Aging and Longevity in Animal Models and Humans

Aging and Longevity in Animal Models and Humans
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  Chapter 11 Aging and Longevity in Animal Modelsand Humans Miriam Capri, Stefano Salvioli, Elisa Cevenini, Laura Celani, FedericaSevini, Elena Bellavista, Catia Lanzarini, Stella Lukas, Paolo Tieri,Francesco Lescai, Daniela Monti, and Claudio Franceschi M. Capri, S. Salvioli, E. Cevenini, L. Celani, F. Sevini, E. Bellavista,C. Lanzarini, S. Lukas, P. Tieri, F. Lescai, and C. Franceschi ( * )Department of Experimental Pathology, University of Bologna, Via S. Giacomo 12,40126, Bologna, ItalyC.I.G.-Interdepartmental Centre “L. Galvani,” University of Bologna, Via Selmi 3,40126, Bologna, Italye-mail: claudio.franceschi@unibo.itD. MontiDepartment of Experimental Pathology and Oncology, University of Florence, Florence, Italy Abstract   How many animal models are adequate to study human aging? Agingis an adaptive process performed by an integrated panel of evolutionarily selectedmechanisms aimed at maintaining soma integrity. The possibility of extrapolatingresults from animal models to human beings has to be addressed in an ecologicalcontext. Model systems fit basic requirements of scientific research, and experi-mental animals show a series of advantages for the study of aging and longevityin humans. However, animal models have intrinsic constraints because they areartificial: Humans are not inbred and live in different conditions from both an envi-ronmental and a socio-anthropological-cultural point of view. Even if research onaging and longevity has been performed primarily in model systems such as yeast,worms, and flies, results obtained in humans are not only of basic importance but arealso largely unexpected, probably because of the peculiar characteristics of humans(protected environment, culture, economic conditions, stochasticity). In some cases,studies in animal models or humans have led to analogous results, largely becausebasic mechanisms involved in aging have been conserved throughout evolution. Inother cases, results are different or even opposite, as is described in this chapter.Animal models are often not sufficiently adequate for the study of human longevity,but their usefulness in achieving knowledge at different levels (molecular, cellular,physiological, behavioral) is unquestionable. Thus, it seems that the concomitantand integrated use of  ad hoc models, also comparing different species, together withnew in silico and high throughput strategies, will be the general framework withinwhich studies on human aging and longevity should be performed to accelerate theidentification of new determinants of healthy aging and longevity. C. Sell et al. (eds.),  Life-Span Extension, Aging Medicine, 175DOI 10.1007/978-1-60327-507-1_11,© Humana Press, a Part of Springer Science + Business Media, LLC 2009  176 M. Capri et al. Keywords   Aging • longevity • animal models • p66shc • PON1 • nuclear factor- k  B • TP53 • SIRT1 • insulin-like growth factor I • caloric restriction Abbreviations   CR: Caloric restriction; FOXO1A: Forkhead box 01A; IGF-I: Insulin-like growth factor I; IGF-IR: Insulin-like growth factor I receptor; NF- k  B: Nuclear factor- k  B; PI3KCB: Phosphoinositide 3-kinase; PON1: Paraoxonase 1; VNTR: Variable number tandem repeat 11.1 Human Aging and Longevity Withinan Evolutionary Perspective Human longevity is determined by the interaction of genetic, epigenetic, andenvironmental components with stochastic factors. Aging should be considered adynamic process leading to continuous adaptation of the body to the life-longexposure to harmful stressors, as conceptualized in the remodeling theory of aging ( 1, 2 ) . These stressors include damaging agents, produced by the organism as aconsequence of inescapable physiological metabolic processes (e.g., reactive oxygenspecies, from oxidative metabolism), as well as those derived from exposure to avariety of physical (e.g., ultraviolet rays from sun exposure) and biological (viruses,bacteria, parasites) agents. Collectively, they represent the environment  into whichthe body is plunged. The body has to counteract and neutralize the negative effectsof such stressors with a panel of antistressor mechanisms. Stressors acting at differentlevels include the following: •  Molecular stressors : they induce heat shock protein and other chaperone proteinproduction, increased protein and organelle turnover, antioxidant and detoxify- ing systems, and DNA repair mechanisms.• Cellular stressors : they induce apoptosis and autophagic cell death (or cellsenescence), phagocytosis and scavenging of damaged cells, and replacement of dead cells by progenitors derived from stem cells (cell and tissue renewal). • Systemic stressors: they stimulate immune and inflammatory responses, stressresponses, and neuroendocrine responses. • Organismal stressors : they alter behavioral responses designed to minimizedanger and damage.All these integrated responses, which also depend on stressor types and exposuretime, contribute to survival. It can be predicted that the global rate of aging and themaximum life span (final longevity) attained by a species is equal to (or greaterthan) the sum of all these mechanisms (adaptation or remodeling capacity for eachspecies). During evolution, a positive selection process occurred to maximize theoverall efficiency of these defense mechanisms because they were critical to maintain ahealthy status and to maximize reproductive capacity and fitness. This is the mainreason why, from an evolutionary perspective, we may assume that the fundamental  11 Aging and Longevity in Animal Models and Humans 177 biological mechanisms playing a major role in the aging process are highly con-served throughout evolution, and that, accordingly, extrapolation from model sys-tems to humans is reasonable. Comparative data on single genes or gene familiesthroughout evolution fit with this assumption. It is also clear that, despite such aconservative scenario, major changes occurred in evolution, particularly regardingbiological regulatory processes and integration between and among pathways, andthat major differences among species also emerged during evolution. This consid-eration is particularly important for  Homo sapiens and his biologic characteristics,including aging. Moreover, from an ecological systemic perspective of the differentlife spans of various species, it is possible to assume that, owing to the extremelycomplex relationship and interactions among different species in a defined environ-ment and the reciprocal constraints in terms of predator/prey, their life spans shouldfit a general, ecological equilibrium. In other words, we can speculate that theunexpected  plasticity and malleability of the aging process and longevity that areemerging in biogerontologic studies have a strong evolutionary basis, being a pre-requisite for adaptation to ecological changes that require a plastic, malleable lifespan of all the species present in a specific environment, in order to attain a generalecological equilibrium among species.Therefore, we may predict that the variable longevity of individuals within aspecies can be explained by assuming a different individual adaptation and remod-eling capacity. This capacity is based on subtle differences among individualsregarding the efficiency of the above-mentioned set of defense mechanisms, evo-lutionarily selected for a certain level of efficiency in each species as a whole.Thus, aging is an adaptive process (remodeling) modulated by an integrated panelof evolutionarily selected mechanisms. The possibility of extrapolating resultsfrom animal models to human beings has to be addressed in an ecological context,starting from animal models as a basis for elucidating the aging process inhumans. 11.2 Advantages and Successes of Model Systems:The Crucial Importance of the Reductionist Approach The essential role of the ecological niche or habitat is evident if we take intoaccount some domesticated animals. They can attain longer or shorter lives than if they were living in their wild habitat. The reasons may be new life style, change of diet, disease, or absence of predators. The maximum life span of a given animal isdetermined by factors such as species-specific genes and environmental and sto-chastic factors, in a way similar to humans but the importance of the differentingredients probably differs quantitatively and qualitatively.A variety of model systems have been developed to assess the role played by the above-mentioned antistressor mechanisms in the aging process. DNA repair mecha -nisms (  3–5 ) , telomere length, telomerase activity, and all of the previously mentionedprocesses have been studied in different animal models ( 6–8 ) . Comparative studies  178 M. Capri et al. of stress resistance in primary cultures (  9, 10 ) showed that cells from long-livedspecies are indeed better protected by somatic maintenance and repairmechanisms.Ultimately, birds may be considered the more suitable models of longevity thanthe short-lived laboratory rodents. Studies in birds may reveal routes for therapeuticintervention in diseases of human aging ( 11 ) .Animal models have been used in all fields of biology and genetics of aging withremarkable success. This approach is reductionist by definition and the basicassumption is that the simpler the organism, the more successful will be the invest-igation on the fundamental “cause” of aging and longevity. Model systems fit basicrequirements of scientific research. Indeed, experimental animals have the follow-ing advantages for the study of aging and longevity: (1) they are inexpensive, can be easily handled, and reproduce quickly; (2) they are well-characterized geneti - cally (usually pure inbreed strains); (3) their environment is well controlled (feasi -ble to change environmental conditions) and constant. These advantages assure thepossibility to replicate the results in different laboratories (reproducibility), anotherbasic requirement of scientific research. 11.3 Disadvantages and Intrinsic Constraintsof Model Systems Animal models have intrinsic constraints because they are artificial. Humans arenot inbred and live in remarkably different conditions from both environmental (climate, food, and water availability; exposure to pathogens) and socio-anthropo -logical-cultural (economic conditions, availability of social and medical care)points of view. In particular, the disadvantages of animal models are as follows:1. Life span is frequently measured in knockout animals created in the laboratoryunder controlled conditions. It is, therefore, necessary to consider the meaningof an increase or a decrease in the life span of such animal models because it isdifficult to predict the effective role of these mutations and how long these ani-mals could survive in the wild and adapt themselves to frequently changingenvironmental conditions (such as temperature, food availability, predators). Knockout animals are far from an evolutionary setting. Moreover, we should be careful in transferring the results to humans. We can assume that our geneticvariants have been selected by evolution to enable us to survive in conditionscompletely different from those in which we currently live.2. The entire aging process of animal models such as  Drosophila melanogaster  and Caenorhabditis elegans (invertebrates) differs from that of humans because theformer are composed mainly of postmitotic cells that are unable to proliferate(postmitotic animals). In contrast, higher vertebrates and humans are composedof both postmitotic and proliferating cells, with stem cells able to generate newcells that replace the damaged and dead ones. Although we have learned a great  11 Aging and Longevity in Animal Models and Humans 179 deal about developmental biology from worms, flies, and mice, detailedinformation on the pathophysiology of aging and on the variations amonggenetically heterogeneous wild-type populations, particularly worms and flies,is scarce. In contrast, the literature on these and all other aspects of humanbiology, including remarkable progress in human genetics, is extensive.Moreover, physicians have provided detailed descriptions of late-in-life disabili-ties and diseases, including cancer in human populations.  D. melanogaster  and C. elegans do not seem to undergo similar pathologic processes ( 12 ) . 3. Additional, unique DNA sequences have evolved in  H. sapiens , including rap-idly evolving and functionally significant intronic sequences that distinguish usfrom our nearest relative, the common chimpanzee ( Pan troglodytes ), whose lifespan is approximately half that of humans ( 13, 14 ) .4. A major problem with studies of the immune system is the fact that animalmodels live in pathogen-free conditions in which it is not possible to evaluateparameters such as the role of climate, food intake, water availability, infectionsonset, and intestinal flora. Moreover, in  D. melanogaster  and C. elegans, theimmune system is composed only of innate immunity, whereas in the mouse,adaptive immunity is also present, but the life span is short and not comparableto the human life span. 5. Studies on the effect of the large number of mitochondrial DNA genetic variants on aging and longevity are appropriately performed only in humans because of the specific evolutionary history of   H. sapiens . This example illustrates theimportant, peculiar interconnection between the evolutionary history of a spe-cies and the determinants of its longevity.6. Genetic studies on humans, especially centenarians, performed in differentEuropean countries were often not reproducible. The reasons are complex andare due, at least in part, to the fact that the centenarian phenotype is highly het-erogeneous ( 15 ) . Such differences are of great general interest and may accountfor many problems of reproducibility of the genetic studies on human longevity ( 16  ) . Indeed, we believe that genetic studies should not always and necessarilybe reproducible in different populations because the centenarian phenotype and,in general, human aging are the results of a complex relationship between genet-ics and the environment (postreproductive or unusual genetics of centenarians).These peculiar interactions, unique for each individual, contribute to the sub-stantial heterogeneity of the aging process. Some of the characteristics areshared by many individuals or groups, whereas others are “private” ones –mechanisms that are present only in particular subsets of individuals or even insingle individuals ( 17–19 ) .  H. sapiens shows a higher level of complexity andheterogeneity than do other animal models, even if this level of complexity seems more correlated with the number of DNA spacer sequences than with the number of genes. The number of cellular identities also can give a measure of human complexity when compared with those of other species. It has been cal-culated that C. elegans , which is composed of about 18,000 genes and 1,179somatic cells (in males) or 1,090 somatic cells (in females) precisely mapped,have 10 3 cellular identities, taking into account their specific ontogeny and their
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