Pustaka

Hawkey et al 2012
1. Loneliness is defined as a distressing feeling that accompanies the perception that one’s social
needs are not being met by the quantity or especially the quality of one’s social relationships
(Peplau & Perlman, 1982 in Hawkey et. al. 2012).
2. Loneliness has been associated with impaired cellular and humoral immunity. In lonely
relative to nonlonely nonpsychotic psychiatric patients, elevations in urinary levels of cortisol
were accompanied by lower natural killer cell activity and poorer T-lymphocyte response to
mitogen stimulation (Kiecolt-Glaser et al., 1984a, Kiecolt-Glaser et al., 1984b)
3. Other studies have shown that reactivation of latent herpes virus (Glaser et al., 1985) and
Epstein-Barr virus (Kiecolt-Glaser et al., 1984c) is greater in lonely than nonlonely
individuals, effects that are consistent with glucocorticoid immunosuppression of cellular
control of latent virus.
4. Namely, cortisol stimulates an increase in circulating concentrations of neutrophils and a
decrease in concentrations of lymphocytes and monocytes such that the greater the exposure
to cortisol the greater should be the ratio of neutrophils to lymphocytes (NLR) or monocytes
(NMR)
Carroll et. al. 2013
1. Low social support is asociated with shorter leucocyte telomere length. As telomeres
progressively shorten over the lifespan, they can reach a critically short length and the cell is
forced into a senescent state
2. Social support may act as a buffer, to evaluations of threat, and thereby reduce the magnitude
of the stress response to adverse conditions
3. It is well known that stress responses activate the hypothalamic-pituitary-adrenal axis and
sympatho-adrenal system, leading to the release of cortisol, epinephrine, and norepinephrine.
These stress hormones signal a multitude of physiological changes that can increase
inflammation (Irwin et al 2011 in carroll et al 2013) and oxidative stress (Epel et al 2004 in
carroll et al 2013). These factors are primary contributors to telomere loss in leukocytes.
4. Telomerase, the enzyme that rebuilds telomeres, is also modified by stress hormones. Recent
evidence reports a decline in telomerase activity upon cortisol exposure in vitro (Choi et al
2008), an inverse association of telomerase with nocturnal urinary epinephrine, and lower
telomerase activity in those with exaggerated cardiovascular responses to a stressful task
(Epel et al 2006).
5. Importantly, telomerase is not only important for rebuilding telomeres, but can also protect
older cells from entering senescence by capping the end of the chromosomes (Blackburn
2005). In late life this compromise in telomere capping may be more detrimental to health as
there are greater proportions of late differentiated cells that are vulnerable to senescence.
These senescent cells cause further damage to nearby cells and tissue (Campisi 2005), and in
this way may further promote telomere erosion.
Friedler et al 2015
1. Isolation is a major source of psychosocial stress and is associated with an increased

prevalence of vascular and neurological diseases
2. At least three major biological systems have been implicated; the neuroendocrine (HPA) axis,
the immune system, and the autonomic nervous system
3. Several of these studies showed that poor social support is linked to higher mortality rates
(Table 1).
4. people with high levels of social support or large social networks exhibit lower all-cause
mortality and more rapid and extensive functional
5. In contrast, social isolation (SI) is associated with increased morbidity and mortality in
patients with established vascular disease and in animal models [7, 51, 127]. A recent
metaanalysis of 148 studies that included over 300,000 participants found that people with
strong social relationships had a 50% increased likelihood of survival compared to isolated
individuals
6. Data from the U.S. Census show an increase in the number of people living alone from 17.1%
of households in 1970 to 27.4% in 2012
7. Objective social isolation and perceived social isolation (loneliness) are distinct biological
stressors associated with unique downstream effects and susceptibility to disease, although
they may have mechanistic overlap. Loneliness has been defined as “how individuals evaluate
their level and quality of social contact and engagement” [132]. Absent from that definition is
the quantity of relationships. Social isolation, by contrast, is an objective term that refers to
the lack of social contacts (spouse, family, friends, colleagues etc.).
8. isolation induces progressive social withdrawal after brain injury. Pair housing reversed this
depressive phenotype and was associated with increased brain derived neurotrophic factor
(BDNF) levels and neurogenesis [127, 93].
9. Chronic stressors contribute to persistent increases in plasma glucocorticoids in both humans
and animals, and the body ultimately adapts through various pathological processes. An
elevated serum glucocorticoid level globally overstimulates the GR, reducing the receptor’s
sensitivity- particularly in murine splenic macrophages [101] and human leukocytes [84].
One potential mechanism of GR desensitization involves p38 (a mitogen activated protein
kinase) phosphorylation of the GR, inhibiting its nuclear translocation [134]. The GR
normally functions as a transcriptional repressor of the pro-inflammatory transcription factor
NFκ-B. Given the diverse functions of the HPA axis, it follows logically that its disruption
would invoke multi-system pathology.
10. Immunological changes are prevalent in socially isolated individuals. In large nationwide
samples, serum fibrinogen levels were significantly increased in SI men of all ages, with older
men displaying an elevated overall inflammation burden index [140]. Moreover, SI has been
associated with elevated circulating levels of C-reactive protein (CRP), but again, only in men
[81]. Greater serum IL-6 concentrations were reported in both sexes scoring low on a social
network index compared to those with higher scores [82]. This isolationdependent pro-
inflammatory environment, often referred to as the ‘Conserved Transcriptional Response to
Adversity’ (CTRA)
11. Cole et al. [19] analyzed differences in the adult leukocyte gene profile attributable to
loneliness and found significant increases in leukocyte pro-inflammatory gene expression and
significant decreases in antiviral gene expression in chronically lonely individuals. This
pattern increases the risk of infections and exacerbates diseases with inflammatory
components, such as atherosclerosis.
12. Repeated social disruption, a model of psychosocial stress, results in a significant increase in
pro-inflammatory myelopoietic cell egress from the bone marrow of mice, indicating that
chronic social stress may alter hematopoiesis [99].
13. Norepinephrine (as well as other circulating catecholamines) secreted from sympathetic
nerves act on hematopoietic stem cell β-adrenergic receptors located in the bone marrow to
initiate hematopoiesis [32]
14. Social isolation has been identified as a risk factor for incident CVD [43]
15. SI [126] in CVD patients has been associated with increased recurrent cardiac morbidity and
mortality, and accelerated development of carotid atherosclerosis is seen in isolated CVD
patients [104]. Chronically elevated heart rate and blood pressure in response to psychological
stress may generate a ‘hyperresponsive’ SNS in some individuals; these patients are more
susceptible to plaque deposition than their socially integrated counterparts [104].
16. SI has been associated with increased risk of incident stroke in both males [70] and females
with established CVD including suspected MI [106].
17. The Atherosclerosis Risk in Communities (ARIC) study reports a 44% increased risk of
incident stroke in both males and females with a small social network [88].
18. One proposed mechanism that is gaining attention is abnormal regulation of oxytocin (OT), a
hypophyseal-secreted peptide that increases with affiliative social interaction [121]. OT has
antioxidative and antiinflammatory properties in both vascular endothelial cells as well as
macrophages [121].
Williams et al 2009
1. Chronic social isolation was associated with up-regulated lipid synthesis and glycolytic
pathway gene expression—both pathways are known to contribute to increased breast cancer
growth
2. Among the metabolic genes, significantly increased gene expression was identified in genes
encoding three key enzymes known to be associated with cancer development: ATP citrate
lyase (Acly), acetyl-CoA carboxyl ase α (Acaca), and hexokinase 2
3. HK2, the human orthologue of mouse Hk2, is overexpressed in many human cancers (38) and
encodes a protein that catalyzes a critical step in the glycolytic pathway; that is, the
phosphorylation of glucose to glucose-6-phosphate (39). Unlike other hexokinase isoforms,
the activity of mitochondrial-bound HK2 is not inhibited by glucose-6-phosphate production
(40). As Pedersen describes in his review of the Warburg effect (41), this lack of inhibition,
along with the close proximity of HK2 to ATP synthesis at the inner mitochondrial
membrane, allows HK2 to effectively “jump start” glycolysis. As a result, the glycolytic
pathway accounts for a significant proportion of the cancerous cell energy production due to
over-expression of HK2. In addition, the increased rate of glycolysis provides the
premalignant or cancerous cells with many bio-synthetic precursors that are necessary for
rapid proliferation. Importantly, the increased rate of glycolysis in tumor tissues is observed
even in the presence of oxygen and is therefore not simply a result of reduced mitochondrial
energy production in hypoxic conditions. It has also been shown that increased HK2
expression inhibits apoptosis through binding to the voltage-dependent anion channel and
interfering with proapoptotic Bax activity (24). Therefore, the finding that murine
Hk2expression is significantly increased in the premalignant mammary glands from isolated
mice suggests that the social environment may be associated with subsequent tumor growth
through changes in mammary gland gene expression.
4. The first, Acly, encodes the enzyme that converts citrate into cytosolic acetyl-CoA.
Acaca,another upregulated gene, encodes the enzyme required for conversion of acetyl-CoA
to malonyl-CoA, the rate-determining step of lipogenesis (42). These CoA derivatives, in
conjunction with products from the glycolytic pathway, provide important lipids necessary for
enhanced tumor cell proliferation (43).
5. up-regulated ACCαmRNA expression (47, 48) and increased ACL activity (49) have been
previously linked to GR signaling
Wei Chen et al 2016
1. Social isolation significantly increased both the immunoreactivity and protein expression of
ADAR1 (p110) in the hippocampus and frontal cortex
2. ADAR1 proteins possess two types of nucleic acid binding domains. Three copies of a
double-stranded RNA binding motif are present in the central region of the p110 and p150
proteins (Patterson & Samuel, 1995; Liu & Samuel, 1996; Fierro-Monti & Mathews, 2000).
3. Both p150 and p110 are active enzymes that catalyze the C6 deamination of adenosine in
duplex RNA structures. Genetic disruption of the mouse ADAR1 gene by knocking out the
expression of both p150 and p110 ADAR1 proteins results in embryonic lethality (Hartner et
al., 2004; Wang et al., 2004;George, John & Samuel, 2014).
4. ADAR1-mediated RNA editing has been shown to affect a number of biological responses
including virus growth and persistence, cell proliferation, neurotransmitters, and innate
immune responses (Bombail et al., 2014; Cattenoz et al., 2013; Mattick & Mehler, 2008).
Moreover, pre-mRNA of 5-HT2C receptor (Schirle et al., 2010; Schmauss et al., 2010),
AMPA receptor, GABA receptor, and KV1.1 potassium channel catalyzed by ADAR family
have been reported to have closed relation to cognition (Bombail et al., 2014; Cattenoz et al.,
2013; Mattick & Mehler, 2008).

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Hawkey et al 2012

Carroll et. al. 2013

1. Isolation is a major source of psychosocial stress and is associated with an increased

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