temperatures. The evidence on hand (Denlinger, 2022a) suggests no reason to suspect that the endocrine regulators of diapause differ in these regions, but what is likely to be quite different are the cues used to detect the changing seasons. Species living near the equator are denied the powerful signaling system based on photoperiodism. We are left with few good examples of how diapause is environmentally regulated under these circumstances. Nowhere is this more apparent than among the mosquito species that vector diseases such as malaria. Despite the huge resources devoted to malaria suppression, we understand embarrassingly little about how the anopheline vector species bridge the dry season (Dao et al., 2014; Krajacich et al., 2020). Evidence that diapause is central to the vector's survival during the dry season continues to mount (Faiman et al., 2022), yet the environmental cues that trigger entry into diapause remain unclear. Likewise, at high latitudes, we have a poor understanding of the environment's role in regulating overwintering dormancy. There are some indications that such dormancies are more akin to quiescence than to diapause, but this has not been vigorously investigated.

What is the mechanism underlying maternal effects on diapause?

Diapause is sometimes programmed by the mother, who transfers environmental information she receives to her progeny. Though maternal effects most commonly dictate the diapause fate of embryos produced by the mother, the effects sometimes extend to later developmental stages and even to the following generation. How is this fascinating intergenerational transfer of information achieved? Although the role of diapause hormone in this process is fairly well understood for Bombyx mori (Yamashita, 1996; Horie et al., 2000), the Bombyx story is rather unique and is not likely to be representative of most other maternal effects. Maternal effects can operate to either induce diapause, as in the parasitoid Nasonia vitripennis (Saunders, 1965), or prevent the expression of diapause, as in the flesh fly Sarcophaga bullata (Henrich and Denlinger, 1982). Compelling new evidence from N. vitripennis indicates a role for JH as a regulator of the maternal effect in this species (Mukai et al., 2022). Transcriptomic data point to reduction in transcripts involved in JH biosynthesis, especially juvenile hormone acid o-methyltransferase (jhmat) in short-day wasps programmed to produce diapausing progeny, and JH titers are lower in such wasps. RNA interference directed against jhmat in long-day wasps causes such females to produce diapausing progeny, and JH application to short-day wasps averts diapause in the progeny. Thus, an elegant set of experiments provides strong evidence that JH is a critical regulator of the maternal effect in N. vitripennis. A role for jhmat is also likely for the maternal effect in B. mori (Egi and Sakamoto, 2022). It will be interesting to see whether this regulatory scheme also applies to other maternal effects and to decipher the exact role of JH.

How are multiple cues integrated to regulate diapause?

Temperature and photoperiod commonly interact to dictate the diapause fate, but it is not at all clear, mechanistically, how these two environmental cues interact to program diapause. Thermocycles can sometimes completely replace light:dark cycles as a cue for diapause entry (Denlinger, 2022a), implying that both signaling systems somehow feed into the same downstream regulatory scheme. How is this achieved? The same questions arise in understanding how host plant odors and other cues are integrated to regulate diapause processes. What is the common point of entry for multiple signaling systems? What is the internal rank order of diverse cues, and what happens when different drivers offer conflicting signals?

What master switch initiates diapause?

Diapause is a complex phenotype characterized by a suite of features such as cell cycle arrest, suppressed metabolism, enhanced stress tolerance and cold hardiness, for example. What is the master switch that leads to generation of this wide array of attributes? The transcription factor FoxO is a strong candidate that could function in this capacity in the mosquito Culex pipiens (Sim et al., 2015). Is FoxO widely used as such a switch? Recent work on the moth Helicoverpa armigera suggests a similar role for FoxO in regulating pupal diapause in this species as well (Zhang et al., 2022). The H. armigera experiments nicely demonstrate that FoxO exerts its effect by activating the ubiquitin–proteasome system to decrease TGFβ signaling (Li et al., 2022), thereby eliciting the diapause response. FoxO may thus be an important mediator of diapause in a range of species. A further search for targets of FoxO will prove instructive for defining a comprehensive pathway for generating the complete diapause response. However, additional transcription factors may also be involved, and a search for others is likely to be a productive line of pursuit for understanding the switch that engages the diverse attributes of diapause. Most switches are likely to offer redundant pathways that mutually reinforce diapause, as nicely demonstrated by Batz et al. (2019), who showed that diapause in the mosquito Aedes albopictus involves both transcriptional downregulation of the JH synthesis pathway and concurrently promotes the synthesis of JH esterase, the enzyme that degrades JH.

How does diapause differ between laboratory and real-world conditions?

Most studies have examined diapause under tightly controlled laboratory conditions, using a fixed photoperiod and constant temperature, but that is not how the real world operates. Day length is constantly changing, and outside temperatures can vary wildly throughout the overwintering season. As investigators begin to examine more natural conditions, it is becoming apparent that the natural world generates patterns of gene expression that differ from what one observes under tightly controlled laboratory conditions. For example, patterns of gene expression involved in cell cycle regulation and the insulin signaling pathway vary considerably under field conditions for the alfalfa leafcutting bee, Megachile rotundata (Cambron et al., 2021). Such differences have been rarely investigated directly, but may have considerable impact on diapause phenology and the physiological characteristics of the diapausing individual.

How do diapausing insects that migrate long distances find their diapause sites?

For many species, the diapause program includes a migration component; for these species, successive generations often return to the same diapause site. For example, this behavior is observed in the monarch butterfly, Danaus plexippus (Urquhart and Urquhart, 1976), and the endomychid beetle Stenotarsus rotundus (Wolda and Denlinger, 1984). Unlike migrating birds that have previously been to their overwintering site or travel accompanied by their elders, most insects arrive at the overwintering diapause site used by their parents or grandparents without ever having been there before. This is an amazing feat. How is this accomplished?

How do insects manage their energy reserves before and during diapause?

Accumulation of additional energy reserves is commonly observed in insects destined for diapause. What is the molecular switch dictating acquisition of additional reserves? Of equal interest is the question of how these reserves are parsed out to allow the insect to survive the many months of diapause (Hahn and Denlinger, 2011). For some insects, especially those diapausing as pupae, the insect must not only survive diapause but also store sufficient reserves to complete post-diapause quiescence and the energy-intensive phase of pharate (see Glossary) adult development. In fact, in some cases, such as H. cecropia, adults do not feed; hence reserves sequestered by the larva must be sufficient to fuel adult activity as well as to produce eggs.

Effective energy management demands cross-talk between organs. Diapause is frequently viewed as simply a brain-centered decision, because the brain is the site of the regulatory centers dictating the halt or resumption of the endocrine signals that drive the progression of development. In this scenario, other organs have been viewed as simply complying with signals from the brain. But ‘knowing’ when energy supplies have been depleted is critical. We are just beginning to understand roles for the fat body and the hemolymph in providing signals to the brain, as demonstrated for pupal diapause termination in H. armigera (Xu et al., 2012). In this system, cathepsin L activates a matrix of fat body cells to stimulate lipid metabolism, which in turn increases brain metabolic activity at diapause termination (Jia and Li, 2022). Insulin-like peptides appear to be especially important for the organ cross-talk involved in regulating metabolism (Chowański et al., 2021), but much remains to be learned about the finely tuned processes that coordinate energy management during diapause and the roles they may play in the decision to terminate diapause.

Huge gaps persist in our information on mechanisms regulating metabolic suppression, an event essential for energy conservation during diapause. Degeneration of flight muscles, common for adult diapause, is crucial for metabolic suppression, and in the Colorado potato beetle, this mechanism involves reversible mitophagy (see Glossary): diapausing adults of the Colorado potato beetle activate mitophagy at the onset of diapause, resulting in muscle degradation and metabolic suppression, and at the end of diapause they regrow mitochondria within their flight muscles so they can resume activity. The transcript Parkin appears to be central to this response, and its expression pattern offers an important insight into these processes (Lebenzon et al., 2022).

What mechanisms underly prolonged diapause?

Prolonged diapause (i.e. one lasting more than 1 year) is an extraordinary challenge for temperate insects, as the insect must survive one or more summers, challenging seasons with high temperatures that would be expected to rapidly deplete energy reserves in an ectotherm. Prolonged diapause is usually seen in only a portion of the population. What determines which individuals enter prolonged diapause? The fact that prolonged diapauses can sometimes persist for multiple years (e.g. up to 30 years in the yucca moth; Powell, 2001) makes this phenomenon especially noteworthy. Are individuals that enter prolonged diapause physiologically distinct, or are we overestimating the energetic demands imposed by diapause?

What are the costs associated with diapause?

Diapause is a developmental alternative and it is unlikely that the decision to enter diapause comes without cost. The survival benefit of diapause is obvious, but what costs are associated with this decision? This question has, surprisingly, been addressed rather rarely (Denlinger, 2022a). In some species, no costs are apparent, and some species actually perform better after exiting diapause than their non-diapausing counterparts. However, others show distinct costs, reflected in reduced post-diapause reproductive output and other indices of reduced fitness. The depletion of energy reserves implicit in diapause can be expected to exact a toll on the diapausing individual, especially among species that rely strictly on pre-diapause sequestration of reserves for diapause survival, post-diapause development and reproduction. Cost–benefit analyses may help predict whether and when an insect employs the diapause strategy. A recent paper examining the cherry fruit fly, Rhagoletis cerasi, explored the additional fitness costs of a prolonged diapause, compared with a diapause lasting only a single year, and nicely demonstrated how fitness monitoring can be a powerful tool for evaluating the cost of diapause and chilling durations (Moraiti et al., 2022).

What is the molecular pathway leading from photoreception to implementation of diapause?

We now know many components of the molecular pathway leading from photoperiodic perception to enactment of the diapause program, but there are still many missing links as well as numerous new players that are involved in ways that are not yet clear. It is my hope that in the future we will be able to connect the many steps in the pathway leading from photoreception to expression of the diapause phenotype. The ability to identify brain cells that function as the circadian clock makes it possible to make inferences about critical pathways for photoperiodism. Among recent advances in this arena is a report on the bean bug Riptortus pedestris that traces the pathway for photoperiodic information from the lateral neuron lateral to a region of the medulla anterior base that appears to serve as the hub to receive photoperiodic and clock information (Koide et al., 2021). Continued progress with such studies within the brain hold great promise for eventually tracing the neural circuitry that leads to the diapause response. The Chinese oak silk moth, Antheraea pernyi, a species that played a prominent role in early studies of diapause, offers a particularly attractive model for probing the transmission of photoperiodic cues to prompt termination of diapause. Unlike most insect species, diapausing pupae of A. pernyi use photoperiodic cues (long day length) to break diapause. The action is immediate and thus is not confounded by the long delay usually associated with diapause responses that use day length to program a diapause that occurs at a much later stage of development. Recent work with A. pernyi directly links enzymatic activity of arylalkylamine N-acetyltransferase (aaNAT) in cells housing the circadian clock to the release of prothoracicotropic hormone, the endocrine trigger needed to elicit the breaking of diapause (Takeda and Suzuki, 2022). These authors propose an attractive model in which aaNAT, a clock-controlled gene, functions as a binary switch for the photoperiodic response.

The long-ranging controversy over the possibility of multiple mechanisms for photoperiodic time measurement (i.e. circadian versus hourglass) persists, although the bulk of evidence supports involvement of a circadian mechanism. Yet, good examples support an hourglass timer (see Glossary) for a few species, thus suggesting possible roles for both types of time measurement operating within the huge Class Insecta (Denlinger, 2022a,b,c).

How is the diapause program stored within the brain?

Among the missing components in our understanding of diapause are the critical events involved in storing seasonal information to trigger the diapause program within the brain. Diapause is most frequently programmed far in advance of its actual enactment. How is this information stored and how does the insect ‘know’ when to engage the program? The mechanism used to ‘count’ the number of photoinductive days for the programming of diapause is also poorly understood.

What evolutionary forces dictate the stage of diapause entry?

Diapause has evolved numerous times within the insect lineage. In some cases, closely related species within the same genus enter diapause at different stages (e.g. Drosophila; Lumme, 1978), whereas the diapausing stage is highly consistent in others (e.g. the family Sarcophagidae consistently enter diapause as pupae; Denlinger, 2022b). Why is diapause a highly conserved trait in some taxa but not in others? What are the driving forces dictating the stage and timing of diapause entry? Most diapause features, such as the capacity to regulate the cell cycle and developmental rate, are ancestral features that appear to have been co-opted for use in diapause, but how these regulatory schemes become linked to a particular life stage for establishing a diapause remains an intriguing question. We still lack ambitious phylogenetic analyses that enable us to draw conclusions about the deep history of diapause.

Is there is common diapause toolbox?

Although diapause has evolved independently many times, certain common themes prevail, such as cell cycle arrest, suppression of metabolism and enhanced defense responses. At the genetic level, I argue that there is not a common toolbox for diapause across species. There simply are many ways to reach the same endpoint. For example, the cell cycle can be halted at numerous checkpoints, and there is no reason to anticipate that all insects will employ the exact same mechanism to reach that end. Though the concept of a diapause toolbox has limited support at the level of specific genes, it is supported at the level of more general metabolic pathways. There are still few species for which the transcriptome has been examined in relation to diapause, but several recent papers add to our collection of diapause transcriptomes, including adult diapause in the convergent lady beetle Hippodamia convergens (Nadeau et al., 2022), adult overwintering in the honey bee Apis mellifera (Bresnahan et al., 2022), larval diapause in the beet webworm Loxostege sticticalis (Cui et al., 2022), pupal diapause in the silk moth Antheraea pernyi (Du et al., 2022) and embryonic diapause in the silk moth B. mori (Egi and Sakamoto, 2022). This increase in the number of available diapause transcriptomes gives us a richer database for comparative studies. Interesting comparisons go beyond the insect literature and include transcriptomic analysis of diapause in copepods (Lenz et al., 2021; Roncalli et al., 2021), brine shrimp (Chen et al., 2021) and killifish (Thompson and Ortí, 2016; Romney and Podrabsky, 2017), and the dauer state in nematodes (Wang and Kim, 2003), among others. It is particularly interesting to see players such as insulin signaling (Fielenbach and Antebi, 2008), the FoxO transcription factor (Oh et al., 2006) and the polycomb complex (Hu et al., 2020) emerge as key players in non-insect examples of dormancy, as these are also known to be involved in insect diapause.

What is the role of epigenetics in regulating diapause?

Epigenetic processes (e.g. DNA methylation, histone modification, polycomb group proteins and heterochromatin protein 1) and small noncoding RNAs (e.g. microRNAs, small-interfering RNAs and piwi-associated RNAs) are likely to emerge as important posttranscriptional regulators of diapause. At this point, most of the evidence is correlative, as reviewed by Reynolds (2017), and the field remains fraught with technical challenges. Linking specific microRNAs with specific targets is not easy, because each microRNA can regulate multiple transcripts. But progress in this area is essential, and we are beginning to see links. One good example is recent work with adult diapause of the beetle Galeruca daurica (Duan et al., 2022), in which microRNA let-7-5p appears to regulate diapause by targeting the JH response gene Krüppel homolog 1.

How does the microbiome affect diapause?

Our growing awareness of the importance of the microbiome foretells the possibility that the microbiome contributes to insect diapause. Indeed, the first papers on this subject are beginning to appear. For example, in the mosquito C. pipiens, the diapause-associated accumulation of lipids is restricted when the microbiome is altered (Didion et al., 2021), and axenic (see Glossary) diapausing larvae of the parasitoid N. vitripennis fail to generate the high glucose and glycerol levels needed for overwintering (Dittmer and Brucker, 2021). The dramatic differences in gut processes during diapause versus non-diapause also suggest that we might expect distinctions in microbiome composition between these two states, and this appears to be the case, as documented in N. vitripennis (Dittmer and Brucker, 2021). The field still awaits careful gnotobiotic (see Glossary) experiments.

Do differences in diapause lead to speciation?

Seasonal timing is a potential driver of speciation, and central to this point is the duration of diapause. Altering the duration of diapause can enable a population to switch host plants, as nicely demonstrated for the host switch in Rhagoletis pomonella from hawthorn to apple (Feder et al., 2010). Such shifts in diapause duration are not simple responses but involve complex genetic associations among a number of alleles (Calvert et al., 2022). The European corn borer, Ostrinia nubilalis, is another interesting example, showing two distinct populations distinguished by duration of their larval diapause (Wadsworth et al., 2020). Recent advances help explain how these diapause distinctions are maintained by barriers to gene flow between different populations (Kunerth et al., 2022). Reproductive isolation of this sort can lead to allochronic speciation (see Glossary). Understanding the molecular underpinnings of shifts in the diapause response is central to comprehending the basis of this form of speciation.

How will climate change affect diapause?

Our changing climate will likely affect diapause responses, as these are so finely coordinated with seasonal change. Although temperatures are changing in a changing climate, photoperiod is not. Thus, photoperiodic responses that regulate most diapauses must be modified to respond to changing temperatures. This raises numerous issues related to seasonal synchronization of insects with their host plants. A warmer climate alters overwintering responses, allowing range expansion for some and range restriction for others (Bale and Hayward, 2010). What I find especially intriguing are questions surrounding the genetic architecture and plasticity that allows an insect to adapt to change by modifying its diapause response. For example, what are the genetic features that must be altered to elicit shifts in the critical photoperiod, alterations in energy management, modifications in the timing of diapause termination, and possible shifts in voltinism?

What impact will other anthropogenic effects have on insect diapause?

Other environmental challenges of potential concern are artificial light at night (ALAN) and urban heat islands. Although we have long known that light influences the diapause decision and can sometimes even be employed for insect control, few studies have documented the impact of ALAN on insect diapause under natural conditions. A recent study in Japan with the flesh fly Sarcophaga similis (Mukai et al., 2021) suggests that ALAN may be more of a challenge to insects than is commonly recognized. In this study, diapause entry in dark rural areas was compared with that in an urban setting with light pollution. The study found a 4-week delay for diapause entry in the urban setting (Mukai et al., 2021). Such a result underscores the impact that light can be expected to exert on the diapause response. The growing use of light-emitting diodes is also a concern, because it shifts the dominant spectra of artificial light toward more emission of blue wavelengths, to which insects are particularly sensitive. Urban areas are also warmer, and, for Lepidoptera, urban heat islands correlate with a lowering of the day length threshold used to prompt the diapause response (Merckx et al., 2021). Both of these recent studies nicely demonstrate the local adaptations that may be operating to dictate the diapause responses observed in nature. Though we have a good knowledge base for estimating the timing of diapause entry, we are more poorly equipped to estimate the timing of diapause termination and spring emergence, and thus the impact of anthropogenic effects at the end of winter is less clear than at diapause entry in the autumn.

Can we develop methods to induce diapause entry and exit?

Tools for both promoting diapause as well as breaking diapause are quite valuable for pest management, as discussed in a recent review (Denlinger, 2022c). For the biological control industry, being able to increase the shelf life of parasitoids is an attractive option, but to exploit diapause to attain this goal requires a deep knowledge of diapause regulation and how storage can influence the effectiveness of the biological control agent. The natural stress resistance associated with diapause also facilitates shipping, thus improving survivorship. Conversely, there are numerous species (e.g. many of the economically important fruit flies) that could be targets for release of sterile individuals, but in some cases, mass rearing is made more difficult by an obligate diapause that greatly prolongs the rearing process. Simple tools that break diapause are sorely needed for such ventures to be successful. However, tools that are highly effective in one species are frequently not effective in others. For example, vapors of hexane are potent stimulants for breaking pupal diapause in flesh flies in the genus Sarcophaga (Denlinger et al., 1980), but have little effect on other species, suggesting that there may be few shortcuts in the search for diapause-breaking agents in different species.

How can studies of diapause inform research on human health?

It is my hope that we will continue to see researchers exploit diapause for insights into human health, including obesity (diapausing insects usually store more fat), longevity (a naturally occurring consequence of diapause), ischemia (diapausing insects frequently survive in reduced oxygen environments), stress resistance (which is high during diapause) and pharmacological prospecting (identifying agents used by diapausing insects to combat bacteria, viruses and fungi). A paper touting the merits of germline stem cell longevity in diapausing Drosophila (Easwaran et al., 2022) is one recent example underscoring the potential that diapause offers for examining issues relating to human health. Roles for new pathways in diapause regulation, such as protein carbonylation in pupae of H. armigera (Geng et al., 2022) shed new light on longevity, with the promise of defining new mechanisms for extending lifespan. A recent review (Hutfilz, 2022) highlights the utility of diapause for understanding lifespan determination.

The issues identified here, along with many other equally fascinating questions, suggest that diapause research has a rich future, one that not only will continue to offer insights into broad biological questions but also can be leveraged to improve approaches for effective pest management. The rich diversity in the diapause response among species suggests that diapause has arisen numerous times during evolution but has converged on a similar phenotype that results in cell cycle arrest, suppressed metabolism, a switch from aerobic to anaerobic metabolism, and enhanced stress responses, among other traits. Yet, distinct transcriptomic signatures reveal that the end result can be achieved by targeting different genes in the same general pathway.

One of the beautiful aspects of diapause is that it offers the opportunity to address exciting questions across a range of fields from the ecological to the molecular, from basic to applied biology. It is tempting to assume that we are beyond the descriptive studies that dominated the early diapause literature, but such studies are still urgently needed for new, emerging pest species whose life history remains poorly understood. If, when and how their diapause is expressed is central to understanding the natural history of the vast majority of species that have yet to be examined. In our changing climate, new understandings of how the diapause response can adapt to change will be essential for predicting successful range expansions or possible range contractions. A need remains for more field experiments to bridge the gap between somewhat contrived laboratory work and ecologically relevant conditions in the field.

It is interesting to note that diapause is no longer a topic examined exclusively in Europe, North America and Japan. The rise of interest in diapause from researchers in China is particularly striking. This can be quantified by comparing the number of references from Chinese laboratories cited in Tauber et al. (1986) (0 out of 1853 references) with the number of such references in Denlinger (2022a) (140 out of 1813 references, 8%). This geographic expansion of the field helps to democratize the discipline, resulting in a broader scope and more comprehensive overview of diapause. The Southern Hemisphere, however, still remains underrepresented. Although we may assume that diapause in the Southern Hemisphere will mirror the phenomenon in the north, there are climate distinctions that may render this conclusion incorrect. We know, for example, that the capacity to be freeze tolerant is considerably more prevalent in the Southern Hemisphere (85% of examined species) than in the Northern Hemisphere (29%) (Sinclair et al., 2003; Sinclair and Chown, 2005). This distinction may be symptomatic of other differences in overwintering strategies used in different geographic regions.

In summary, the many exciting questions that have been identified here suggest that diapause will continue to offer ample intellectual challenges and rewards for the next generation of insect scientists worldwide.

Thanks to Dan Hahn (University of Florida) and Megan Meuti (Ohio State University), as well as three anonymous reviewers, for thoughtful input on this Commentary.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors.

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Competing interests

The author declares no competing or financial interests.