SCHRES-07366; No of Pages 5

Schizophrenia Research xxx (2017) xxx–xxx

Contents lists available at ScienceDirect

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
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 fac-
tor 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 in-
trinsic age-related process of loss of viability and increase in vulnerabil-
ity” (Comfort, 1964). Medawar (1952) defined aging as “a collection of
changes that render human beings more likely to die.” This quote de-
rives 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 coa-
lesce. 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: bkirkpatrick2@aol.com (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 in-
stance, 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 senes-
cence in the immune system (Frasca and Blomberg, 2016). These find-
ings 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 au-
thors tested this hypothesis they found the opposite, that people with
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
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 abnor-
mal aging in the brain and did not suggest this abnormality extended
to the rest of the body. When we suggested schizophrenia was a syn-
drome of accelerated aging, we cited studies of brain structure and func-
tion, 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 seg-
mental progeroid syndrome, that is, only some aspects of accelerated
aging may be present. This possibility complicates interpretation of ev-
idence on the hypothesis of accelerated aging in schizophrenia and re-
lated 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 schizophre-
nia 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 re-
view 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 pres-
sure, 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 schizophre-
nia compared to control subjects (Ho et al., 2007). We suggested further
tests of the hypothesis could include studies of other physiological mea-
sures 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, includ-
ing 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 oxi-
dative stress (Finkel and Holbrook, 2000; Miller et al., 2014) are also
consistent with the hypothesis of accelerated aging. Contradictory find-
ings 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 con-
comitant increases in inflammation and glucose intolerance. Glucose in-
tolerance and inflammation are both aging-related conditions and may
induce other aging-related changes. As a consequence, without compar-
ison groups with similar exposure to antipsychotics, findings on age-
related 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 physio-
logical measures associated with aging and so confound associations
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
with age-related phenomena. These include the familiar variables of
age, ethnicity, and gender. However, to use the example of glucose tol-
erance, 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 child-
hood 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 relation-
ship 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 spe-
cific etiopathophysiological group or groups within schizophrenia is as-
sociated 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 cate-
gorization 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) inflam-
mation (Miller et al., 2011; Kirkpatrick and Miller, 2013). Level of func-
tion, 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 func-
tion/good function groups may weaken any signal-to-noise ratio.
4. Aging: mechanisms and pathways
The breadth of evidence on accelerated aging, which includes epide-
miological 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 net-
work may have more unpredictable outcomes.
 B. Kirkpatrick, B.K. Kennedy / Schizophrenia Research xxx (2017) xxx–xxx
4.1. Epigenetic changes
A number of recent studies have pointed to the importance of epige-
netic regulation in the control of aging (Brunet and Rando, 2017). For in-
stance, altering levels of several chromatin-modifying factors can affect
lifespan in a variety of organisms. Moreover, epigenetic changes are in-
creasingly 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 bio-
marker for aging (Chen et al., 2016). With this clock, chronological age
can be predicted with a high degree of consistency in a number of tis-
sues. This raises the interesting question of whether schizophrenia pa-
tients 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 dis-
ease (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).
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 in-
flammatory 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) wheth-
er 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 function-
al. 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 au-
tophagy, 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 path-
way is dysregulated in primary blood lymphocytes or in isolated fibro-
blasts 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.
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
3
4.4. Adult stem cell function
Aging is characterized by a decline in adult stem cell function, lead-
ing to reduced capacity to regenerate tissues (Goodell and Rando,
2015). This is characteristic of many adult tissues. Within the hemato-
poietic 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 differ-
ent lineages should be conducted on schizophrenia patients to determine
whether they have abnormal skewing related to aging.
4.5. Metabolic changes
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-
tween 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). Mito-
chondrial dysfunction is another common feature of aging; direct as-
sessments 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 lym-
phocytes from schizophrenia patients. Finally, as increasing evidence in-
dicates that the gut microbiome changes dramatically during aging and
given the influence of the microbiome on metabolism, it would be of in-
terest 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 path-
ways 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 chal-
lenged with different kinds of stresses and the responses can be
assessed. These studies would provide initial insight into stress re-
sponse pathways associated with aging.
4.7. Macromolecular damage
Damage can happen to a range of molecules in cells, including pro-
teins, lipids and nucleic acids. Damage to proteins and their clearance
is part of proteostasis pathways, mentioned above. Lipid-related dam-
age 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 di-
rectly using assays for DNA damage in isolated cells. Interestingly, single
cell sequencing is now possible and by determining differences be-
tween two cells from the same individual, it is possible to measure the
rate of damage over time (Gundry et al., 2012). These studies would
4 B. Kirkpatrick, B.K. Kennedy / Schizophrenia Research xxx (2017) xxx–xxx
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 ev-
idence suggests that an array of diseases may also accelerate aspects of
aging. Published studies consistent with accelerated aging in schizo-
phrenia and related disorder involve brain abnormalities, including im-
aging 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 relat-
ed 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 abnor-
malities 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, therapeu-
tic approaches could be tested within the foreseeable future. A number
of candidate interventions, ranging from lifestyle modifications to phar-
macologic agents such as the mTOR inhibitor rapamycin, have been pro-
posed to delay aging; these may be useful either as therapies to improve
functional outcomes in schizophrenia patients and/or to delay associat-
ed diseases that may emerge from an acceleration of aging. Attention to
the specific mechanisms of aging discussed above would aid in the de-
velopment 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 dis-
ease: L-Nutra, Mt. Tam Biotechnologies, and Ponce de Leon Pharmaceu-
ticals. 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 Re-
search 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 Post-
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
Acknowledgements
Does not apply.
References
Brunet, A., Rando, T.A., 2017. Interaction between epigenetic and metabolism in aging
stem cells. Curr. Opin. Cell Biol. 45, 1–7.
Chen, B.H., Marioni, R.E., Colicino, E., et al., 2016. DNA methylation-based measures of bi-
ological age: meta-analysis predicting time to death. Aging 8, 1844–1865.
Comfort, A., 1964. Ageing: The Biology of Senescence. Routledge & Kegan Paul, London.
DeLisi, L.E., 1997. Is schizophrenia a lifetime disorder of brain plasticity, growth and
aging? Schizophr. Res. 23 (2), 119–129.
Dickerson, F., Schroeder, J., Stallings, C., Origoni, A., Bahn, S., Yolken, R., 2015. Multianalyte
markers of schizophrenia and bipolar disorder: a preliminary study. Schizophr. Res.
168 (1–2), 450–455.
Fernandez-Egea, E., Bernardo, M., Parellada, et al., 2008. Glucose abnormalities in the sib-
lings of people with schizophrenia. Schizophr. Res. 103 (1–3), 110–113.
Fernandez-Egea, E., Bernardo, M., Donner, T., et al., 2009a. Metabolic profile of
antipsychotic-naive individuals with non-affective psychosis. Br. J. Psychiatry 194
(5), 434–438.
Fernandez-Egea, E., Bernardo, M., Heaphy, C.M., et al., 2009b. Telomere length and pulse
pressure in newly diagnosed, antipsychotic-naive patients with nonaffective psycho-
sis. Schizophr. Bull. 35 (2), 437–442.
Fernandez-Egea, E., Garcia-Rizo, C., Miller, B., et al., 2011. Testosterone in antipsychotic-
naïve men with nonaffective psychosis: a test of the accelerated aging hypothesis.
Psychosom. Med. 73 (8), 643–647.
Finkel, T., Holbrook, N.J., 2000. Oxidants, oxidative stress and the biology of ageing. Nature
408 (6809), 239–247.
Flatow, J., Buckley, P., Miller, B.J., 2013. Meta-analysis of oxidative stress in schizophrenia.
Biol. Psychiatry 74 (6), 400–409.
Franceschi, C., Garagnani, P., Vitale, G., et al., 2017. Inflammaging and ‘Garb-aging’. Trends
Endocrinol. Metab. 28, 199–212.
Frasca, D., Blomberg, B.B., 2016. Aging, cytomegalovirus (CMV) and influenza vaccine re-
sponses. Hum. Vaccin. Immunother. 12 (3), 682–690.
Garcia-Rizo, C., Fernandez-Egea, E., Oliveira, C., Justicia, A., Bernardo, M., Kirkpatrick, B.,
2012a. Inflammatory markers in antipsychotic-naive patients with nonaffective psy-
chosis and deficit vs. nondeficit features. Psychiatry Res. 198 (2), 212–215.
Garcia-Rizo, C., Fernandez-Egea, E., Oliveira, C., et al., 2012b. Prolactin concentrations in
newly diagnosed, antipsychotic-naïve patients with nonaffective psychosis.
Schizophr. Res. 134 (1), 16–19.
Garcia-Rizo, C., Fernandez-Egea, E., Miller, B.J., Oliveira, C., Justicia, A., Griffith, J.K., Heaphy,
C.M., Bernardo, M., Kirkpatrick, B., 2013. Abnormal glucose tolerance, white blood cell
count, and telomere length in newly diagnosed, antidepressant-naïve patients with
depression. Brain Behav. Immun. 28, 49–53 (Feb).
Garcia-Rizo, C., Kirkpatrick, B., Fernandez-Egea, E., Oliveira, C., Bernardo, M., 2016. Abnor-
mal glycemic homeostasis at the onset of serious mental illnesses: a common path-
way. Psychoneuroendocrinology 67, 70–75 (May).
González-Blanco, L., Greenhalgh, A.M., Garcia-Rizo, C., Fernandez-Egea, E., Miller, B.J.,
Kirkpatrick, B., 2016. Prolactin concentrations in antipsychotic-naïve patients with
schizophrenia and related disorders: a meta-analysis. Schizophr. Res. 174 (1–3),
156–160.
Goodell, M.A., Rando, T.A., 2015. Stem cells and healthy aging. Science 350, 1199–1204.
Gottheil, E., Joseph, R.J., 1968. Age, appearance, and schizophrenia. Arch. Gen. Psychiatry
19 (2), 232–238.
Greenhalgh, A.M., Gonzalez-Blanco, L., Garcia-Rizo, C., et al., 2017. Meta-analysis of glu-
cose tolerance, insulin, and insulin resistance in antipsychotic-naïve patients with
nonaffective psychosis. Schizophr. Res. 179, 57–63.
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
lifespan in patients with schizophrenia? J. Clin. Psychiatry 75 (Suppl. 2), 34–38.
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
assessments. Schizophr. Bull. 33, 335.
Horvath, S., Ritz, B.R., 2015. Increased epigenetic age and granulocyte counts in the blood
of Parkinson's disease patients. Aging 7, 1130–1142.
Horvath, S., Garagnani, P., Bacalini, M.G., et al., 2015. Accelerated epigenetic aging in down
syndrome. Aging Cell 14 (3), 491–495.
Horvath, S., Langfelder, P., Kwak, S., et al., 2016. Huntington's disease accelerates epige-
netic aging of human brain and disrupts DNA methylation levels. Aging (Albany
NY) 8 (7), 1485–1512.
Irani, F., Kalkstein, S., Moberg, E.A., Moberg, P.J., 2011. Neuropsychological performance in
older patients with schizophrenia: a meta-analysis of cross-sectional and longitudinal
studies. Schizophr. Bull. 37 (6), 1318–1326.
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.
Jorgensen, A., Broedbaek, K., Fink-Jensen, A., et al., 2013. Increased systemic oxidatively
generated DNA and RNA damage in schizophrenia. Psychiatry Res. 209 (3), 417–423.
Kaushik, S., Cuervo, A.M., 2015. Proteostasis and aging. Nat. Med. 21 (12), 1406–1415.
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.
Kennedy, B.K., Berger, S.L., Brunet, A., et al., 2014. Geroscience: linking aging to chronic
disease. Cell 159 (4), 709–713.
Kirkpatrick, B., Miller, B.J., 2013. Inflammation and schizophrenia. Schizophr. Bull. 39 (6),
1174–1179 (Nov).
 B. Kirkpatrick, B.K. Kennedy / Schizophrenia Research xxx (2017) xxx–xxx
Kirkpatrick, B., Messias, E., Harvey, P.D., Fernandez-Egea, E., Bowie, C.R., 2008. Is schizo-
phrenia a syndrome of accelerated aging? Schizophr. Bull. 34, 1024–1032.
Kirkpatrick, B., Fernandez-Egea, E., Garcia-Rizo, C., Bernardo, M., 2009. Differences in glu-
cose tolerance between deficit and nondeficit schizophrenia. Schizophr. Res. 107 (2–
3), 122–127.
Kirkpatrick, B., Garcia-Rizo, C., Tang, K., Fernandez-Egea, E., Bernardo, M., 2010. Cholester-
ol and triglycerides in antipsychotic-naive patients with nonaffective psychosis. Psy-
chiatry Res. 178 (3), 559–561.
Kirkpatrick, B., Miller, B.J., Garcia-Rizo, C., Fernandez-Egea, E., Bernardo, M., 2012. Is ab-
normal glucose tolerance in antipsychotic-naïve patients with nonaffective psychosis
confounded by poor health habits? Schizophr. Bull. 38 (2), 280–284.
Kirkwood, T.B., 2005. Understanding the odd science of aging. Cell 120 (4), 437–447.
LeBrasseur, N.K., Tchkonia, T., Kirkland, J.L., 2015. Cellular senescence and the biology of
aging, disease, and frailty. Nestle. Nutr. Inst. Workshop Ser. 83, pp. 11–18.
Lee, E.E., Eyler, L.T., Wolkowitz, O.M., et al., 2016. Elevated plasma F2-isoprostane levels in
schizophrenia. Schizophr. Res. 176, 320–326.
Lopez-Otin, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., 2013. The hallmarks of
aging. Cell 153 (6), 1194–1217.
Malaspina, D., Gilman, C., Kranz, T.M., 2015. Paternal age and mental health of offspring.
Fertil. Steril. 103 (6), 1392–1396 (Jun).
Malt, E.A., Dahl, R.C., Haugsand, T.M., et al., 2013. Health and disease in adults with down
syndrome. Tidsskr. Nor. Laegeforen. 133 (3), 290–294.
Medawar, P.B., 1952. Unsolved problem of biology. Med. J. Aust. 1 (24), 854–855.
Miller, B.J., Buckley, P., Seabolt, W., Mellor, A., Kirkpatrick, B., 2011. Meta-analysis of cyto-
kine alterations in schizophrenia: clinical status and antipsychotic effects. Biol. Psy-
chiatry 70 (7), 663–671 (Oct 1).
Moehrle, B.M., Geiger, H., 2016. Aging of hematopoietic stem cells: DNA damage and mu-
tations? Exp. Hematology 44 (10), 895–901.
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
5
Nacarelli, T., Azar, A., Sell, C., 2015. Aberrant mTOR activation in senescence and aging: a
mitochondrial stress response? Exp. Gerontol. 68, 66–70.
Pang, W.W., Schrier, S.L., Weissman, I.L., 2017. Age-associated changes in human hemato-
poietic stem cells. Semin. Hematol. 54 (1), 39–42.
Rodriguez-Jimenez, R., Dompablo, M., Bagney, A., et al., 2015. The MCCB impairment pro-
file in a Spanish sample of patients with schizophrenia: effects of diagnosis, age, and
gender on cognitive functioning. Schizophr. Res. 169 (1–3), 116–120.
Sacchet, M.D., Camacho, M.C., Livermore, E.E., Thomas, E.A.C., Gotlib, I.H., 2017. Accelerat-
ed aging of the putamen in patients with major depressive disorder. J. Psychiatry
Neurosci. 42 (3), 164–171 (May).
Steffen, K.K., Dillin, A., 2016. A ribosomal perspective on proteostasis and aging. Cell
Metab. 23 (6), 1004–1012.
Thompson, W.K., Savla, G.N., Vahia, I.V., Depp, C.A., O'Hara, R., Jeste, D.V., Palmer, B.W.,
2013. Characterizing trajectories of cognitive functioning in older adults with schizo-
phrenia: does method matter? Schizophr. Res. 143 (1), 90–96 (Jan).
Vasconcelos-Moreno, M.P., Fries, G.R., Gubert, C., Dos Santos, B.T., Fijtman, A., Sartori, J.,
Ferrari, P., Grun, L.K., Parisi, M.M., Guma, F.T., Barbé-Tuana, F.M., Kapczinski, F.,
Rosa, A.R., Yatham, L.N., Kauer-Sant'Anna, M., 2017. Telomere length, oxidative stress,
inflammation and BDNF levels in siblings of patients with bipolar disorder: implica-
tions for accelerated cellular aging. Int. J. Neuropsychopharmacol. (Epub ahead of
print).
Vieta, E., Popovic, D., Rosa, A.R., Solé, B., Grande, I., Frey, B.N., Martinez-Aran, A., Sanchez-
Moreno, J., Balanzá-Martínez, V., Tabarés-Seisdedos, R., Kapczinski, F., 2013. The clin-
ical implications of cognitive impairment and allostatic load in bipolar disorder. Eur.
Psychiatry 28 (1), 21–29 (Jan).