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Does senescence give rise to disease?
Mechanisms of Ageing and Development 129 (2008) 693–699
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Review
Does senescence give rise to disease? Bruce A. Carnes *, David O. Staats, William E. Sonntag Reynolds Department of Geriatric Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 April 2008 Received in revised form 26 August 2008 Accepted 26 September 2008 Available online 10 October 2008
The distinctions between senescence and disease are blurred in the literature of evolutionary biology, biodemography, biogerontology and medicine. Theories of senescence that have emerged over the past several decades are based on the concepts that organisms are a byproduct of imperfect structural designs built with imperfect materials and maintained by imperfect processes. Senescence is a complex mixture of processes rather than a monolithic process. Senescence and disease have overlapping biological consequences. Senescence gives rise to disease, but disease does not give rise to senescence. Current data indicate that treatment of disease can delay the age of death but there are no convincing data that these interventions alter senescence. An understanding of these basic tenets suggests that there are biological limits to duration of life and the life expectancy of populations and reveal biological domains where the development of interventions and/or treatments may modulate senescence.
Keywords: Senescence Disease Aging
Senectus ipsast morbu [old age is a disease itself]. Terentius Afer, Phormio, 575
BC.
ß 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Nowhere is the human compulsion to classify more evident than in science. Giving a name to something signifies both recognition and some degree of understanding. Labels are assigned to specific entities (e.g., electron and carbon atom) as well as generic groupings. Disease is a term that belongs to the latter category. Although qualifiers like genetic, infectious and parasitic add specificity to the term disease, the subgroups of disease still retain their generic nature. Degenerative diseases (e.g., arteriosclerosis and osteoporosis) produce a progressive deterioration of structure and function over time, effects that are also attributed to senescence. The similarities between senescence and disease (Kohn, 1982) raise the fundamental question examined in this paper ‘‘Is senescence a disease?’’ Evolutionary theories for why senescence occurs (Hamilton, 1966; Kirkwood and Holliday, 1979; Medawar, 1952; Williams, 1957) are almost universally accepted and share a common logic. The central premise is that even if indefinite survival (immortality) was theoretically possible, the environments of earth are too hostile for any organism to escape death. The
* Corresponding author at: The University of Oklahoma Health Sciences Center, Reynolds Department of Geriatric Medicine, 921 N.E. 13th Street (11G), Oklahoma City, OK, USA. Tel.: +1 405 271 8550; fax: +1 405 271 3887. E-mail address: [email protected] (B.A. Carnes). 0047-6374/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2008.09.016
biological solution to this dilemma became one of the defining characteristics of living matter; namely, the ability to reproduce. The race between reproduction and death has profound consequences for rates of growth and development. Animals under intense mortality pressures achieve sexual maturity quickly while those experiencing lower mortality pressures follow a slower trajectory to sexual maturity. Although species evolve strategies for investing their physiological resources into the biology of reproduction and maintenance of the soma (body), the inevitability of death dictates that reproduction has a higher investment priority than maintenance. Since perfect maintenance strategies are unattainable, the logic of the disposable soma theory leads to the conclusion that senescence cannot be avoided (Kirkwood and Holliday, 1979). Evolutionary theory provides a second insight into why we senesce; namely, an undirected process like evolution cannot lead to perfection in either structure or function. Instead, organisms are a byproduct of imperfect structural designs (Gould, 1981) built with imperfect materials (Hayflick, 2007) and maintained by imperfect processes (Holliday, 1995, 2007). Soma emerging from this evolutionary milieu are, therefore, subject to warranty periods with expiration dates reflecting the timeframe (longevity or longevity determination) required to implement species specific adaptations (e.g., growth, development and reproduction) to the inevitability of death (Carnes et al., 2003). In a now classic article, Medawar (1952) described ‘‘aging’’ as an ‘‘unsolved problem of biology.’’ The absence of scientifically proven
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interventions that slow, stop or reverse the deleterious consequences of senescence (Olshansky et al., 2002a,b) has led some to argue that aging remains an unsolved problem (Carnes et al., 2005). Despite this, it can also be said that a great deal is known about mechanisms of aging. There is abundant evidence, for example, that perturbations of structure and function generated by molecular entropy, mutation, reactive oxygen species (ROS) and other generators of accumulated biological damage are fundamental causes of senescence (Finch and Kirkwood, 2000; Harman, 1956; Holliday, 2007; Vijg, 2007). As such, it is possible to know how we senesce in the broad sense (i.e., molecular entropy and imperfect repair), but still lack the scientific knowledge needed in the narrow sense (i.e., specific mechanisms) to develop effective interventions (Kirkwood, 2008). Theories on senescence exist for every level of biological organization and are too numerous to enumerate (see Bengtson and Schaie, 1999; Bittles, 1991; Dice, 1993; Hayflick, 1985; Medvedev, 1990; Rattan, 2006; Weinert and Timiras, 2003 for reviews). The sheer number of these theories is illuminating. They reveal an enormous range of biological effects attributed to senescence and they reveal a level of biological complexity that suggests senescence must involve multiple modalities acting and interacting at virtually every level of biological organization. The unrepaired consequences arising from this accumulated damage has blurred the boundary between senescence and disease. In this mini-review we will: (1) describe how, why and when we age, (2) provide biological and medical perspectives on the relationships between senescence, the aging phenotype and disease, (3) reprise Strehler’s (1959) framework for distinguishing senescence from non-senescence, and (4) discuss the implications of these issues for science and medicine. 2. How we age Comprehensive explanations for how senescence occurs must reconcile observations made at all levels of biological organization. Although lacking specificity, evolutionary theories of senescence provide that integration, and the concept of natural selection is the foundation upon which those theories are based. Natural selection is the summation of all forces capable of revealing heritable differences in the ability of individuals to propagate their genes. Selection establishes the priorities for allocating physiological resources (Kirkwood and Holliday, 1979) into maintaining the body (longevity) and producing its replacement (reproduction). As unique experiments in life, all species make physiological investments that reflect their unique role (niche) in nature and determine their specific life history strategy (Stearns, 1992). Maintenance processes exist at all levels of biological organization and can be subdivided into those maintaining normal function and those responsible for damage control. Changes in structure and/or function occur when intrinsic (e.g., transcription and translation errors) or extrinsic (e.g., chemicals and radiation) stressors disrupt these maintenance processes (Strehler, 1959). Although extrinsic stressors are avoidable to some degree, intrinsic stressors are more intractable because they are built into the system (Carnes and Olshansky, 1997). For example, ROS are unavoidable byproducts of cellular respiration that have been causally linked to both disease (Knight, 1998; McCord, 2000) and senescence (Harman, 1956). Disruptions of structure and function in somatic cells have no heritable effect but they do contribute to both senescent and disease processes. Conversely, while disruptions of structure and function in germ cells are not directly detrimental to the individual, they pose potential health and mortality risks for the progeny of that individual.
The mutation accumulation theory (Medawar, 1952) continues to exert considerable influence on scientific thought concerning how genes contribute to senescence. According to traditional Darwinian logic, heritable mutations (alleles) that compromise reproduction also diminish the odds of their own propagation. Medawar’s insight was to recognize that the frequency of these alleles in the gene pool could be increased if the age of their deleterious expression could be delayed. Thus, the evolutionary penalty (reduced prevalence) for deleterious gene expression is greatest before reproduction begins and diminishes to a vanishing point when reproduction ends. This logic, now confirmed experimentally (Ackermann et al., 2007), led Medawar to describe the post-reproductive period as a ‘‘genetic dustbin’’ where evolutionary neglect (the absence of selection) permits mutations and their senescent consequences to accumulate over evolutionary time. The antagonistic pleiotropy theory of senescence (Williams, 1957) provides another way for genes to make a contribution to senescence. Williams postulated that alleles having beneficial effects early in life (i.e., contribute to reproductive fitness) would increase in frequency within the gene pool even if their effects late in life were detrimental. These pleiotropic effects should be possible because natural selection is strong at young ages but weak or nonexistent at older ages. Thus, in addition to the delayed expression of mutated genes (mutation accumulation), senescence can also result from normal genes having abnormal consequences when expressed at ages beyond the reach of selection. Genetic diseases that appear in the late reproductive and early post-reproductive periods, like Huntington’s disease and other diseases of the central nervous system are consistent with the expectations from the mutation accumulation theory. Late life cancers behave in what could be considered an antagonist pleiotropy manner. For example, growth and development involves cell proliferation and proto-oncogenes are normal participants in those processes (Darnell et al., 1990). Once their tasks are completed, however, these genes are often inactivated because the high rate of cell proliferation needed for growth and development is no longer needed or desirable. An inadvertent reactivation (dysregulation) of these genes within the postreproductive period could produce an effect (cancerous transformation) consistent with antagonist pleiotropy (Cutler and Semsei, 1989). This brief review of how senescence occurs also reveals how a conflation of senescence and disease could have occurred. Medawar (1952) explicitly identified heritable genetic diseases as components of senescence. Williams (1957) also envisioned senescence as heritable in that it involves normal genes having abnormal effects at evolutionarily irrelevant times. The modern theories of senescence (e.g., Brunk and Terman, 2002; Finch and Kirkwood, 2000; Vijg, 2007) are more similar to the theories of Orgel (1963) and Harman (1956) who interpreted senescence as a byproduct of accumulated damage caused by stochastic processes. In the former scenario senescence could evolve while in the latter scenario senescence is a byproduct of processes that are beyond the reach of selection. The explicit linkages between senescence and disease in these respected theories blur rather than clarify the distinction between them. 3. When aging begins The post-reproductive phase of the life span is typically characterized as a period of physiological decline, disease and death. Trajectories of decline beginning as early as 30 years of age have been extensively documented for a wide range of human physiological parameters (e.g., Falzone and Shock, 1956; Naka-
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mura and Miyao, 2003; Sehl and Yates, 2001). The constellation of age-related changes (ARCs) in appearance and function that emerges after maturation is commonly referred to as the ‘‘aging phenotype.’’ Although ‘‘aging phenotype’’ provides an accurate portrayal of what is observed (Fried et al., 2001), it can create the false impression that maturation or the post-reproductive period marks the onset of senescence. It also confounds the phenotypic consequences of senescence with those arising from disease whose underlying cause can be behavioral (e.g., drug use and smoking), environmental (e.g., toxins) or genetic (e.g., progeria). Although the ‘‘aging phenotype’’ becomes most visible in the post-reproductive period, its antecedents begin much earlier. Consider human ova; they are finite in number and achieve postmitotic status before the female carrying them is even born. Over a course of reproductive senescence that can span decades, they become less fertile and more likely to produce genetic abnormalities (e.g., Down’s syndrome) when fertilized. Presumably, the forces responsible for these detrimental changes are the same ones responsible for how we age. As such, it is biologically reasonable to suggest that senescence begins in the ova of the unborn females who become the mothers of the next generation. An aging phenotype that emerges in the early 30s for humans is consistent with a life history strategy molded by the harsh environments of our ancient ancestors (Hawkes et al., 1998; Packer et al., 1998; Stearns, 1992). Delayed reproduction was not an option for them; women would have begun reproducing at 13–15 years of age and could easily have been grandmothers multiple times over by their early 30s (Ellison, 2001). Even in the protected world of today, the vast majority of children are born to parents younger than 35 years of age (Carnes et al., 2003). Although senescence begins when life begins, detectable senescence (the aging phenotype) is a hallmark of ages when the soma has survived long enough to be disposable (i.e., time enough to mature, reproduce and nurture). 4. Aging phenotype and disease The findings derived from an examination of ARCs in physiological systems of the body also produce a blurring between senescence and disease. Clinical and pathologic changes in the brains of people with sporadic Alzheimer’s disease (e.g., brain weight and volume declines, glutamatergic hyperactivity, neocortical neuron loss, accumulation of senile plaques and neurofibrillary tangles) are also found in the brains of ‘‘normal aged’’ people (Drachman, 2006; Esiri, 2007). ARCs of the heart (e.g., left ventricular hypertrophy, reduced early diastolic filling and increased late diastolic filling, peak cardiac output) and arteries (e.g., thickened intima, endothelial dysfunction and vascular stiffness) of people with cardiovascular disease (heart failure, arteriosclerosis, atherosclerosis, hypertension and stroke) are also attributed to ‘‘normative aging’’ (Ferrari et al., 2003; Greenwald, 2007; Lakatta and Levy, 2003a,b; Lakatta, 2003; Najjar et al., 2005). Similarly, ARCs in the amount and composition of bone, chondroid tissue, ligaments and skeletal muscle are considered risk factors for such degenerative diseases as osteoarthritis, osteoporosis and sarcopenia (Dirks and Leeuwenburgh, 2005; Freemont and Hoyland, 2007; Roubenoff and Hughes, 2000). Normal ARCs in the endocrine (e.g., declines in testosterone, estrogen, growth hormone, IGF-I) and immune system (loss of bone marrow, reduced bone marrow stem cell output, increased number of compromised macrophages, fewer common lymphoid progenitors) produce an array of changes (e.g., decrease in lean body mass, increased fat mass, insulin resistance, degraded immune function and thymic atrophy) that become risk factors for cardiovascular disease,
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metabolic syndrome, obesity and infection (Miller, 1996; Chahal and Drake, 2007; Gruver et al., 2007). Several recurring themes emerge from this system-based review of clinical literature. The most common theme is that ARCs attributed to senescence are indistinguishable from those observed in the pathogenesis and progression of many disease processes. A common corollary of this observation is that senescence and disease interact and that senescence often exacerbates disease and increases its severity. In this sense, disease is superimposed on a background milieu of senescence. A stronger corollary is that senescence is a risk factor for disease. An even stronger and less common theme is that senescence is either a prodromal stage of disease or could be considered a disease in itself. In other words, ARCs are the early (preclinical) manifestations of a process that transitions into clinically manifest disease. As is the case in the biological literature, the distinction between senescence and disease is clearly blurred in the clinical literature. 5. Distinguishing senescence from non-senescence In a now classic paper, Strehler (1959) examined whether exposure to ionizing radiation actually ‘‘accelerated aging’’ or only mimicked the biological consequences of senescence. Although the radiation biology community was the target audience, this paper represents one of the earliest and most significant attempts to develop criteria that allow the biological effects of senescence to be distinguished from those arising from other causes. As such, it provides a useful starting point for determining whether a distinction can or should be made between senescence and disease. Strehler focused on processes that have effects on biological structures and, hence their function. Although the acronym CUPID used to characterize senescence-induced changes in structure and function was not coined until later (e.g., Arking, 1991), Strehler identified the criteria that form the acronym: Cumulative (identified but not given separate status in the original paper), Universal, Progressive, Intrinsic and Deleterious. These criteria have generated considerable debate among scientists. The ‘‘universal’’ criterion, in particular, has played a central role in the debates over the relationship between senescence and disease. Since age-associated pathologies (disease) are not universal, Hayflick (2004) argues that knowledge about disease will not advance our understanding of senescence. Conversely, Holliday (2004) argues that knowledge about the pathogenesis of disease provides invaluable insights into the changes in biological structure and function that accompany senescence. Which of these alternative views is correct has considerable implications for public health and medicine, especially in an era of global population aging. If senescence and disease are unrelated, then treating one would have no impact on the health and life span consequences of the other. However, if they are causally related, then a single intervention for senescence could conceivably reap the cumulative health and life-extending benefits currently derived from multiple treatments applied to a spectrum of diseases (Butler et al., 2008; Tinetti and Fried, 2004; Holliday, 1984). 6. Taxonomy of senescence Strehler (1959) also developed a conceptual classification of causes for the decline in function observed in organisms. The first partition of this classification distinguished between determinate and ancillary processes, where the former processes always occur and the latter do not. Ancillary processes were predominately
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environmental factors that are either modifiable or avoidable. Determinate processes like ‘‘normal aging’’ were considered an ‘‘inherent part of the machine’’ (Strehler, 1959, p. 123). This dichotomy of change imposed on organisms by outside forces or arising from their intrinsic biology is a recurring theme in the history of thought on senescence (see Carnes and Olshansky, 1997; Carnes et al., 2006 for overviews of this literature). The determinate or intrinsic processes of change were, in turn, partitioned by Strehler into either stochastic or genetic processes. Genetic processes are conceptually straightforward and were described earlier in the discussion of evolutionary theories of senescence (e.g., Medawar, 1952; Williams, 1957). Stochastic processes, however, seem incompatible with the ‘‘determinate’’ or ‘‘universal’’ criterion established by Strehler to identify senescent changes. This apparent dilemma is resolved once it is recognized that it is the outcomes of a stochastic process that are neither predetermined nor universal, rather than the process itself. Consider ROS, they are an unavoidable (determinate/universal) byproduct of cellular respiration. ROS-induced damage (e.g., mutation of DNA or damage to a protein), however, produces an array of possible stochastic outcomes (e.g., cancer, mitochondrial diseases) rather than a single predetermined outcome. Thus, the occurrence of a stochastic event is probabilistic rather than deterministic, and that probability changes as a function of age (Fig. 1). This age dependence arises from a temporal competition for expression among stochastic events (competing risks) that differ in pathophysiology as well as the ability of the body to adapt (homeostasis: detection and repair) to that pathophysiology. Nonstochastic processes, on the other hand, have a predetermined outcome that occurs among all individuals (within species) who do not die prematurely. As such, it is the severity of a non-stochastic effect rather than its occurrence that is a probabilistic function of age (Fig. 1). 7. Stochastic effects The role of stochastic effects in the physiochemical processes that influence the ‘‘kinetics of senescence’’ can be traced to research performed early in the 20th century (Loeb and Northrop, 1917; Brody, 1924). Given its long history, the most influential of all stochastic theories of senescence is the free radical hypothesis of aging which also had its roots in radiation chemistry (Harman, 1956). Interestingly, Harman is one of the only modern scientists to explicitly declare that ‘‘aging may also be viewed as a disease’’ (Harman, 1991, p. 5362). Another prominent voice for the importance of stochastic processes is Hayflick (1994) who
Fig. 1. Senescence viewed as a mixture of stochastic and non-stochastic effects and the influence of age on those effects.
identifies entropy and the loss of molecular fidelity that arises from it as a fundamental cause of senescence (see also Failla, 1958; Orgel, 1963; Finch and Kirkwood, 2000). A review of the stochastic effects that emerge from the biochemistry of life is beyond the purview of this paper and would divert attention from the goals of the paper. We will, instead, identify review articles that discuss prominent stochastic effects within the context of senescence and disease: (1) epigenetic changes (Fraga et al., 2005; Holliday, 1987; Richardson, 2003), (2) genomic instability (Vijg, 2007), (3) glycation (Cerami et al., 1987; Ravichandran et al., 2005; Suji and Sivakami, 2004), (4) imperfect autophagocytosis or the junk theory of aging (Brunk and Terman, 2002; Terman et al., 2007); (5) bioactivity of nitric oxide (McCann et al., 1998), and (6) post-synthetic protein modification and turnover (Gafni, 2001; Nakamura et al., 2007; Rattan, 1996; So¨ti and Csermely, 2007). These stochastic processes are linked to a wide range of diseases. Thus, the literature on stochastic changes in the structure and function of molecules involved in the machinery of life also blurs the boundary between senescence and disease. 8. Non-stochastic (determinate) effects Non-stochastic effects fulfill all the criteria of CUPID developed by Strehler (1959) to identify senescence-induced changes in structure and function. Some of these effects are so familiar to geriatricians and clinical researchers (i.e., loss of nerves, muscle and bone) that names have been given to the processes that give rise to them (e.g., denervation, sarcopenia and osteopenia). Reductions in vascularization and oxygen absorption are other well known physiological degradations of structure and function with age that conform to CUPID, and if words existed for these processes they might be called ‘‘angiopenia’’ and ‘‘oxypenia’’. Nonstochastic senescent processes are predominately observed at the cellular or tissue level rather than the molecular level where the effects of stochastic processes are most evident. In addition, non-stochastic effects are more common in organs/ systems (e.g., brain, cartilage, heart, kidney, lung parenchyma and spinal cord) where terminally differentiated cells have a low turnover and exhibit limited regenerative capacity (Ballard and Edelberg, 2007; Carlson, 1998; Goldspink et al., 2003; Rando, 2006). Non-stochastic processes produce a broad spectrum of agerelated declines in the function of physiological processes (e.g., basal metabolic rate, blood volume, cardiac index, glomerular filtration rate, maximal breathing capacity and nerve conduction velocity) that were enumerated by the early biogerontologists (Falzone and Shock, 1956; Shock, 1957) and geriatricians (Anderson and Cowan, 1955; Rowe et al., 1976) and continue to be identified (Aalami et al., 2003; Nakamura and Miyao, 2003; Olivetti et al., 1991; Sehl and Yates, 2001; Weale, 1993). The non-stochastic effects of senescence could be considered an emergent manifestation of stochastic processes rather than byproducts of non-stochastic processes. In other words, the predetermined rather than probabilistic nature of these effects is something novel that could not have been predicted from the behavior of the stochastic processes that give rise to them (i.e., the whole is greater than the sum of parts). Emergent behaviors permeate every level of biological organization (Sole´ and Goodman, 2002), and in part, reflect the additional complexity that arises from the adaptive interactions occurring within and between levels of organization that we call homeostasis. Thus, the potential existence of these pseudo non-stochastic effects cannot be dismissed. Processes like osteopenia and cellular senescence (Campisi et al., 2001; Marcotte and Wang, 2002), however, have known mechanisms that are consistent with actual non-stochastic processes. Finally, the senescent effects associated with the wear and
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tear that occurs at all levels of biological organization are consistent with both the disposable soma theory of senescence (Kirkwood and Holliday, 1979) and the expected behavior of nonstochastic processes. As such, maintaining a distinction been stochastic and non-stochastic processes (and their effects) appears justified. The key point is that stochastic effects occur in everyone who lives long enough and the severity of their impact invariably increases with age. 9. Implications for intervention research There are ample reasons for optimism regarding the search for ways to favorably modulate senescence: (1) our bodies are not designed for indefinite survival, but neither are they designed to fail, (2) genes evolved to promote health and vigor, not ensure decrepitude and death, (3) senescence is ubiquitous, and is not driven by a single process, and (4) senescence is a byproduct of evolutionary neglect, not evolutionary intent. These biological realities suggest that there should be many opportunities for the development of interventions that improve health, quality of life and extend survival. Biological logic also provides a framework for narrowing the search for these interventions. This narrowing begins with recognizing the difference between longevity and senescence. The inevitability of death has two profound biological consequences. It dictates that the fundamental purpose of an organism is to reproduce and it defines the timeframe (i.e., longevity) within which that reproduction must occur. The biology of organisms is simply the means by which this biological imperative is achieved. Since biology is predominantly a product of genes, so is longevity. Senescence, however, is not a direct product of genes, but is instead an inadvertent byproduct of the biology created by genes. If biology is likened to an illuminated statue, then senescence is the shadow cast by that statue. Just as altering the statue will alter its shadow, senescence will be altered, albeit indirectly, by interventions that modify the biology responsible for longevity determination. The most serious threats to organisms are those that threaten the longevity needed to replace themselves; life history strategies
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(i.e., an integrated biology) evolve to mitigate these threats. Scientists are actively identifying ‘‘longevity assurance’’ genes in model organisms and their efforts will reveal a hierarchy of longevity processes (e.g., maintenance and repair), their relative importance, their interactions, and ways to intervene in them. One caveat to this valuable line of research is that modifying genes almost always produces unintended consequences that can offset or diminish the benefit of the intended effect (Vijg, 2007). Interventions for senescence are being actively sought. This area of research is complicated by the fact that senescence is an omnipresent complex mixture of modalities that vary in their degree of interdependency. As such, the efficacy of targeted interventions (e.g., most pharmaceuticals) is questionable. Instead, systemic interventions will be needed to effectively intervene in senescence. Interventions in this category would include efforts to retard non-stochastic (e.g., denervation, osteopenia and sarcopenia) and stochastic (e.g., free radical damage, genomic instability and methylation) effects of senescence. Identifying true interventions for senescence will be a challenge because they can be confused with interventions that simply delay death. Medical interventions that delay death (i.e., extend life) by suppressing the symptoms of disease (rather than curing it) are commonplace. Innovations of modern society, in the collective, have successfully reduced deaths during every phase of the human life course. In so doing, they have raised life expectancies and made population aging a global phenomenon (Olshansky et al., 1993). Although the beneficiaries of these interventions live longer, their underlying senescence has remained unaltered. Progress in the search for interventions has been hampered by an insufficient clarity of the distinction between senescence and non-senescence. Strehler’s (1959) C.U.P.I.D. criteria provide a strong conceptual foundation for this problem, but appear not to have become part of the current intervention paradigm. Another insight on interventions for senescence starts with the premise that all deaths are premature. Living a perfect life in a perpetually perfect environment and avoiding all avoidable mortality risks is impossible. This scenario implies the existence of a ‘‘potential lifespan’’ that the real world of mortality risks puts beyond the grasp of any individual (Fig. 2). Human ingenuity, however, keeps
Fig. 2. Schematic illustrating the relationship of observed life span to potential life span and the difference between interventions that reclaim survival time as opposed to those that extend survival by modifying senescence.
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finding ways to reclaim increments of this lost survival time. In order to be a true intervention for senescence under this conceptual construct, survival must be extended beyond the potential lifespan. Another implication of this line of reasoning is that extending the observed life span (the current gold standard) provides necessary but insufficient evidence to demonstrate that senescence itself has been modified. The detection of true interventions for senescence will require detailed pathological information. However, if senescence does not generate unique pathology, then pathology observed at death is still not sufficient to demonstrate the efficacy of an intervention for senescence. A true intervention for senescence should delay age at death, and must also delay the age at onset for senescent diseases and processes. Thus, detecting the success of these interventions requires a surveillance of pathological changes throughout the life span of individuals. Unless the intervention effect is dramatic, small-scale studies will be of limited value. Further, given the uncertainty surrounding the relevance of animal models, validation of these interventions will require proof of efficacy in multiple animal models. Although the technology already exists to perform longitudinal intervention studies on senescence, pursuing them will require overcoming significant logistic and economic barriers. 10. Discussion/conclusion The most salient theme emerging from this review of the scientific and medical literature is that the boundary between aging and disease is blurred. This blurring, however, is both inevitable and revealing. Although diseases have many causes (e.g., genetic, toxin and microbe), this review suggests that aging is one of them. Diseases not caused by aging arise from knowable causes with knowable pathogenesis. This class of disease can, in theory, be cured (e.g., appendicitis) or eliminated (e.g., smallpox). Aging, however, is not a single entity and its causes are deterministic and stochastic as well as omnipresent and ubiquitous. As such, aging can be mitigated but it can be neither ‘‘cured’’ nor eliminated. Our bodies are not designed for immortality; they are designed to replace themselves. Longevity provides the time for that to occur and aging is simply a byproduct of surviving beyond that timeframe. Within the context of human reproductive biology and the environments from which it emerged, a century is practically an eternity. Physicians need not fear that science will put them out of work. A better scientific understanding of the mechanisms of senescence is the ultimate way to better understand diseases of old age, thereby improving the health of an aging and increasingly long-lived population. There is some urgency to finding the solution to Medawar’s unsolved problem in biology because the health consequences of population aging (i.e., comorbidity, frailty and disability) have already become and will continue to be one of the biggest biomedical challenges ever faced by humanity. References Aalami, O.O., Fang, T.D., Song, H.M., Nacamuli, R.P., 2003. Physiological features of aging persons. Arch. Surg. 138, 1068–1076. Ackermann, M., Schauerte, A., Stearns, S.C., Jenal, U., 2007. Experimental evolution of aging in a bacterium. BMC Evol. Biol. 7, 126–135. Anderson, W.F., Cowan, N.R., 1955. A consultative center for people. Lancet 1, 1117– 1120. Arking, R., 1991. Biology of Aging: Observations and Principles. Englewood Cliffs, Prentice Hall. Ballard, L.T., Edelberg, J.M., 2007. Stem cells and the regeneration of the aging cardiovascular system. Circ. Res. 100, 1116–1127. Bengtson, V.L., Schaie, K.W. (Eds.), 1999. Handbook of Theories of Aging. Springer Publishing Company, New York.
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Contents lists available at ScienceDirect
Mechanisms of Ageing and Development journal homepage: www.elsevier.com/locate/mechagedev
Review
Does senescence give rise to disease? Bruce A. Carnes *, David O. Staats, William E. Sonntag Reynolds Department of Geriatric Medicine, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 28 April 2008 Received in revised form 26 August 2008 Accepted 26 September 2008 Available online 10 October 2008
The distinctions between senescence and disease are blurred in the literature of evolutionary biology, biodemography, biogerontology and medicine. Theories of senescence that have emerged over the past several decades are based on the concepts that organisms are a byproduct of imperfect structural designs built with imperfect materials and maintained by imperfect processes. Senescence is a complex mixture of processes rather than a monolithic process. Senescence and disease have overlapping biological consequences. Senescence gives rise to disease, but disease does not give rise to senescence. Current data indicate that treatment of disease can delay the age of death but there are no convincing data that these interventions alter senescence. An understanding of these basic tenets suggests that there are biological limits to duration of life and the life expectancy of populations and reveal biological domains where the development of interventions and/or treatments may modulate senescence.
Keywords: Senescence Disease Aging
Senectus ipsast morbu [old age is a disease itself]. Terentius Afer, Phormio, 575
BC.
ß 2008 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Nowhere is the human compulsion to classify more evident than in science. Giving a name to something signifies both recognition and some degree of understanding. Labels are assigned to specific entities (e.g., electron and carbon atom) as well as generic groupings. Disease is a term that belongs to the latter category. Although qualifiers like genetic, infectious and parasitic add specificity to the term disease, the subgroups of disease still retain their generic nature. Degenerative diseases (e.g., arteriosclerosis and osteoporosis) produce a progressive deterioration of structure and function over time, effects that are also attributed to senescence. The similarities between senescence and disease (Kohn, 1982) raise the fundamental question examined in this paper ‘‘Is senescence a disease?’’ Evolutionary theories for why senescence occurs (Hamilton, 1966; Kirkwood and Holliday, 1979; Medawar, 1952; Williams, 1957) are almost universally accepted and share a common logic. The central premise is that even if indefinite survival (immortality) was theoretically possible, the environments of earth are too hostile for any organism to escape death. The
* Corresponding author at: The University of Oklahoma Health Sciences Center, Reynolds Department of Geriatric Medicine, 921 N.E. 13th Street (11G), Oklahoma City, OK, USA. Tel.: +1 405 271 8550; fax: +1 405 271 3887. E-mail address: [email protected] (B.A. Carnes). 0047-6374/$ – see front matter ß 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mad.2008.09.016
biological solution to this dilemma became one of the defining characteristics of living matter; namely, the ability to reproduce. The race between reproduction and death has profound consequences for rates of growth and development. Animals under intense mortality pressures achieve sexual maturity quickly while those experiencing lower mortality pressures follow a slower trajectory to sexual maturity. Although species evolve strategies for investing their physiological resources into the biology of reproduction and maintenance of the soma (body), the inevitability of death dictates that reproduction has a higher investment priority than maintenance. Since perfect maintenance strategies are unattainable, the logic of the disposable soma theory leads to the conclusion that senescence cannot be avoided (Kirkwood and Holliday, 1979). Evolutionary theory provides a second insight into why we senesce; namely, an undirected process like evolution cannot lead to perfection in either structure or function. Instead, organisms are a byproduct of imperfect structural designs (Gould, 1981) built with imperfect materials (Hayflick, 2007) and maintained by imperfect processes (Holliday, 1995, 2007). Soma emerging from this evolutionary milieu are, therefore, subject to warranty periods with expiration dates reflecting the timeframe (longevity or longevity determination) required to implement species specific adaptations (e.g., growth, development and reproduction) to the inevitability of death (Carnes et al., 2003). In a now classic article, Medawar (1952) described ‘‘aging’’ as an ‘‘unsolved problem of biology.’’ The absence of scientifically proven
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interventions that slow, stop or reverse the deleterious consequences of senescence (Olshansky et al., 2002a,b) has led some to argue that aging remains an unsolved problem (Carnes et al., 2005). Despite this, it can also be said that a great deal is known about mechanisms of aging. There is abundant evidence, for example, that perturbations of structure and function generated by molecular entropy, mutation, reactive oxygen species (ROS) and other generators of accumulated biological damage are fundamental causes of senescence (Finch and Kirkwood, 2000; Harman, 1956; Holliday, 2007; Vijg, 2007). As such, it is possible to know how we senesce in the broad sense (i.e., molecular entropy and imperfect repair), but still lack the scientific knowledge needed in the narrow sense (i.e., specific mechanisms) to develop effective interventions (Kirkwood, 2008). Theories on senescence exist for every level of biological organization and are too numerous to enumerate (see Bengtson and Schaie, 1999; Bittles, 1991; Dice, 1993; Hayflick, 1985; Medvedev, 1990; Rattan, 2006; Weinert and Timiras, 2003 for reviews). The sheer number of these theories is illuminating. They reveal an enormous range of biological effects attributed to senescence and they reveal a level of biological complexity that suggests senescence must involve multiple modalities acting and interacting at virtually every level of biological organization. The unrepaired consequences arising from this accumulated damage has blurred the boundary between senescence and disease. In this mini-review we will: (1) describe how, why and when we age, (2) provide biological and medical perspectives on the relationships between senescence, the aging phenotype and disease, (3) reprise Strehler’s (1959) framework for distinguishing senescence from non-senescence, and (4) discuss the implications of these issues for science and medicine. 2. How we age Comprehensive explanations for how senescence occurs must reconcile observations made at all levels of biological organization. Although lacking specificity, evolutionary theories of senescence provide that integration, and the concept of natural selection is the foundation upon which those theories are based. Natural selection is the summation of all forces capable of revealing heritable differences in the ability of individuals to propagate their genes. Selection establishes the priorities for allocating physiological resources (Kirkwood and Holliday, 1979) into maintaining the body (longevity) and producing its replacement (reproduction). As unique experiments in life, all species make physiological investments that reflect their unique role (niche) in nature and determine their specific life history strategy (Stearns, 1992). Maintenance processes exist at all levels of biological organization and can be subdivided into those maintaining normal function and those responsible for damage control. Changes in structure and/or function occur when intrinsic (e.g., transcription and translation errors) or extrinsic (e.g., chemicals and radiation) stressors disrupt these maintenance processes (Strehler, 1959). Although extrinsic stressors are avoidable to some degree, intrinsic stressors are more intractable because they are built into the system (Carnes and Olshansky, 1997). For example, ROS are unavoidable byproducts of cellular respiration that have been causally linked to both disease (Knight, 1998; McCord, 2000) and senescence (Harman, 1956). Disruptions of structure and function in somatic cells have no heritable effect but they do contribute to both senescent and disease processes. Conversely, while disruptions of structure and function in germ cells are not directly detrimental to the individual, they pose potential health and mortality risks for the progeny of that individual.
The mutation accumulation theory (Medawar, 1952) continues to exert considerable influence on scientific thought concerning how genes contribute to senescence. According to traditional Darwinian logic, heritable mutations (alleles) that compromise reproduction also diminish the odds of their own propagation. Medawar’s insight was to recognize that the frequency of these alleles in the gene pool could be increased if the age of their deleterious expression could be delayed. Thus, the evolutionary penalty (reduced prevalence) for deleterious gene expression is greatest before reproduction begins and diminishes to a vanishing point when reproduction ends. This logic, now confirmed experimentally (Ackermann et al., 2007), led Medawar to describe the post-reproductive period as a ‘‘genetic dustbin’’ where evolutionary neglect (the absence of selection) permits mutations and their senescent consequences to accumulate over evolutionary time. The antagonistic pleiotropy theory of senescence (Williams, 1957) provides another way for genes to make a contribution to senescence. Williams postulated that alleles having beneficial effects early in life (i.e., contribute to reproductive fitness) would increase in frequency within the gene pool even if their effects late in life were detrimental. These pleiotropic effects should be possible because natural selection is strong at young ages but weak or nonexistent at older ages. Thus, in addition to the delayed expression of mutated genes (mutation accumulation), senescence can also result from normal genes having abnormal consequences when expressed at ages beyond the reach of selection. Genetic diseases that appear in the late reproductive and early post-reproductive periods, like Huntington’s disease and other diseases of the central nervous system are consistent with the expectations from the mutation accumulation theory. Late life cancers behave in what could be considered an antagonist pleiotropy manner. For example, growth and development involves cell proliferation and proto-oncogenes are normal participants in those processes (Darnell et al., 1990). Once their tasks are completed, however, these genes are often inactivated because the high rate of cell proliferation needed for growth and development is no longer needed or desirable. An inadvertent reactivation (dysregulation) of these genes within the postreproductive period could produce an effect (cancerous transformation) consistent with antagonist pleiotropy (Cutler and Semsei, 1989). This brief review of how senescence occurs also reveals how a conflation of senescence and disease could have occurred. Medawar (1952) explicitly identified heritable genetic diseases as components of senescence. Williams (1957) also envisioned senescence as heritable in that it involves normal genes having abnormal effects at evolutionarily irrelevant times. The modern theories of senescence (e.g., Brunk and Terman, 2002; Finch and Kirkwood, 2000; Vijg, 2007) are more similar to the theories of Orgel (1963) and Harman (1956) who interpreted senescence as a byproduct of accumulated damage caused by stochastic processes. In the former scenario senescence could evolve while in the latter scenario senescence is a byproduct of processes that are beyond the reach of selection. The explicit linkages between senescence and disease in these respected theories blur rather than clarify the distinction between them. 3. When aging begins The post-reproductive phase of the life span is typically characterized as a period of physiological decline, disease and death. Trajectories of decline beginning as early as 30 years of age have been extensively documented for a wide range of human physiological parameters (e.g., Falzone and Shock, 1956; Naka-
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mura and Miyao, 2003; Sehl and Yates, 2001). The constellation of age-related changes (ARCs) in appearance and function that emerges after maturation is commonly referred to as the ‘‘aging phenotype.’’ Although ‘‘aging phenotype’’ provides an accurate portrayal of what is observed (Fried et al., 2001), it can create the false impression that maturation or the post-reproductive period marks the onset of senescence. It also confounds the phenotypic consequences of senescence with those arising from disease whose underlying cause can be behavioral (e.g., drug use and smoking), environmental (e.g., toxins) or genetic (e.g., progeria). Although the ‘‘aging phenotype’’ becomes most visible in the post-reproductive period, its antecedents begin much earlier. Consider human ova; they are finite in number and achieve postmitotic status before the female carrying them is even born. Over a course of reproductive senescence that can span decades, they become less fertile and more likely to produce genetic abnormalities (e.g., Down’s syndrome) when fertilized. Presumably, the forces responsible for these detrimental changes are the same ones responsible for how we age. As such, it is biologically reasonable to suggest that senescence begins in the ova of the unborn females who become the mothers of the next generation. An aging phenotype that emerges in the early 30s for humans is consistent with a life history strategy molded by the harsh environments of our ancient ancestors (Hawkes et al., 1998; Packer et al., 1998; Stearns, 1992). Delayed reproduction was not an option for them; women would have begun reproducing at 13–15 years of age and could easily have been grandmothers multiple times over by their early 30s (Ellison, 2001). Even in the protected world of today, the vast majority of children are born to parents younger than 35 years of age (Carnes et al., 2003). Although senescence begins when life begins, detectable senescence (the aging phenotype) is a hallmark of ages when the soma has survived long enough to be disposable (i.e., time enough to mature, reproduce and nurture). 4. Aging phenotype and disease The findings derived from an examination of ARCs in physiological systems of the body also produce a blurring between senescence and disease. Clinical and pathologic changes in the brains of people with sporadic Alzheimer’s disease (e.g., brain weight and volume declines, glutamatergic hyperactivity, neocortical neuron loss, accumulation of senile plaques and neurofibrillary tangles) are also found in the brains of ‘‘normal aged’’ people (Drachman, 2006; Esiri, 2007). ARCs of the heart (e.g., left ventricular hypertrophy, reduced early diastolic filling and increased late diastolic filling, peak cardiac output) and arteries (e.g., thickened intima, endothelial dysfunction and vascular stiffness) of people with cardiovascular disease (heart failure, arteriosclerosis, atherosclerosis, hypertension and stroke) are also attributed to ‘‘normative aging’’ (Ferrari et al., 2003; Greenwald, 2007; Lakatta and Levy, 2003a,b; Lakatta, 2003; Najjar et al., 2005). Similarly, ARCs in the amount and composition of bone, chondroid tissue, ligaments and skeletal muscle are considered risk factors for such degenerative diseases as osteoarthritis, osteoporosis and sarcopenia (Dirks and Leeuwenburgh, 2005; Freemont and Hoyland, 2007; Roubenoff and Hughes, 2000). Normal ARCs in the endocrine (e.g., declines in testosterone, estrogen, growth hormone, IGF-I) and immune system (loss of bone marrow, reduced bone marrow stem cell output, increased number of compromised macrophages, fewer common lymphoid progenitors) produce an array of changes (e.g., decrease in lean body mass, increased fat mass, insulin resistance, degraded immune function and thymic atrophy) that become risk factors for cardiovascular disease,
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metabolic syndrome, obesity and infection (Miller, 1996; Chahal and Drake, 2007; Gruver et al., 2007). Several recurring themes emerge from this system-based review of clinical literature. The most common theme is that ARCs attributed to senescence are indistinguishable from those observed in the pathogenesis and progression of many disease processes. A common corollary of this observation is that senescence and disease interact and that senescence often exacerbates disease and increases its severity. In this sense, disease is superimposed on a background milieu of senescence. A stronger corollary is that senescence is a risk factor for disease. An even stronger and less common theme is that senescence is either a prodromal stage of disease or could be considered a disease in itself. In other words, ARCs are the early (preclinical) manifestations of a process that transitions into clinically manifest disease. As is the case in the biological literature, the distinction between senescence and disease is clearly blurred in the clinical literature. 5. Distinguishing senescence from non-senescence In a now classic paper, Strehler (1959) examined whether exposure to ionizing radiation actually ‘‘accelerated aging’’ or only mimicked the biological consequences of senescence. Although the radiation biology community was the target audience, this paper represents one of the earliest and most significant attempts to develop criteria that allow the biological effects of senescence to be distinguished from those arising from other causes. As such, it provides a useful starting point for determining whether a distinction can or should be made between senescence and disease. Strehler focused on processes that have effects on biological structures and, hence their function. Although the acronym CUPID used to characterize senescence-induced changes in structure and function was not coined until later (e.g., Arking, 1991), Strehler identified the criteria that form the acronym: Cumulative (identified but not given separate status in the original paper), Universal, Progressive, Intrinsic and Deleterious. These criteria have generated considerable debate among scientists. The ‘‘universal’’ criterion, in particular, has played a central role in the debates over the relationship between senescence and disease. Since age-associated pathologies (disease) are not universal, Hayflick (2004) argues that knowledge about disease will not advance our understanding of senescence. Conversely, Holliday (2004) argues that knowledge about the pathogenesis of disease provides invaluable insights into the changes in biological structure and function that accompany senescence. Which of these alternative views is correct has considerable implications for public health and medicine, especially in an era of global population aging. If senescence and disease are unrelated, then treating one would have no impact on the health and life span consequences of the other. However, if they are causally related, then a single intervention for senescence could conceivably reap the cumulative health and life-extending benefits currently derived from multiple treatments applied to a spectrum of diseases (Butler et al., 2008; Tinetti and Fried, 2004; Holliday, 1984). 6. Taxonomy of senescence Strehler (1959) also developed a conceptual classification of causes for the decline in function observed in organisms. The first partition of this classification distinguished between determinate and ancillary processes, where the former processes always occur and the latter do not. Ancillary processes were predominately
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environmental factors that are either modifiable or avoidable. Determinate processes like ‘‘normal aging’’ were considered an ‘‘inherent part of the machine’’ (Strehler, 1959, p. 123). This dichotomy of change imposed on organisms by outside forces or arising from their intrinsic biology is a recurring theme in the history of thought on senescence (see Carnes and Olshansky, 1997; Carnes et al., 2006 for overviews of this literature). The determinate or intrinsic processes of change were, in turn, partitioned by Strehler into either stochastic or genetic processes. Genetic processes are conceptually straightforward and were described earlier in the discussion of evolutionary theories of senescence (e.g., Medawar, 1952; Williams, 1957). Stochastic processes, however, seem incompatible with the ‘‘determinate’’ or ‘‘universal’’ criterion established by Strehler to identify senescent changes. This apparent dilemma is resolved once it is recognized that it is the outcomes of a stochastic process that are neither predetermined nor universal, rather than the process itself. Consider ROS, they are an unavoidable (determinate/universal) byproduct of cellular respiration. ROS-induced damage (e.g., mutation of DNA or damage to a protein), however, produces an array of possible stochastic outcomes (e.g., cancer, mitochondrial diseases) rather than a single predetermined outcome. Thus, the occurrence of a stochastic event is probabilistic rather than deterministic, and that probability changes as a function of age (Fig. 1). This age dependence arises from a temporal competition for expression among stochastic events (competing risks) that differ in pathophysiology as well as the ability of the body to adapt (homeostasis: detection and repair) to that pathophysiology. Nonstochastic processes, on the other hand, have a predetermined outcome that occurs among all individuals (within species) who do not die prematurely. As such, it is the severity of a non-stochastic effect rather than its occurrence that is a probabilistic function of age (Fig. 1). 7. Stochastic effects The role of stochastic effects in the physiochemical processes that influence the ‘‘kinetics of senescence’’ can be traced to research performed early in the 20th century (Loeb and Northrop, 1917; Brody, 1924). Given its long history, the most influential of all stochastic theories of senescence is the free radical hypothesis of aging which also had its roots in radiation chemistry (Harman, 1956). Interestingly, Harman is one of the only modern scientists to explicitly declare that ‘‘aging may also be viewed as a disease’’ (Harman, 1991, p. 5362). Another prominent voice for the importance of stochastic processes is Hayflick (1994) who
Fig. 1. Senescence viewed as a mixture of stochastic and non-stochastic effects and the influence of age on those effects.
identifies entropy and the loss of molecular fidelity that arises from it as a fundamental cause of senescence (see also Failla, 1958; Orgel, 1963; Finch and Kirkwood, 2000). A review of the stochastic effects that emerge from the biochemistry of life is beyond the purview of this paper and would divert attention from the goals of the paper. We will, instead, identify review articles that discuss prominent stochastic effects within the context of senescence and disease: (1) epigenetic changes (Fraga et al., 2005; Holliday, 1987; Richardson, 2003), (2) genomic instability (Vijg, 2007), (3) glycation (Cerami et al., 1987; Ravichandran et al., 2005; Suji and Sivakami, 2004), (4) imperfect autophagocytosis or the junk theory of aging (Brunk and Terman, 2002; Terman et al., 2007); (5) bioactivity of nitric oxide (McCann et al., 1998), and (6) post-synthetic protein modification and turnover (Gafni, 2001; Nakamura et al., 2007; Rattan, 1996; So¨ti and Csermely, 2007). These stochastic processes are linked to a wide range of diseases. Thus, the literature on stochastic changes in the structure and function of molecules involved in the machinery of life also blurs the boundary between senescence and disease. 8. Non-stochastic (determinate) effects Non-stochastic effects fulfill all the criteria of CUPID developed by Strehler (1959) to identify senescence-induced changes in structure and function. Some of these effects are so familiar to geriatricians and clinical researchers (i.e., loss of nerves, muscle and bone) that names have been given to the processes that give rise to them (e.g., denervation, sarcopenia and osteopenia). Reductions in vascularization and oxygen absorption are other well known physiological degradations of structure and function with age that conform to CUPID, and if words existed for these processes they might be called ‘‘angiopenia’’ and ‘‘oxypenia’’. Nonstochastic senescent processes are predominately observed at the cellular or tissue level rather than the molecular level where the effects of stochastic processes are most evident. In addition, non-stochastic effects are more common in organs/ systems (e.g., brain, cartilage, heart, kidney, lung parenchyma and spinal cord) where terminally differentiated cells have a low turnover and exhibit limited regenerative capacity (Ballard and Edelberg, 2007; Carlson, 1998; Goldspink et al., 2003; Rando, 2006). Non-stochastic processes produce a broad spectrum of agerelated declines in the function of physiological processes (e.g., basal metabolic rate, blood volume, cardiac index, glomerular filtration rate, maximal breathing capacity and nerve conduction velocity) that were enumerated by the early biogerontologists (Falzone and Shock, 1956; Shock, 1957) and geriatricians (Anderson and Cowan, 1955; Rowe et al., 1976) and continue to be identified (Aalami et al., 2003; Nakamura and Miyao, 2003; Olivetti et al., 1991; Sehl and Yates, 2001; Weale, 1993). The non-stochastic effects of senescence could be considered an emergent manifestation of stochastic processes rather than byproducts of non-stochastic processes. In other words, the predetermined rather than probabilistic nature of these effects is something novel that could not have been predicted from the behavior of the stochastic processes that give rise to them (i.e., the whole is greater than the sum of parts). Emergent behaviors permeate every level of biological organization (Sole´ and Goodman, 2002), and in part, reflect the additional complexity that arises from the adaptive interactions occurring within and between levels of organization that we call homeostasis. Thus, the potential existence of these pseudo non-stochastic effects cannot be dismissed. Processes like osteopenia and cellular senescence (Campisi et al., 2001; Marcotte and Wang, 2002), however, have known mechanisms that are consistent with actual non-stochastic processes. Finally, the senescent effects associated with the wear and
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tear that occurs at all levels of biological organization are consistent with both the disposable soma theory of senescence (Kirkwood and Holliday, 1979) and the expected behavior of nonstochastic processes. As such, maintaining a distinction been stochastic and non-stochastic processes (and their effects) appears justified. The key point is that stochastic effects occur in everyone who lives long enough and the severity of their impact invariably increases with age. 9. Implications for intervention research There are ample reasons for optimism regarding the search for ways to favorably modulate senescence: (1) our bodies are not designed for indefinite survival, but neither are they designed to fail, (2) genes evolved to promote health and vigor, not ensure decrepitude and death, (3) senescence is ubiquitous, and is not driven by a single process, and (4) senescence is a byproduct of evolutionary neglect, not evolutionary intent. These biological realities suggest that there should be many opportunities for the development of interventions that improve health, quality of life and extend survival. Biological logic also provides a framework for narrowing the search for these interventions. This narrowing begins with recognizing the difference between longevity and senescence. The inevitability of death has two profound biological consequences. It dictates that the fundamental purpose of an organism is to reproduce and it defines the timeframe (i.e., longevity) within which that reproduction must occur. The biology of organisms is simply the means by which this biological imperative is achieved. Since biology is predominantly a product of genes, so is longevity. Senescence, however, is not a direct product of genes, but is instead an inadvertent byproduct of the biology created by genes. If biology is likened to an illuminated statue, then senescence is the shadow cast by that statue. Just as altering the statue will alter its shadow, senescence will be altered, albeit indirectly, by interventions that modify the biology responsible for longevity determination. The most serious threats to organisms are those that threaten the longevity needed to replace themselves; life history strategies
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(i.e., an integrated biology) evolve to mitigate these threats. Scientists are actively identifying ‘‘longevity assurance’’ genes in model organisms and their efforts will reveal a hierarchy of longevity processes (e.g., maintenance and repair), their relative importance, their interactions, and ways to intervene in them. One caveat to this valuable line of research is that modifying genes almost always produces unintended consequences that can offset or diminish the benefit of the intended effect (Vijg, 2007). Interventions for senescence are being actively sought. This area of research is complicated by the fact that senescence is an omnipresent complex mixture of modalities that vary in their degree of interdependency. As such, the efficacy of targeted interventions (e.g., most pharmaceuticals) is questionable. Instead, systemic interventions will be needed to effectively intervene in senescence. Interventions in this category would include efforts to retard non-stochastic (e.g., denervation, osteopenia and sarcopenia) and stochastic (e.g., free radical damage, genomic instability and methylation) effects of senescence. Identifying true interventions for senescence will be a challenge because they can be confused with interventions that simply delay death. Medical interventions that delay death (i.e., extend life) by suppressing the symptoms of disease (rather than curing it) are commonplace. Innovations of modern society, in the collective, have successfully reduced deaths during every phase of the human life course. In so doing, they have raised life expectancies and made population aging a global phenomenon (Olshansky et al., 1993). Although the beneficiaries of these interventions live longer, their underlying senescence has remained unaltered. Progress in the search for interventions has been hampered by an insufficient clarity of the distinction between senescence and non-senescence. Strehler’s (1959) C.U.P.I.D. criteria provide a strong conceptual foundation for this problem, but appear not to have become part of the current intervention paradigm. Another insight on interventions for senescence starts with the premise that all deaths are premature. Living a perfect life in a perpetually perfect environment and avoiding all avoidable mortality risks is impossible. This scenario implies the existence of a ‘‘potential lifespan’’ that the real world of mortality risks puts beyond the grasp of any individual (Fig. 2). Human ingenuity, however, keeps
Fig. 2. Schematic illustrating the relationship of observed life span to potential life span and the difference between interventions that reclaim survival time as opposed to those that extend survival by modifying senescence.
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finding ways to reclaim increments of this lost survival time. In order to be a true intervention for senescence under this conceptual construct, survival must be extended beyond the potential lifespan. Another implication of this line of reasoning is that extending the observed life span (the current gold standard) provides necessary but insufficient evidence to demonstrate that senescence itself has been modified. The detection of true interventions for senescence will require detailed pathological information. However, if senescence does not generate unique pathology, then pathology observed at death is still not sufficient to demonstrate the efficacy of an intervention for senescence. A true intervention for senescence should delay age at death, and must also delay the age at onset for senescent diseases and processes. Thus, detecting the success of these interventions requires a surveillance of pathological changes throughout the life span of individuals. Unless the intervention effect is dramatic, small-scale studies will be of limited value. Further, given the uncertainty surrounding the relevance of animal models, validation of these interventions will require proof of efficacy in multiple animal models. Although the technology already exists to perform longitudinal intervention studies on senescence, pursuing them will require overcoming significant logistic and economic barriers. 10. Discussion/conclusion The most salient theme emerging from this review of the scientific and medical literature is that the boundary between aging and disease is blurred. This blurring, however, is both inevitable and revealing. Although diseases have many causes (e.g., genetic, toxin and microbe), this review suggests that aging is one of them. Diseases not caused by aging arise from knowable causes with knowable pathogenesis. This class of disease can, in theory, be cured (e.g., appendicitis) or eliminated (e.g., smallpox). Aging, however, is not a single entity and its causes are deterministic and stochastic as well as omnipresent and ubiquitous. As such, aging can be mitigated but it can be neither ‘‘cured’’ nor eliminated. Our bodies are not designed for immortality; they are designed to replace themselves. Longevity provides the time for that to occur and aging is simply a byproduct of surviving beyond that timeframe. Within the context of human reproductive biology and the environments from which it emerged, a century is practically an eternity. Physicians need not fear that science will put them out of work. A better scientific understanding of the mechanisms of senescence is the ultimate way to better understand diseases of old age, thereby improving the health of an aging and increasingly long-lived population. There is some urgency to finding the solution to Medawar’s unsolved problem in biology because the health consequences of population aging (i.e., comorbidity, frailty and disability) have already become and will continue to be one of the biggest biomedical challenges ever faced by humanity. References Aalami, O.O., Fang, T.D., Song, H.M., Nacamuli, R.P., 2003. Physiological features of aging persons. Arch. Surg. 138, 1068–1076. Ackermann, M., Schauerte, A., Stearns, S.C., Jenal, U., 2007. Experimental evolution of aging in a bacterium. BMC Evol. Biol. 7, 126–135. Anderson, W.F., Cowan, N.R., 1955. A consultative center for people. Lancet 1, 1117– 1120. Arking, R., 1991. Biology of Aging: Observations and Principles. Englewood Cliffs, Prentice Hall. Ballard, L.T., Edelberg, J.M., 2007. Stem cells and the regeneration of the aging cardiovascular system. Circ. Res. 100, 1116–1127. Bengtson, V.L., Schaie, K.W. (Eds.), 1999. Handbook of Theories of Aging. Springer Publishing Company, New York.
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