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Schizophrenia Research xxx (2017) xxx–xxx

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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
b
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, MD 7, 8 Medical Drive, Singapore 117596, Singapore
c
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

a r t i c l e i n f o a b s t r a c t

Article history: Several lines of evidence suggest schizophrenia is a segmental progeria, that is, some but not all aspects of accel-
Received 8 April 2017 erated aging may be present. However, the evidence has not been consistent. Problems with matching and con-
Received in revised form 15 June 2017 founding may account for some of these discrepancies. Given the etiopathophysiological heterogeneity of
Accepted 19 June 2017
schizophrenia, it is possible that only a specific pathophysiological group within schizophrenia is associated
Available online xxxx
with progeroid features, while others are not, or that one group is associated with a particular segment of
Keywords:
aging features, while other progeroid features are found in another pathophysiological subgroup. In the aging re-
Schizophrenia search field, significant progress has been made in identifying the molecular pathways that confer aging: epige-
Psychosis netic changes, inflammation, proteostasis, adult stem cell function, metabolic changes, and adaptation to stress,
Aging and macromolecular damage. In addition to replication and clarification of existing kinds of evidence, examining
Longevity these aging pathways would improve our understanding of progeria in schizophrenia.
© 2017 Published by Elsevier B.V.

1. Introduction (Lopez-Otin et al., 2013), there is for the first time a strong sense in
the aging field that clear themes are emerging.
Nearly everyone contemplates aging at some point. People worry A class of diseases termed progeroid disorders exhibit segmental
about getting older because they will get sick and lose their ability to aging, that is, some but not all features of aging appear to be accelerated.
enjoy life and contribute to the world around them. The notion that Hutchinson-Gilford and Werner syndrome are two classic examples,
aging begets disease seems obvious and yet it is only in recent years and debate has continued for decades as to whether the causes of
that a consensus has emerged recognizing aging as the biggest risk fac- these diseases are overlapping with those of normal aging. Another
tor for a wide range of chronic diseases, including Alzheimer's, a range theme has also emerged: that classical non-aging diseases may either
of degenerative neurologic conditions, metabolic and cardiovascular be associated with segmental aging or may accelerate aging. In other
syndromes and most forms of adult-onset cancer, to name just a few. words, disease may beget aging which in turn begets disease. For in-
Aging is a “progressive deterioration of physiological function, an in- stance, Down's syndrome patients have early onset Alzheimer's disease,
trinsic age-related process of loss of viability and increase in vulnerabil- as well as a range of other age-related conditions (Malt et al., 2013).
ity” (Comfort, 1964). Medawar (1952) defined aging as “a collection of Chronic viral infection, notably cytomegalovirus, may be an example
changes that render human beings more likely to die.” This quote de- of a disease that drives aspects of aging, in this case accelerating senes-
rives from Medawar's famous book, An Unsolved Problem in Biology, a cence in the immune system (Frasca and Blomberg, 2016). These find-
title that in 1952 was certainly true. While the work of Medawar and ings suggest that we are just beginning to understand the relationship
many others has provided plausible evolutionary theories of aging between aging and disease.
(Kirkwood, 2005), a mechanistic understanding of the physiologic
changes driving pathology during aging has only recently begun to coa- 2. Schizophrenia and aging
lesce. A recent review from a diverse collection of scientists in the aging
field defined seven processes that collectively influence aging (Kennedy In 1968, two psychiatrists wrote, “There is a rather common notion
et al., 2014). While these processes can be defined in different ways among psychiatrists that patients with schizophrenia appear younger
than their chronological age” (Gottheil and Joseph, 1968). When the au-
⁎ Corresponding author. thors tested this hypothesis they found the opposite, that people with
E-mail address: bkirkpatrick2@aol.com (B. Kirkpatrick). schizophrenia were judged to look older than control subjects. To our

http://dx.doi.org/10.1016/j.schres.2017.06.034
0920-9964/© 2017 Published by Elsevier B.V.

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
2 B. Kirkpatrick, B.K. Kennedy / Schizophrenia Research xxx (2017) xxx–xxx

knowledge, this is the first article that could be considered to suggest with age-related phenomena. These include the familiar variables of
schizophrenia was associated with accelerated aging. Nearly thirty age, ethnicity, and gender. However, to use the example of glucose tol-
years later, DeLisi (1997) suggested that schizophrenia was a “lifetime erance, several other variables are also known to be important: alcohol,
disorder of brain plasticity, growth, and aging.” She focused on abnor- smoking, diet, cortisol, and body mass index or waist-hip ratio.
mal aging in the brain and did not suggest this abnormality extended Matching on socioeconomic status of family of origin is also desirable
to the rest of the body. When we suggested schizophrenia was a syn- as this should minimize possible confounding by factors such as child-
drome of accelerated aging, we cited studies of brain structure and func- hood nutrition, lifetime diet, and exposure to environmental toxins. To
tion, but also pointed out findings raising the possibility that abnormal our knowledge, only one study of an aging-related variable in people
aging occurs in the periphery as well (Kirkpatrick et al., 2008). with nonaffective psychosis either dealt with these factors through
If schizophrenia is a syndrome of accelerated aging, it may be a seg- matching or choice of patient population, or examined their relation-
mental progeroid syndrome, that is, only some aspects of accelerated ship to the outcome variable, in this case glucose tolerance
aging may be present. This possibility complicates interpretation of ev- (Fernandez-Egea et al., 2009a; Kirkpatrick et al., 2012).
idence on the hypothesis of accelerated aging in schizophrenia and re- Another difficulty in testing the accelerated aging hypothesis is that
lated disorders, as a failure to find a specific aspect of normal aging schizophrenia is itself a heterogeneous disorder. It is possible that a spe-
would not refute the hypothesis. cific etiopathophysiological group or groups within schizophrenia is as-
We describe below an approach to determine whether schizophre- sociated with progeroid features, while others are not, or that one group
nia indeed resembles segmental aging and, if so, which aging pathways is associated with a particular segment of aging features, while other
are affected. As the purpose of this article is to suggest directions for progeroid features are found in another pathophysiological subgroup.
more definitive hypothesis testing, we do not present a thorough re- For instance, preliminary evidence suggests that deficit and nondeficit
view of the literature. groups, that is, those with and without primary, enduring negative
symptoms, may differ on two aging-related measures, inflammation
3. Research strategy and glucose tolerance (Garcia-Rizo et al., 2012a,b; Kirkpatrick et al.,
2009). Replication is needed for these findings, but they illustrate the
In our 2008 article (Kirkpatrick et al., 2008) we discussed evidence kind of complexity that may be encountered.
related to mortality patterns, cognitive decline, diabetes, and pulse pres- There a number of strategies other than the deficit/nondeficit cate-
sure, as well as risk factors shared by schizophrenia and aging-related gorization that may prove to be useful in defining pathophysiological
disorders such as diabetes. We also cited a single imaging study that subgroups. Examples include a comparison between patients with and
found an increased rate of brain volume loss in people with schizophre- without a specific environmental or genetic risk factor (Malaspina
nia compared to control subjects (Ho et al., 2007). We suggested further et al., 2015), differing trajectories of cognitive impairment (Thompson
tests of the hypothesis could include studies of other physiological mea- et al., 2013), or differences in biomarkers such as (state or trait) inflam-
sures known to change with normal aging, including insulin resistance, mation (Miller et al., 2011; Kirkpatrick and Miller, 2013). Level of func-
blood lipid concentrations, pulse pressure, bone density, clouding of the tion, or a variation of level of function such as community living vs.
eye lens, thinning and wrinkling of the skin, thinning of the hair, and institutionalization, seems less promising as there are many paths to
muscle mass. Since that time, our meta-analyses of studies of poor functional status. For instance, deficit patients have poor function
antipsychotic-naïve patients have found abnormal glucose tolerance compared to patients without primary, enduring negative symptoms,
and insulin resistance, as well as elevated prolactin concentrations in but severe and treatment-nonresponsive positive symptoms can also
both men and women (Greenhalgh et al., 2017; González-Blanco cause poor function. Combining such groups in a study of poor func-
et al., 2016). However, studies of aging and cognition have had mixed tion/good function groups may weaken any signal-to-noise ratio.
results (e.g., Harvey, 2014; Irani et al., 2011; Rodriguez-Jimenez et al.,
2015). Other measures linked to aging have also been examined, includ-
ing telomere length, pulse pressure, levels of androgens in males, and 4. Aging: mechanisms and pathways
prostaglandin concentrations (Fernandez-Egea et al., 2011; Lee et al.,
2016). Findings of increased inflammation (Miller et al., 2011) and oxi- The breadth of evidence on accelerated aging, which includes epide-
dative stress (Finkel and Holbrook, 2000; Miller et al., 2014) are also miological studies, physiological challenges, and imaging, is intriguing
consistent with the hypothesis of accelerated aging. Contradictory find- but to date it largely consists of studies of aging-related variables that
ings have been published on some of these measures, for instance on do not bring us much closer to an understanding of any
telomere length (Fernandez-Egea et al., 2009a,b; Jeste et al., 2016). mechanism(s) of accelerated aging. Studies that test for the presence
There is a relative lack of longitudinal studies of the accelerated aging of abnormalities in the relevant mechanistic pathways would be
hypothesis, but such studies would be helpful in testing associations desirable.
found using a cross-sectional design. In the aging research field, significant progress has been made in
There are many possible causes of contradictory results in this area. identifying the molecular pathways that confer aging. A recent review
To conduct stronger tests of the accelerated aging hypothesis, it will be listed seven areas of biology that are implicated in aging (Kennedy
important to consider confounding by antipsychotic medications. Most et al., 2014), and other reviews have come to similar conclusions
antipsychotics in current use are associated with weight gain, with con- (Lopez-Otin et al., 2013). These areas are understood at differing levels
comitant increases in inflammation and glucose intolerance. Glucose in- of mechanistic depth; however, they serve as a good framework
tolerance and inflammation are both aging-related conditions and may for discussing the known links between schizophrenia and aging
induce other aging-related changes. As a consequence, without compar- and for designing future studies. Each of the seven is briefly discussed
ison groups with similar exposure to antipsychotics, findings on age- below.
related variables are vulnerable to confounding, leaving the field with It should be noted that these pathways have a surprising level of
ambiguous interpretations of the evidence. Several findings consistent inter-connectedness. Disruption of any one pathway during aging can
with accelerated aging, with medium to large effect sizes, have been easily lead to dysfunction in others. Therefore, while aging may have
found in antipsychotic-naïve patients (Fernandez-Egea et al., 2009a,b, several drivers, the process can be considered as a network. Initial
2011), and study of this population is an important strategy for the changes during aging drive other changes, leading to a progressive
study of aging. loss of homeostasis. In a segmental progeria, where dysfunction in
A number of other factors can also influence metabolic and physio- only a subset of pathways of aging is observed, perturbations of the net-
logical measures associated with aging and so confound associations work 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
B. Kirkpatrick, B.K. Kennedy / Schizophrenia Research xxx (2017) xxx–xxx 3

4.1. Epigenetic changes 4.4. Adult stem cell function

A number of recent studies have pointed to the importance of epige- Aging is characterized by a decline in adult stem cell function, lead-
netic regulation in the control of aging (Brunet and Rando, 2017). For in- ing to reduced capacity to regenerate tissues (Goodell and Rando,
stance, altering levels of several chromatin-modifying factors can affect 2015). This is characteristic of many adult tissues. Within the hemato-
lifespan in a variety of organisms. Moreover, epigenetic changes are in- poietic system, stem cells increase with age but they have decreased
creasingly linked to a decline in stem cell regenerative capacity with self-renewal capacity upon transplantation and generate lineages skewed
aging. The epigenetic clock, which integrates data on DNA methylation toward myeloid populations at the expense of lymphoid cell number
state from over 350 promoters, has emerged as a leading candidate bio- (Pang et al., 2017). HSC lineages also become more clonal with age for
marker for aging (Chen et al., 2016). With this clock, chronological age reasons that are not clearly established. It would be good to determine
can be predicted with a high degree of consistency in a number of tis- the self-renewal capacity of stem cells from a range of adult tissues in
sues. This raises the interesting question of whether schizophrenia pa- schizophrenia patients. Analysis of the relative numbers of cells in differ-
tients have methylation patterns associated with enhanced aging and, ent lineages should be conducted on schizophrenia patients to determine
if so, in what tissues. An abnormality of this kind has been demonstrated whether they have abnormal skewing related to aging.
in other diseases, for instance affected brain regions in Huntington's dis-
ease (Horvath et al., 2016), the immune system of Parkinson's patients 4.5. Metabolic changes
(Horvath and Ritz, 2015), and multiple tissues in Down's syndrome
(Horvath et al., 2015). Meta-analysis has shown that antipsychotic-naive patients have ab-
normal glucose tolerance and insulin resistance (Fernandez-Egea et al.,
2008; Greenhalgh et al., 2017). A single study found no difference be-
4.2. Inflammation tween antipsychotic-naive patients and matched control subjects in
total cholesterol, high-density lipoproteins, low-density lipoproteins,
Elevated chronic sterile inflammation is strongly associated with or triglycerides (Kirkpatrick et al., 2010). Additional studies of these
aging and increasing evidence indicates that it may be a driving factor characteristics would be helpful. Extensive panels of metabolites and
in multiple age-related diseases. In schizophrenia, levels of specific in- lipid markers have also been assayed (e.g., Dickerson et al., 2015). Mito-
flammatory cytokines such as IL-6 and TNF-α have been assessed with chondrial dysfunction is another common feature of aging; direct as-
variable results (Franceschi et al., 2017). There is a need to examine sessments of mitochondrial respiratory activity would provide useful
large inflammatory cytokine panels and compare changes to known information. There appears to be increased oxidative stress in whole
changes in aging. blood in schizophrenia (Flatow et al., 2013); the production of reactive
One source of inflammation is the increasing presence of senescent oxygen species could be assessed further in isolated fibroblasts and lym-
cells during aging, which have a unique secretome compared to normal phocytes from schizophrenia patients. Finally, as increasing evidence in-
cells that is characterized by high levels of inflammatory factors dicates that the gut microbiome changes dramatically during aging and
(LeBrasseur et al., 2015). Thus senescent cells can have paracrine and given the influence of the microbiome on metabolism, it would be of in-
possibly endocrine effects on normal cells that promote inflammatory terest to assess fecal samples for age-related changes.
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 4.6. Adaptation to stress
numbers are increased relative to age-matched controls, and (2) wheth-
er increases in senescent cell populations can account for alterations in Cellular adaptation to stress declines during the aging process. This
inflammatory cytokines. is reflected in changes in stress response pathways such as autophagy,
proteasome activity, and endoplasmic reticulum stress response path-
ways in cells isolated from aged individuals. These changes could be
4.3. Proteostasis assessed in lymphocytes and fibroblasts from schizophrenia patients.
In addition, isolated cells, either fibroblasts or lymphocytes, can be chal-
Protein synthesis and turnover are highly coordinated processes in lenged with different kinds of stresses and the responses can be
cells, with newly synthesized proteins being generated to support cell assessed. These studies would provide initial insight into stress re-
growth and replace those that are misfolded and/or no longer function- sponse pathways associated with aging.
al. Several components of the proteostasis machinery are implicated in
aging, including mTOR, a signaling factor that regulates cellular nutrient 4.7. Macromolecular damage
and stress status by coordinating stress response pathways, protein
translation components, and protein turnover pathways including au- Damage can happen to a range of molecules in cells, including pro-
tophagy, mitophagy and proteasome function (discussed in the teins, lipids and nucleic acids. Damage to proteins and their clearance
Adaptation to stress section; Kaushik and Cuervo, 2015; Steffen and is part of proteostasis pathways, mentioned above. Lipid-related dam-
Dillin, 2016). The mTOR pathway is strongly implicated in aging, in age occurs during aging but remains poorly understood. In contrast,
which a chronic upregulation of mTORC1 activity can be detected in a the prevalence of DNA damage has been extensively assessed during
range of tissues, including hematopoietic lineages (Nacarelli et al., aging. Increased DNA damage is evident in a wide range of tissues and
2015). Moreover, pharmacologic and genetic interventions that reduce cell types with aging, although the contribution that damage makes to
mTOR signaling extend lifespan in a range of model organisms and have different aspects of aging remains unclear. DNA damage in HSC lineages
promise for similar effects in humans (Kennedy and Lamming, 2016). has been particularly well defined, leading to tumor development and
With regard to schizophrenia, it is important to see if the mTOR path- clonality (Moehrle and Geiger, 2016). Schizophrenia patients have
way is dysregulated in primary blood lymphocytes or in isolated fibro- been found to have increased markers of DNA and RNA damage in
blasts at levels disproportionate with age. Activation of the mTOR urine (Jorgensen et al., 2013). DNA damage should be tested more di-
pathway, as well as levels of protein translation, can also be inferred rectly using assays for DNA damage in isolated cells. Interestingly, single
from transcriptomic analysis of cells. As a first step, it would be helpful cell sequencing is now possible and by determining differences be-
to measure the phosphorylation state of mTORC1 substrates, which tween two cells from the same individual, it is possible to measure the
are elevated in HSC lineages with age. 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
4 B. Kirkpatrick, B.K. Kennedy / Schizophrenia Research xxx (2017) xxx–xxx

generate a more comprehensive assessment of whether DNA mutations Acknowledgements


are accelerated in schizophrenia patients. Does not apply.

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Contributors Gottheil, E., Joseph, R.J., 1968. Age, appearance, and schizophrenia. Arch. Gen. Psychiatry
Drs. Kennedy and Kirkpatrick wrote the first draft of the manuscript, and both had 19 (2), 232–238.
final approval. Greenhalgh, A.M., Gonzalez-Blanco, L., Garcia-Rizo, C., et al., 2017. Meta-analysis of glu-
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Funding body agreements and policies Gundry, M., Li, W., Maqbool, S.B., Vijg, J., 2012. Direct, genome-wide assessment of DNA
mutations in single cells. Nucleic Acids Res. 40, 2032–2040.
Harvey, P.D., 2014. What is the evidence for changes in cognition and functioning over the
Research in Dr. Kennedy's lab on aging is supported by NIH grants lifespan in patients with schizophrenia? J. Clin. Psychiatry 75 (Suppl. 2), 34–38.
R01 AG050441 and AG047497. Ho, B., Nopoulos, P., Arndt, S., Pierson, R., Ziebell, S., Andreasen, N., 2007. Longitudinal
study of MRI brain morphology in schizophrenia involving multiple within-subject
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Conflicts of interest Horvath, S., Ritz, B.R., 2015. Increased epigenetic age and granulocyte counts in the blood
of Parkinson's disease patients. Aging 7, 1130–1142.
Dr. Kennedy is a member of the Board of Trustees of three companies Horvath, S., Garagnani, P., Bacalini, M.G., et al., 2015. Accelerated epigenetic aging in down
syndrome. Aging Cell 14 (3), 491–495.
seeking to exploit aging pathways to modify aging and age-related dis- Horvath, S., Langfelder, P., Kwak, S., et al., 2016. Huntington's disease accelerates epige-
ease: L-Nutra, Mt. Tam Biotechnologies, and Ponce de Leon Pharmaceu- netic aging of human brain and disrupts DNA methylation levels. Aging (Albany
ticals. He also is a science advisor for Affirmativ Health. NY) 8 (7), 1485–1512.
Irani, F., Kalkstein, S., Moberg, E.A., Moberg, P.J., 2011. Neuropsychological performance in
Dr. Kirkpatrick has received licensing royalties and travel support
older patients with schizophrenia: a meta-analysis of cross-sectional and longitudinal
from ProPhase for use of the Brief Negative Symptom Scale (BNSS) by studies. Schizophr. Bull. 37 (6), 1318–1326.
for-profit groups; these fees are donated the Brain and Behavior Re- Jeste, D.V., Wolkowitz, O.M., Martin, A.S., et al., 2016. Leukocyte telomere length: effects of
schizophrenia, age, and gender. J. Psychiatr. Res. 85, 42–48.
search Foundation. Dr. Kirkpatrick has also received consulting fees
Jorgensen, A., Broedbaek, K., Fink-Jensen, A., et al., 2013. Increased systemic oxidatively
and travel support from Genentech/Roche, Minerva Neurosciences, generated DNA and RNA damage in schizophrenia. Psychiatry Res. 209 (3), 417–423.
and ProPhase LLC, consulting fees from anonymized pharmaceutical Kaushik, S., Cuervo, A.M., 2015. Proteostasis and aging. Nat. Med. 21 (12), 1406–1415.
companies through Decision Resources, Inc. and L.E.K. Consulting, and Kennedy, B.K., Lamming, D.W., 2016. The mechanistic target of rapamycin: the grand con-
ducTOR of metabolism and aging. Cell Metab. 23 (6), 990–1003.
from an investment capital company through Guideposts. Dr. Kennedy, B.K., Berger, S.L., Brunet, A., et al., 2014. Geroscience: linking aging to chronic
Kirkpatrick also receives fees from Walsh Medical Media for editorial disease. Cell 159 (4), 709–713.
services, and received fees for editorial services from Physicians Post- Kirkpatrick, B., Miller, B.J., 2013. Inflammation and schizophrenia. Schizophr. Bull. 39 (6),
1174–1179 (Nov).
graduate Press, Inc.

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
B. Kirkpatrick, B.K. Kennedy / Schizophrenia Research xxx (2017) xxx–xxx 5

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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