ArticlePDF Available

Anti-Aging Genes Improve Appetite Regulation and Reverse Cell Senescence and Apoptosis in Global Populations


Abstract and Figures

Appetite regulation by nutritional intervention is required early in life that involves the anti-aging gene Sirtuin 1 (Sirt 1) with Sirt 1 maintenance of other cellular anti-aging genes involved in cell circadian rhythm, senescence and apoptosis. Interests in anti-aging therapy with appetite regulation improve an individual's survival to metabolic disease induced by gene-environment interactions by maintenance of the anti-aging genes connected to the metabolism of bacterial lipopoly-saccharides, drugs and xenobiotics. Interventions to the aging process involve early calorie restriction with appetite regulation connected to appropriate genetic mechanisms that involve mi-tochondrial biogenesis and DNA repair in neurons. In the aging process as the anti-aging genes are suppressed as a result of transcriptional dysregulation chronic disease accelerates and is connected to insulin resistance, non-alcoholic fatty liver disease (NAFLD) and neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. Interests in the gene-environment interaction indicate that the anti-aging gene Sirt 1that regulates food intake has been repressed early in the aging process in various global populations. The connections between Sirt 1 and other anti-aging genes such as Klotho, p66Shc (longevity protein) and Forkhead box proteins (FOXO1/ FOXO3a) have been associated with programmed cell death and alterations in these anti-aging genesregulate glucose, lipid and amyloid beta metabolism that are important to various chronic diseases.
Content may be subject to copyright.
Advances in Aging Research, 2016, 5, 9-26
Published Online January 2016 in SciRes.
How to cite this paper: Martins, I.J. (2016) Anti-Aging Genes Improve Appetite Regulation and Reverse Cell Senescence and
Apoptosis in Global Populations. Advances in Aging Research, 5, 9-26.
Anti-Aging Genes Improve Appetite
Regulation and Reverse Cell Senescence
and Apoptosis in Global Populations
Ian James Martins1,2,3
1Centre of Excellence in Alzheimers Disease Research and Care, School of Medical Sciences, Edith Cowan
University, Joondalup, Australia
2School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Nedlands, Australia
3McCusker Alzheimers Research Foundation, Holywood Medical Centre, Nedlands, Australia
Received 6 January 2016; accepted 25 January 2016; published 28 January 2016
Copyright © 2016 by author and Scientific Research Publishing Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY).
Appetite regulation by nutritional intervention is required early in life that involves the anti-aging
gene Sirtuin 1 (Sirt 1) with Sirt 1 maintenance of other cellular anti-aging genes involved in cell
circadian rhythm, senescence and apoptosis. Interests in anti-aging therapy with appetite regula-
tion improve an individual’s survival to metabolic disease induced by gene-environment interac-
tions by maintenance of the anti-aging genes connected to the metabolism of bacterial lipopoly-
saccharides, drugs and xenobiotics. Interventions to the aging process involve early calorie re-
striction with appetite regulation connected to appropriate genetic mechanisms that involve mi-
tochondrial biogenesis and DNA repair in neurons. In the aging process as the anti-aging genes are
suppressed as a result of transcriptional dysregulation chronic disease accelerates and is con-
nected to insulin resistance, non-alcoholic fatty liver disease (NAFLD) and neurodegenerative
diseases such as Parkinson’s disease and Alzheimer’s disease. Interests in the gene-environment
interaction indicate that the anti-aging gene Sirt 1that regulates food intake has been repressed
early in the aging process in various global populations. The connections between Sirt 1 and other
anti-aging genes such as Klotho, p66Shc (longevity protein) and Forkhead box proteins (FOXO1/
FOXO3a) have been associated with programmed cell death and alterations in these anti-aging
genesregulate glucose, lipid and amyloid beta metabolism that are important to various chronic
Anti-Aging Genes, Appetite, Environment, Nutrition, Senescence
I. J. Martins
1. Introduction
The hypothalamus is involved with many biological functions and includes appetite and body weight control,
feeding, emotion, memory, thermoregulation, fluid balance and insulin regulation [1]-[3]. The hypothalamic nu-
clei that are involved in food intake include the arcuate nucleus, the paraventricular nucleus, the lateral hypotha-
lamic area, the ventromedial nucleus and dorsomedial nucleus. Arcuate nucleus neurons at the bottom of the
hypothalamus near the third ventricle have direct contact with peripheral satiety factors like leptin and insulin.
Neurons in the hypothalamus are responsible for various connections to other brain regions and one of the im-
portant functions of the hypothalamus is control of the daily light dark cycle. The suprachiasmatic nucleus
(SCN) that coordinate the neuronal, humoural systems and the circadian rhythms activate the arcuate nucleus
that releases neuropeptide Y (NPY) and agouti related protein (AgRP) that control physiological functions
(body) temperature, melatonin release, glucocorticoid secretion and behavioural functions (feeding and mem-
ory). The SCN and peripheral oscillators are altered by food availability with calorie restriction important in the
maintenance of the SCN and the synchrony of the peripheral clocks. The neurons in the hypothalamus (appetite
centre) are sensitive to apoptosis and become senescent early in life with relevance to global chronic diseases
such as non-alcoholic fatty liver disease (NAFLD), obesity and diabetes.
In neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD) neurons in
specific regions of the brain become apoptotic later in life but may not involve the neurons in the appetite centre.
Neurodegenerative diseases such as PD and AD have become the cornerstone of brain research with appetite
dysregulation and insulin resistance now closely connected to these diseases. Early neuron transcriptional dys-
regulation that involves the SCN leads to food intake disorders and it cannot be excluded that neurons in the ap-
petite centre are defective early in life in global populations with appetite dysregulation associated with neu-
rodegenerative diseases such as PD and AD. Appetite dysregulation is connected to the anti-aging gene Sirtuin 1
(Sirt 1) that is connected to the circadian rhythm with effects on the endocrine and metabolic systems that in-
volve diseases of the adipose tissue, heart, liver, pancreas and brain [4]-[6]. Neuron apoptosis and survival
[7]-[10] is determined by Sirt 1 and other anti-aging genes and interventions that prevent down regulation of
anti-aging genes may allow appetite regulation with prevention of other chronic diseases. The rise in NAFLD in
global populations [11] [12] has required early intervention with connections to the severity of diseases such as
obesity, diabetes and neurodegenerative diseases. Interests in the calorie restriction with stabilization of anti-
aging genes have accelerated in recent years to delay and prevent programmed cell death linked to the various
chronic diseases (Figure 1). Interventions such as diet and lifestyle in chronic diseases such as obesity, diabetes
and cardiovascular disease involve abnormal post-prandial lipid metabolism [13] [14]. Diet is strongly associ-
ated with insulin and insulin like growth factor-1 (IGF-1) with cell senescence (mitochondrial apoptosis) and
genotoxic stress linked to the global NAFLD and neurodegeneration [15]-[21].
Interest in genomics that leads to the identification of novel genetic pathways assists in the treatment of vari-
ous chronic diseases with the new knowledge that may delay early programmed cell death pathways in cells.
Nutritional interventions that are controlled by the consumption of a low calorie diet indicate the maintenance of
connections between Sirt 1 and other anti-aging genes such as Klotho, p66Shc (longevity protein) and FOXO1/
FOXO3a that have been connected to the cell death by effects on glucose, lipid and amyloid beta metabolism.
These anti-aging genes in neurons are involved in transcriptional regulation with effects that are important to
SCN control of food intake and to the survival and stability of neurons. High fat diets that induce cell senes-
cence are linked to cell transformation and are associated with liver cell dysfunction (NAFLD), adipogenesis
disorders (obesity) and other organ diseases (Figure 1). The severity of endocrine and metabolism disorders are
associated with poor neuron survival with early neuron transformation that leads to appetite dysregulation with
overeating linked to metabolic disease. Major advances in the early diagnosis of diseases such as NAFLD and
neurodegenerative disease associated with obesity and diabetes are required. Diagnostic blood assays such as
plasma cholesterol measurements may not determine early senescence and programmed cell death [22] and ex-
tensive blood testing that is now underway in global populations may not be relevant to liver cell or neuron
apoptosis (neurodegenerative diseases). The role of diets that control the absorption of bacterial lipopolysaccha-
rides (LPS) are critical to prevent NAFLD and neurdegeneration [23] and the repression of anti-aging genes are
possibly linked to LPS with the acceleration of appetite dysregulation and chronic diseases. The effects of LPS
may also interfere with IGF-1 mediated expression of anti-aging genes with IGF-1/p53 transcriptional regulation
linked to Sirt 1 regulation of cell survival in aged and stressed cells [15]-[21]. To improve appetite dysregulation
I. J. Martins
Figure 1. Anti-aging strategies involve the maintenance of appetite regulation and
insulin resistance that are connected to the anti-aging genes that are suppressed early
in life. Appetite dysregulation accelerates abnormal post-prandial lipid metabolism
and NAFLD in global populations and early intervention is required to prevent the
severity of diseases such as obesity, diabetes and neurodegenerative diseases. Appetite
maintenance improves the endocrine and metabolic system that is connected to blood
brain barrier (BBB) disease and various organs diseases.
and prevent overeating that is linked to gene-environment effects (stress) on metabolic disease the maintenance
of the apelinergic pathway [24] early in life is essential. Nitric oxide (NO) is involved in appetite regulation and
NO disturbances have been reported in various chronic diseases [25]. Diets that are high in NO override cell NO
maintenance that is controlled by Sirt 1 relevant to endocrine, metabolic disease and thrombosis [24]-[27]. The
effects of stress and xenobiotics (environment) are associated with cell NO disturbances that prevent the reversal
of cell senescence (Figure 2). The nutritional diets that maintain the anti-aging genes and NO cell homeostasis
possibly involve Sirt1/IGF-1 [29]-[36] with the effects of dietary LPS involved in the NO dyshomeostasis, neu-
ron senescence and apoptosis.
Zinc deficiency and chronic disease has become important with zinc levels relevant to hormone bioactivity [3],
Sirt 1 activity [28] and IGF-1 functions [37] [38]. Zinc supplementationhas become important to LPS toxicity
with relevance to inflammation in various global populations [39] [40]. Appetite regulation has been associated
with various neuropeptides such as brain derived neurotrophic factor (BDNF) and NPY, hormones such as insu-
lin, adiponectin, leptin and various intestinal peptides [3] [41]-[43]. The role of zinc and Sirt 1 that involved in
the regulation of the anti-aging genes has become important since repression of these genes do not maintain the
action of the various neuropeptides, hormones and intestinal factors involved in appetite regulation with rele-
vance to chronic diseases. Anti-aging therapy that maintains appetite regulation improves an individual’s sur-
vival against autonomous disease induced by the environment (bacterial lipopolysaccharides, drugs, xenobiotics)
in various communities. Diets that are nutritional activate cellular anti-aging genes with the prevention of cell
senescence and apoptosis. Appetite regulation maintains the autonomic innervation of the liver by the brain with
the maintenance of rapid post-prandial lipid metabolism [13] [14] and the prevention of diseases of the adipose
tissue, heart, and pancreas.
2. Repression of Anti-Aging Genes Determine Food Intake Regulation, Insulin
Resistance and Neurodegenerative Disease
Overnutrition in chronic disease is involved with central nervous system dysregulation of neuropeptides with
abnormal peripheral hormone signalling from the pancreas (insulin), adipose tissue (leptin and adiponectin) and
gastrointestinal tract (neuropeptides) involved in chronic diseases. The increases in global chronic disease in the
I. J. Martins
Figure 2. The acceleration of chronic diseases involve NO disturbances
linked to stress, consumption of unhealthy diets and xenobiotics (gene-envi-
ronment interactions). Endocrine and metabolic diseases are linked to appetite
dysregulation with NO disturbances that involve defective apelinergic path-
ways. Nutritional diets maintain the anti-aging genesand NO cell homeostasis
with the importance of Sirt1/IGF-1 interactions in NO homeostasis, neuron
senescence and apoptosis. Sirt 1 is involved with the circadian rhythm and
platelet apoptosis with relevance to thrombosis and embolism.
past 20 years have indicated that insulin resistance and organ suicide are closely connected. The role of the mi-
tochondria in organ function is critical with increased mitochondrial apoptosis with accelerated aging. The role
of anti-aging genes in organ disease has become of central interest to maintain mitochondria functions and the
identification of longevity genes that determine their function is critical to the maintenance of chronic diseases.
The association between senescence and chronic disease now indicate that the anti-aging genes have been sup-
pressed (autonomous disease) and insulin resistance, IGF-1 levels and neuropeptide disturbances are closely
connected to mitochondria aging and cell senescence. Defective anti-aging genes are associated with glucose
dysregulation with inhibition of insulin signalling involved with mitochondrial apoptosis. In SCN neurons
within the brain the anti-aging genes that are involved with appetite regulation become altered by altered gene
expression and abnormal posttranscriptional regulation closely connected to appetite dysregulation. The SCN
synchrony between neurons is essential to maintain circadian rhythms and disturbances between neurons are as-
sociated with autonomous neuron disease linked to the anti-aging gene repression and liver dysfunction.
The gene that is involved in the regulation of food intake is Sirtuin 1 (Sirt 1) that is linked to life span, obesity
and cardiovascular disease with effects on NAFLD, inflammation, energy metabolism, cognition, mitochondrial
biogenesis, neurogenesis, glucose/cholesterol metabolism and amyloidosis. Sirt 1 is a nicotinamide adenine di-
nucleotide (NAD+) dependent class III histone deacetylase (HDAC) that targets transcription factors to adapt
gene expression to metabolic activity and is involved in the deacetylation of the nuclear receptors with its criti-
cal involvement in insulin resistance. Sirt 1 is also involved in telomerase reverse transcriptase and genomic
DNA repair with its involvement in telomere maintenance that maintains chromosome stability and cell prolif-
eration. Sirt1 is essential for neurogenesis and calorie restriction activates Sirt1 with effects on longevity by
modulation of phosphoinositide 3 kinase pathways and age associated cardiovascular changes. Tissue nuclear
receptors undergo deacetylation of histone and non-histone targets by Sirt 1 that targets transcription factors
peroxisome proliferator-activated receptor-gamma coactivator (PGC-1 alpha), p53, pregnane x receptor (PXR)
to adapt gene expression to metabolic activity, insulin resistance and inflammation. Sirt 1 is linked to glucose
regulation with the involvement of Forkhead box protein O1 (FOXO1) deacetylation (apoptosis) that involve
p53 transcriptional dysregulation and peroxisome proliferator activated receptor (PPAR) gamma nuclear recep-
tor. Furthermore Sirt 1/p53 interactions may regulate adipocytokines and immune responses that may be impor-
tant to NAFLD, obesity and neurodegeneration. Interests in calorie restriction, appetite regulation and neurode-
generation that involve Sirt 1 mediated regulation of other anti-aging genes involve p53 and FOXO deacetyla-
I. J. Martins
tion that has attracted interest in relation to autonomous disease of the brain and liver. In these tissues Sirt 1 is an
important gene involved in maintenance of the mitochondria and deacetylation of the transcriptional factor
FOXO3a that represses Rho-associated protein kinase-1 gene expression with activation of the non amyloido-
genic α-secretase processing of the amyloid precursor protein and reduction of amyloid beta (Aβ) generation in
neurons. Sirt 1 is also involved with hepatic cholesterol regulation with effects on liver nuclear receptors in-
volved with cholesterol flux and metabolism. Overnutrition is associated with the repression of Sirt 1 and other
anti-aging genes (Figure 3) such as Klotho, p66Shc (longevity protein) and FOXO1/FOXO3a that is now con-
nected to autonomous diseases of the brain and liver with SCN disturbances induced by Sirt 1 repression and
IGF-1 dysregulation involved in programmed cell death relevant to various chronic diseases such as obesity,
diabetes, PD and AD.
2.1. Klotho
The klotho (KL) gene is composed of 5 exons and encodes a type-I single pass transmembrane protein (1014-
amino acid-long), short intracellular domain (10-amino acidlong). The extracellular domain is composed of two
domains, termed KL1 and KL2, with weak homology. Klotho knockout mice have a short life span with in-
creased oxidative stress associated with atherosclerosis, osteoporosis, infertility, and cognitive decline. The gene
for the mammalian KL has two transcripts encode a long type I transmembrane protein and a short secreted pro-
tein that is released from the cell membrane and found in the serum and cerebrospinal fluid (CSF) [44] [45]. Sirt
1 and its close involvement as a histone deacetylase may be involved with Kotho gene expression and Sirt 1
downregulation may be intimately involved in the secretion and release of the protein into the serum or CSF.
Resveratrol is closely involved in Sirt 1 upregulation and studies indicate that Klotho gene expression and secre-
tion is upregulated by resveratrol [46]. Klotho gene has been identified as an important regulator of age related
diseases and is involved with cell senescence by upregulation of p21 [47]. Klotho is an anti-aging gene and in
Klotho-deficient mice Klotho has been associated with a premature aging-like syndrome. These results demon-
strate that Klotho normally regulates cellular senescence by repressing the p53/p21 pathway that is activated by
DNA damage and causes G(1)-phase arrest in mammalian cells. Klotho has been reported as a secreted Wnt an-
tagonist and a tumor suppressor [48]. Epigenetic silencing of klotho has been shown as a major pathway with
the involvement of histone deacetylation in the transcriptional repression of Klotho is correlated with promoter
Figure 3. The anti-aging gene Sirt 1 is associated with transcriptional regulation and linked to insulin
resistance, cancer and NAFLD. Sirt 1 regulation of p53, PGC1-alpha, PXR, PPAR, AMPK, FOXO1
involve nutrient, xenobiotic metabolism with relevance to DNA repair and the immune system. Tran-
scriptional regulation of Sirt 1/p53 interactions are associated with alpha synuclein and amyloid beta
interactions with the abnormal p53 transcriptional regulation of the anti-aging genes (Sirt 1, Klotho,
p66Shc (longevity protein), FOXO1/FOXO3a) associated with IGF-1 and cancer.
I. J. Martins
CpG hypermethylation and linked to Sirt 1 gene silencing that involve CpG island methylation. Klotho protein
has been indicated to be a hormone that inhibits the intracellular insulin/IGF-1 signaling cascade [49] [50]. In
other studies Klotho has been shown not inhibit IGF-1 and/or insulin signaling in various cells such as HEK293,
L6, and HepG2 cells and indicate against the role of Klotho in insulin resistance as an important regulator of
aging. Klotho gene expression was not associated with telomere length and the association with aging via other
mechanisms [51]. Klotho has been associated with cognition [52] and chronic kidney disease via the fibroblast
growth factor 23 but klotho levels have remained unchanged [53].
2.2. p66Shc
The gene SHC1 is located on chromosome 1 and encodes 3 main protein isoforms: p66Shc, p52Shc and p46Shc
and differ in molecular weight. p66Shc, a 66 kDa proto-oncogene Src collagen homologue (Shc) adaptor protein
is a longevity protein and has many effects involved with cell receptor tyrosine kinase signal transduction, nu-
trient metabolism and increased levels of p66Shc (Ser phosphorylation) have been shown to block mitosis, in-
hibit glucose metabolism and associated with the regulation of reactive oxygen species induced cell apoptosis
[54]-[57]. p66Shc antagonizes insulin and mTOR effects which limits glucose uptake and inhibits anabolic me-
tabolism [58] [59]. The p66shc protein plays key role in oxidative stress, stroke, metabolic disease in various
organs and tissues in obesity and diabetes [60]-[64]. The p66Shc isoform has inhibitory effects on the Erk path-
way [65] in skeletal muscle myoblasts, actin cytoskeleton polymerization and glucose transport. p66Shc inhibits
ERK1/2 activity and antagonize mitogenic and survival abilities of T-lymphoma Jurkat cell lines. The
MAPK/Erk signaling cascade is activated by a wide variety of receptors involved in growth and differentiation
including receptor tyrosine kinases (RTKs), integrins, and ion channels. Oxidized lipids and LDL have been
shown to stimulate p66Shc expression that is associated with abnormal redox balance, endothelial dysfunction
and cardiovascular disease [66]-[68]. p66Shc is involved with the expression of p53 and p53 isoform (p44/p53),
oxidative stress and G2M cell cycle arrest [69]-[71]. The induction of angiotensin II regulated p66Shc is con-
trolled by stress activated p53 and indicates that post transcriptional regulation by p53 of p66Shc is essential for
endothelium dependent vascular relaxation [72]. Sirt 1 is primarily involved in the deacetylation of p53 with
control of p66Shc cellular senescence associated with the progression of NAFLD. Repression of p66Shc expres-
sion by Sirt 1 has been shown to be involved with liver injury and hyperglycemia induced endothelium dysfunc-
tion [73]. Palmitic acid is an inhibitor of Sirt 1 and palmitate has been shown to increase p66Shc (Ser phos-
phorylation) in pancreatic beta cells [74]. p53 is closely involved with the palmitate-induced increase in p66Shc
expression and beta cell apoptosis. Sirt 1 that is actively involved in Aβ metabolism in neurons and Aβ has now
been connected to the phosphorylation of p66Shc at the serine 36 residue with increased oxidative stress that
leads to cell death [75] [76]. Antioxidants have been shown to be involved with reduced oxidative stress by in-
terfering with the phosphorylation of p66Shc. Sirt 1 has effects on brain and liver alpha-synuclein and Aβ me-
tabolism closely linked metabolic disease [77] [78] with effects of p53 transcriptional regulation by intracellular
alpha-synuclein and Aβ metabolism in the liver and brain linked to the regulation of anti-aging genes and cellu-
lar apoptosis [78] [79].
2.3. FOXO3a
FOXOs belong to the O subclass of the Forkhead family of transcription factors which are characterized by a
Forkhead DNA binding domain. There are three main proteins (FOXO1, FOXO3a and FOXO4) from which
FOXO3a protein is considered to be a regulator of cancer and aging [80]-[83]. FOXO1 proteins are involved
with adipocyte lipid metabolism and ROS-dependent cascades. FOXO3a is found in the nucleus but is redistrib-
uted to the cytosol by the actions of ROS and activation of this pathway (insulin/insulin-like growth factor-1
(IGF-1)/phosphatidylinositol-3 kinase (PI3K)/Akt/FOXO3a) is associated with senescence [84]. p66Shc partici-
pates in Akt signaling pathway and is involved with inactivated FOXO3a and ROS effects that involve activated
p38 and JNK and inactivated by Akt kinase in cells. Sirt 1 has been shown to deacetylate FOXO3 and FOXO4
with the regulation of FOXO-induced apoptosis and cell-cycle arrest not connected to p53 deacetylation. Sirt 1
has been shown to interact with FOXO3a and induce cell apoptosis [85] [86]. Nuclear Sirt 1 actively involved in
Aβ metabolism and possibly regulates FOXO associated senescent effects with control of cell survival. Klotho
has been shown to activate FOXO and to inhibit the insulin/IGF-1/PI3K/Akt signaling cascade. The connections
between Sirt 1 and Kotho for cell senescence possibly are connected via FOXO1/FOXO3a mediated glucose
I. J. Martins
homeostasis and ROS pathways. Bacterial lipopolysaccharides (LPS) are involved in the repression of Sirt 1
with the actions on other anti-aging genes. Zinc is the activator of Sirt 1 function with LPS closely connected to
zinc deficiency with zinc supplementation essential to reduce LPS toxicity [38] [39]. Sirt 1’s effects on cellular
cholesterol homeostasis is by its deacetylase activity and ubiquitination of liver X receptor (LXR) proteins with
the regulation of ATP-binding cassette transporter (ABCA1) and sterol regulatory element-binding protein
1cinvolved in cell cholesterol homeostasis [78] [79]. LPS interferes with Sirt 1 and ABCA1 interactions by in-
hibition of cholesterol flux via LXR-ABCA1 pathways [78] [79]. Sirt 1 regulation of PGC1 alpha is well under-
stood with PGC1 alpha involved in the inactivation of prostaglandain E2 (PGE2) with fat accumulation [11].
LPS is involved in the biosynthesis of PGE2 with LPS effects in the liver and other cells that override Sirt 1and
PGC1 alpha effects in these cells [87] [88]. The major effects of Sirt 1 as a deacetylase is regulation of the tran-
scription factor p53 involved in the regulation of cell glucose and cholesterol metabolism [79]. LPS is involved
in the post-transcriptional regulation of p53 with interference of Sirt 1/p53 cell regulation pathways involved in
cell maintenance [79]. LPS induces mitochondrial apoptosis with toxic effects on the SCN neurons involved
with appetite regulation that involve Sirt 1 dysregulation linked to anti-aging genes [78] [79]. IGF-1 levels and
its connections to Sirt 1 and the anti-aging genes possibly involve corruption by LPS with LPS effects that in-
volve dysregulation ofcircadian regulation of IGF-1 with IGF-1 effects on nuclear genes (cancer) and mitochon-
dria within cells [17]-[19] [89]-[91]. Sirt 1 and its regulation of the SCN and appetite centre are inhibited by
LPS via interference of the Sirt 1/p53 pathways that involve the other anti-aging genes.
3. Dysregulation of Neuropeptides and Endocrine Hormones by LPS Determine
Appetite and Metabolism Disorders
The SCN in the brain is closely involved with appetite regulation and LPS induced posttranscriptional regulation
in neurons is now closely connected to appetite dysregulation. The SCN synchrony between neurons is essential
to maintain circadian rhythms and disturbances between neurons are associated with autonomous neuron disease
linked to appetite dysregulation. LPS has a number of effects on various cells and tissues in the periphery and in
the brain. LPS induces dyslipidemia and NAFLD with effects on apolipoproteins (apo E, apo AI), acute phase
proteins, cytokines, albumin, alpha synuclein and amyloid beta [77] [78]. Its preference for binding to choles-
terol and sphingomyelin sites on cell membranes indicates its role in the electrostatic interaction of amyloid beta
[23] [77]. LPS has marked effects on receptors and on the astrocyte-neuron interaction with the induction of
neuroinflammation [77]. LPS effects on the sleep/wake cycle determines food intake regulation and LPS effects
on appetite regulation involves Sirt 1 repression and alpha synuclein/IGF-1 metabolism [78] [92]-[95]. Neurons
in the hypothalamus are responsible to various brain regions and LPS induction of nuclear, mitochondria and
cell membrane interactions induces autonomous cell behaviour with appetite dysregulation linked to reorganiza-
tion cell signalling and astrocyte-neuron synchrony in the brain. Autonomous disease interferes with the effects
of neuropeptides and hormones that are no longer effective and are now connected to nuclear receptors dysfunc-
tion associated with the anti-aging genes. Appetite regulation has been associated with various neuropeptides
such as BDNF and NPY, hormones such as insulin, adiponectin, leptin and various intestinal peptides [96].
The interests in LPS in the induction of autonomous neuron disease involve inflammation with the connec-
tions to poor neuropeptide/receptor and peripheral hormones interactions that promote appetite dysregulation in
the brain. NO has been clearly linked to food intake regulation and autonomous neuron disease induced by LPS
is relevant overeating and metabolic disease in global populations (Figure 2). The effects of LPS induce mito-
chondrial apoptosis with NO dyshomeostasis [97]-[100] and corrupt appetite regulation by interference with
neuropeptides and peripheral hormones that are also involved in the maintenance of mitochondrial stability. The
effects of LPS on nuclear Sirt 1 repression in neurons disturb Sirt 1 regulation of cell NO metabolism with Sirt 1
linked to mitochondrial biogenesis [79]. The effects of LPS in the brain and the liver corrupt the autonomic in-
nervation of the liver by the brain [101] with the liver clocks under autonomous regulation with sensitivity to
disturbed post-prandial metabolism, liver steatosis and NAFLD. Interest in metabolic disorders indicate that the
communication between the gastrointestinal tract neuropeptides involve the hypothalamus and brain stem [3].
These regions of the brain integrate peripheral signals such as various factors released from the gut and adi-
pose tissue that have effects on neuronal activity of the hypothalamus and brain stem that control appetite regu-
lation. In response to food intake various gut and adipose tissue hormones have effects on the hypothalamus that
release various neuropeptides that effect appetite, food intake and energy balance. Cholecystokinin (CCK) is an
I. J. Martins
intestinal hormone and after a meal CCK levels rise to inhibit food intake. Other peptides involved in appetite
regulation include glucagon like peptide (GLP-1) that increases in the blood plasma released from the L cells of
the gastrointestinal tract. Pancreatic islet beta cells release insulin and another peptide referred to as amylin is
released with relevance to reduced food intake. Other proglucagon cleavage peptides including oxyntomodulin
(OXM) and peptide YY (PYY) are secreted with GLP-1 in response to high calorie foods. Pancreatic polypep-
tide (PP) is secreted from the pancreatic islets and is similar in structure to PYY with reduction in food intake
after administration to rodents and humans. PP has effects on gastric ghrelin and gene expression of hypotha-
lamic peptides such as NPY and AGRP that control food intake. Ghrelin is 28 amino acid peptide hormone and
has been characterized as an appetite stimulating hormone with effects on appetite control related to hypotha-
lamic NPY/AgRP neurones which express the ghrelin receptors [3].
Future therapies that involve control of body size and adiposity will involve assessment of diets that reduce
LPS absorption [23] with relevance to LPS effects on the hypothalamus and on the poor regulation of various
intestinal and brain neuropeptides that influence appetite regulation. Influence on appetite regulation and feeding
are also related to leptin, melanortin, adiponectin, melanin concentrating hormone (MCH), orexins and endo-
cannabinoids that communicate with peripheral signals such as nutrients (glucose, amino acids, fatty acids) and
gastrointestinal peptide hormones such as CCK and ghrelin. Thyroid hormones may act directly on the hypotha-
lamic appetite circuits and signalling factors such as thyroid stimulating hormone, triiodothyronine (T3) and
thyroxine (T4) have recently shown to directly influence food intake. Hypothalamic control of appetite regula-
tion and energy expenditure not only involves the hypothalamus but also the hypothalamic pituitary axis (HPT).
Recent evidence indicates that the HPT axis can control food intake and effects on appetite and body weight is
mediated by thyroid hormones and LPS has become important to appetite regulation [102] [103]. Interests in the
neuroendocrine system, energy metabolism and peripheral cholesterol metabolism have increased with the
strong genetic identification andinvolvement NPY in plasma cholesterol regulation.
The CNS and its control of lipidmetabolism has identified hypothalamic NPY with evidence that NPY has
effects onY1 receptors to promote hepatic lipoprotein secretion to promote VLDL secretionvia the sympathetic
nervous system [104] [105] and on Y2 receptors to promote feeding. Sirt 1 regulation of BDNF [106]-[108] has
been shown (Figure 4) and associated with altered NPY levels in the brain [109] [110] and several studies have
indicated its involvement in neuronal plasticity, behaviour, appetite control andbody weight regulation. BDNF is
involved in the regulation of food intake and the levels of BDNF controlled by high fat diets. In mature neurons
the BDNF peptide is involved with the regulation of synaptic plasticity and neuro transmission in the peripheral
Figure 4. Bacterial LPS suppresses Sirt 1 expression with effects on
neuropeptides such as brain derived neurotrophic factor, neuropeptide Y
and IGF-1 that are involved in the appetite regulation (food intake) in
the brain and in the periphery LPS interrupts hepatic glucose, lipopro-
tein and cholesterol metabolism. LPS is involved in cell zinc homeosta-
sis with the importance of zinc relevant to the maintenance of Sirt 1 activ-
ity and the function of hormones such as insulin and the adipokines (ad-
iponectin, leptin) involved in appetite regulation in the hypothalamus.
I. J. Martins
and central nervous system. BDNF is involved in regulation of CB1 receptor expression and the proliferation,
survival and maintenance of neurons. In individuals with the metabolic syndrome Sirt 1 downregulation is pos-
sibly related to BDNF levels [111], IGF-1 levels and abnormal NPY regulation involved with appetite dysregu-
lation and neurodegeneration.
Zinc deficiency has marked effects on brain zinc homeostasis and is associated with alterations in behaviour,
learning and mental function. Under stress, anxiety and depression disorders zinc levels alter with marked ef-
fects on health and well being of the individuals. Stress has been linked to body weight regulation and evidence
suggests zinc’s involvement in the molecular mechanisms of brain function and appetite control. Zinc is in-
volved with regulation of leptin, insulin and adiponectin levels, adipose tissue cytokines (interleukin 2 and tu-
mour necrosis factor) with long term effects on appetite regulation in the brain.
In zinc deficiency NPY levels in the hypothalamus are increased and release of NPY from the paraventricular
nucleus is impaired with effects on regulation of food intake [112] [113]. In zinc deficiency NPY is unable to
bind to its receptors to intiate an orexigenic response. Zinc is involved in the expression of brain BDNF and
NPY synthesis and its effects on insulin, leptin and adiponectin [3] in the peripheryindicates its role in the close
relationship between appetite control and cholesterolhomeostasis. Zinc is an activator of Sirt 1 and plays a criti-
cal role in the biology of p53 that is involved in the binding of p53 to DNA [114]. Interests in alpha-synuclein
and food intake have increased [92] [93] and its relevance to p53 transcriptional regulation has been shown with
LPS involvement [78] [79]. LPS regulation of apo E (23) has become important with relevance to apo E sup-
pression of food intake [115]-[117] and LPS effects on leptin synthesis may determine appetite regulation [118]
[119]. Leptin is a 16 kda protein identified in 1994 (14) is synthesized by fat cells and acts as a satiety factor at
the hypothalamus mediated through the leptin receptor. The amount of leptin released is proportional to the size
of adipose tissue and regulates food intake. LPS has effects on adipose tissue with release of free fatty acids as-
sociated with insulin resistance [120]. Dietary fat that promotes LPS absorption may determine apo E and leptin
synthesis in the hypothalamus with relevance to chronic automomic disease that involveszinc deficiency, appe-
tite dysregulation and insulin resistance.
4. Anti-Aging Therapy Involves Reversal of Appetite Disorders in Autonomous
Chronic Diseases
In the aging process appetite dysregulation (overeating) is connected to the suppression of the anti-aging genes
as a result of transcriptional dysregulation. Interests in the gene-environment interaction [121] [122] indicate
that the anti-aging gene Sirt 1 that regulates food intake is repressed early in the aging process in various global
populations. Repression of Sirt 1 and other anti-aging genes such as Klotho, p66Shc (longevity protein) and
FOXO1/FOXO3a lead to abnormal regulation of glucose, lipid and amyloid beta metabolism that are associated
with programmed cell death in the liver and brain. Dietary effects on stress sensitive anti-aging genes (repres-
sion) may be associated with Sirt 1 downregulation with appetite dysregulation and accelerated disease progres-
sion. Anti-aging therapy that maintains appetite regulation improves an individual’s survival against autono-
mous disease induced by the environment in various communities. Bacterial lipopolysaccharides, drugs, and
xenobiotics consumed early in life induce autonomous chronic disease and corrupt the Sirt 1 circadian clock
gene with dysregulation of other cellular anti-aging genes now associated with cell senescence and apoptosis.
Furthermore the lack of ingestion of nutritional doses of phosphatidylinositol (appetite regulation) leads to liver
steatosis and acceleration to NAFLD. In the current global NAFLD in developing countries [122] [123] the in-
duction of autonomous liver disease by consumption of high calorie diets that contain LPS, xenobiotics and
drugs is now relevant to neurodegenerative diseases such as PD and AD. LPS and xenobiotics inactivate liver
cells (autonomous liver disease) with relevance to the defective peripheral sink abeta clearance pathway that is
now relevant to many chronic diseases [11] [124] that before may have been previously only associated with
neurodegeneration [77]. The role of anti-aging genes in various communities in the developing world may be
altered early in life with the acceleration of various diseases [11]. In the developed world the xenobiotic free diet
and appropriate zinc consumption may activate hepatic nuclear receptors and with the metabolic syndrome the
malfunction of various organ diseases may not be associated with the insulin resistance epidemic [125]. To
maintain the cell anti-aging gene mechanisms and prevent early programmed cell death diets that are very low
carbohydrate diets need to be ingested to avoid the intestinal absorption of LPS into the blood that is found in
various foods [14]. The low calorie diet will maintain the nuclear Sirt 1 activity with relevance to p66Shc
I. J. Martins
mechanisms that are sensitive to the ingestion of high palmitic acid and leads to cell cycle dysregulation with
cell apoptosis [74] [126]. Short chain fatty acids (SCFA) have become important to appetite regulation with the
consumption ofacetate, propionic acid and butyric acid at therapeutic doses applicable to central appetite regula-
tion [127] [128]. Butyric acid has been associated with the inhibition of zinc associated HDACs and administra-
tion of butyric acid doses in man for the reduction of alpha-synuclein and Aβ oligomers [78] [129] may inhibit
the zinc sensitive HDACs such as Sirt 1 involved in cell NO homeostasis [129]. LPS sensitive butyric acid
events have been associated with T cell apoptosis and cancer (Figure 5) with butyric acid derivatives important
to cancer treatment [130]. The use of SCFA in nutritional diets has attracted interest to appetite regulation but
the doses of the SCFA have become of concern for use in man and administration of butyric acid may need to be
assessed with relevance to plasma LPS levels that may corrupt the neuroprotective effects of a ketogenic diet
Sirt 1 activators (nutrients) and inhibitors (drugs, alcohol) have been previously described [11] and their con-
sumption in various countries will determine nuclear receptor function and insulin resistance and determine the
origin of autonomous chronic disease associated with early liver dysfunction linked to organ disease progression.
Diets that are high in NO override the Sirt 1/ p66Shc regulation of cell NO (Figure 5) and mitochondrial apop-
tosis linked to cell autonomous disease are possibly associated with the acceleration of obesity, diabetes and
neurodegeneration [25] [132]. The major interest in cell anti-aging genes is relevant to specific dietary intake
that allows Sirt 1 cell function to belinked to therapeutic neuropeptide and endocrine responses that lead to the
maintenance of anti-aging cellprocesses with the prevention of NO related apoptosis [133]-[135]. Interactions
between cells in various tissues such as the liver and brain have become important with the brain involved in the
autonomic regulation of liver function. The liver clock [136] may override the automonic regulation of brain
control by autonomous behaviour between cells that may be induced by LPS, mycotoxins or xenobiotics [137]
with dysregulation of neuropeptides and endocrine hormones. Mycotoxins, LPS and xenobiotics that may be
transported to the brain may induce cell desynchrony with appetite dysregulation and overeating related to dys-
regulation of neuropeptides and endocrine hormones important to insulin and the IGF-1 signaling cascade. The
synergism between LPS, mycotoxin and xenobiotics in diets may override the function of the anti-aging genes
with the liver autonomous to brain regulation with the development of obesity and diabetes. The intestine and its
release of lipid particles such as chylomicrons after a meal [14] has become important to human disease with in-
testinal release of lipid particles that contain LPS, xenobiotics and mycotoxins. The fat content of diet that re-
leases the number and size of the intestinal particles has become important [138] to the function of the anti-ag-
ing genes in liver cells and food restriction (chylomicron release) that allows maintenance of anti-aging gene
function is required. Under fasting conditions or timed meal conditions the release from the intestine of chy-
lomicrons with LPS, xenobiotic or mycotoxin to the liver may allow rapid hepatic metabolism and elimination
Figure 5. The short chain fatty acid butyric acid has been shown to be involved in the inhibi-
tion of Sirt 1 activity with effects of butyric acid and LPS on T cell apoptosis and cancer. Bu-
tyric acid regulation of brain appetite signals involves other short chain fatty acids such as
acetate and propionic that are important to central appetite regulation. Butyric acid inhibits Sirt
1 with effects on the metabolism of alpha synuclein and amyloid beta metabolism in cells.
Administration of dietary phenyl butyric acid reducesalpha synuclein and amyloid beta oli-
gomers in the brain in mice.
I. J. Martins
of various drugs into the bile [122] [137]. Tests for postprandial lipid metabolism in obesity indicate that in the
fed and the fasting conditions dietary chylomicron remnant metabolism is defective with liver programmed cell
death [14]. The various blood tests [22] and tests for postprandial lipid metabolism [14] may not allow early di-
agnosis of autonomous liver disease independent of appetite regulation that may be the primary disease associ-
ated with the current global obesity linked diabetes epidemic relevant to neurodegeneration [3] [22] [139]. The
addition of zinc to the diet may not reverse the cell autonomy and may require the addition of various nutrients
and the removal of various Sirt 1 inhibitors required for anti-aging cell processes. In the developing world, ab-
normal blood lipids (cholesterol, triglyceride) and liver enzymesmay not interpret the effects of LPS and my-
cotoxin on anti-aging genes in the liver and brain that are defective and the effects of the anti-aging therapy such
as consumption of a very low carbohydrate or a low fat diet [11] are possibly able to reverse the autonomous
cell behaviour (nuclear-mitochondria interactions) that is linked to the nuclear senescence with mitochondrial
apoptosis [79]. The use of diet as therapy for reversal of the aging process may stabilize the apelinergic system
[25] that is defective in individuals with insulin resistance and important to the optimal function of the brain and
peripheral organs. The anti-aging genes in people at risk for various diseases in global populations may be de-
fective early in life and not connected to DNA methylation profile associated with aging and longevity [140].
5. Discussion
In Western countries and the developing world the metabolic syndrome and NAFLD and neurodegenerative
disease has reached approximate 30% of the global population. Accelerated age related disease associated with
cell senescence interfere the anti-aging genes that are involved with cell growth and healthy aging. Dietary in-
terventions with calorie restriction early in life prevent the tissue accumulation of LPS, mycotoxin, xenobiotics
and drugs by maintenance of post-prandial lipid metabolism associated with delivery of various foreign com-
pounds to the liver relevant to facilitate many tissue cell to cell communications with the prevention of autono-
mous organ diseases. Anti-aging strategies that involve nutritional diets allow neuropeptides and endocrine
hormones to maintain cell and mitochondrial functions to facilitate nutrient metabolism in the liver and brain.
Prevention of insulin resistance has become the major prevention program in global populations with improve-
ment in zinc intake and maintenance of nitric oxide homeostasis in cells central to prevent early alterations in
multiple anti-aging genes, neuropeptides and endocrine hormones that are associated with appetite regulation,
insulin resistance and cell apoptosis.
6. Conclusion
The regulation of food intake and calorie restriction is important to appetite regulation with relevance to the
progression of chronic disease and neurodegeneration. Appetite dysregulation involves neurons associated with
the suppression of the anti-aging gene Sirt 1 and other anti-aging genes such as Klotho, p66Shc and FOXO1/
FOXO3a that are connected to the programmed cell death (mitochondrial apoptosis) and dysregulation of glu-
cose, lipid and amyloid beta metabolism. Nutritional intervention early in life with the consumption of very low
carbohydrate diets has been recommended that allows maintenance of the autonomic innervation of the liver by
the brain. In the aging process unhealthy diets disconnect the liver from the brain with the ingestion of LPS,
myoctoxin and xenobiotics that induce autonomous liver disease, metabolic disease and neurodegeneration. The
brain and liver dysregulation are connected to various chronic diseases associated with abnormal post-prandial
lipid metabolism, cardiovascular disease, obesity and diabetes. The anti-aging therapy involves low calorie diets
that do not contain LPS, mycotoxin or xenobiotics and these diets maintain brain and liver Sirt 1 activity with
appetite regulation closely linked to zinc and nitric oxide homeostasis connected to the autonomic control of the
liver by the brain.
This work was supported by grants from Edith Cowan University, the McCusker Alzheimers Research Founda-
tion and the National Health and Medical Research Council.
[1] Ahima, R.S. and Antwi, D.A. (2008) Brain Regulation of Appetite and Satiety. Endocrinology and Metabolism Clinics
I. J. Martins
of North America, 37, 811-823.
[2] King, M.W. (2015) Gut-Brain Interrelationships and Control of Eating Behaviour, 1996-2014, The Medical Biochem-
istry Page. Org, info @ Last Modified 9 April.
[3] Martins, I.J. (2015) Appetite Dysregulation and Obesity in Western Countries. Lambert Book Appetite, E-Book, First
Edited by Jones, E., LAP LAMBERT Academic Publishing, ISBN 978-3-659-40372-9, 2013.
[4] Li, X. (2013) SIRT1 and Energy Metabolism. Acta Biochimica Biophysica Sinica, 45, 51-60.
[5] Boutant, M. and Cantó, C. (2013) SIRT1 Metabolic Actions: Integrating Recent Advances from Mouse Models. Mo-
lecular Metabolism, 3, 5-18.
[6] Chang, H.C. and Guarente, L. (2013) SIRT1 Mediates Central Circadian Control in the SCN by a Mechanism That
Decays with Aging. Cell, 153, 1448-1460.
[7] Mohawk, J.A. and Takahashi, J.S. (2011) Cell Autonomy and Synchrony of Suprachiasmatic Nucleus Circadian Oscil-
lators. Trends in Neurosciences, 34, 349-358.
[8] Cavallaro, S. (2015) Cracking the Code of Neuronal Apoptosis and Survival. Cell Death and Disease, 6, e1963.
[9] Portt, L., Norman, G., Clapp, C., Greenwood, M. and Greenwood, M.T. (2011) Anti-Apoptosis and Cell Survival: A
Review. Biochimica Biophysica Acta, 1813, 238-259.
[10] Morrison, R.S., Kinoshita, Y., Johnson, M.D., Ghatan, S., Ho, J.T. and Garden, G. (2002) Neuronal Survival and Cell
Death Signaling Pathways. Advances in Experimental Medicine and Biology, 513, 41-86.
[11] Martins, I.J. (2015) Nutrition Increases Survival and Reverses NAFLD and Alzheimers Disease. First Edition Edited
by Berdos, A., 01/ 2015, E-Book/Printed Book, LAP LAMBERT, ISBN: 978-3-659-78371-5.
[12] Radziuk, J.M. (2013) The Suprachiasmatic Nucleus, Circadian Clocks, and the Liver. Diabetes, 62, 1017-1019.
[13] Zock, P.L. (2007) Postprandial Lipoprotein Metabolism—Pivot or Puzzle? American Journal of Clinical Nutrition, 85,
[14] Martins, I.J. and Redgrave, T.G. (2004) Obesity and Post-Prandial Lipid Metabolism. Feast or Famine? The Journal of
Nutritional Biochemistry, 15, 130-141.
[15] Tang, B.L. (2006) SIRT1, Neuronal Cell Survival and the Insulin/IGF-1 Aging Paradox. Neurobiology of Aging, 27,
[16] Tran, D., Bergholz, J., Zhang, H., He, H., Wang, Y., Zhang, Y., Li, Q., Kirkland, J.L. and Xiao, Z.X. (2014) Insu-
lin-Like Growth Factor-1 Regulates the SIRT1-p53 Pathway in Cellular Senescence. Aging Cell, 13, 669-678.
[17] Gu, Y., Wang, C. and Cohen, A. (2004) Effect of IGF-1 on the Balance between Autophagy of Dysfunctional Mito-
chondria and Apoptosis. FEBS Letters, 577, 357-360.
[18] Ribeiro, M., Rosenstock, T.R., Oliveira, A.M., Oliveira, C.R. and Rego, A.C. (2014) Insulin and IGF-1 Improve Mito-
chondrial Function in a PI-3K/Akt-Dependent Manner and Reduce Mitochondrial Generation of Reactive Oxygen
Species in Huntington’s Disease Knock-In Striatal Cells. Free Radical Biology Medicine, 74, 129-144.
[19] Yin, F., Jiang, T. and Cadenas, E. (2013) Metabolic Triad in Brain Aging: Mitochondria, Insulin/IGF-1 Signalling and
JNK Signalling. Biochemical Society Transactions, 41, 101-105.
[20] Monteserin-Garcia, J., Al-Massadi, O., Seoane, L.M., Alvarez, C.V., Shan, B., Stalla, J., Paez-Pereda, M., Casanueva,
F.F., Stalla, G.K. and Theodoropoulou, M. (2013) Sirt1 Inhibits the Transcription Factor CREB to Regulate Pituitary
Growth Hormone Synthesis. FASEB Journal, 27, 1561-1571.
[21] Yamamoto, M., Iguchi, G., Fukuoka, H., Suda, K., Bando, H., Takahashi, M., Nishizawa, H., Seino, S. and Takahashi,
Y. (2013) SIRT1 Regulates Adaptive Response of the Growth Hormone—Insulin-Like Growth Factor-I Axis under
Fasting Conditions in Liver. Proceedings of the National Academy of Sciences of the United States of America, 110,
[22] Martins, I.J. (2015) Diabetes and Organ Dysfunction in the Developing and Developed World. Global Journal of
Medical Research, 15, 14-22.
[23] Martins, I.J. (2015) LPS Regulates Apolipoprotein E and Aβ Interactions with Effects on Acute Phase Proteins and
Amyloidosis. Advances in Aging Research, 4, 69-77.
[24] Esch, T., Stefano, G.B., Fricchione, G.L. and Benson, H. (2002) Stress-Related Diseases: A Potential Role for Nitric
I. J. Martins
Oxide. Medical Science Monitor, 8, RA103-RA118.
[25] Martins, I.J. (2015) Nutritional Diets Accelerate Amyloid Beta Metabolism and Prevent the Induction of Chronic Dis-
eases and Alzheimer’s Disease. Photon eBooks, UBN: 015-A94510112017.
[26] Kumari, S., Chaurasia, S.N., Nayak, M.K., Mallick, R.L. and Dash, D. (2015) Sirtuin Inhibition Induces Apop-
tosis-Like Changes in Platelets and Thrombocytopenia. The Journal of Biological Chemistry, 290, 12290-12299.
[27] Breitenstein, A., Stein, S., Holy, E.W., Camici, G.G., Lohmann, C., Akhmedov, A., Spescha, R., Elliott, P.J., Westphal,
C.H., Matter, C.M., Lüscher, T.F. and Tanner, F.C. (2011) Sirt1 Inhibition Promotes in vivo Arterial Thrombosis and
Tissue Factor Expression in Stimulated Cells. Cardiovascular Research, 89, 464-472.
[28] Chen, L., Feng, Y., Zhou, Y., Zhu, W., Shen, X., Chen, K., Jiang, H. and Liu, D. (2010) Dual Role of Zn2+ in Main-
taining Structural Integrity and Suppressing Deacetylase Activity of SIRT1. Journal of Inorganic Biochemistry, 104,
[29] Gatenby, K.V., Imrie, H. and Kearney, M. (2013) The IGF-1 Receptor and Regulation of Nitric Oxide Bioavailability
and Insulin Signalling in the Endothelium. Pflügers ArchivEuropean Journal of Physiology, 465, 1065-1074.
[30] Abbas, A., Viswambharan, H., Imrie, H., Rajwani, A., Kahn, M., Gage, M., Cubbon, R., Surr, J., Wheatcroft, S. and-
Kearney, M. (2011) A Endothelial Cell Nitric Oxide Bioavailability and Insulin Sensitivity Are Regulated by IGF-1
and Insulin Receptor Levels. Heart, 97, A1-A2
[31] Abbas, A., Imrie, H., Viswambharan, H., Sukumar, P., Rajwani, A., Cubbon, R.M., Gage, M., Smith, J., Galloway, S.,
Yuldeshava, N., Kahn, M., Xuan, S., Grant, P.J., Channon, K.M., Beech, D.J., Wheatcroft, S.B. and Kearney, M.T.
(2011) The Insulin-Like Growth Factor-1 Receptor Is a Negative Regulator of Nitric Oxide Bioavailability and Insulin
Sensitivity in the Endothelium. Diabetes, 60, 2169-2178.
[32] Galli, G., Pinchera, A., Piaggi, P., Fierabracci, P., Giannetti, M., Querci, G., Scartabelli, G., Manetti, L., Ceccarini, G.,
Martinelli, S., Di Salvo, C., Anselmino, M., Bogazzi, F., Landi, A., Vitti, P., Maffei, M. and Santini, F. (2012) Serum
Insulin-Like Growth Factor-1 Concentrations Are Reduced in Severely Obese Women and Raise after Weight Loss
Induced by Laparoscopic Adjustable Gastric Banding. Obesity Surgery, 22, 1276-1280.
[33] Tuncel, D., Tolun, F.I. and Toru, I. (2009) Serum Insulin-Like Growth Factor-1 and Nitric Oxide Levels in Parkinson’s
Disease. Mediators of Inflammation, 2009, Article ID: 132464.
[34] Zheng, W.H., Kar, S., Doré, S. and Quirion, R. (2000) Insulin-Like Growth Factor-1 (IGF-1): A Neuroprotective Tro-
phic Factor Acting via the Akt Kinase Pathway. Journal of Neural Transmission Supplementation, 60, 261-272.
[35] Zheng, W.H. and Quirion, R. (2004) Comparative Signaling Pathways of Insulin-Like Growth Factor-1 and Brain-De-
rived Neurotrophic Factor in Hippocampal Neurons and the Role of the PI3 Kinase Pathway in Cell Survival. Journal
of Neurochemistry, 89, 844-852.
[36] Carro, E. and Torres-Aleman, I. (2009) Insulin-Like Growth Factor I and Alzheimers Disease: Therapeutic Prospects?
Biochemical Biophysica Research Communications, 385, 434-438.
[37] Alves, C.X., Vale, S.H., Dantas, M.M., Maia, A.A., Franca, M.C., Marchini, J.S, Leite, L.D. and Brandao-Neto, J.
(2012) Positive Effects of Zinc Supplementation on Growth, GH, IGF1, and IGFBP3 in Eutrophic Children. Journal
Pediatry Endocrinology Metabolism, 25, 881-887.
[38] Rocha, É.D., de Brito, N.J., Dantas, M.M., Silva, A., Almeida, M. and Brandão-Neto, J. (2015) Effect of Zinc Supple-
mentation on GH, IGF1, IGFBP3, OCN, and ALP in Non-Zinc-Deficient Children. Journal of the American College of
Nutrition, 34, 290-299.
[39] Wan, Y., Petris, M.J. and Peck, S.C. (2014) Separation of Zinc-Dependent and Zinc-Independent Events during Early
LPS-Stimulated TLR4 Signaling in Macrophage Cells. FEBS Letters, 588, 2928-2935.
[40] Haase, H., Ober-Blöbaum, J.L., Engelhardt, G., Hebel, S., Heit, A., Heine, H. and Rink, L. (2008) Zinc Signals Are
Essential for Lipopolysaccharide-Induced Signal Transduction in Monocytes. Journal of Immunology, 181, 6491-6502.
[41] Anubhuti, A.S. (2006) Role of Neuropeptides in Appetite Regulation and Obesity: A Review. Neuropeptides, 40, 375-
[42] Baranowska, B., Wolinska-Witort, E., Wasilewska-Dziubinska, E., Roguski, K., Martynska, L. and Chmielowska, M.
(2003) The Role of Neuropeptides in the Disturbed Control of Appetite and Hormone Secretion in Eating Disorders.
Neuroendocrinology Letters, 24, 431-434.
I. J. Martins
[43] Nyberg, F. (2011) Neuropeptides in Neuroprotection and Neuroregeneration. June 2012 by CRC Press, 319 Pages—4
Color & 81 B/W Illustrations, ISBN: 9781439830628.
[44] Sharma, R.K. and Sethi, A. (2011) Klotho An Anti-Aging Gene. International Journal of Pharma and Bio Sciences, 2,
[45] Yamamoto, M., Clark, J.D., Pastor, J.V., Gurnani, P., Nandi, A., Kurosu, H., Miyoshi, M., Ogawa, Y., Castrillon, D.H.,
Rosenblatt, K.P. and Kuro-o, M. (2005) Anti-Aging Hormone Klotho Regulation of Oxidative Stress by the Mecha-
nisms of Signal Transduction. The Journal of Biological Chemistry, 280, 38029-38034.
[46] Hsua, S.-C., Huanga, S.-M, Chena, A., Sund, C.-Y., Lina, S.-H., Chena, J.-H., Liub, S.-T. and Hsua, Y.-J. (2014) Res-
veratrol Increases Anti-Aging Klotho Gene Expression via the Activating Transcription Factor 3/c-Jun Complex-Me-
diated Signaling Pathway. The International Journal of Biochemistry & Cell Biology, 53, 361-371.
[47] de Oliveira, R.M. (2006) Klotho RNAi Induces Premature Senescence of Human Cells via a p53/p21 Dependent Path-
way. FEBS Letters, 580, 5753-5758.
[48] Lee, J., Jeong, D.-J., Kim, J., Lee, S., Park, J.-H., Chang, B., Jung, S.-I., et al. (2010) The Anti-Aging Gene KLOTHO
Is a Novel Target for Epigenetic Silencing in Human Cervical Carcinoma. Molecular Cancer, 9, 109.
[49] Wolf, I., Levanon-Cohen, S., Bose, S., Ligumsky, H., Sredni, B., Kanety, H., Kuro-o, M., Karlan, B., Kaufman, B.,
Koeffler, H.P. and Rubinek, T. (2008) Klotho: A Tumor Suppressor and a Modulator of the IGF-1 and FGF Pathways
in Human Breast Cancer. Oncogene, 27, 7094-7105.
[50] Bartke, A. (2006) Long-Lived Klotho Mice: New Insights into the Roles of IGF-1 and Insulin in Aging. Trends in En-
docrinology and Metabolism, 17, 33-35.
[51] Zhang, F., Kato, B.S., Gardner, J.P., Kimura, M., Spector, T.D. and Ahmadi, K.R. (2007) Lack of Association between
Leukocyte Telomere Length and Genetic Variants in Two Ageing-Related Candidate Genes. Mechanisms of Ageing
Development, 128, 415-422.
[52] Dubal, D.B. (2014) Life Extension Factor Klotho Enhances Cognition. Cell Reports, 7, 1065-1076.
[53] Drüeke, T.B. and Massy, Z.A. (2013) Circulating Klotho Levels: Clinical Relevance and Relationship with Tissue
Klotho Expression. Kidney International, 83, 13-15.
[54] Trinei, M., Berniakovich, I., Beltrami, E., Migliaccio, E., Fassina, A., Pelicci, P.G. and Giorgio, M. (2009) p66Shc
Signals to Age. AGING, 1, 503-510.
[55] Bhat, S.S., Anand, D. and Khanday, F.A. (2015) p66Shc as a Switch in Bringing about Contrasting Responses in Cell
Growth: Implications on Cell Proliferation and Apoptosis. Molecular Cancer, 14, 76.
[56] Skulachev, V.P. (2000) The p66Shc Protein: A Mediator of the Programmed Death of an Organism? IUBMB Life, 49,
[57] Migliaccio, E., Giorgio, M. and Pelicci, P.G. (2013) P53 and Aging: Role of p66Shc. Aging (Albany NY), 5, 488-489.
[58] Zlotorynski, E. (2014) P66Shc Inhibits Anabolic Metabolism. Nature Reviews Molecular Cell Biology, 15, 222.
[59] Soliman, M.A., Rahman, A.M.A., Lamming, D.A., Birsoy, K., Pawling, J., Frigolet, M.E., Lu, H., Fantus, I.G., Pas-
culescu, A., Zheng, Y., Sabatini, D.M., Dennis, J.W. and Pawson, T. (2014) The Adaptor Protein p66Shc Inhibits
mTOR-Dependent Anabolic Metabolism. Science Signal, 7, ra17.
[60] Sun, L., Xiao, L., Nie, J., Liu, F.Y., Ling, G.H., Zhu, X.J., Tang, W.B., Chen, W.C., Xia, Y.C., Zhan, M., Ma, M.M.,
Peng, Y.M., Liu, H., Liu, Y.H. and Kanwar, Y.S. (2010) p66Shc Mediates High-Glucose and Angiotensin II-Induced
Oxidative Stress Renal Tubular Injury via Mitochondrial-Dependent Apoptotic Pathway. American Journal of Physi-
ology Renal Physiology, 299, F1014-F1025.
[61] Graiani, G., Lagrasta, C., Migliaccio, E., Spillmann, F., Meloni, M., Madeddu, P., Quaini, F., Padura, I.M., Lanfran-
cone, L., Pelicci, P. and Emanueli, C. (2005) Genetic Deletion of the p66Shc Adaptor Protein Protects from Angio-
tensin II-Induced Myocardial Damage. Hypertension, 46, 433-440.
[62] De Marchi, E., Baldassari, F., Bononi, A., Wieckowski, M.R. and Pinton, P. (2013) Oxidative Stress in Cardiovascular
Diseases and Obesity: Role of p66Shc and Protein Kinase C. Oxidative Medicine and Cellular Longevity, 2013, Article
ID: 564961.
[63] Spescha, R.D., Klohs, J., Semerano, A., Giacalone, G., Derungs, R.S., Reiner, M.F., Gutierrez, D.R., Mendez-Car-
mona, N., et al. (2015) Post-Ischaemic Silencing of p66Shc Reduces Ischaemia/Reperfusion Brain Injury and Its Ex-
I. J. Martins
pression Correlates to Clinical Outcome in Stroke. European Heart Journal, 36, 1590-1600.
[64] Spescha, R.D., Shi, Y., Wegener, S., Keller, S., Weber, B., Wyss, M.M., Lauinger, N., Tabatabai, G., Paneni, F.,
Cosentino, F., Hock, C., Weller, M., Nitsch, R.M, Lüscher, T.F. and Camici, G.G. (2013) Deletion of the Ageing Gene
p66Shc Reduces Early Stroke Size Following Ischaemia/Reperfusion Brain Injury. European Heart Journal, 34, 96-
[65] Natalicchio, A., Tortosa, F., Perrini, S., Laviola, L. and Giorgino, F. (2011) p66Shc, a Multifaceted Protein Linking
Erk Signalling, Glucose Metabolism, and Oxidative Stress. Archives of Physiology and Biochemistry, 117, 116-124.
[66] Kim, Y.R., Kim, C.S., Naqvi, A., Kumar, A., Kumar, S., Hoffman, T.A. and Irani, K. (2012) Epigenetic Upregulation
of p66Shc Mediates Low-Density Lipoprotein Cholesterol-Induced Endothelial Cell Dysfunction. American Journal
of Physiology: Heart and Circulatory Physiology, 303, H189-H196.
[67] Berniakovich, I., Trinei, M., Stendardo, M., Migliaccio, E., Minucci, S., Bernardi, P., Pelicci, P.G. and Giorgio, M.
(2008) p66Shc-Generated Oxidative Signal Promotes Fat Accumulation. The Journal of Biological Chemistry, 283,
[68] Giovannini, C., Scazzocchio, B., Matarrese, P., Varì, R., DArchivio, M., Di Benedetto, R., Casciani, S., Dessì, M.R.,
Straface, E., Malorni, W. and Masella, R. (2008) Apoptosis Induced by Oxidized Lipids Is Associated with
Up-Regulation of p66Shc in Intestinal Caco-2 Cells: Protective Effects of Phenolic Compounds. Journal of Nutritional
Biochemistry, 19, 118-128.
[69] Favetta, L.A., Robert, C., King, W.A. and Betts, D.H. (2004) Expression Profiles of p53 and p66Shc during Oxidative
Stress-Induced Senescence in Fetal Bovine Fibroblasts. Experimental Cell Research, 299, 36-48.
[70] Ziolkowski, W., Flis, D.J., Halon, M., Vadhana, D.M., Olek, R.A., Carloni, M., Antosiewicz, J., Kaczor, J.J. and Gab-
bianelli, R. (2015) Prolonged Swimming Promotes Cellular Oxidative Stress and p66Shc Phosphorylation, but Does
Not Induce Oxidative Stress in Mitochondria in the Rat Heart. Free Radical Research, 49, 7-16.
[71] Trinei, M., Giorgio, M., Cicalese, A., Barozzi, S. and Ventura, A. (2002) A p53-p66Shc Signalling Pathway Controls
Intracellular Redox Status, Levels of Oxidation-Damaged DNA and Oxidative Stress-Induced Apoptosis. Oncogene,
21, 3872-3878.
[72] Kim, C.-S., Jung, S.-B., Naqvi, A., Hoffman, T.A., DeRicco, J., Yamamori, T., Cole, M.P., Jeon, B.H. and Irani, K.
(2008) P53 Impairs Endothelium-Dependent Vasomotor Function through Transcriptional Upregulation of p66Shc.
Circulation Research, 103, 1441-1450.
[73] Zhou, S., Chen, H.Z., Wan, Y.Z., Zhang, Q.J., Wei, Y.S., Huang, S., Liu, J.J., Lu, Y.B., Zhang, Z.Q., Yang, R.F.,
Zhang, R., Cai, H., Liu, D.P. and Liang, C.C. (2011) Repression of p66Shc Expression by SIRT1 Contributes to the
Prevention of Hyperglycemia-Induced Endothelial Dysfunction. Circulation Research, 109, 639-648.
[74] Natalicchio, A., Tortosa, F., Labarbuta, R., Biondi, G., Marrano, N. and Carchia, E. (2015) The p66Shc Redox Adaptor
Protein Is Induced by Saturated Fatty Acids and Mediates Lipotoxicity-Induced Apoptosis in Pancreatic Beta Cells.
Diabetologia, 58, 1260-1271.
[75] Smith, W.W., Norton, D.D., Gorospe, M., Jiang, H., Nemoto, S., Holbrook, N.J., Finkel, T. and Kusiak, J.W. (2005)
Phosphorylation of p66Shc and Forkhead Proteins Mediates A Beta Toxicity. Journal of Cell Biology, 169, 331-339.
[76] Bashir, M., Parray, A.A., Baba, R.A., Bhat, H.F., Bhat, S.S., Mushtaq, U., Andrabi, K.I. and Khanday, F.A. (2014)
β-Amyloid-Evoked Apoptotic Cell Death Is Mediated through MKK6-p66Shc Pathway. Neuromolecular Medicine,
16, 137-149.
[77] Martins, I.J. (2015) Unhealthy Diets Determine Benign or Toxic Amyloid Beta States and Promote Brain Amyloid
Beta Aggregation. Austin Journal of Clinical Neurology, 2, 1060-1066.
[78] Martins, I.J. (2015) Diabetes and Cholesterol Dyshomeostasis Involve Abnormal α-Synuclein and Amyloid Beta
Transport in Neurodegenerative Diseases. Austin Alzheimers Journal of Parkinsons Disease, 2, 1020-1028.
[79] Martins, I.J. (2015) Unhealthy Nutrigenomic Diets Accelerate NAFLD and Adiposity in Global Communities. Journal
of Molecular and Genetic Medicine, 9, 1-11.
[80] Ausserlechner, M.J., Hagenbuchner, J., Fuchs, S., Geiger, K. and Obexer, P. (2012) FOXO Transcription Factors as
Potential Therapeutic Targets in Neuroblastoma Neuroblastoma. Present and Future Edited by Prof. Shimada, H.,
ISBN: 978-953-307-016-2, Hard Cover, 366 p, Publisher InTech, Published Online.
I. J. Martins
[81] Shang, Y.C., Chong, Z.Z., Hou, J. and Maiese, K. (2009) The Forkhead Transcription Factor FOXO3a Controls Mi-
croglial Inflammatory Activation and Eventual Apoptotic Injury through Caspase 3. Current Neurovascular Research,
6, 20-31.
[82] Gilley, J., Coffer, P.J. and Ham, J. (2003) FOXO Transcription Factors Directly Activate Bim Gene Expression and
Promote Apoptosis in Sympathetic Neurons. Journal of Cell Biology, 162, 613-622.
[83] Gross, D.N., van den Heuvel, A.P.J. and Birnbaum, M.J. (2008) The Role of FoxO in the Regulation of Metabolism.
Oncogene, 27, 2320-2336.
[84] Zhu, W., Bijur, G.N., Styles, N.A. and Li, X. (2004) Regulation of FOXO3a by Brain-Derived Neurotrophic Factor in
Differentiated Human SH-SY5Y Neuroblastoma Cells. Molecular Brain Research, 126, 45-56.
[85] Brunet, A., et al. (2004) Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase. Sci-
ence, 303, 2011-2015.
[86] Hori, Y.S., Kuno, A., Hosoda, R. and Horio, Y. (2013) Regulation of FOXOs and p53 by SIRT1 Modulators under
Oxidative Stress. PLoS ONE, 8, e73875.
[87] Shemi, D., Azab, A.N. and Kaplanski, J. (2000) Time-Dependent Effect of LPS on PGE2 and TNF-Alpha Production
by Rat Glial Brain Culture: Influence of COX and Cytokine Inhibitors. Journal of Endotoxin Research, 6, 377-381.
[88] Henkel, J., Frede, K., Schanze, N., Vogel, H., Schürmann, A., Spruss, A., Bergheim, I. and Püschel, G.P. (2012)
Stimulation of Fat Accumulation in Hepatocytes by PGE2-Dependent Repression of Hepatic Lipolysis, β-Oxidation
and VLDL-Synthesis. Laboratory Investigation, 92, 1597-1606.
[89] Boucher, J., Charalambous, M., Zarse, K., Mori, M.A., Kleinridders, A., Ristow, M., Ferguson-Smith, A.C. and Kahn,
C.R. (2014) Insulin and Insulin-Like Growth Factor 1 Receptors Are Required for Normal Expression of Imprinted
Genes. Proceedings of the National Academy of Sciences of the United States of America, 111, 14512-14517.
[90] Djiogue, S., Kamdje, A.H.N., Vecchio, L., Kipanyula, M.J., Farahna, M., Aldebasi, Y. and Etet, P.F.S. (2013) Insulin
Resistance and Cancer: The Role of Insulin and IGFs. Endocrine Related Cancer, 20, R1-R17.
[91] Arcidiacono, B., Iiritano, S., Nocera, A., Possidente, K., Nevolo, M.T., Ventura, V., Foti, D., Chiefari, E. and Brunetti,
A. (2012) Insulin Resistance and Cancer Risk: An Overview of the Pathogenetic Mechanisms. Experimental Diabetes
Research, 2012, Article ID: 789174.
[92] Hallett, P.J., McLean, J.R., Kartunen, A., Langston, J.W. and Isacson, O. (2012) Alpha-Synuclein Overexpressing
Transgenic Mice Show Internalorgan Pathology and Autonomic Deficits. Neurobiology Disease, 47, 258-267.
[93] Tai, Y., Chen, L., Huang, E., Liu, C., Yang, X., Qiu, P. and Wang, H. (2014),Protective Effect of Alpha-Synuclein
Knockdown on Methamphetamine-Induced Neurotoxicity in Dopaminergic Neurons. Neural Regeneration Research, 9,
[94] Kao, S.Y. (2011) Rescue of Alpha-Synuclein Cytotoxicity by Insulin-Like Growth Factors. Neurosignals, 19, 86-96.
[95] Chung, J.Y., Lee, S.J., Lee, S.H., Jung, Y.S., Ha, N.C., Seol, W. and Park, B.J. (2011) Direct Interaction of α-Synu-
clein and AKT Regulates IGF-1 Signaling: Implication of Parkinson Disease. Neurosignals, 19, 86-96.
[96] Martins, I.J., Creegan, R., Lim, W.L.F. and Martins, R.N. (2013) Molecular Insights into Appetite Control and Neuro-
endocrine Disease as Risk Factors for Chronic Diseases in Western Countries. Open Journal of Endocrine and Meta-
bolic Diseases, 3, 11-33.
[97] Liu, J., Shen, W., Zhao, B., Wang, Y., Wertz, K., Weber, P. and Zhang, P. (2009) Targeting Mitochondrial Biogenesis
for Preventing and Treating Insulin Resistance in Diabetes and Obesity: Hope from Natural Mitochondrial Nutrients.
Advanced Drug Delivery Reviews, 61, 1343-1352.
[98] Zamora, M. and Villena, J.A. (2014) Targeting Mitochondrial Biogenesis to Treat Insulin Resistance. Current Phar-
maceutical Design, 20, 5527-5557.
[99] Brown, G.C. (1999) Nitric Oxide and Mitochondrial Respiration. Biochimica Biophysica Acta, 1411, 351-369.
[100] Nisoli, E. and Carruba, M.O. (2006) Nitric Oxide and Mitochondrial Biogenesis. Journal of Cell Science, 119, 2855-
[101] Yi, C.X., la Fleur, S.E., Fliers, E. and Kalsbeek, A. (2010) The Role of the Autonomic Nervous Liver Innervation in
the Control of Energy Metabolism. Biochimica Biophysica Acta, 1802, 416-431.
I. J. Martins
[102] Xu, M., Iwasaki, T., Shimokawa, N., Sajdel-Sulkowska, E.M. and Koibuchi, N. (2013) The Effect of Low Dose
Lipopolysaccharide on Thyroid Hormone-Regulated Actin Cytoskeleton Modulation and Type 2 Iodothyronine Deio-
dinase Activity in Astrocytes. Endocrine Journal, 60, 1221-1230.
[103] Vélez, M.L., Costamagna, E., Kimura, E.T., Fozzatti, L., Pellizas, C.G., Montesinos, M.M., Lucero, A.M., Coleoni,
A.H., Santisteban, P. and Masini-Repiso, A.M. (2006) Bacterial Lipopolysaccharide Stimulates the Thyrotropin-De-
pendent Thyroglobulin Gene Expression at the Transcriptional Level by Involving the Transcription Factors Thyroid
Transcription Factor-1 and Paired Box Domain Transcription Factor 8. Endocrinology, 147, 3260-3275.
[104] Stafford, J.M., Yu, F., Printz, R., Hasty, A.H., Swift, L.L. and Niswender, K.D. (2008) Central Nervous System Neu-
ropeptide Y Signaling Modulates VLDL Triglyceride Secretion. Diabetes, 57, 1482-1490.
[105] Rojas, J.M., Bruinstroop, E., Printz, R.L., Alijagic-Boers, A., Foppen, E., Turney, M.K., George, L., Beck-Sickinger,
A.-G, Kalsbeek, A. and Niswender, K.D. (2015) Central Nervous System Neuropeptide Y Regulates Mediators of He-
patic Phospholipid Remodeling and Very Low-Density Lipoprotein Triglyceride Secretion via Sympathetic Innervation.
Molecular Metabolism, 4, 210-221.
[106] Ng, F., Wijaya, L. and Tang, B.L. (2015) SIRT1 in the Brain-Connections with Aging-Associated Disorders and Life-
span. Frontier Cell Neuroscience, 9, 64.
[107] Zocchi, L. and Sassone-Corsi, P. (2012) SIRT1-Mediated Deacetylation of MeCP2 Contributes to BDNF Expression.
Epigenetics, 7, 695-700.
[108] Jeong, H., Cohen, D.E., Cui, L., Supinski, A., Savas, J.N., Mazzulli, J.R., Yates, J.R., Bordone, L., Guarente, L. and
Krainc, D. (2011) Sirt1 Mediates Neuroprotection from Mutant Huntingtin by Activation of the TORC1 and CREB
Transcriptional Pathway. Nature Medicine, 18, 159-165.
[109] Xapelli, S., Bernardino, L., Ferreira, R., Grade, S., Silva, A.P., Salgado, J.R., Cavadas, C., Grouzmann, E., Poulsen,
F.R., Jakobsen, B., Oliveira, C.R. and Zimmer, J. (2008) Interaction between Neuropeptide Y (NPY) and Brain-De-
rived Neurotrophic Factor in NPY-Mediated Neuroprotection against Excitotoxicity: A Role for Microglia. European
Journal of Neuroscience, 27, 2089-2102.
[110] Reibel, S., Vivien-Roels, B., Lê, B.T., Larmet, Y., Carnahan, J., Marescaux, C. and Depaulis, A. (2000) Overexpres-
sion of Neuropeptide Y Induced by Brain-Derived Neurotrophic Factor in the Rat Hippocampus Is Long Lasting.
European Journal of Neuroscience, 12, 595-605.
[111] Golden, E., Emiliano, A., Maudsley, S., Windham, B.G., Carlson, O.D. and Egan, J.M. (2010) Circulating Brain-De-
rived Neurotrophic Factor and Indices of Metabolic and Cardiovascular Health: Data from the Baltimore Longitudinal
Study of Aging. PLoS ONE, 5, e10099.
[112] Lee, R.G., Rains, T.M., Tovar-Palacio, C., Beverly, J.L. and Shay, N.F. (1998) Zinc Deficiency Increases Hypotha-
lamic Neuropeptide Y and Neuropeptide Y mRNA Levels and Does Not Block Neuropeptide Y-Induced Feeding in
Rats. Journal of Nutrition, 128, 1218-1223.
[113] Williamson, P.S., Browning, J.D., Sullivan, M.J., O’Dell, B.L. and Macdonald, R.S. (2002) Neuropeptide Y Fails to
Normalize Food Intake in Zinc-Deficient Rats. Nutrition Neuroscience, 5, 19-25.
[114] Puca, R., Nardinocchi, L., Porru, M., Simon, A.J., Rechavi, G., Leonetti, C., Givol, D. and DOrazi, G. (2011) Restor-
ing p53 Active Conformation by Zinc Increases the Response of Mutant p53 Tumor Cells to Anticancer Drugs. Cell
Cycle, 10, 1679-1689.
[115] Shen, L., Tso, P., Woods, S.C., Clegg, D.J., Barber, K.L., Carey, K. and Liu, M. (2008) Brain Apolipoprotein E: An
Important Regulator of Food Intake in Rats. Diabetes, 57, 2092-2098.
[116] Shen, L., Tso, P., Wang, D.Q., Woods, S.C., Davidson, W.S., Sakai, R. and Liu, M. (2009) Up-Regulation of Apolipo-
protein E by Leptin in the Hypothalamus of Mice and Rats. Physiology Behaviour, 98, 223-228.
[117] Knight, D.S., Mahajan, D.K. and Qiao, X. (2001) Dietary Fat Up-Regulates the Apolipoprotein E mRNA Level in the
Zucker Lean Rat Brain. Neuroreport, 12, 3111-3115.
[118] Mastronardi, C.A., Yu, W.H., Srivastava, V.K., Dees, W.L. and McCann, S.M. (2001) Lipopolysaccharide-Induced
Leptin Release Is Neurally Controlled. Proceedings of the National Academy of Sciences of the United States of Amer-
ica, 98, 14720-14725.
[119] Sachot, C., Poole, S. and Luheshi, G.N. (2004) Circulating Leptin Mediates Lipopolysaccharide-Induced Anorexia and
Fever in Rats. Journal of Physiology, 561, 263-272.
[120] Zu, L., He, J., Jiang, H., Xu, C., Pu, S. and Xu, G. (2009) Bacterial Endotoxin Stimulates Adipose Lipolysis via Toll-
I. J. Martins
Like Receptor 4 and Extracellular Signal-Regulated Kinase Pathway. Journal of Biological Chemistry, 284, 5915-5926.
[121] Hunter, D.J. (2005) Gene-Environment Interactions in Human Diseases. Nature Reveiw Genetics, 6, 287-298.
[122] Martins, I.J. (2013) Increased Risk for Obesity and Diabetes with Neurodegeneration in Developing Countries. Journal
of Molecular and Genetic Medicine, S1, 001.
[123] Martins, I.J. (2014) Induction of NAFLD with Increased Risk of Obesity and Chronic Diseases in Developed Countries.
Open Journal of Endocrine and Metabolic Diseases, 4, 90-110.
[124] Scott, M.J., Liu, S., Su, G.L., Vodovotz, Y. and Billiar, T.R. (2005) Hepatocytes Enhance Effects of Lipopolysaccha-
ride on Liver Nonparenchymal Cells through Close Cell Interactions. Shock, 23, 453-458.
[125] Qatanani, M. and Lazar, M.A. (2007) Mechanisms of Obesity-Associated Insulin Resistance: Many Choices on the
Menu. Genes Development, 21, 1443-1455.
[126] Belosludtsev, K., Saris, N.E., Andersson, L.C., Belosludtseva, N., Agafonov, A., Sharma, A., Moshkov, D.A. and Mi-
ronova, G.D. (2006) On the Mechanism of Palmitic Acid-Induced Apoptosis: The Role of a Pore Induced by Palmitic
Acid and Ca2+ in Mitochondria. Journal of Bioenergetics and Biomembranes, 38, 113-120.
[127] Darzi, J., Frost, G.S. and Robertson, M.D. (2011) Do SCFA Have a Role in Appetite Regulation? Proceedings of the
Nutrition Society, 70, 119-128.
[128] Frost, G., Sleeth, M.L., Sahuri-Arisoylu, M., Lizarbe, B., Cerdan, S., Brody, L., Anastasovska, J., Ghourab, S., Hankir,
M., Zhang, S., Carling, D., Swann, J.R., Gibson, G., Viardot, A., Morrison, D., Louise, T.E. and Bell, J.D. (2014) The
Short-Chain Fatty Acid Acetate Reduces Appetite via a Central Homeostatic Mechanism. Nature Communications, 5,
[129] Licciardi, P.V., Ververis, K. and Karagiannis, T.C. (2011) Histone Deacetylase Inhibition and Dietary Short-Chain
Fatty Acids. International Scholarly Research Network ISRN Allergy, 2011, Article ID: 869647.
[130] Pouillart, P.R. (1998) Role of Butyric Acid and Its Derivatives in the Treatment of Colorectal Cancer and Hemoglobi-
nopathies. Life Science, 63, 1739-1760.
[131] Gasior, M., Rogawski, M.A. and Hartman, A.L. (2006). Neuroprotective and Disease-Modifying Effects of the Keto-
genic Diet. Behavioural Pharmacology, 17, 431-439.
[132] Magenta, A., Greco, S., Capogrossi, M.C., Gaetano, C. and Martelli, F. (2014) Nitric Oxide, Oxidative Stress, and
p66Shc Interplay in Diabetic Endothelial Dysfunction. BioMed Research International, 2014, Article ID: 193095.
[133] Litvinova, L., Atochin, D.N., Fattakhov, N., Vasilenko, M., Zatolokin, P. and Kirienkova, E. (2015) Nitric Oxide and
Mitochondria in Metabolic Syndrome. Frontier Physiology, 17, 20.
[134] Morley, J.E., Farr, S.A, Sell, R.L., Hileman, S.M. and Banks, W.A. (2011) Nitric Oxide Is a Central Component in
Neuropeptide Regulation of Appetite. Peptides, 32, 776-780.
[135] Vieira, H. and Kroemer, G. (2003) Mitochondria as Targets of Apoptosis Regulation by Nitric Oxide. IUBMB Life, 55,
[136] Stokkan, K.A., Yamazaki, S., Tei, H., Sakaki, Y. and Menaker, M. (2001) Entrainment of the Circadian Clock in the
Liver by Feeding. Science, 291, 490-493.
[137] Martins, I.J. (2015) Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenera-
tive Diseases. International Journal of Molecular Science, 16, 29554-29573.
[138] Martins, I.J, Mortimer, B.C., Miller, J. and Redgrave, T.G. (1996) Effects of Particle Size and Number on the Plasma
Clearance of Chylomicrons and Remnants. Journal of Lipid Research, 37, 2696-2705.
[139] Martins, I.J. (2015) Nutritional and Genotoxic Stress Contributes to Diabetes and Neurodegenerative Diseases Such as
Parkinson’s and Alzheimers Diseases. In: Atta-ur-Rahma, Eds., Frontiers in Clinical Drug ResearchCNS and Neu-
rological Disorders, Vol. 3, Bentham Science Publishers, Sharjah, 158-192.
[140] Gentilini, D., Mari, D., Castaldi, D., Remondini, D., Ogliari, G., Ostan, R., Bucci, L., Sirchia, S.M., Tabano, S.,
Cavagnini, F., Monti, D., Franceschi, C., Di Blasio, A.M. and Vitale, G. (2013) Role of Epigenetics in Human Aging
and Longevity: Genome-Wide DNA Methylation Profile in Centenarians and Centenarians’ Offspring. Age (Dordr), 35,
... One possible mechanism of these findings might be gene alternation. Specifically, the anti-aging gene Sirtuin 1 repression is associated with the onset of diabetes, cardiovascular disease and sarcopenia (Martins, 2016(Martins, , 2017(Martins, , 2018, which in turn leads to BMI variation, eventually resulting in Aβ deposition. Another possible explanation is that these medical diseases might result in both greater BMI variation and Aβ positivity, although we excluded participants with severe medical diseases using Christensen's criteria (Christensen et al., 1991). ...
Full-text available
Objectives The relationship of body mass index (BMI) changes and variability with amyloid-β (Aβ) deposition remained unclear, although there were growing evidence that BMI is associated with the risk of developing cognitive impairment or AD dementia. To determine whether BMI changes and BMI variability affected Aβ positivity, we investigated the association of BMI changes and BMI variability with Aβ positivity, as assessed by PET in a non-demented population.Methods We retrospectively recruited 1,035 non-demented participants ≥50 years of age who underwent Aβ PET and had at least three BMI measurements in the memory clinic at Samsung Medical Center. To investigate the association between BMI change and variability with Aβ deposition, we performed multivariable logistic regression. Further distinctive underlying features of BMI subgroups were examined by employing a cluster analysis model.ResultsDecreased (odds ratio [OR] = 1.68, 95% confidence interval [CI] 1.16–2.42) or increased BMI (OR = 1.60, 95% CI 1.11–2.32) was associated with a greater risk of Aβ positivity after controlling for age, sex, APOE e4 genotype, years of education, hypertension, diabetes, baseline BMI, and BMI variability. A greater BMI variability (OR = 1.73, 95% CI 1.07–2.80) was associated with a greater risk of Aβ positivity after controlling for age, sex, APOE e4 genotype, years of education, hypertension, diabetes, baseline BMI, and BMI change. We also identified BMI subgroups showing a greater risk of Aβ positivity.Conclusion Our findings suggest that participants with BMI change, especially those with greater BMI variability, are more vulnerable to Aβ deposition regardless of baseline BMI. Furthermore, our results may contribute to the design of strategies to prevent Aβ deposition with respect to weight control.
... The inactivation of sirtuin 1 (SIRT1) is connected to the progression of insulin resistance associated with SS. Diabetes in people with short stature may be induced later in life with relevance to sirtuin 1 repression (Martins, 2016;Martins, 2017). Therefore, it becomes necessary and urgent to identify critical targets and mechanisms for childhood short stature. ...
Nowadays, short stature (SS) in childhood is a common condition encountered by pediatricians, with an increase in not just a few families. Various studies related to the variations in key metabolites and their biological mechanisms that lead to SS have increased our understanding of the pathophysiology of the disease. However, little is known about the role of metabolite variation in different types of childhood SS that influence these biological processes and whether the understanding of the key metabolites from different types of childhood SS would predict the disease progression better. We performed a systematic investigation using the metabonomics method and studied the correlation between the three groups, namely, the control, idiopathic short stature (ISS), and short stature due to growth hormone deficiency (GHD). We observed that three pathways (viz., purine metabolism, sphingolipid signaling pathway, and sphingolipid metabolism) were significantly enriched in childhood SS. Moreover, we reported that two short peptides (Thr Val Leu Thr Ser and Trp Ile Lys) might play a significant role in childhood SS. Various metabolites in different pathways including 9,10-DiHOME, 12-HETE, 12(13)-EpOME, arachidonic acid methyl ester, glycerophospho-N-arachidonoyl ethanolamine, curvulinic acid (2-acetyl-3,5-dihydroxyphenyl acetic acid), nonanoic acid, and N'-(2,4-dimethylphenyl)-N-methylformamidine in human serum were compared between 60 children diagnosed with SS and 30 normal-height children. More investigations in this area may provide insights and enhance the personalized treatment approaches in clinical practice for SS by elucidating pathophysiology mechanisms of experimental verification.
... The COVID-19 epidemic and global chronic disease epidemic is expected to cost billions of dollars in the next 20 years. The role of various chronic diseases such as NAFLD, diabetes, cardiovascular disease and neurodegenerative disease research may now be relevant to the COVID-19 pandemic with the anti-aging gene repression connected to mitophagy [1,2] and the severity of the COVID-19 and heart disease. The role of critical anti-aging genes such as Sirtuin 1 (Sirt 1) have attracted interest in cardiovascular disease with a critical role of Sirt 1 in the determination of cell death and survival involved with the severity of cardiovascular disease [3,4]. ...
Full-text available
The COVID-19 epidemic and global chronic disease epidemic is expected to cost billions of dollars in the next 20 years. The role of various chronic diseases such as NAFLD, diabetes, cardiovascular disease and neurodegenerative disease research may now be relevant to the COVID-19 pandemic with the anti-aging gene repression connected to mitophagy and the severity of the COVID-19 and heart disease. The role of critical anti-aging genes have attracted interest in cardiovascular disease with determination of cell death and survival involved with the severity of cardiovascular disease.
... Therefore, it is likely that LDL-C-associated SNPs, such as rs6475606 and rs12740374, also play a significant role in AD patients by the mechanism of inflammation, which is in accordant with the aforementioned "neuroinflammation" mechanism in AD development. In addition, the anti-aging gene Sirtuin 1 can regulate neuron proliferation in various populations and is linked to cardiovascular disease with effects on inflammation, energy, cognition, glucose/cholesterol levels, amyloidosis, and neurogenesis (52,53). Neurons in the brain with Sirtuin 1 repression may undergo early programmed cell death with altered astrocyte neuron interactions, which may lead to accelerated brain aging (54). ...
Full-text available
Background: Previous observational studies provided conflicting results on the association between low-density lipoprotein cholesterol (LDL-C) level and the risk of Alzheimer's disease (AD). Objective: We used two-sample Mendelian randomization (MR) study to explore the causal associations between LDL-C level and the risks of individual, paternal, maternal, and family history of AD. Methods: Summary-level genetic data for LDL-C were acquired from results of the UK Biobank GWAS. Corresponding data for paternal, maternal, and family history of AD were obtained from the NHGRI-EBI Catalog of human genome-wide association studies. Data for individual AD were obtained from the MR-Base platform. A two-sample MR study was performed to explore the causal association between LDL-C level and the risks of individual, paternal, maternal, and family history of AD. Results: Genetically predicted LDL-C was positively associated with individual [Odds ratio (OR) = 1.509, 95% confidence interval (CI) = 1.140–1.999; P = 4.0 × 10 ⁻³ ], paternal [OR = 1.109, 95% CI = 1.053–1.168; P = 9.5 × 10 ⁻⁵ ], maternal [OR = 1.132, 95% CI = 1.070–1.199; P = 2.0 × 10 ⁻⁵ ], and family history of AD [OR = 1.124, 95% CI = 1.070–1.181; P = 3.7 × 10 ⁻⁶ ] in inverse variance weighted analysis. After performing weighted median and MR-Egger analysis, consistent results were observed. There was no horizontal pleiotropy in the two-sample MR analysis. Conclusions: High level of LDL-C may increase the risks of both individual and familial AD. Decreasing the LDL-C to a reasonable level may help to reduce the related risk.
Full-text available
This thesis aimed to understand the role that the hypothalamus-pituitary-thyroid (HPT) axis plays in appetite regulation of goldfish (Carassius auratus). I altered nutritional and thyroid statuses to measure the response of thyroid axis components and appetite-regulating peptides. I predicted that fasting would downregulate the thyroid axis and trigger an orexigenic response, while overfeeding would upregulate the thyroid axis and trigger an anorexigenic response. Additionally, I predicted that hyperthyroid conditions would lead to negative feedback of the thyroid axis and an orexigenic response, whilst opposite under hypothyroid conditions. I uncovered for both experiments that the thyroid axis in goldish is most responsive to overfeeding and hyperthyroidism. Overfeeding led to a time-dependent increase in central thyroid transcripts while fasting decreased thyroid hormone degradation peripherally with no central response, no treatment altered levels of thyroid hormone in circulation. Hyperthyroidism resulted in negative feedback to the pituitary, but not hypothalamus, and did not lead to an increase in food intake despite an increase in the levels of thyroxine. The thyroid inhibitor, propylthiouracil, did not induce hypothyroidism or alter the expression of any thyroid axis transcript. Appetite-regulating peptides correlated weakly to changes in the thyroid, suggesting an overall poor association in goldfish between appetite regulation and thyroid status.
Heart failure (HF) is a leading cause of death that has remained incurable. Recently, stem cell therapy has emerged as a promising tool in cardiac regenerative medicine. Human amniotic membrane-derived mesenchymal stem cells (hAMSCs) with unique characteristics can be used in HF treatment. Here, we aimed to examine the effects of hAMSCs transplantation on cardiac fibrosis in a rat model of ISO-induced HF. Forty male Wistar rats were divided into four groups: sham, isoproterenol-induced HF ((Iso)-)ISO, ISO + culture medium, and ISO + hAMSCs. HF was induced by subcutaneous injection of isoproterenol 170 mg/kg/d in 4 consecutive days. Four weeks later, in ISO + hAMSCs, 3 × 106 hAMSCs were injected into the myocardium, whereas the ISO + culture medium was only injected by cell culture medium. Finally, cardiac functions and hemodynamic parameters were measured. Immunohistochemistry (IHC), Western blot, and histological assessment were performed to evaluate myocardial fibrosis and detect vascular endothelial growth factor (VEGF) collagen type I and III expression level. HF model caused a decrease in ejection fraction (EF) and fraction shortening, whereas both were increased after hAMSCs transplantation. IHC and Western blot and Western blot analyses confirmed that hAMSCs could attenuate fibrosis, reduce collagen I and III depositions, and increase VEGF expression. Intramyocardial transplantation of hAMSCs improves cardiac functions and myocardial structure caused by HF. A rise in VEGF expression presents hAMSCs as a compatible source of stem cell therapy for HF.
Full-text available
The literature reports that the impact of inflammatory bowel disease (IBD) has risen in the developing and developed world. The understanding of the variation in IBD trend levels in various countries is crucial for the development of effective strategies for preventing and treating IBD. Research studies indicate that Sirtuin 1 activity is reduced in inflammatory bowel disease models and associated with the increased production of proinflammatory cytokines and oxidative stress with relevance to colitis. Research studies now show the IBD is linked to NAFLD, obesity, diabetes and neurodegenerative diseases and Sirtuin 1 repression may be the defective gene with relevance to these various chronic diseases.
Full-text available
Using samples of small cell lung tumors, a research team led by biologist Dr. Raymond discovered two new ways to induce tumor cell death. By activating ferroptosis, one of two subtypes of tumor cells can be targeted: first, iron-dependent cell death due to oxidative stress, and second, oxidative stress. Therefore, cell death can also be induced in a different way. Both types of cell death must be caused by drugs at the same time to eliminate the majority of the tumor mass. It is currently in clinical trials for cancer treatment. Auranofin, which inhibits the production of protective antioxidants in cancer cells, has been used to treat rheumatoid arthritis for decades. Future clinical trials using this combination therapy will determine the extent to which this targeted treatment option improves the prognosis of Journal of Lung Cancer Epidemiology Freely Available Online Lung cancer is the leading cause of cancer death in the United States. Despite evidence of molecular abnormalities in biological specimens, progress in this disease is hampered by the lack of diagnostic markers useful for clinical practice. The majority of patients with lung cancer are still diagnosed at an advanced stage, when prognosis is poor. This article reviews new strategies being studied for the early detection of lung cancer. These strategies involve new methods of imaging (including low-dose computed tomography [CT] scanning), DNA analysis, and proteomic-based techniques. These strategies have not only improved our understanding of lung cancer but show promise in offering better survival to patients with this deadly disease. Of paramount importance in the search for methods of early detection is the need for the identification of the ideal population to screen, a multidisciplinary approach, and validation of promising techniques.
Full-text available
The COVID-19 epidemic and global chronic disease epidemic is expected to cost Biomarker Research billion of dollars in the next 20 years. Biomarkers such as Sirtuin 1 are now relevant to the COVID-19 epidemic and chronic diseases such as diabetes, Alzheimer’s disease and neurodegenerative disease research. Sirtuin 1 may now be relevant to the COVID-19 pandemic with the Sirtuin 1 repression connected to severity of the COVID-19 disease with programmed cell death. The role of the anti-aging gene Sirtuin 1 is now critical to the success of therapy in COVID-19 ill individuals with relevance to myocardial infarction, lung disease and neurodegeneration and the improved survival in COVID-19 individuals. The role of diets, drugs and lifestyles may be critical in the reduction of the severity of the COVID-19 illness in the developing and developed world. The success of genomic medicine will be important to COVID-19 patients and Vaccine technologies. Strategies and therapy that target the immune system and Sirtuin 1 will reduce the severity of the COVID-19 epidemic and the risk of multiple organ disease syndrome in these infected individuals. Indian spices and relevance to the immune system as a booster may need to be reassessed with relevance to Sirtuin 1 repression versus activation.
Conference Paper
Full-text available
The First Invited Notable (Principal Research Fellow) Speaker at the PLENARY FORUM at the 4th Annual Global Health Conference-2016, Kaohsiung, Taiwan. Plenary Forum Presentation Attached as Conference Presentation, Title: Nutritional diets accelerate amyloid beta metabolism and prevent the induction of chronic diseases and Alzheimer’s disease. This ORAL presentation at the AGHC-2016 is related to the scholarly publication in PHOTON but differ with relevance to the International Agency for Standards recognition of the written publication that is associated with the Richard Kuhn Research Award-2015 (Endocrinology and Metabolism) presented to Ian James Martins. ABSTRACT The inductions of chronic diseases and neurodegeneration have become a major concern in various countries in the developed and developing world. Central co-ordination and homeostasis of neuroendocrine systems and renin-angiotensin systems (RAS) are influenced by external stressors, diet and lifestyles that lead to abnormal nitric oxide and neural pathways, appetite dysregulation and organ disease. The alteration in circadian photic signals in the neuroendocrine system involve the hypothalamus and the suprachiasmatic nucleus that are linked to apelinergic dysregulation associated with appetite disorders and various organ diseases. The peripheral sink amyloid beta hypothesis indicates that amyloid beta (Aβ) is rapidly removed by the liver and chronic diseases are connected to apelinergic dysfunction with abnormal amyloidogenic pathways. Environmental pollutants associated with unhealthy nutritional habits increase xenobiotics in plasma and may further promote neuroendocrine disease, kidney disease and non alcoholic fatty liver disease (NAFLD) with poor Aβ metabolism. Furthermore stress and unhealthy nutritional lifestyles increase oxidative stress with abnormal apelin and RAS regulation associated with poor nitric oxide and vascular Aβ metabolism with the acceleration of neuroendocrine diseases that include obesity, diabetes, cardiovascular disease and neurodegenerative diseases
Full-text available
Accelerated aging in various communities has led to the current global obesity and diabetes epidemic. The connections between diabetes and various chronic diseases in various global communities override racial differences with a new understanding of diet, drugs, bacteria and xenobiotics that may provide novel gene pathways that may stabilize the progression of these chronic diseases. Food restriction has become important to various communities and indicate the importance of the transport of lipoproteins bacterial lipopolysaccharides and xenobiotics into the blood plasma. The rapid removal of the lipopolysaccharides are important to prevent inflammation and acceleration of amyloidogenic pathways that are connected to organ suicide and involve tissues such as the liver, adipose tissue, heart, lungs, kidneys and brain. Understanding discoveries in science allow the role of nutritional therapy to improve thinking and intelligence with improved endotoxin and xenobiotic metabolism in the periphery to prevent the inflammatory processes in the brain that involve global organ disease in obesity and diabetes in various racial groups.
Full-text available
Chronic neurodegenerative diseases are now associated with obesity and diabetes and linked to the developing and developed world. Interests in healthy diets have escalated that may prevent neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. The global metabolic syndrome involves lipoprotein abnormalities and insulin resistance and is the major disorder for induction of neurological disease. The effects of bacterial lipopolysaccharides (LPS) on dyslipidemia and NAFLD indicate that the clearance and metabolism of fungal mycotoxins are linked to hypercholesterolemia and amyloid beta oligomers. LPS and mycotoxins are associated with membrane lipid disturbances with effects on cholesterol interacting proteins, lipoprotein metabolism, and membrane apo E/amyloid beta interactions relevant to hypercholesterolemia with close connections to neurological diseases. The influence of diet on mycotoxin metabolism has accelerated with the close association between mycotoxin contamination from agricultural products such as apple juice, grains, alcohol, and coffee. Cholesterol efflux in lipoproteins and membrane cholesterol are determined by LPS with involvement of mycotoxin on amyloid beta metabolism. Nutritional interventions such as diets low in fat/carbohydrate/cholesterol have become of interest with relevance to low absorption of lipophilic LPS and mycotoxin into lipoproteins with rapid metabolism of mycotoxin to the liver with the prevention of neurodegeneration.
Full-text available
In the present review, we stress the importance of the purine nucleosides, adenosine and guanosine, in protecting the nervous system, both centrally and peripherally, via activation of their receptors and intracellular signaling mechanisms. A most novel part of the review focus on the mechanisms of neuronal regeneration that are targeted by nucleosides, including a recently identified action of adenosine on axonal growth and microtubule dynamics. Discussion on the role of the purine nucleosides transversally with the most established neurotrophic factors, e.g. brain derived neurotrophic factor (BDNF), glial derived neurotrophic factor (GDNF), is also focused considering the intimate relationship between some adenosine receptors, as is the case of the A2A receptors, and receptors for neurotrophins.
Conference Paper
Full-text available
The understanding of molecular mechanisms underlying diet and Alzheimer’s disease and the cholesterol connection are important for prevention and treatment of Alzheimer’s disease linked to Type 3 diabetes and aberrant lipid metabolism. Cholesterol modulates amyloid beta generation with the ATP-binding cassette transporter 1 as a major regulator of cholesterol and phospholipids from cell membranes involved in amyloid beta transport from the brain to the liver for metabolism. In Parkinson’s disease the α-synuclein protein binds to cholesterol (tilted peptide 67-78/isooctyl chain) in cell membranes. Fatty acids, cholesterol and phospholipids such as phosphatidylinositol in membranes are sensitive to amyloid beta and α-synuclein binding/aggregation indicate the involvement of lipids in the progression of AD and PD. The global obesity and Type 2 diabetes epidemic indicate that down regulation of Sirtuin 1 is associated with increased plasma α-synuclein levels in the modulation of membrane ion channels, impairments in protein degradation with abnormal endoplasmic reticulum-mitochondrial interactions associated with disturbed peripheral amyloid beta metabolism common to both Parkinson’s disease and Alzheimer’s disease.
Full-text available
Neuronal apoptosis and survival are tightly controlled processes that regulate cell fate during the development of the central nervous system and its homeostasis throughout adulthood. A new study in primary cultures of cerebellar granule neurons identified common transcriptional cascades during rescue from apoptosis by insulin-like growth factor-1 (Igf1) and pituitary adenylyl cyclase-activating polypeptide (Pacap), thus suggesting the existence of a high degree of conservation of cell survival pathways.
Full-text available
The understanding of molecular mechanisms underlying diet and Alzheimer's disease and the cholesterol connection are important for the prevention and treatment of Alzheimer's disease linked to Type 3 diabetes and aberrant lipid metabolism. Cholesterol modulates amyloid beta generation with the ATP-binding cassette transporter 1 as a major regulator of cholesterol and phospholipids from cell membranes that are involved in amyloid beta transport from the brain to the liver for metabolism. In Parkinson's disease, the α-synuclein protein binds to cholesterol (tilted peptide 67-78/isooctyl chain) in cell membranes. Fatty acids and phospholipids such as phosphatidylinositol in membranes sensitive to amyloid beta and α-synuclein binding/aggregation indicate the involvement of lipids in the progression of Alzheimer's disease. Atherogenic diets with abnormal cell cholesterol homeostasis exist as a cellular mechanism, which is common to the aggregation of amyloid beta and α-synuclein proteins that induce both Alzheimer's disease and Parkinson's disease. Sirtuin 1,a nuclear receptor known to regulate cell functions by deacetylating both histone and non-histone targets when down regulated is associated with circadian abnormalities and with poor glucose and cholesterol metabolism linked to abnormal amyloid beta metabolism in Alzheimer's disease and increased α-synuclein aggregation in Parkinson's disease. The global obesity and Type 2 diabetes epidemic indicate that the down regulation of Sirtuin 1 with increased inflammatory processes and abnormal immune responses associated with increased plasma α-synuclein levels, has become important for the modulation of membrane ion channels and impairments in protein degradation with abnormal endoplasmic reticulum-mitochondrial interactions associated with disturbed peripheral amyloid beta metabolism common to both Parkinson's disease and Alzheimer's disease. has become important for the possible prevention and treatment of AD and it is now linked to diabetes and poor cholesterol metabolism. Plasma cholesterol profiles such as elevated low density lipoprotein and decreased high density lipoprotein (HDL) levels have been associated with AD and are important risk factors for cardiovascular diseases. Furthermore, diets that are rich in fat and cholesterol have been associated with brain amyloidosis in rabbits and AD transgenic mice. Diabetes and dyslipidemia are linked to amyloidosis with relevance to calcium dyshomeostasis and neurodegenerative diseases [4]. Cholesterol modulates APP processing and Aβ generation with the action of 3 proteases [5-7]. Depletion of cholesterol and inhibition of intracellular transport of cholesterol or cholesterol esterification by drugs inhibited the production of Aβ formation in hippocampal neurons [8-13]. Studies indicate that cholesteryl ester (CE) levels are correlated with Aβ levels, and that cholesterol lowering drugs such as ACAT inhibitors directly modulate Aβ generation through the control of CE generation [14]. The ATP-binding cassette transporter 1 (ABCA1) is a major regulator of HDL with the transport of cholesterol and phospholipids from cell membranes to HDL possibly plays a central role in cholesterol flux and Aβtransport from the CNS
Full-text available
The global epidemic indicates that one third of adults in the United States are obese and over 11% of these individuals have diabetes with the incidence of diabetes predicated to increase to 21% by 2050. In various continents, the rise in the global diabetes epidemic has been associated with the pathogenetic involvement of cell suicide in various organ diseases that are related to obesity, Type 2 diabetes and neurodegenerative diseases. Therapeutics to control and stabilize the severity of the metabolic syndrome and diabetes in various Western communities are required to prevent mental illness and early cellular senescence that is connected to the lifespan of diabetic individuals. The increased cell senescence in diabetes has been associated with the limited ability of cells to divide with indication of telomere shortening and genomic instability of cells that is connected to cell suicide. Diet and liver diseases are closely connected and are of central importance with aging and programmed cell death pathways. Nutritional therapy and appetite control have become of central importance to nutrigenomics as early nutritional therapy may assist genes to delay liver and brain diseases associated with diabetes, cancer and aging. Interests in the global epidemic in Type 2 diabetes have been associated with accelerated dementia and even with progression to Parkinson’s disease (PD) and Alzheimer’s disease (AD). Anti-aging therapies such as diet, exercise and selective drug therapy early in life may prevent calorie overload and activation of calorie sensitive genes Sirtuin 1 (Sirt 1) that control genotoxic stress in cardiovascular disease and diabetes that accelerates aging, PD and AD.
Full-text available
Interests in amyloid beta oligomers and their relevance to mechanisms for toxic amyloid beta species has accelerated with effects on neuronal apoptosis in Alzheimer’s disease. Unhealthy diets that accelerate amyloidogenic pathways may involve lipids such as palmitic acid and cholesterol that promote hydrophobic self association reactions with amyloid beta aggregation in the brain. These diets corrupt membrane amyloid beta homeostasis and determine neuron senescence and the aging process. Amyloid beta oligomers generated by cell membrane cholesterol and phospholipids interact with acute phase reactants that determine the benign or toxic amyloid beta conformational states. In yeast amyloid beta oligomers have different toxicities and are relevant to human amyloid beta oligomers in the brain. In mammalian cells the dynamic nature of the amyloid beta oligomer states may be altered by bacterial lipopolysaccharides that involve membrane amphiphilic and charge polarization. Lipopolysaccarides partition in cell membranes and its interaction with apolipoprotein E corrupts the peripheral amyloid beta metabolism with effects on toxic amyloid beta generation in the brain with relevance to neurodegeneration and Alzheimer’s disease. The role of atherogenic diets involve dysregulation of peripheral lipopolysaccharide metabolism with effects on apolipoprotein E/amyloid beta and albumin/amyloid beta interactions associated with increased lipopolysaccharides in brain cells that determine neuroinflammation with relevance to toxic amyloid beta behaviour and memory disorders.
The klotho gene, identified by insertional mutagenesis in mice, is a suppressor of the expression of multiple aging phenotypes. The klotho gene plays a critical role in regulating aging and the development of age-related diseases in mammals: Loss of klotho can result in multiple aging-like phenotypes, while overexpression of klotho gene extends lifespan by 20-30%. Mice lacking KL exhibit many changes that occur during aging, including atherosclerosis, osteoporosis, infertility, and cognitive decline. The gene for the mammalian KL has two transcripts that encode a long type I transmembrane protein and a short secreted protein. The long isoform of KL, originating from the transmembrane isoform, is found in serum and cerebrospinal fluid (CSF), suggesting that the extracellular domain of KL is cleaved and released from the cell membrane.