Design New Research Paradigms to Assess Healthspan, Its Enhancement, and Prolongation in Experimental Research Animals

TASK GROUP DESCRIPTION

Background

Enhancing and prolonging human health is a worthy social goal as specifically expressed in the mission statement of the U.S. National Institutes of Health. Indeed, a remarkable decline in disability among people 65 and older in the United States has been thoroughly documented since 1982 (Manton et al., 2006). By contrast, increasing lifespan without prolonging healthspan could easily be viewed as a societal catastrophe, necessitating an ever-growing fraction of national resources to be devoted to the treatment and care of the disabled elderly.

Basic biological researchers, fascinated by the prospect of altering the rate of aging, have been remarkably successful over the past two decades in discovering genetic, pharmaceutical, and environmental treatments that increase the lifespan of laboratory research animals. Specifically, laboratory longevity of the roundworm, Caenorhabditis elegans, has been experimentally increased more than sixfold; the fruit fly, Drosophila melanogaster, more than twofold; and the house mouse, Mus musculus, by as much as 75 percent (Bartke et al., 2001; Partridge and Gems, 2002). However, aside from a handful of studies of fruit flies (Burger and Promislow, 2006; Van Voorhies et al., 2006), comparatively little effort has gone toward determining whether these longevity-extending treatments also enhance and prolong animal health and functional capacities (Bartke, 2005). Some evidence suggests that experimentally enhanced longevity may have deleterious



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Design New Research Paradigms to Assess Healthspan, Its Enhancement, and Prolongation in Experimental Research Animals TASK GROuP DESCRIPTION background Enhancing and prolonging human health is a worthy social goal as spe- cifically expressed in the mission statement of the U.S. National Institutes of Health. Indeed, a remarkable decline in disability among people 65 and older in the United States has been thoroughly documented since 1982 (Manton et al., 2006). By contrast, increasing lifespan without prolonging healthspan could easily be viewed as a societal catastrophe, necessitating an ever-growing fraction of national resources to be devoted to the treatment and care of the disabled elderly. Basic biological researchers, fascinated by the prospect of altering the rate of aging, have been remarkably successful over the past two decades in discovering genetic, pharmaceutical, and environmental treatments that increase the lifespan of laboratory research animals. Specifically, laboratory longevity of the roundworm, caenorhabditis elegans, has been experimen- tally increased more than sixfold; the fruit fly, Drosophila melanogaster, more than twofold; and the house mouse, Mus musculus, by as much as 75 percent (Bartke et al., 2001; Partridge and Gems, 2002). However, aside from a handful of studies of fruit flies (Burger and Promislow, 2006; Van Voorhies et al., 2006), comparatively little effort has gone toward determin- ing whether these longevity-extending treatments also enhance and prolong animal health and functional capacities (Bartke, 2005). Some evidence suggests that experimentally enhanced longevity may have deleterious 

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 THE FuTuRE oF HuMan HEalTHSPan early-life consequences (Jenkins et al., 2004) and even the most extensively documented life- and health-extending treatment (calorie restriction) may increase susceptibility to some common infectious diseases (Gardner, 2005). Furthermore, treatments such as chronic exercise that appear to enhance health but have negligible impact on lifespan have received little interest or attention from biogerontologists (Holloszy, 1997). The aim of this task group is to provide strategies for assessing the life- long health and functional capacities of animals traditionally used in aging research and thus to aid in the discovery of new medical treatments that improve health and healthspan irrespective of their effects on lifespan. Initial Issues to Consider • How should we define health and healthspan? Are they simply the lack of specific disabilities or should they encompass positive measures of functionality? • To what extent can the typical laboratory environment with its superabundant food; its constant, benign, pathogen-defined environment; and its limitations on physical activity allow the assessment of animal health and well-being? • How might the living environment of the laboratory be altered to reveal more about animal health? • In addition to designing a living environment that is more revealing about animal health, would periodic challenges be useful to assess cognitive, sensory, and physical capacities as well? • How much can we infer about animal health from demographic information alone? • Would alternative animal models allow better assessment of health measures relevant for humans? Initial References Bartke, A. 2005. Minireview: Role of the growth hormone/insulin-like growth factor system in mammalian aging. Endocrinology 146(9):3718-3723. Bartke, A., J. C. Wright, J. A. Mattison, D. K. Ingram, R. A. Miller, and G. S. Roth. 2001. Extending the lifespan of long-lived mice. Nature 414(6862):412. Burger, J. M., and D. E. Promislow. 2006. Are functional and demographic senescence genetically independent? Experimental Gerontology 41(11):1108-1116.

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 DESIGn nEW RESEaRcH PaRaDIGMS Gardner, E. M. 2005. Caloric restriction decreases survival of aged mice in response to primary influenza infection. Journals of Gerontology A—Biological and Medical Sciences 60(6):688-694. Holloszy, J. O. 1997. Mortality rate and longevity of food-restricted exercising male rats: A reevaluation. Journal of Applied Physiology 82(2):399-403. Jenkins, N. L., G. McColl, and G. J. Lithgow. 2004. Fitness cost of extended lifespan in caenorhabditis elegans. Proceedings: Biological Sciences 271(1556):2523-2526. Manton, K. G., X. Gu, and V. L. Lamb. 2006. Change in chronic disability from 1982 to 2004/2005 as measured by long-term changes in function and health in the U.S. elderly population. Proceedings of the National Academy of Sciences U.S.A. 103(48):18374- 18379. Partridge, L., and D. Gems. 2002. Mechanisms of ageing: Public or private? Nature Reviews Genetics 3(3):165-175. Van Voorhies, W. A., J. W. Curtsinger, and M. R. Rose. 2006. Do longevity mutants always show trade-offs? Experimental Gerontology 41(10):1055-1058. Due to the popularity of this topic, two groups explored this subject. Please be sure to review the second write-up, which immediately follows this one. TASK GROuP MEMbERS—GROuP A • Kath Bogie, Case Western Reserve University • Daofen Chen, National Institutes of Health, National Institute of Neurological Disorders and Stroke Neuroscience Center • Matt Kaeberlein, University of Washington • Karim Nader, McGill University • Corinna Ross, University of Texas Health Science Center • Richard Sprott, Ellison Medical Foundation • Heidi A. Tissenbaum, University of Massachusetts Medical School • John Cannon, University of California, Santa Cruz TASK GROuP SuMMARy—GROuP A By John cannon, Graduate Science Writing Student, university of california, Santa cruz Richard Foster, board member of the W. M. Keck Foundation and managing partner of the Millbrook Management Group LLC, drew in- spiration from the life of William Keck during his opening address to the 2007 National Academies Keck Futures Initiative conference. As a wildcatter

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0 THE FuTuRE oF HuMan HEalTHSPan working on the oil rigs in early 20th-century California, Keck eventually started the Superior Oil Company, and was said to have drilled 23 dry wells before striking “black gold” on his 24th try. The idea was not to drill dry wells, Foster said, but calculated risk in the spirit of Keck’s innovative thinking can have great potential. “Think big, risky projects,” Foster said. And that’s exactly what this task group did when charged with ad- dressing healthspan research in animal models. Instead of examining just a few specific models, then delineating their respective pros and cons and proposing a set of recommendations, the group decided it would be more beneficial in the long run to invest in a physical and virtual center—a repository of available models where scientists could go and learn the best strategies for answering their questions of interest. Establishing the Problem Representing engineering, biology, and neuroscience, the group of seven researchers each brought a different set of experiences in the realm of animal models. Collectively they agreed that huge gains had been made in extending the lifespan of animals. More difficult was deciding whether those gains included correlated advances in healthspan as well. “Is lifespan not a sufficient proxy [for healthspan]?” said Matt Kaeberlein, assistant professor of pathology at the University of Washing- ton. To answer this question the group needed to hammer out ways to dissociate longevity from the process of healthy aging. An early suggestion was to search for ways to increase the healthspan of an animal without increasing its lifespan. Only then would the investigator understand the effect of whatever she had chosen to manipulate, according to that line of thinking. Michael Rose, professor of ecology and evolutionary biology at the University of California, Irvine, and a floater during the conference, thought it might be more productive to steer the group in a slightly differ- ent direction. “That’s a really cool idea, but as someone who does this for a living, it would be really hard,” Rose said. Instead, he proposed it would be more straightforward to find attributes that increase both lifespan and healthspan. “We have selected on characters that are initially correlated with lifespan, like acute stress resistance, for example. We have generally found that when you select for increased late-life function, then you find almost all your measures of what you consider healthy for the organism increase.”

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 DESIGn nEW RESEaRcH PaRaDIGMS At issue here was a definition of health, something much more difficult to measure than the days, months, or years that can be added to life. And so a working definition of health began to materialize: the ability of a system to maintain or return to homeostasis in response to challenges. It wasn’t perfect and didn’t encompass every aspect. But the definition provided the group with a starting point to answer the question of how to quantify health. Then, by extension, healthspan would be how long an individual could maintain good health. “If that’s our definition of healthspan, how are we actually going to test it?” asked Heidi Tissenbaum, associate professor at the University of Massachusetts Medical School. In keeping with the intended focus of the task group, the discussion turned to differentiating what makes certain animal models good candidates for measuring healthspan. There has been a tendency to stick to a few well-known animal models when it comes to aging research, said Corinna Ross, a primate behaviorist and postdoctoral fellow at the University of Texas Health Science Center at San Antonio. “We already know all kinds of things about mice, but I don’t think there is enough thinking ‘outside the box.’ Even bringing wild mice into the lab was a completely unusual thing.” “Maybe one of the suggestions a group like this could provide is the de- velopment of a center for alternative models,” said Richard Sprott, a behav- ior geneticist and executive director of the Ellison Medical Foundation. Development of the Idea Choosing one specific animal to research can be a daunting task. Each model has its advantages and drawbacks. For example, the worm c. elegans is a common model in aging and other types of research. Scientists have been able to increase its longevity at least sixfold, but it also can enter a dauer stage in which the organism doesn’t age—something that compli- cates extrapolating findings to humans. So, although there’s a lot we can learn from this quirky nematode, it isn’t a perfect model, just as no model is perfect. So too, members of the group expressed concern that researchers might be limited by their own institutions. Say, for instance, that a researcher is interested in a set of questions dealing with aging and does find an “ideal” animal model to begin researching. That’s just the first step. Perhaps the researcher’s institution doesn’t have the facilities to accommodate that particular species. Or maybe the institution’s leadership has a decided bias

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 THE FuTuRE oF HuMan HEalTHSPan toward an entirely different model, one that doesn’t have the potential of the ideal organism. In both cases the only solution would be to leave that stone unturned and move on to another question, perhaps losing the opportunity to contribute significantly to the field’s base of knowledge. Kath Bogie, senior research associate in orthopedics at Case Western Reserve University, was struggling with just those sorts of troubling issues. Her investigations into ischemic wound healing in rabbits hadn’t quite pro- duced the results she had hoped for, and she asked for advice about other available animal models. As the discussion ensued, the proposed center seemed as though it would be an excellent resource to come to the aid of researchers with ques- tions similar to Bogie’s. The particulars of any idea with such a large scale are always tricky, but there was no devil in these details. The collective experience of the group came together, jettisoning this big idea into a plausible innovation. Central to the mission of the institution should be to shed light on the models that have the most potential to answer a particular question about aging. Further, the center shouldn’t address only which animal model, the group concluded, but also which challenges might yield the most telling results, given the specific question. Not long into the discussion did the issue of money arise. “How much would a center like this cost?” asked Karim Nader, associ- ate professor of psychology at McGill University. Richard Sprott, citing a past venture with a similar mission, speculated that with a startup cost of $10 million, the center could get off the ground with an annual budget of between $5 million and $7 million. But steps should be taken so that it would be able to weather the storms of fickle funding sources. “As a practical matter it would require a long-term business plan to describe how it gets to self-sufficiency in something like a 10-year span,” Sprott said. Proposed Solution As the second day of discussions drew to a close, the group assembled a presentation justifying the need for such a center and detailing what they saw as the next step in the process of its inception. The strengths and limitations of the few most popular animal models are well known, but the center would allow for the exploration of alternative

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 DESIGn nEW RESEaRcH PaRaDIGMS models—ones that could help address specific problems more precisely— with the intent to make them available to researchers who are involved with the center. In the spirit of the NAKFI conference and the free exchange of ideas, the center would have an open-access capacity so that researchers would have the best access possible to available models. In doing so, this would also create interdisciplinary cooperation. Perhaps most importantly the center would be established to advise researchers on the most appropri- ate models for their area of interest in healthspan research. The Next Step To further this idea the group decided a future meeting should be convened. Invitees should include prominent figures in the aging research community, as well as representatives of potential funding sources and from the National Academies to discuss more specifically what models and assays would be included in the initial development of the center. They would also be charged with drumming up support from the broader aging research community and hammering out the initial details of what the actual center would entail. Among the questions they would address are: What will be its physical presence? How will virtual models be incorporated into the center’s design? What are the best ways to encourage the participation of investigators? “In talking to a few people about what our group had developed, I got two responses. One was skepticism,” Kaeberlein said at the close of the con- ference. “There’s reason to be skeptical. But the other response, which even the skeptics had, was unanimous support for the idea that aging research is ready for this idea for this type of center. Maybe this isn’t the perfect model, but I think it’s a great place to start.” TASK GROuP MEMbERS—GROuP b • Allyson Bennett, Wake Forest University • James Carey, University of California, Davis • James Herndon, Emory University • Lauren Gerard Koch, University of Michigan • Sean Leng, Johns Hopkins University • Daniel Perry, Alliance for Aging Research • Shane Rea, University of Colorado • Felipe Sierra, National Institute on Aging

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 THE FuTuRE oF HuMan HEalTHSPan • David Waters, Purdue University • Molly Webster, New York University TASK GROuP SuMMARy—GROuP b By Molly Webster, Science Writing Graduate Student, Science, Health, and Environmental Reporting Program, new York university Traditionally, aging has been studied as a finite period in an organism’s life history. Our task group, however, quickly concluded that this is the wrong way to look at the event. An organism does not go from healthy to dead: It moves through a process that shuttles it from the first point to the last. Therefore, aging should be studied throughout a lifespan (defined as birth until death). Additionally, aging is not only a life course event, it has also been shown to be multigenerational. An ancestral generation’s ge- netic makeup or its socioeconomic parameters will affect how a subsequent generation ages. To account for these new ideas the task group decided to focus on studying longevity in animal models, using a continuous, trans- generational approach. Declining health is a natural part of aging, but it became apparent that though health is something we can abstractly understand, varying perceptions make concretely defining it tricky. Few 14-year-olds will think a 60-year-old healthy, but the elder feels he is fitter than a 52-year-old heart attack victim. Similarly, according to a task group member, many physically disabled patients consider themselves healthy, even though the nondisabled would not. The definition of health, and subsequently healthspan (the time of life before the frailty period), obviously varies per person and per de- mographic group. Therefore, we concluded that health cannot be defined. Rather, it needs to be established (1) per species, (2) by individual investi- gators, and (3) per particular environment. Having established these more general guidelines, the task group moved on to consider the reality of an ideal animal model. Answering this question helped us then talk about new research approaches for studying aging as we defined it. Lastly, we discussed the merits of benign lab environments. The Arc of Aging Plotting the aging life history of lab animals will be critical to un- derstanding aging in every model species. This plan means following and

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 DESIGn nEW RESEaRcH PaRaDIGMS documenting the aging arc of a lab model from birth until death. There are at least three ways to document this arc: (1) behaviorally, (2) physiologi- cally, and (3) cognitively. Naturally, when plotting the changes an organism undergoes related to aging, longevity phases would emerge. Already it’s assumed aging can at least be broken down into periods, such as youth, middle age, old age, and frailty, but these divisions are as of yet vague and uncharacterized, and perhaps more will emerge. Clearer definitions of these periods should allow researchers to locate quantitative points where an or- ganism noticeably shifts from one phase to the next. We called these points thresholds, or endpoints, and we imagined them analogous to quantitative points physicians currently use to diagnose, such as blood pressure. Just as anything above 140:90 is considered high blood pressure, while anything below is healthy, once we’ve plotted the life history of a species, we will come to know that anything below x is expressive of one longevity phase, while above it is indicative of another. The two age phases that the task group primarily focused on were death and frailty. What constitutes frailty will differ for every type of animal model, but based on currently available data in human studies, researchers can use five parameters to help judge a model’s health: • Exhaustion; • Muscle strength (measured by grip strength); • Weight loss; • Walking speed; and • Exercise or physical activity level. For example, entomologists observe that fruit flies tend to flip over on their backs when they are not doing well or are frail. Researchers working with c. elegans also notice changes in physical appearance and movement trajectories of worms when they become frail. It is clear then that there are signs of frailty that are readily observable in animals and thus can be used to define frailty in a species. It was suggested that animal models with long frailty periods—and perhaps our lab rats or female organisms already express this—would be a good model choice, because this longer frailty period would allow for multiple different experiments. Death was tenuously proposed as a phase of aging at first; presently it is not coupled with aging. But seeing as death is a process (and it is a process) that normally follows frailty, we thought that it would be important to clearly understand, espe- cially to determine the threshold between it and frailty. The group realized

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6 THE FuTuRE oF HuMan HEalTHSPan that studying death is an enterprising area of research that is currently not a viable research avenue. “We don’t get to let our animals live until they die,” said one group member. Instead, as most researchers are aware, institutional animal care and use committee (IACUC) regulations require euthanasia of lab animals before this life event. IACUC regulations must be changed, the group determined. The best way for this to happen is for the National Academy of Sciences to endorse studies of the dying process, and to propose regulations that would allow this to happen. The task group felt the weight of the Academy is the only way to change existing regulations. Once we establish a baseline diagram of what aging looks like in a specific organism, we can then manipulate the organism and see how that affects longevity. Perhaps we can turn a gene off during one life stage, and watch to see how that changes the process of getting older. An important part of tracking aging in lab animals is remembering that aging takes place across an entire organism; we would want to see its progression at every level of function, particularly the tissue level. Perhaps the liver ages more slowly than the skin. If so, why? It would behoove researchers to know whether the liver possesses a molecular attribute that increases its healthspan and/or lifespan. If we look only at one organ, or one element of an organism, we will limit our knowledge and potentially miss a piece of the puzzle. Not only that, if we minutely characterize aging, perhaps scientists or medical experts will be able to treat it prophylactically. If we can understand how illnesses like diabetes and aging work together at a molecular level, for example, there’s a chance we could predict the disease event before an organism starts to express it symptomatically. “C. Elegans Need Not Apply” When we talk about studying longevity in animal models, what is the ideal animal model for these experiments? Our group, whose members represented c. elegans, fruit flies, lab mice, rats, and dogs, as well as labs that use monkeys and humans, agreed that there is no ideal longevity animal model; every species offers something unique. For example, if we are trying to understand how socioeconomic factors affect aging, it was suggested that dogs would be the ideal animal model, for they live in the socioeconomic environment of their owner. If a researcher was interested in a transgenera- tional study, however, fruit flies would be preferred to dogs as they have higher fecundity rates. The research question should drive what model is used in the experiment.

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 DESIGn nEW RESEaRcH PaRaDIGMS Also, when determining the appropriate animal model, researchers should be encouraged to look beyond those ordinarily used, in an effort to gather as much information about aging as we can. Group members suggest studying wild-type species, such as porcupines, gerbils, and butterflies—all of which have shown extended longevity in the field. Someone also pointed out that if dogs were a resource, perhaps other pets, such as hamsters, could be as well. However, the complaint is that right now research funding is so tight, finding monetary support for any experiment is problematic, let alone one proposing we study aging in an unknown animal species. The group recommends that this needs to change, describing that there should be a sanctioned search for a new animal model: a call to experimentation that can be described as “c. elegans need not apply.” Once the appropriate animal model is chosen for an aging study, it can be used by researchers in two different ways: Either it will help establish the arc of aging in the ways previously described, or it will be employed to test hypotheses. The hypotheses models would undergo manipulations, ranging from environmental to genetic, and then researchers would see how these affect the established aging process. Interventions can also be done on the hypotheses model: We can use organisms to test reversing aspects of aging. If turning off a gene causes z, can we use a model to see whether something can be done to reverse z? Or if z happens naturally, a researcher could use animal models as a method for learning how to prevent the event. Environmental Factors One of the questions posed to this task group was whether or not the benign lab environment was a sufficient setting for aging research. It’s obvi- ous to any researchers that lab settings are not a great mimic of the natural world: The environment is sterile, food is abundant, and there are no chal- lenges or stresses posed to the organism. While the group didn’t think lab environments should change—they are necessary to cancel out experimen- tal variables—there are ways we can improve the data obtained from them. For starters, the task group decided any promising longevity experimental results should be further tested in different, nonbenign environments, with the model undergoing different advantages and disadvantages. So, if a type of Drosophila, with a genetic manipulation, seems to be living longer than average, this fly should then be brought into a different lab setting to see how its lifespan plays out under different conditions. Does it still express a longer than average longevity if population density increases? Or if food

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 THE FuTuRE oF HuMan HEalTHSPan becomes scarce? Along with this, we also concluded that challenges, or stresses, should become part of the lab environment. As one group member pointed out, when a doctor is trying to determine what members of a group of males have a bad heart, he doesn’t take their resting EKG; he throws them onto a treadmill to see how their heart acts under stress, and how long it takes for it to return to homeostasis. A similar stress test should be done with lab animals; lab mice should see a cat every once in awhile, especially if they are showing promising results in aging studies. Just as stress is one of the best determining factors for heart conditions, stresses are critical for better, more thorough lab experiments. Public Sentiment The point was raised that informal comment sessions have shown the public isn’t particularly keen to live longer. In our discussion we assumed that that’s because they assume a longer life will also include a longer frailty period. But we believe that increased healthspan is part and parcel of aging studies; there is no point in having humans live longer if they are incapacitated. While scientists understand where the lay audience is com- ing from, they fear that their concerns will negatively affect aging research. There was also consensus that while scientists at some point need to make it clear—without overextrapolating—how their research in fruit flies relates to humans, it is not up to them to market their research to lay audiences.