Biology of Aging Summit Report

IN September 2008, the Division of Aging Biology (DAB) of the National Institute on Aging (NIA) held a summit to assess the current state of research in the field of biogerontology and to attempt to delineate goals for the future. The 3-day meeting, held in Gaithersburg, Maryland, brought together a group of 40 well-respected scientists, from both within and outside the field, with sufficient expertise to address the global issues at hand. The main part of the meeting was a series of 15 sessions (with groups of three to four sessions in parallel), where rather than the usual presentation and discussion of data from individual speakers, free discussion of ideas was encouraged, partially driven by a set of questions chosen in advance by the session chairs and DAB. The subjects of discussion, as well as participants, were chosen by a steering committee chosen by DAB staff. The topics discussed are reflected in the accompanying articles in this issue of the Journals of Gerontology, which delineate the gaps and opportunities identified within various research areas, and summarize the collective conclusions reached by each of the discussion groups. As a way of introduction, it is relevant to indicate some (new) areas that came up repeatedly during the sessions and pervaded many of the discussions. Expand our metrics beyond life span: Foremost among the recommendations was the overwhelming feeling that there is a need to enhance our reliance on life span as the critical end point for aging research, by adding measurements of health quality to such studies. As a result of the Longevity Assurance Genes initiative of the NIA, enormous progress has been made in understanding the genetic basis of longevity. However, it is clear that increasing life span would be meaningless, and even counter-productive, if healthspan were not increased concomitantly. Furthermore, several recent examples in the literature point toward treatments that extend health without altering life span, a positive development by itself. Of course, the problem is that although life span is an easy-to-measure binary end point (the organism is either alive or dead), healthspan is much more difficult to assess, and parameters will be both multiple and continuous in nature. Nevertheless, the need has to be acknowledged, and research efforts should be put into it. Specific proposals in this arena include the need to consult with geriatricians about measurements that can be done in animal models but which somehow reflect those changes in humans that eventually lead to frailty or age-related disease. In other words, definition of whether a manipulation affects age-related healthspan should be based on parameters that are relevant to human aging. In this regard, it will also be important to choose or create (eg, by genetic engineering) animals that accurately model humans for specific disease or frailty end points. Address potential differences in aging of mitotic versus postmitotic cells: A second area was the concern that, again for reasons of ease, most studies on the genetics of longevity have been done in round worms and flies, organisms that are (mostly) postmitotic as adults. Vertebrates are made up of a mixture of proliferative and nonproliferative cells and tissues. We have learned a lot about how nonmitotic tissues might age, but proliferative cells and tissues might obey a very different set of rules, where cellular homeostasis, cellular decisions between life and death, proliferation, or quiescence (or senescence) might be as important (or more so) than the genetic determinants identified so far. There was therefore a strong sense that new organisms, genetically tractable and with proliferative tissues as adults, need to be brought into the bestiary already being used. Strengthen the focus on cellular responses to stress: The free radical theory of aging has been central to much of the work done on aging biology over the past few decades. We have learned much in terms of identifying the source of damage to macromolecules, as well as the nature of the damage and the identity of those molecules that are at higher risk for damage (eg, mitochondrial DNA). However, recent reports suggest that organisms can sustain significant amounts of damage without an effect on life span (healthspan has not been measured in most of the studies), and together with indications that the ability of organisms (at least within a species) to be long-lived correlates with the ability of their cells to mount an adequate response to stress, the participants suggested that probably the cellular response to stress might be more relevant to aging research than either the source or the target of damage itself. The role of inflammation as an emerging paradigm: We currently have a cadre of researchers investigating the role of the immune system in aging, and there is a need to put more effort on the possible role of innate responses. Inflammation has been identified as playing a role in a variety of age-related diseases and conditions. In addition, an increase in circulating proinflammatory cytokines has long been observed to correlate with age in both humans and rodents, and in humans, high levels of circulating cytokines such as interleukin-6 correlate with poor prognosis and frailty. Cytokines can come primarily from macrophages, but data discussed at the summit indicated that, during aging, a more prominent role appears to be played by both local senescent cells and fat cells, both of which increase with aging and are known to secrete cytokines. In fact, besides not even knowing the source of these cytokines, we also do not know whether their increase is due to bona fide generalized (or local) inflammation, or if, as in the case of insulin and diabetes, the increase in cytokines is a secondary effect due to a loss of cytokine sensitivity in target cells. Stem cells represent an additional new paradigm: The field of stem cells and aging is still virtually wide open. We need to devote energy and resources to understanding the effect of aging on stem cells and their niches, as well as their role (or not) in both the maintenance and the repair of tissues with aging. The potential use of stem cell therapy in aging, including the possible use of induced pluripotent stem cells, requires a much deeper understanding of the normal biology of stem and precursor cells within an aging organism. Of necessity, this brief summary leaves out much of the rich discussion that occurred both before and during the summit, and the reader is urged to read the individual summaries as they relate to his or her own specific interests. Although most of the discussions and the resulting articles presented here addressed concerns and opportunities that represent considerable overlap, an attempt has been made to arrange the articles somewhat thematically, starting with healthspan, then moving to stress and damage, genetics, and finally some of the new areas and directions, including systems biology, stem cells. and the ever important issue of translation of the results from basic biology of aging research into preclinical and clinical applications. The challenge for the future will be to gather the necessary support from different groups in society, to generate the funding required to accomplish the goals emphasized by these discussants. In this regard, a discussion of the longevity dividend reinforced the notion that tackling the basic biology of aging is likely to be the most efficient and economic way to address the rise in chronic age-related diseases affecting many countries across the world. Certainly, these goals cannot be reached in a short or medium time frame with the current funding levels available from the U.S. federal government, and completion of the goals will require a coordinated effort with other economic sectors as well as other governmental entities, both within and outside of the United States. Engaging these other economic forces is a challenge that all interested parties need to take to heart, and scientists need to do their best, not only to produce the scientific data sought but also to inform the public, lawmakers, nonprofit organizations, and other relevant entities that could be engaged to help with this endeavor. A healthy aged population is the prize, and we believe this goal is achievable.

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