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Accelerated aging in schizophrenia and related disorders: Future research
SCHRES-07366; No of Pages 5 Schizophrenia Research xxx (2017) xxx–xxx
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Accelerated aging in schizophrenia and related disorders: Future research Brian Kirkpatrick a,⁎, Brian K. Kennedy b,c,d a
Department of Psychiatry and Behavioral Sciences, University of Nevada, Reno School of Medicine, 5190 Neil Road, Suite 215, Reno, NV 89502, United States Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD 7, 8 Medical Drive, Singapore 117596, Singapore Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, United States d Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD 7, 8 Medical Drive, Singapore 117596, Singapore b c
a r t i c l e
i n f o
Article history: Received 8 April 2017 Received in revised form 15 June 2017 Accepted 19 June 2017 Available online xxxx Keywords: Schizophrenia Psychosis Aging Longevity
a b s t r a c t Several lines of evidence suggest schizophrenia is a segmental progeria, that is, some but not all aspects of accelerated aging may be present. However, the evidence has not been consistent. Problems with matching and confounding may account for some of these discrepancies. Given the etiopathophysiological heterogeneity of schizophrenia, it is possible that only a specific pathophysiological group within schizophrenia is associated with progeroid features, while others are not, or that one group is associated with a particular segment of aging features, while other progeroid features are found in another pathophysiological subgroup. In the aging research field, significant progress has been made in identifying the molecular pathways that confer aging: epigenetic changes, inflammation, proteostasis, adult stem cell function, metabolic changes, and adaptation to stress, and macromolecular damage. In addition to replication and clarification of existing kinds of evidence, examining these aging pathways would improve our understanding of progeria in schizophrenia. © 2017 Published by Elsevier B.V.
1. Introduction Nearly everyone contemplates aging at some point. People worry about getting older because they will get sick and lose their ability to enjoy life and contribute to the world around them. The notion that aging begets disease seems obvious and yet it is only in recent years that a consensus has emerged recognizing aging as the biggest risk factor for a wide range of chronic diseases, including Alzheimer's, a range of degenerative neurologic conditions, metabolic and cardiovascular syndromes and most forms of adult-onset cancer, to name just a few. Aging is a “progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability” (Comfort, 1964). Medawar (1952) defined aging as “a collection of changes that render human beings more likely to die.” This quote derives from Medawar's famous book, An Unsolved Problem in Biology, a title that in 1952 was certainly true. While the work of Medawar and many others has provided plausible evolutionary theories of aging (Kirkwood, 2005), a mechanistic understanding of the physiologic changes driving pathology during aging has only recently begun to coalesce. A recent review from a diverse collection of scientists in the aging field defined seven processes that collectively influence aging (Kennedy et al., 2014). While these processes can be defined in different ways ⁎ Corresponding author. E-mail address: [email protected] (B. Kirkpatrick).
(Lopez-Otin et al., 2013), there is for the first time a strong sense in the aging field that clear themes are emerging. A class of diseases termed progeroid disorders exhibit segmental aging, that is, some but not all features of aging appear to be accelerated. Hutchinson-Gilford and Werner syndrome are two classic examples, and debate has continued for decades as to whether the causes of these diseases are overlapping with those of normal aging. Another theme has also emerged: that classical non-aging diseases may either be associated with segmental aging or may accelerate aging. In other words, disease may beget aging which in turn begets disease. For instance, Down's syndrome patients have early onset Alzheimer's disease, as well as a range of other age-related conditions (Malt et al., 2013). Chronic viral infection, notably cytomegalovirus, may be an example of a disease that drives aspects of aging, in this case accelerating senescence in the immune system (Frasca and Blomberg, 2016). These findings suggest that we are just beginning to understand the relationship between aging and disease. 2. Schizophrenia and aging In 1968, two psychiatrists wrote, “There is a rather common notion among psychiatrists that patients with schizophrenia appear younger than their chronological age” (Gottheil and Joseph, 1968). When the authors tested this hypothesis they found the opposite, that people with schizophrenia were judged to look older than control subjects. To our
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Please cite this article as: Kirkpatrick, B., Kennedy, B.K., Accelerated aging in schizophrenia and related disorders: Future research, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.034
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knowledge, this is the first article that could be considered to suggest schizophrenia was associated with accelerated aging. Nearly thirty years later, DeLisi (1997) suggested that schizophrenia was a “lifetime disorder of brain plasticity, growth, and aging.” She focused on abnormal aging in the brain and did not suggest this abnormality extended to the rest of the body. When we suggested schizophrenia was a syndrome of accelerated aging, we cited studies of brain structure and function, but also pointed out findings raising the possibility that abnormal aging occurs in the periphery as well (Kirkpatrick et al., 2008). If schizophrenia is a syndrome of accelerated aging, it may be a segmental progeroid syndrome, that is, only some aspects of accelerated aging may be present. This possibility complicates interpretation of evidence on the hypothesis of accelerated aging in schizophrenia and related disorders, as a failure to find a specific aspect of normal aging would not refute the hypothesis. We describe below an approach to determine whether schizophrenia indeed resembles segmental aging and, if so, which aging pathways are affected. As the purpose of this article is to suggest directions for more definitive hypothesis testing, we do not present a thorough review of the literature. 3. Research strategy In our 2008 article (Kirkpatrick et al., 2008) we discussed evidence related to mortality patterns, cognitive decline, diabetes, and pulse pressure, as well as risk factors shared by schizophrenia and aging-related disorders such as diabetes. We also cited a single imaging study that found an increased rate of brain volume loss in people with schizophrenia compared to control subjects (Ho et al., 2007). We suggested further tests of the hypothesis could include studies of other physiological measures known to change with normal aging, including insulin resistance, blood lipid concentrations, pulse pressure, bone density, clouding of the eye lens, thinning and wrinkling of the skin, thinning of the hair, and muscle mass. Since that time, our meta-analyses of studies of antipsychotic-naïve patients have found abnormal glucose tolerance and insulin resistance, as well as elevated prolactin concentrations in both men and women (Greenhalgh et al., 2017; González-Blanco et al., 2016). However, studies of aging and cognition have had mixed results (e.g., Harvey, 2014; Irani et al., 2011; Rodriguez-Jimenez et al., 2015). Other measures linked to aging have also been examined, including telomere length, pulse pressure, levels of androgens in males, and prostaglandin concentrations (Fernandez-Egea et al., 2011; Lee et al., 2016). Findings of increased inflammation (Miller et al., 2011) and oxidative stress (Finkel and Holbrook, 2000; Miller et al., 2014) are also consistent with the hypothesis of accelerated aging. Contradictory findings have been published on some of these measures, for instance on telomere length (Fernandez-Egea et al., 2009a,b; Jeste et al., 2016). There is a relative lack of longitudinal studies of the accelerated aging hypothesis, but such studies would be helpful in testing associations found using a cross-sectional design. There are many possible causes of contradictory results in this area. To conduct stronger tests of the accelerated aging hypothesis, it will be important to consider confounding by antipsychotic medications. Most antipsychotics in current use are associated with weight gain, with concomitant increases in inflammation and glucose intolerance. Glucose intolerance and inflammation are both aging-related conditions and may induce other aging-related changes. As a consequence, without comparison groups with similar exposure to antipsychotics, findings on agerelated variables are vulnerable to confounding, leaving the field with ambiguous interpretations of the evidence. Several findings consistent with accelerated aging, with medium to large effect sizes, have been found in antipsychotic-naïve patients (Fernandez-Egea et al., 2009a,b, 2011), and study of this population is an important strategy for the study of aging. A number of other factors can also influence metabolic and physiological measures associated with aging and so confound associations
with age-related phenomena. These include the familiar variables of age, ethnicity, and gender. However, to use the example of glucose tolerance, several other variables are also known to be important: alcohol, smoking, diet, cortisol, and body mass index or waist-hip ratio. Matching on socioeconomic status of family of origin is also desirable as this should minimize possible confounding by factors such as childhood nutrition, lifetime diet, and exposure to environmental toxins. To our knowledge, only one study of an aging-related variable in people with nonaffective psychosis either dealt with these factors through matching or choice of patient population, or examined their relationship to the outcome variable, in this case glucose tolerance (Fernandez-Egea et al., 2009a; Kirkpatrick et al., 2012). Another difficulty in testing the accelerated aging hypothesis is that schizophrenia is itself a heterogeneous disorder. It is possible that a specific etiopathophysiological group or groups within schizophrenia is associated with progeroid features, while others are not, or that one group is associated with a particular segment of aging features, while other progeroid features are found in another pathophysiological subgroup. For instance, preliminary evidence suggests that deficit and nondeficit groups, that is, those with and without primary, enduring negative symptoms, may differ on two aging-related measures, inflammation and glucose tolerance (Garcia-Rizo et al., 2012a,b; Kirkpatrick et al., 2009). Replication is needed for these findings, but they illustrate the kind of complexity that may be encountered. There a number of strategies other than the deficit/nondeficit categorization that may prove to be useful in defining pathophysiological subgroups. Examples include a comparison between patients with and without a specific environmental or genetic risk factor (Malaspina et al., 2015), differing trajectories of cognitive impairment (Thompson et al., 2013), or differences in biomarkers such as (state or trait) inflammation (Miller et al., 2011; Kirkpatrick and Miller, 2013). Level of function, or a variation of level of function such as community living vs. institutionalization, seems less promising as there are many paths to poor functional status. For instance, deficit patients have poor function compared to patients without primary, enduring negative symptoms, but severe and treatment-nonresponsive positive symptoms can also cause poor function. Combining such groups in a study of poor function/good function groups may weaken any signal-to-noise ratio.
4. Aging: mechanisms and pathways The breadth of evidence on accelerated aging, which includes epidemiological studies, physiological challenges, and imaging, is intriguing but to date it largely consists of studies of aging-related variables that do not bring us much closer to an understanding of any mechanism(s) of accelerated aging. Studies that test for the presence of abnormalities in the relevant mechanistic pathways would be desirable. In the aging research field, significant progress has been made in identifying the molecular pathways that confer aging. A recent review listed seven areas of biology that are implicated in aging (Kennedy et al., 2014), and other reviews have come to similar conclusions (Lopez-Otin et al., 2013). These areas are understood at differing levels of mechanistic depth; however, they serve as a good framework for discussing the known links between schizophrenia and aging and for designing future studies. Each of the seven is briefly discussed below. It should be noted that these pathways have a surprising level of inter-connectedness. Disruption of any one pathway during aging can easily lead to dysfunction in others. Therefore, while aging may have several drivers, the process can be considered as a network. Initial changes during aging drive other changes, leading to a progressive loss of homeostasis. In a segmental progeria, where dysfunction in only a subset of pathways of aging is observed, perturbations of the network may have more unpredictable outcomes.
Please cite this article as: Kirkpatrick, B., Kennedy, B.K., Accelerated aging in schizophrenia and related disorders: Future research, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.034
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4.1. Epigenetic changes
4.4. Adult stem cell function
A number of recent studies have pointed to the importance of epigenetic regulation in the control of aging (Brunet and Rando, 2017). For instance, altering levels of several chromatin-modifying factors can affect lifespan in a variety of organisms. Moreover, epigenetic changes are increasingly linked to a decline in stem cell regenerative capacity with aging. The epigenetic clock, which integrates data on DNA methylation state from over 350 promoters, has emerged as a leading candidate biomarker for aging (Chen et al., 2016). With this clock, chronological age can be predicted with a high degree of consistency in a number of tissues. This raises the interesting question of whether schizophrenia patients have methylation patterns associated with enhanced aging and, if so, in what tissues. An abnormality of this kind has been demonstrated in other diseases, for instance affected brain regions in Huntington's disease (Horvath et al., 2016), the immune system of Parkinson's patients (Horvath and Ritz, 2015), and multiple tissues in Down's syndrome (Horvath et al., 2015).
Aging is characterized by a decline in adult stem cell function, leading to reduced capacity to regenerate tissues (Goodell and Rando, 2015). This is characteristic of many adult tissues. Within the hematopoietic system, stem cells increase with age but they have decreased self-renewal capacity upon transplantation and generate lineages skewed toward myeloid populations at the expense of lymphoid cell number (Pang et al., 2017). HSC lineages also become more clonal with age for reasons that are not clearly established. It would be good to determine the self-renewal capacity of stem cells from a range of adult tissues in schizophrenia patients. Analysis of the relative numbers of cells in different lineages should be conducted on schizophrenia patients to determine whether they have abnormal skewing related to aging.
4.2. Inflammation Elevated chronic sterile inflammation is strongly associated with aging and increasing evidence indicates that it may be a driving factor in multiple age-related diseases. In schizophrenia, levels of specific inflammatory cytokines such as IL-6 and TNF-α have been assessed with variable results (Franceschi et al., 2017). There is a need to examine large inflammatory cytokine panels and compare changes to known changes in aging. One source of inflammation is the increasing presence of senescent cells during aging, which have a unique secretome compared to normal cells that is characterized by high levels of inflammatory factors (LeBrasseur et al., 2015). Thus senescent cells can have paracrine and possibly endocrine effects on normal cells that promote inflammatory aspects of aging. The concentrations of senescent cells could be assessed in accessible tissues (lymphocyte populations, skin tissue and isolated fibroblasts) from schizophrenia patients to determine (1) whether numbers are increased relative to age-matched controls, and (2) whether increases in senescent cell populations can account for alterations in inflammatory cytokines.
4.3. Proteostasis Protein synthesis and turnover are highly coordinated processes in cells, with newly synthesized proteins being generated to support cell growth and replace those that are misfolded and/or no longer functional. Several components of the proteostasis machinery are implicated in aging, including mTOR, a signaling factor that regulates cellular nutrient and stress status by coordinating stress response pathways, protein translation components, and protein turnover pathways including autophagy, mitophagy and proteasome function (discussed in the Adaptation to stress section; Kaushik and Cuervo, 2015; Steffen and Dillin, 2016). The mTOR pathway is strongly implicated in aging, in which a chronic upregulation of mTORC1 activity can be detected in a range of tissues, including hematopoietic lineages (Nacarelli et al., 2015). Moreover, pharmacologic and genetic interventions that reduce mTOR signaling extend lifespan in a range of model organisms and have promise for similar effects in humans (Kennedy and Lamming, 2016). With regard to schizophrenia, it is important to see if the mTOR pathway is dysregulated in primary blood lymphocytes or in isolated fibroblasts at levels disproportionate with age. Activation of the mTOR pathway, as well as levels of protein translation, can also be inferred from transcriptomic analysis of cells. As a first step, it would be helpful to measure the phosphorylation state of mTORC1 substrates, which are elevated in HSC lineages with age.
4.5. Metabolic changes Meta-analysis has shown that antipsychotic-naive patients have abnormal glucose tolerance and insulin resistance (Fernandez-Egea et al., 2008; Greenhalgh et al., 2017). A single study found no difference between antipsychotic-naive patients and matched control subjects in total cholesterol, high-density lipoproteins, low-density lipoproteins, or triglycerides (Kirkpatrick et al., 2010). Additional studies of these characteristics would be helpful. Extensive panels of metabolites and lipid markers have also been assayed (e.g., Dickerson et al., 2015). Mitochondrial dysfunction is another common feature of aging; direct assessments of mitochondrial respiratory activity would provide useful information. There appears to be increased oxidative stress in whole blood in schizophrenia (Flatow et al., 2013); the production of reactive oxygen species could be assessed further in isolated fibroblasts and lymphocytes from schizophrenia patients. Finally, as increasing evidence indicates that the gut microbiome changes dramatically during aging and given the influence of the microbiome on metabolism, it would be of interest to assess fecal samples for age-related changes. 4.6. Adaptation to stress Cellular adaptation to stress declines during the aging process. This is reflected in changes in stress response pathways such as autophagy, proteasome activity, and endoplasmic reticulum stress response pathways in cells isolated from aged individuals. These changes could be assessed in lymphocytes and fibroblasts from schizophrenia patients. In addition, isolated cells, either fibroblasts or lymphocytes, can be challenged with different kinds of stresses and the responses can be assessed. These studies would provide initial insight into stress response pathways associated with aging. 4.7. Macromolecular damage Damage can happen to a range of molecules in cells, including proteins, lipids and nucleic acids. Damage to proteins and their clearance is part of proteostasis pathways, mentioned above. Lipid-related damage occurs during aging but remains poorly understood. In contrast, the prevalence of DNA damage has been extensively assessed during aging. Increased DNA damage is evident in a wide range of tissues and cell types with aging, although the contribution that damage makes to different aspects of aging remains unclear. DNA damage in HSC lineages has been particularly well defined, leading to tumor development and clonality (Moehrle and Geiger, 2016). Schizophrenia patients have been found to have increased markers of DNA and RNA damage in urine (Jorgensen et al., 2013). DNA damage should be tested more directly using assays for DNA damage in isolated cells. Interestingly, single cell sequencing is now possible and by determining differences between two cells from the same individual, it is possible to measure the rate of damage over time (Gundry et al., 2012). These studies would
Please cite this article as: Kirkpatrick, B., Kennedy, B.K., Accelerated aging in schizophrenia and related disorders: Future research, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.034
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generate a more comprehensive assessment of whether DNA mutations are accelerated in schizophrenia patients. 5. Conclusions Aging increases the risk of many chronic diseases, but increasing evidence suggests that an array of diseases may also accelerate aspects of aging. Published studies consistent with accelerated aging in schizophrenia and related disorder involve brain abnormalities, including imaging studies and cognition, as well as abnormalities in the periphery, such as abnormal glucose tolerance and increased inflammation in antipsychotic-naïve patients. Future studies will need to deal with the potentially confounding factors listed above if they are to serve as strong tests of the hypothesis of accelerated aging. Weaknesses in study design, either in matching or otherwise, has been such a common problem that the validity of the accelerated aging hypothesis remains in doubt. To advance the field, it would also be helpful to conduct studies that focus on the mechanistic pathways listed above. Studies in antipsychotic-naïve patients would be particularly useful since the drugs used to treat the condition can evoke an array of side effects related to aging. Determining whether schizophrenia is associated with accelerated aging is of substantial practical interest to people with this disorder. It is also of broader medical interest, as an understanding of accelerated aging in schizophrenia, should it exist, may deepen understanding of aging more generally. There is some evidence suggesting depression and bipolar disorder may also be associated with accelerated aging, and that there may be some common pathophysiology of these abnormalities across diagnostic lines (Garcia-Rizo et al., 2013, 2016; Sacchet et al., 2017; Vasconcelos-Moreno et al., 2017; Vieta et al., 2013). Should the hypothesis of accelerated aging be confirmed, therapeutic approaches could be tested within the foreseeable future. A number of candidate interventions, ranging from lifestyle modifications to pharmacologic agents such as the mTOR inhibitor rapamycin, have been proposed to delay aging; these may be useful either as therapies to improve functional outcomes in schizophrenia patients and/or to delay associated diseases that may emerge from an acceleration of aging. Attention to the specific mechanisms of aging discussed above would aid in the development of treatments. Contributors Drs. Kennedy and Kirkpatrick wrote the first draft of the manuscript, and both had final approval.
Funding body agreements and policies Research in Dr. Kennedy's lab on aging is supported by NIH grants R01 AG050441 and AG047497. Conflicts of interest Dr. Kennedy is a member of the Board of Trustees of three companies seeking to exploit aging pathways to modify aging and age-related disease: L-Nutra, Mt. Tam Biotechnologies, and Ponce de Leon Pharmaceuticals. He also is a science advisor for Affirmativ Health. Dr. Kirkpatrick has received licensing royalties and travel support from ProPhase for use of the Brief Negative Symptom Scale (BNSS) by for-profit groups; these fees are donated the Brain and Behavior Research Foundation. Dr. Kirkpatrick has also received consulting fees and travel support from Genentech/Roche, Minerva Neurosciences, and ProPhase LLC, consulting fees from anonymized pharmaceutical companies through Decision Resources, Inc. and L.E.K. Consulting, and from an investment capital company through Guideposts. Dr. Kirkpatrick also receives fees from Walsh Medical Media for editorial services, and received fees for editorial services from Physicians Postgraduate Press, Inc.
Acknowledgements
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Schizophrenia Research journal homepage: www.elsevier.com/locate/schres
Accelerated aging in schizophrenia and related disorders: Future research Brian Kirkpatrick a,⁎, Brian K. Kennedy b,c,d a
Department of Psychiatry and Behavioral Sciences, University of Nevada, Reno School of Medicine, 5190 Neil Road, Suite 215, Reno, NV 89502, United States Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD 7, 8 Medical Drive, Singapore 117596, Singapore Buck Institute for Research on Aging, 8001 Redwood Blvd., Novato, CA 94945, United States d Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, MD 7, 8 Medical Drive, Singapore 117596, Singapore b c
a r t i c l e
i n f o
Article history: Received 8 April 2017 Received in revised form 15 June 2017 Accepted 19 June 2017 Available online xxxx Keywords: Schizophrenia Psychosis Aging Longevity
a b s t r a c t Several lines of evidence suggest schizophrenia is a segmental progeria, that is, some but not all aspects of accelerated aging may be present. However, the evidence has not been consistent. Problems with matching and confounding may account for some of these discrepancies. Given the etiopathophysiological heterogeneity of schizophrenia, it is possible that only a specific pathophysiological group within schizophrenia is associated with progeroid features, while others are not, or that one group is associated with a particular segment of aging features, while other progeroid features are found in another pathophysiological subgroup. In the aging research field, significant progress has been made in identifying the molecular pathways that confer aging: epigenetic changes, inflammation, proteostasis, adult stem cell function, metabolic changes, and adaptation to stress, and macromolecular damage. In addition to replication and clarification of existing kinds of evidence, examining these aging pathways would improve our understanding of progeria in schizophrenia. © 2017 Published by Elsevier B.V.
1. Introduction Nearly everyone contemplates aging at some point. People worry about getting older because they will get sick and lose their ability to enjoy life and contribute to the world around them. The notion that aging begets disease seems obvious and yet it is only in recent years that a consensus has emerged recognizing aging as the biggest risk factor for a wide range of chronic diseases, including Alzheimer's, a range of degenerative neurologic conditions, metabolic and cardiovascular syndromes and most forms of adult-onset cancer, to name just a few. Aging is a “progressive deterioration of physiological function, an intrinsic age-related process of loss of viability and increase in vulnerability” (Comfort, 1964). Medawar (1952) defined aging as “a collection of changes that render human beings more likely to die.” This quote derives from Medawar's famous book, An Unsolved Problem in Biology, a title that in 1952 was certainly true. While the work of Medawar and many others has provided plausible evolutionary theories of aging (Kirkwood, 2005), a mechanistic understanding of the physiologic changes driving pathology during aging has only recently begun to coalesce. A recent review from a diverse collection of scientists in the aging field defined seven processes that collectively influence aging (Kennedy et al., 2014). While these processes can be defined in different ways ⁎ Corresponding author. E-mail address: [email protected] (B. Kirkpatrick).
(Lopez-Otin et al., 2013), there is for the first time a strong sense in the aging field that clear themes are emerging. A class of diseases termed progeroid disorders exhibit segmental aging, that is, some but not all features of aging appear to be accelerated. Hutchinson-Gilford and Werner syndrome are two classic examples, and debate has continued for decades as to whether the causes of these diseases are overlapping with those of normal aging. Another theme has also emerged: that classical non-aging diseases may either be associated with segmental aging or may accelerate aging. In other words, disease may beget aging which in turn begets disease. For instance, Down's syndrome patients have early onset Alzheimer's disease, as well as a range of other age-related conditions (Malt et al., 2013). Chronic viral infection, notably cytomegalovirus, may be an example of a disease that drives aspects of aging, in this case accelerating senescence in the immune system (Frasca and Blomberg, 2016). These findings suggest that we are just beginning to understand the relationship between aging and disease. 2. Schizophrenia and aging In 1968, two psychiatrists wrote, “There is a rather common notion among psychiatrists that patients with schizophrenia appear younger than their chronological age” (Gottheil and Joseph, 1968). When the authors tested this hypothesis they found the opposite, that people with schizophrenia were judged to look older than control subjects. To our
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Please cite this article as: Kirkpatrick, B., Kennedy, B.K., Accelerated aging in schizophrenia and related disorders: Future research, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.034
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knowledge, this is the first article that could be considered to suggest schizophrenia was associated with accelerated aging. Nearly thirty years later, DeLisi (1997) suggested that schizophrenia was a “lifetime disorder of brain plasticity, growth, and aging.” She focused on abnormal aging in the brain and did not suggest this abnormality extended to the rest of the body. When we suggested schizophrenia was a syndrome of accelerated aging, we cited studies of brain structure and function, but also pointed out findings raising the possibility that abnormal aging occurs in the periphery as well (Kirkpatrick et al., 2008). If schizophrenia is a syndrome of accelerated aging, it may be a segmental progeroid syndrome, that is, only some aspects of accelerated aging may be present. This possibility complicates interpretation of evidence on the hypothesis of accelerated aging in schizophrenia and related disorders, as a failure to find a specific aspect of normal aging would not refute the hypothesis. We describe below an approach to determine whether schizophrenia indeed resembles segmental aging and, if so, which aging pathways are affected. As the purpose of this article is to suggest directions for more definitive hypothesis testing, we do not present a thorough review of the literature. 3. Research strategy In our 2008 article (Kirkpatrick et al., 2008) we discussed evidence related to mortality patterns, cognitive decline, diabetes, and pulse pressure, as well as risk factors shared by schizophrenia and aging-related disorders such as diabetes. We also cited a single imaging study that found an increased rate of brain volume loss in people with schizophrenia compared to control subjects (Ho et al., 2007). We suggested further tests of the hypothesis could include studies of other physiological measures known to change with normal aging, including insulin resistance, blood lipid concentrations, pulse pressure, bone density, clouding of the eye lens, thinning and wrinkling of the skin, thinning of the hair, and muscle mass. Since that time, our meta-analyses of studies of antipsychotic-naïve patients have found abnormal glucose tolerance and insulin resistance, as well as elevated prolactin concentrations in both men and women (Greenhalgh et al., 2017; González-Blanco et al., 2016). However, studies of aging and cognition have had mixed results (e.g., Harvey, 2014; Irani et al., 2011; Rodriguez-Jimenez et al., 2015). Other measures linked to aging have also been examined, including telomere length, pulse pressure, levels of androgens in males, and prostaglandin concentrations (Fernandez-Egea et al., 2011; Lee et al., 2016). Findings of increased inflammation (Miller et al., 2011) and oxidative stress (Finkel and Holbrook, 2000; Miller et al., 2014) are also consistent with the hypothesis of accelerated aging. Contradictory findings have been published on some of these measures, for instance on telomere length (Fernandez-Egea et al., 2009a,b; Jeste et al., 2016). There is a relative lack of longitudinal studies of the accelerated aging hypothesis, but such studies would be helpful in testing associations found using a cross-sectional design. There are many possible causes of contradictory results in this area. To conduct stronger tests of the accelerated aging hypothesis, it will be important to consider confounding by antipsychotic medications. Most antipsychotics in current use are associated with weight gain, with concomitant increases in inflammation and glucose intolerance. Glucose intolerance and inflammation are both aging-related conditions and may induce other aging-related changes. As a consequence, without comparison groups with similar exposure to antipsychotics, findings on agerelated variables are vulnerable to confounding, leaving the field with ambiguous interpretations of the evidence. Several findings consistent with accelerated aging, with medium to large effect sizes, have been found in antipsychotic-naïve patients (Fernandez-Egea et al., 2009a,b, 2011), and study of this population is an important strategy for the study of aging. A number of other factors can also influence metabolic and physiological measures associated with aging and so confound associations
with age-related phenomena. These include the familiar variables of age, ethnicity, and gender. However, to use the example of glucose tolerance, several other variables are also known to be important: alcohol, smoking, diet, cortisol, and body mass index or waist-hip ratio. Matching on socioeconomic status of family of origin is also desirable as this should minimize possible confounding by factors such as childhood nutrition, lifetime diet, and exposure to environmental toxins. To our knowledge, only one study of an aging-related variable in people with nonaffective psychosis either dealt with these factors through matching or choice of patient population, or examined their relationship to the outcome variable, in this case glucose tolerance (Fernandez-Egea et al., 2009a; Kirkpatrick et al., 2012). Another difficulty in testing the accelerated aging hypothesis is that schizophrenia is itself a heterogeneous disorder. It is possible that a specific etiopathophysiological group or groups within schizophrenia is associated with progeroid features, while others are not, or that one group is associated with a particular segment of aging features, while other progeroid features are found in another pathophysiological subgroup. For instance, preliminary evidence suggests that deficit and nondeficit groups, that is, those with and without primary, enduring negative symptoms, may differ on two aging-related measures, inflammation and glucose tolerance (Garcia-Rizo et al., 2012a,b; Kirkpatrick et al., 2009). Replication is needed for these findings, but they illustrate the kind of complexity that may be encountered. There a number of strategies other than the deficit/nondeficit categorization that may prove to be useful in defining pathophysiological subgroups. Examples include a comparison between patients with and without a specific environmental or genetic risk factor (Malaspina et al., 2015), differing trajectories of cognitive impairment (Thompson et al., 2013), or differences in biomarkers such as (state or trait) inflammation (Miller et al., 2011; Kirkpatrick and Miller, 2013). Level of function, or a variation of level of function such as community living vs. institutionalization, seems less promising as there are many paths to poor functional status. For instance, deficit patients have poor function compared to patients without primary, enduring negative symptoms, but severe and treatment-nonresponsive positive symptoms can also cause poor function. Combining such groups in a study of poor function/good function groups may weaken any signal-to-noise ratio.
4. Aging: mechanisms and pathways The breadth of evidence on accelerated aging, which includes epidemiological studies, physiological challenges, and imaging, is intriguing but to date it largely consists of studies of aging-related variables that do not bring us much closer to an understanding of any mechanism(s) of accelerated aging. Studies that test for the presence of abnormalities in the relevant mechanistic pathways would be desirable. In the aging research field, significant progress has been made in identifying the molecular pathways that confer aging. A recent review listed seven areas of biology that are implicated in aging (Kennedy et al., 2014), and other reviews have come to similar conclusions (Lopez-Otin et al., 2013). These areas are understood at differing levels of mechanistic depth; however, they serve as a good framework for discussing the known links between schizophrenia and aging and for designing future studies. Each of the seven is briefly discussed below. It should be noted that these pathways have a surprising level of inter-connectedness. Disruption of any one pathway during aging can easily lead to dysfunction in others. Therefore, while aging may have several drivers, the process can be considered as a network. Initial changes during aging drive other changes, leading to a progressive loss of homeostasis. In a segmental progeria, where dysfunction in only a subset of pathways of aging is observed, perturbations of the network may have more unpredictable outcomes.
Please cite this article as: Kirkpatrick, B., Kennedy, B.K., Accelerated aging in schizophrenia and related disorders: Future research, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.034
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4.1. Epigenetic changes
4.4. Adult stem cell function
A number of recent studies have pointed to the importance of epigenetic regulation in the control of aging (Brunet and Rando, 2017). For instance, altering levels of several chromatin-modifying factors can affect lifespan in a variety of organisms. Moreover, epigenetic changes are increasingly linked to a decline in stem cell regenerative capacity with aging. The epigenetic clock, which integrates data on DNA methylation state from over 350 promoters, has emerged as a leading candidate biomarker for aging (Chen et al., 2016). With this clock, chronological age can be predicted with a high degree of consistency in a number of tissues. This raises the interesting question of whether schizophrenia patients have methylation patterns associated with enhanced aging and, if so, in what tissues. An abnormality of this kind has been demonstrated in other diseases, for instance affected brain regions in Huntington's disease (Horvath et al., 2016), the immune system of Parkinson's patients (Horvath and Ritz, 2015), and multiple tissues in Down's syndrome (Horvath et al., 2015).
Aging is characterized by a decline in adult stem cell function, leading to reduced capacity to regenerate tissues (Goodell and Rando, 2015). This is characteristic of many adult tissues. Within the hematopoietic system, stem cells increase with age but they have decreased self-renewal capacity upon transplantation and generate lineages skewed toward myeloid populations at the expense of lymphoid cell number (Pang et al., 2017). HSC lineages also become more clonal with age for reasons that are not clearly established. It would be good to determine the self-renewal capacity of stem cells from a range of adult tissues in schizophrenia patients. Analysis of the relative numbers of cells in different lineages should be conducted on schizophrenia patients to determine whether they have abnormal skewing related to aging.
4.2. Inflammation Elevated chronic sterile inflammation is strongly associated with aging and increasing evidence indicates that it may be a driving factor in multiple age-related diseases. In schizophrenia, levels of specific inflammatory cytokines such as IL-6 and TNF-α have been assessed with variable results (Franceschi et al., 2017). There is a need to examine large inflammatory cytokine panels and compare changes to known changes in aging. One source of inflammation is the increasing presence of senescent cells during aging, which have a unique secretome compared to normal cells that is characterized by high levels of inflammatory factors (LeBrasseur et al., 2015). Thus senescent cells can have paracrine and possibly endocrine effects on normal cells that promote inflammatory aspects of aging. The concentrations of senescent cells could be assessed in accessible tissues (lymphocyte populations, skin tissue and isolated fibroblasts) from schizophrenia patients to determine (1) whether numbers are increased relative to age-matched controls, and (2) whether increases in senescent cell populations can account for alterations in inflammatory cytokines.
4.3. Proteostasis Protein synthesis and turnover are highly coordinated processes in cells, with newly synthesized proteins being generated to support cell growth and replace those that are misfolded and/or no longer functional. Several components of the proteostasis machinery are implicated in aging, including mTOR, a signaling factor that regulates cellular nutrient and stress status by coordinating stress response pathways, protein translation components, and protein turnover pathways including autophagy, mitophagy and proteasome function (discussed in the Adaptation to stress section; Kaushik and Cuervo, 2015; Steffen and Dillin, 2016). The mTOR pathway is strongly implicated in aging, in which a chronic upregulation of mTORC1 activity can be detected in a range of tissues, including hematopoietic lineages (Nacarelli et al., 2015). Moreover, pharmacologic and genetic interventions that reduce mTOR signaling extend lifespan in a range of model organisms and have promise for similar effects in humans (Kennedy and Lamming, 2016). With regard to schizophrenia, it is important to see if the mTOR pathway is dysregulated in primary blood lymphocytes or in isolated fibroblasts at levels disproportionate with age. Activation of the mTOR pathway, as well as levels of protein translation, can also be inferred from transcriptomic analysis of cells. As a first step, it would be helpful to measure the phosphorylation state of mTORC1 substrates, which are elevated in HSC lineages with age.
4.5. Metabolic changes Meta-analysis has shown that antipsychotic-naive patients have abnormal glucose tolerance and insulin resistance (Fernandez-Egea et al., 2008; Greenhalgh et al., 2017). A single study found no difference between antipsychotic-naive patients and matched control subjects in total cholesterol, high-density lipoproteins, low-density lipoproteins, or triglycerides (Kirkpatrick et al., 2010). Additional studies of these characteristics would be helpful. Extensive panels of metabolites and lipid markers have also been assayed (e.g., Dickerson et al., 2015). Mitochondrial dysfunction is another common feature of aging; direct assessments of mitochondrial respiratory activity would provide useful information. There appears to be increased oxidative stress in whole blood in schizophrenia (Flatow et al., 2013); the production of reactive oxygen species could be assessed further in isolated fibroblasts and lymphocytes from schizophrenia patients. Finally, as increasing evidence indicates that the gut microbiome changes dramatically during aging and given the influence of the microbiome on metabolism, it would be of interest to assess fecal samples for age-related changes. 4.6. Adaptation to stress Cellular adaptation to stress declines during the aging process. This is reflected in changes in stress response pathways such as autophagy, proteasome activity, and endoplasmic reticulum stress response pathways in cells isolated from aged individuals. These changes could be assessed in lymphocytes and fibroblasts from schizophrenia patients. In addition, isolated cells, either fibroblasts or lymphocytes, can be challenged with different kinds of stresses and the responses can be assessed. These studies would provide initial insight into stress response pathways associated with aging. 4.7. Macromolecular damage Damage can happen to a range of molecules in cells, including proteins, lipids and nucleic acids. Damage to proteins and their clearance is part of proteostasis pathways, mentioned above. Lipid-related damage occurs during aging but remains poorly understood. In contrast, the prevalence of DNA damage has been extensively assessed during aging. Increased DNA damage is evident in a wide range of tissues and cell types with aging, although the contribution that damage makes to different aspects of aging remains unclear. DNA damage in HSC lineages has been particularly well defined, leading to tumor development and clonality (Moehrle and Geiger, 2016). Schizophrenia patients have been found to have increased markers of DNA and RNA damage in urine (Jorgensen et al., 2013). DNA damage should be tested more directly using assays for DNA damage in isolated cells. Interestingly, single cell sequencing is now possible and by determining differences between two cells from the same individual, it is possible to measure the rate of damage over time (Gundry et al., 2012). These studies would
Please cite this article as: Kirkpatrick, B., Kennedy, B.K., Accelerated aging in schizophrenia and related disorders: Future research, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.034
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generate a more comprehensive assessment of whether DNA mutations are accelerated in schizophrenia patients. 5. Conclusions Aging increases the risk of many chronic diseases, but increasing evidence suggests that an array of diseases may also accelerate aspects of aging. Published studies consistent with accelerated aging in schizophrenia and related disorder involve brain abnormalities, including imaging studies and cognition, as well as abnormalities in the periphery, such as abnormal glucose tolerance and increased inflammation in antipsychotic-naïve patients. Future studies will need to deal with the potentially confounding factors listed above if they are to serve as strong tests of the hypothesis of accelerated aging. Weaknesses in study design, either in matching or otherwise, has been such a common problem that the validity of the accelerated aging hypothesis remains in doubt. To advance the field, it would also be helpful to conduct studies that focus on the mechanistic pathways listed above. Studies in antipsychotic-naïve patients would be particularly useful since the drugs used to treat the condition can evoke an array of side effects related to aging. Determining whether schizophrenia is associated with accelerated aging is of substantial practical interest to people with this disorder. It is also of broader medical interest, as an understanding of accelerated aging in schizophrenia, should it exist, may deepen understanding of aging more generally. There is some evidence suggesting depression and bipolar disorder may also be associated with accelerated aging, and that there may be some common pathophysiology of these abnormalities across diagnostic lines (Garcia-Rizo et al., 2013, 2016; Sacchet et al., 2017; Vasconcelos-Moreno et al., 2017; Vieta et al., 2013). Should the hypothesis of accelerated aging be confirmed, therapeutic approaches could be tested within the foreseeable future. A number of candidate interventions, ranging from lifestyle modifications to pharmacologic agents such as the mTOR inhibitor rapamycin, have been proposed to delay aging; these may be useful either as therapies to improve functional outcomes in schizophrenia patients and/or to delay associated diseases that may emerge from an acceleration of aging. Attention to the specific mechanisms of aging discussed above would aid in the development of treatments. Contributors Drs. Kennedy and Kirkpatrick wrote the first draft of the manuscript, and both had final approval.
Funding body agreements and policies Research in Dr. Kennedy's lab on aging is supported by NIH grants R01 AG050441 and AG047497. Conflicts of interest Dr. Kennedy is a member of the Board of Trustees of three companies seeking to exploit aging pathways to modify aging and age-related disease: L-Nutra, Mt. Tam Biotechnologies, and Ponce de Leon Pharmaceuticals. He also is a science advisor for Affirmativ Health. Dr. Kirkpatrick has received licensing royalties and travel support from ProPhase for use of the Brief Negative Symptom Scale (BNSS) by for-profit groups; these fees are donated the Brain and Behavior Research Foundation. Dr. Kirkpatrick has also received consulting fees and travel support from Genentech/Roche, Minerva Neurosciences, and ProPhase LLC, consulting fees from anonymized pharmaceutical companies through Decision Resources, Inc. and L.E.K. Consulting, and from an investment capital company through Guideposts. Dr. Kirkpatrick also receives fees from Walsh Medical Media for editorial services, and received fees for editorial services from Physicians Postgraduate Press, Inc.
Acknowledgements
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Please cite this article as: Kirkpatrick, B., Kennedy, B.K., Accelerated aging in schizophrenia and related disorders: Future research, Schizophr. Res. (2017), http://dx.doi.org/10.1016/j.schres.2017.06.034