Lipid Metabolism and Hormonal Interactions: Impact on Cardiovascular Disease & Healthy Aging

Populations in developed nations are aging gradually; it is predicted that by 2050 almost one

quarter of the world’s population will be over 60 years, more than twice the figure at the turn

of the 20th century. Although we are living longer this does not mean the extra years will be

spent in good health. Cardiovascular diseases are the primary cause of ill health and their

prevalence increases with age. Traditionally lipid biomarkers have been utilized to stratify

disease risk and predict the onset of cardiovascular events. However, recent evidence

suggests that hormonal interplay with lipid metabolism could have a significant role to play

in modulating cardiovascular disease risk. This review will explore recent findings which

have investigated the role hormones have on the dynamics of lipid metabolism. The aim is to

offer an insight into potential avenues for therapeutic intervention.

Keywords: Aging, cardiovascular disease, growth hormones, leptin, lipid metabolism, stress hormones

Due to improvements in health care, medicine and living standards, the proportion of the

aged population in the developed world is increasing gradually. It is predicted that by the year

2050 ~22% of the world’s population will be over 60 years, more than twice the figure at the

turn of the 20th century[1]. In the United Kingdom (UK), life expectancy at the start of the

20th century was 50.4 and 53.9 years for males and females respectively, while at the end of

the 20th century the corresponding numbers had risen dramatically to 74.6 and 79.6 years,

respectively[2]. This trend has gained further momentum in the 21st century. Based on the

most recently available data, a child born in England or Wales between 2010-2012 can expect

to live to 79.1 years if male and 89.2 years if female[3]. It has also been revealed that

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between 1971 and 2009 the proportion of the UK population >=75 years increased from 4.7%

to 7.8% and this figure is projected to rise to 11.7% by 2031[4](FIGURE 1). There are also

now five-times more people aged over 85 years in the UK than there were in 1951[2] and it is

predicted that by 2018 the number of individuals aged 65 years or over will outnumber those

below 16 years. It is anticipated that by the year 2051 almost 25% of the UK population will

be over 65 years, while 5% of the UK population will be over 85 years[3]. These trends are

not confined to the UK; the USA has also witnessed a demographic change. In 1950s

America, 8.1% of the population consisted of those individuals >=65 years. As of 2012 this

figure stands at 13.7% and is predicted to rise to ~20.2% by 2050[5]. Remarkably it is

estimated that by 2050, Japan’s population will be made up of 40% of people >=65 years,

making it the most rapidly aging nation[6]. China will also be confronted with an

overwhelming challenge as the number of people >=60 years is predicted to reach ~350

million by 2050[6].

Such dramatic alterations in population demographics present a major challenge to

governments, scientists and health professionals alike, because as the population ages it is

becoming increasingly important to develop strategies to deal with the high incidence of

disease in older people. In the UK those ≥65 years are the main users of the National Health

Service (NHS)[7]. In the USA it has been well established that personal health care costs rise

sharply with age, as the oldest old consume up to three times more health care per person

than those aged between 65-74 years [8]. To help relive the health care burden brought about

by an aging population the Japanese government introduced compulsory public long-term

care insurance to help relive the health care burden brought about by an aging population [9].

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Among the chronic conditions that hamper older people and prevent them benefitting

from a healthy extra few years of life; diseases of the heart and circulatory system, which are

referred to as cardiovascular disease (CVD) are the most common. The reason is that

although death rates from CVD have halved in the last two decades; its prevalence still

increases markedly with advancing age (FIGURE 2) [10]. For example in the UK CVD was

the principal cause of death in 2009, accounting for ~ 200,000 fatalities and its morbidity

remained constant in older age groups [11]. This costs the UK economy > £30 billion per

annum[12], therefore, it is clear that maintaining cardiovascular (CV) health is of central

importance in those countries with an aging population.

Despite the availability of a large number of risk factors for CVD, traditionally health

professionals have relied on lipid biomarkers markers as the gold standard determinant of

CVD risk. The reason is a long established relationship between plasma cholesterol levels

and CVD risk [13]. The biological underpinnings of this relationship are in part due to the

strong association that exists between elevated total cholesterol/low density lipoprotein

cholesterol (LDL-C) and atherosclerosis[14]. Atherosclerosis is a vascular process which is

considered the underlying pathological explanation for coronary heart disease (CHD) and

stroke which are the principle clinical manifestations of CVD. Unlike total cholesterol and

LDL-C, high density lipoprotein cholesterol (HDL-C) has been suggested to have an anti-

atherogenic role to play in reducing CVD risk. This becomes apparent in patients who have

HDL-C levels below 35 mg/dL, as their relative risk of CHD can be almost three times higher

than normal[15, 16]. Mechanistically HDL-C plays a role in reducing CVD risk by taking

part in reverse cholesterol transport (RCT), a process which offers the only route for removal

of excess cholesterol from the body[17]. Its role begins when it acquires excess cholesterol

from the cell membranes of peripheral tissue, this result in the generation of cholesteryl ester-

rich, mature HDL particles. These mature HDLs then transfer the excess cholesterol to the

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liver where it is taken up by hepatocytes and eventually removed from the body via hepatic

conversion into bile acids and subsequent fecal excretion. Recently the lead author developed

a computational model which consolidated the importance of RCT for sustaining whole-body

cholesterol balance during aging[18]. The findings from computational investigations such as

this are important because as outlined RCT acts to ‘fight’ against the arterial deposition of

cholesterol[15, 16]. Moreover it has been recognized that such approaches are needed to

unravel the myriad of mechanistic interactions associated with complex nutrient mediated

biological systems such as lipid metabolism[19].

Lipid based CV risk factors are not exclusively cholesterol based; for over two

decades there has been an established association between circulating triglyceride (TG) levels

and CVD risk. For example, in a recent epidemiological investigation it was found that the

long-term stability of TG values as a correlate for CHD was similar to those of total

cholesterol and blood pressure combined[20]. Mechanistically it remains uncertain how

elevated TGs contribute to CVD risk, however triglyceride-rich lipoproteins (TRLs) have

been tentatively associated with the process of atherosclerosis [21].

It is clear the CVD detection kit of the health professional comes well equipped with a

suite of lipid based parameters that play a key role in the risk stratification and prognosis of

CV events in their patients. It could be argued however, that blood lipids only contribute to

CVD pathologies in a proximate manner and that other underlying factors are the real cause

of CVD. The aim of this paper is to critically appraise the current evidence connecting

hormonal crosstalk with lipid metabolism. The emphasis will be on individuals with a risk of

dyslipidemia due to abnormal hormonal behavior and how this interplay contributes to their

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overall cardiovascular health. The goal of the paper is to help reveal potential avenues for

therapeutic intervention so that CVD does not persist into old age.

Adipose tissue lipolysis and hormonal interplay

The vast majority of the body’s TGs are located in white adipose tissue. When required

metabolically TGs stored in adipose tissue are broken down to fatty acids and glycerol by

lipolysis [22] (FIGURE 3). Once released into the bloodstream the free fatty acids (FFAs) are

transported to peripheral tissues that require energy for their oxidation. Adipose tissue

lipolysis is the main controller of the body’s supply of fat energy as it controls the release of

FFAs into the circulation[23]. In a healthy adult the basal rate of lipolysis during the fasting

state is determined by hormone sensitive lipase (HSL). HSL is in turn regulated by insulin, a

peptide hormone synthesized by the β-cells of the pancreatic islets. The relationship between

these two hormones plays a crucial role in maintaining fatty acid metabolism. The proximity

of this relationship is emphasized after a meal when insulin is released into the blood and its

presence results in the inhibition of HSL. Thus, the close interaction between insulin and

HSL is responsible for dictating the availability of FFAs to the entire body from white

adipose tissue[24, 25] (FIGURE 3). Further evidence of this interconnectivity is provided

when the HSL gene is knocked out in mice, as this has been shown to result in a reduction in

the sensitivity of insulin [26].

A number of studies have shown an association between dyslipidemia and insulin

resistance (IR). For instance, it has been demonstrated that increased adipocyte lipolysis

augments the hepatic removal of FFAs from the circulation, which in turn causes very low

density lipoproteins (VLDLs) secreted from the liver to have an elevated TG content and

subsequent hypertriglyceridemia; a physiological phenomenon that often accompanies IR

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[27]. The etiology of IR is further complicated by genetic polymorphisms, obesity, nutrition,

smoking, chronological age, inadequate physical activity (PA), and pharmacological

interactions. Among these it is acknowledged that obesity is probably the single most

important contributor to IR [28]. However, from the perspective of this review, it is important

to consider the glucocorticoid interactions which contribute to or even cause IR.

Cortisol

Cortisol is a glucocorticoid (GC) hormone that is released in response to stress and is the end

product of the hypothalamic-pituitary-adrenal (HPA) axis [29, 30]. The synthesis of cortisol

from cholesterol in the adrenal gland is stimulated by adrenocorticotropic hormone (ACTH),

released from the pituitary. Production of ACTH is in turn stimulated by corticotrophin-

releasing hormone (CRH) released by the hypothalamus. Cortisol inhibits the secretion of

CRH, resulting in negative-feedback inhibition of ACTH secretion. Under normal conditions,

cortisol has widespread actions which help to maintain homeostasis after stress. Cortisol

molecules reach all tissues, including the brain, readily penetrating cell membranes to interact

with ubiquitous glucocorticoid receptors (GRs), through which they exert a myriad of diverse

actions. For example, cortisol acts as a physiological antagonist to insulin by promoting

gluconeogenesis; it also promotes the breakdown of lipids, proteins and mobilization of

extra-hepatic amino acids[30]. However, recent evidence strongly suggests that continual

exposure to cortisol leads to abnormal insulin levels, which subsequently impinge on lipid

metabolism. For instance, it has been shown that alterations to adipocyte metabolism, which

result in both lipid mobilization and lipid storage are the result of a decline in insulin

sensitivity caused by hypercortisolemia [30].

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Recently, in order to establish the molecular mechanism(s) by which cortisol

antagonistically affects insulin, Park and colleagues examined the metabolic production of

cortisol and its biological functions in developing muscle tissue known as myotubes[31].

Their hypothesis centered on the dysregulation of the enzyme 11β-hydroxysteroid

dehydrogenase 1 (11β-HSD1) which catalyzes GCs into their active form. Myotubes were

supplemented with cortisone to catalyze 11β-HSD1 conversion into cortisol, which in turn

inhibited phosphorylation of protein kinase B (Akt) in response to insulin treatment; resulting

in a reduced uptake of insulin-induced glucose. The results were consolidated by the

application of an inhibitor to the enzyme 11β-HSD1 which reversed the antagonizing effects

of cortisol on insulin action[31]. Their results suggest that 11beta-HSD1 dysregulation in

adipose and muscle tissues could be involved in the development of IR. Rectifying this

impairment could potentially be a worthwhile means of improving insulin regulation.

Hypercortisolemia also has been shown to have an impact on a broad range of CV

parameters. For example, it has been shown that there is an association between elevated

cortisol levels and the redistribution of body fat [32]. Moreover, Rosmond and Björntorp

have shown that impairment of the HPA axis can be used as a predictor of CVD by

measuring serum insulin, TGs, LDL-C and HDL-C along with anthropometric

measurements[33]. This detrimental interaction is compounded by age related changes in the

HPA axis as evidenced by Knoops et al who reported that HPA axis activity showed reduced

variability in older age independent of CV risk factors[34]. Similar findings were reported by

Jokinen and Nordstrom. In this longitudinal study of patients with mood disorder, higher

baseline serum cortisol predicted CVD death in male patients. This group also reported that

among older adults, men respond to psychological stress with greater increases in cortisol and

this greater activation of the HPA axis could translate into an elevated risk for CVD[35].

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Hormonal interaction with lipoprotein lipase

Lipoprotein lipase (LPL) is a hydrolytic enzyme synthetized in a variety of tissues, including

cardiac, skeletal and adipose[36]. LPL is responsible for the enzymatic hydrolysis of the TG

core of circulating lipoproteins, including chylomicrons, and VLDL (FIGURE 3). For

instance, absorbed chylomicrons are released into the blood stream via the lymph and as they

pass through the capillaries of peripheral tissue, their TGs are hydrolyzed by LPL. The FFAs

are then absorbed by the peripheral tissue, while the glycerol backbone of the TGs is

returned, via the blood, to the liver and kidneys. Due to the hydrolysis of the core lipids,

chylomicrons reduce in size to become chylomicron remnants which are taken up by the

liver. It is known that nutrient status/state affects LPL; however its regulation is also

significantly influenced by a variety of hormonal interactions. For example,

hypercortisolemia has been correlated with a reduction in lipolysis; something that was

recognized by Samra and colleagues in the late 1990s when it was found that

hypercortisolemia caused a reduction in arterialized plasma TG concentrations[37].

More recently, Sakayama et al. (2012) investigated whether cortisol inhibited cell

proliferation and the expression of LPL in cultures of a human osteosarcoma cell line[38].

The effect of cortisol exposure on the expression of LPL was assessed by quantifying the

activity and mass of LPL. Interestingly, it was found that the rate and activity of LPL were

lower in the cortisol-treated cultures than in the untreated cultures. This study was significant

because it indicated that cortisol inhibited LPL synthesis, and therefore its activity[38]. Other

studies have also suggested a relationship between GC exposure and LPL activity. An

important much older study that is worth outlining examined GR status in adipose tissue from

omental and steroid converting (sc) abdominal adipose tissue in addition to investigating the

activity of LPL. It was found that LPL activity in omental adipose tissue was ~820 nmol

FFA/h.g in both sexes, whereas LPL activity in sc adipose tissue was two to four-fold lower.

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Moreover, LPL activity in sc adipose tissue was two-fold higher in women than in men and a

positive correlation between LPL activity and glucocorticoid binding was also found [39].

More tentative evidence has associated the HPA axis to LPL dysregulation via association

with acute stress[40]. Moreover, dysregulation of the HPA axis has also been linked with

metabolic syndrome in a variety of population groups[41, 42]. These studies strengthen the

case for a role of GCs in LPL dysregulation. However, the evidence is not completely in

favor of a mechanistic relationship between GCs and LPL dysregulation, as a recent study by

Xu and colleagues found that rats suffering from hypercortisolemia had increased adipocyte

lipolysis[43]. In addition, it has been found that when cortisol is administered in combination

with growth hormone (GH), cortisol increased both systemic and regional lipolysis in

humans[44]. To conclude, the available data on how GCs affects lipolysis/LPL activity is

both contradictory and controversial.

The catecholamines epinephrine and norepinephrine have also been show to affect the

activity of LPL by stimulating LPL expression in resting muscle[45]. This is suggested to

occur when catecholamines activate β-adrenergic receptors (β-ARs) stimulating cyclic

adenosine monophosphate (cAMP) levels to rise in adipocytes and triggering lipolysis[46].

Recently, Horton et al (2009) have suggested that women may be more sensitive to beta-

adrenergically mediated systemic lipolysis. In a three day study which compared the effects

of peripherally infused catecholamine’s and lipolysis rate by using infused glycerol; the

authors were able to demonstrate a significant gender difference mainly due to a significantly

greater glycerol turnover during the first 30 minutes of each infusion[47]. Similar to GCs,

catecholamines have also been shown to decrease the activity of LPL. As far back as the

early 1990s, Ong and colleagues used primary cultures of rat adipocytes to establish a

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decrease in LPL activity that was dependent on the concentration of epinephrine that the cells

were exposed to[48].

Following this investigation a number of other in vitro studies have echoed these

findings and there is an expanding body of data suggesting that obesity is synonymous with

blunted whole-body catecholamine dependent lipolysis. For example, Horowitz and Klein

quantified whole-body and regional lipolytic and adipose tissue blood flow sensitivity to

epinephrine in eight lean and 10 upper body obese (UBO) women. It was found that basal

whole body free fatty acid rate of appearance (FFA Ra) and glycerol rate of appearance

(glycerol Ra) were both greater in obese compared with lean subjects. Epinephrine infusion

significantly increased FFA Ra and glycerol Ra in lean but not obese subjects. In addition,

lipolytic and adipose tissue blood flow (ATBF) sensitivity to epinephrine was blunted in

abdominal but not femoral subcutaneous adipose tissue of obese compared with lean subjects.

It is suggested that lipolytic sensitivity to epinephrine is blunted in women with UBO due to

decreased sensitivity in upper body but not lower body subcutaneous adipose tissue [49].

Jocken et al (2008) then investigated beta-adrenergic stimulation on whole-body and

abdominal subcutaneous adipose tissue lipolysis in lean and obese men and found that in vivo

beta-adrenergically mediated lipolytic response is disrupted systematically and in abdominal

subcutaneous adipose tissue of obese versus lean men[50]. Most recently, Mowers et al have

suggested that pathophysiological obesity is mediated by a chronic inflammatory state, which

in turn is attenuated by the noncanonical IκB kinases IKKε and tank binding kinase 1(TBK1)

enzymes involved in the cellular inflammation response in white adipose tissue. Treatment of

adipocytes with specific inhibitors of these kinases restored β-adrenergic signaling and

lipolysis modulated by tumor necrosis factor alpha (TNFα) and the immune-stimulant

Polyinosinic:polycytidylic acid (Poly (I:C)) [51]. These findings suggest a potential anti-

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inflammatory therapeutic avenue to re-sharpen catecholamrine lipolysis which merits further

exploration.

It is important to acknowledge that other physiological factors including nutrition, PA

and age can all influence the rate of release of glycerol and FFAs from both adipocyte and

non-adipocyte tissue. For instance, aging has been associated with a decrease of between 55-

60% in LPL activity[52-55] which has been associated with hypertriglyceridemia[56, 57].

Interestingly, it has been shown that over expression of LPL in the skeletal muscle of mice

decreases plasma-TG concentrations, increases HDL-C levels and prevent hyperlipidemia

and obesity in rodents[58, 59]. Thus, based on evidence such as this, it could be suggested

that age associated increases in TG concentration could be underpinned by a decrease in the

activity of LPL. It is possible that PA could help to address such changes in LPL with age, as

a study in young rats has shown that PA associated with walking and standing was especially

important for maintaining a high level of LPL activity[55]. Moreover, in humans it has been

shown that PA can induce LPL in muscle independent of adrenergic-receptor signaling.

Considerable crosstalk also exists between insulin and LPL activity. Specifically, insulin has

been found to provoke LPL gene transcription during adipocyte differentiation. Insulin is also

a regulator of LPL activity and controller of LPL mRNA levels via both posttranscriptional

and posttranslational mechanisms[60, 61].

Growth hormone and IGF-1

Growth hormone (GH) a nocturnal stress hormone with a diversity of metabolic functions

stimulates cell growth, renewal and reproduction in both males and females[62]. GH

operates in concert with Insulin-like growth factor 1 (IGF-1) as part of the IGF1/GH axis.

Once GH is released from the pituitary gland, it circulates in the blood to increase IGF-I

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production in many tissues, leading to a rise in blood IGF-I. Circulating IGF-1 in turn

inhibits further pituitary GH secretion. In humans circulating GH levels peak during

adolescence followed by a continuous decline after 30 years of age at a rate of ∼1% per year

until it reaches negligible levels in those >=60 years [63]. From a longevity perspective,

significant recent attention has focused on the interplay between these two hormones [64].

This interest has centered on mutations in genes involved in this pathway having an effect on

longevity in a wide variety of organisms[65]. IGF-1 is part of a family which includes a range

of insulin-like growth factors (IGFs). IGFs differ from insulin in that they do not circulate

freely in the plasma as they are bound to a network of IGF-binding proteins (IGFBPs).The

interactivity between GH and IGF-1 focuses on IGF-1 regulating GH synthesis via negative

feedback. Both IGF-1 and GH signaling affect a plethora of metabolic pathways; however we

will focus on how their behavior impinges on the dynamics of lipid metabolism.

If cholesterol metabolism and GH interaction is examined it is firstly important to

appreciate that there are a number of changes which cholesterol metabolism can undergo with

age. The clinical manifestation of these perturbations are demonstrated by population studies

which have shown that LDL-C rises with age in both males and females[66]. The reason for

an increase in LDL-C in so many individuals across both genders remains unknown, as there

is there is a paucity of mechanistic evidence and the issue is complicated by inter-individual

differences in nutritional status and PA within the population sample. What is known is that

there is a gradual reduction in the fractional clearance rate of LDL-C from the circulation

with age [67-70]. This is consolidated by evidence that both the number and sensitivity of

hepatic low density lipoprotein receptors (HLDLr) in certain species decreases with age[71].

Recent evidence consolidates these long established findings and also suggested that the

magnitude of change in the activity of the LDL receptor(LDLr) is tissue specific and sex

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dependent[72]. A further putative mechanistic alteration concerns the gradual decline in the

removal of cholesterol from the body via bile acids[73]. Rodent studies have also

demonstrated that the conversion of cholesterol to bile acids declines with age[74-76].

It has been suggested that the age related changes in cholesterol metabolism discussed

above can be attributed to a decrease in GH which is a feature of sarcopenia[77]. As evidence

of this, GH has been shown to increase LDLr and HMG-CoA reductase mRNA expression in

mesangial cells [78]. Additionally, a study which used human liver biopsy specimens from

gallstone patients showed that GH was able to induce HLDLrs two-fold. This was also

accompanied by a 25% decrease in total serum cholesterol[79].Experiments in

hypophysectomised rats have also shown that GH is a regulator of the activity of the rate-

limiting enzyme in bile acid synthesis [80]. This is interesting, as rodent studies have

demonstrated that cholesterol absorption efficiency increases markedly with age[74, 81].

There are also sex differences in cholesterol absorption efficiency, suggesting that other

hormones such as estrogen could modulate cholesterol absorption [82]. From the perspective

of IGF-1, findings have centered on homologs of the scavenger receptor of the B class (SR-

BI), which is a receptor for HDL that mediates cellular uptake of HDL cholesteryl ester

(HDL-CE) and is thus central to RCT. For example in rodents continuous infusion of IGF-1

has been shown to decrease the activity of this receptor[83, 84], tentatively linking IGF-1

with RCT regulation.

If the effects of GH and IGF-1 on adipose tissue dynamics/TG turnover are examined,

there are a number of factors to consider. Firstly, GH stimulates adipocyte differentiation, a

process whereby nascent cells mature into large lipid laden adipocytes. The significance of

this is emphasized when GH deficient subjects are studied, as they suffer from a decreased

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volume of adipocytes, which is only rectifiable by hormonal intervention[85]. Moreover,

growth hormone deficient patients have lower levels of adiponectin[86] when compared to

normal individuals[87]. Adiponectin is an important regulator of fatty acid metabolism will

be discussed in further detail in the next section. GH also affects insulin signaling and it is

putatively suggested that GH exposure is the necessary precursor which allows cells to

become responsive to insulin[88]. GH also provokes lipolysis in adipose tissue which could

be mediated by augmenting LPL expression and/or HSL activity. GH is also released in

response to PA and hypoglycemia and could interact to inhibit leptin; a hormone synthesized

in adipocyte tissue which has been strongly associated with obesity[89] and which will be

explored in further detail in the nutrition and medication section.

Adiponectin and CVD

Adiponectin, an adipocyte-secreted adipokine plays an important role in metabolic and CV

homeostasis[90]. Adiponectin has been shown to be involved in protecting the CV system,

although the mechanisms responsible for this cardio-protective effect are not completely

understood. One way in which it could mediate its protective role is via improving insulin

sensitivity. Awazawa and colleagues (2011) showed that mechanistically adiponectin is

capable of up regulating hepatic insulin receptor substrate 2; a molecule which is a key

modulator of both insulin and IGF-1[91]. Adversely it has been found that in older

populations high adiponectin levels have been demonstrated to have undesirable patient

outcomes. Beatty et al. (2012) reported higher levels of adiponectin were associated with

heart failure and mortality among patients with existing ischemic heart disease[92]; and in a

longitudinal investigation of determinants of CVD in older adults Kizer et al. (2012) also

found an association between adiponectin and mortality, particularly in those with greater

baseline CV dysfunction [93].

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Thyroid Hormones

It has long been established that the catabolic activities of both triiodothyronine (T3) and

thyroxin (T4) has an impact on the physiological dynamics of lipid metabolism. Specifically

they mediate their whole-body influence on lipid metabolism by binding to both the α and β

thyroid receptor which is located ubiquitously throughout the body. Their actions have been

show to lower total and LDL-C and also affect adipocyte biology. Mechanistically, it remains

unclear how thyroid hormones modulate lipid metabolism, however Goldberg et al (2012)

recently proposed that thyroid hormone reduces cholesterol via a non-LDL receptor-mediated

pathway. The authors tested if LDLr expression was required for cholesterol reduction by

treating control and LDLr-knockout mice with two different forms of thyroid hormone. High

doses of the hormones significantly lowered total and VLDL/LDL cholesterol. The reduction

was not associated with increased protein or mRNA expression of the hepatic lipoprotein

receptors LDLr-related protein 1 or scavenger receptor-B1[94]. Recent evidence has also

indicated that thyroid stimulating hormone (TSH) has also been associated with changes to

many of the parameters of lipid metabolism. TSH is responsible for provoking the thyroid

gland into secreting thyroxin into the circulation; where the majority of it binds to proteins in

blood serum while the remaining ~1% circulates as free T4. Recent evidence for the

association between TSH and lipid metabolism comes from a cross-sectional study by Chin et

al. (2014) where lipid and thyroid hormones levels in 708 men were quantified to examine

for correlations between them. It was found that TSH levels were significantly associated

with TG. Free T4 levels were also significantly associated with total cholesterol, LDL-C and

HDL-C [95].

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Nutrition and medication

Diet and medication also have a role to play in contributing to the interplay between lipid

metabolism and hormones. For instance, ingestion of drugs including glucocorticoids, beta

adrenergic antagonists and thiazide diuretics exacerbate IR and dysregulate lipid metabolism.

Evidence of this comes from a large meta-analysis of clinical trial data indicating that

diuretics cause increases in both total and LDL-C. Moreover this analysis suggests that beta

adrenergic antagonists raise TGs. Conversely, it was found that α-adrenergic-antagonists

beneficially affected total cholesterol and modestly raised HDL-C in younger individuals[96].

One caveat is that these findings varied depending on population groups.

Considerable recent focus has centered on leptin, a hormone which is a key regulator

of nutrient intake and which is known to mediate lipid metabolism. Leptin is secreted mainly

by white adipose tissue and acts as a regulator of appetite[97]. Mechanistically leptin operates

by binding to receptors on leptin-responsive neurons of the arcuate nucleus in the mediobasal

hypothalamus decreasing their activity and provoking the brain into releasing a signal that

indicates satiety. Thus, in the short term (the fasting state) leptin concentrations drop while a

brief period of overfeeding provokes an increase in leptin. Therefore, leptin increases in

obesity and decreases during fasting and it has been found that blood circulation levels of

leptin are proportional to adipose tissue mass[98, 99]. Furthermore, it has been found that

leptin can increase skeletal muscle lipoprotein lipase and postprandial lipid metabolism in

mice[100]. Its actions may not be confined to LPL, as recently an independent significant

association was found between IR and leptin concentrations in a population study based in

China[101]. This raises the possibility of leptin being a future biomarker for impaired insulin

sensitivity/the initial stages of pathophysiological obesity. Research in to leptin-lipid

crosstalk is ongoing. However, plasma leptin levels have been correlated with other markers

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of CV health most notably C-reactive protein[102]. However more recently, the European

Male Aging Study reported no relationship between this inflammatory marker and leptin

resistance[103]

By far the most studied dietary regime in aging research is caloric restriction (CR).

CR usually refers to diets providing an energy intake 30%-40% less than the base line

unrestricted intake. It does not lead to malnutrition due to lack of vitamins, minerals or

essential biomolecules and has been shown to improve health at all ages and extend life span

in a variety of organisms[104]. Its potential efficacy in humans remains to be fully

determined. The most concrete evidence to date is provided by experiments by the

Comprehensive Assessment of Long- Term Effects of Reducing Calorie Intake (CALORIE)

[105, 106]. This six year CR diet to assess atherosclerosis risk factors in males and females

(35–82 years) compared to age-matched healthy individuals on typical American diets

(control group) resulted in lowered total cholesterol, LDL cholesterol, triglycerides and

fasting insulin levels[107]. These results are interesting and offers the possibility of CR being

used as a future intervention to improve CV health. Recently, a more traditional dietary

regime with similarities to CR was used to investigate adrenergic and insulin-mediated

regulation of lipolysis in subcutaneous adipose tissue in obese women. The women were

subjected to a six month dietary regime which comprised of a one month very low-calorie

diet (VLCD) followed by a two-month low-calorie diet (LCD) and three month weight

maintenance (WM) diet. The dietary interventions resulted in body weight reduction and

improved insulin sensitivity. Moreover there was an adrenaline-induced increase in lipolysis;

highest in the VLCD and LCD compared with baseline conditions. The lipolysis rate returned

to pre-diet levels during WM [108]. The findings of the study center on women, and studies

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of this nature are crucial as dyslipidemia in older people is more common in women than

men[109].

Women versus men

Dyslipidemia is more common in older females than males, with almost half of females over

65 years having elevated total cholesterol levels compared to almost a quarter of males[109].

Despite this in the UK death rates from myocardial infarction remains consistently higher in

males than in females across age strata[12]. There are many possible explanations for this

difference; for example as mentioned above there is a sex difference in cholesterol absorption

efficiency. This suggests female sex hormones have a part to play in dyslipidemia in women.

For instance, estrogen significantly augments the output of biliary bile salt, cholesterol and

bile-flow rate. Thus, high levels of estrogen could impact the dynamics of enterohepatic

circulation. In addition hormonal dependent changes to cholesterol absorption are likely to be

a factor in female age-related dyslipidemia. This is logical when it is considered the risk of

CVD increases after the menopause, although it remains to be determined precisely whether

pre or post menopause is the most effective time point for optimal CVD risk reduction [110].

Interestingly a recent study suggests transdermal estradiol (E2) and not oral conjugated

equine estrogen (CEE) may be an effective way of improving vascular atherosclerosis risk in

females [111, 112]. Moreover aerobic training was recently shown to have a positive

influence on the neuro-endocrine system in females[113].

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Conclusions

To conclude, developed populations are aging which poses a number of health related

challenges; most notably the persistence of CVD into old age. Historically, lipid biomarkers

have been used to predict CVD risk. However, physiological changes that occur during the

ageing process are multi-dimensional and involve the interaction of a myriad of biological

systems with lipid metabolism to modulate the behavior of key lipid based parameters.

Therefore it may no longer be appropriate to rely on the traditional lipid parameters to define

CVD risk in an aging population. This is apparent from the evidence presented in this paper

which highlights the significant role hormonal interactions have on lipid metabolism. Given

that the average lifespan is increasing worldwide and is set to continue to rise; further

understanding of the age-related mechanistic relationships between lipid metabolism and

hormones are certainly merited. This could lead to therapeutic targets which help to prevent

the age dependent pernicious interactions between hormones and lipid metabolism, thus

reducing CVD risk and ultimately promoting healthy aging.

Expert commentary

It is vital that hormonal crosstalk with lipid metabolism is recognized as a modulator of

dyslipidemia. This is crucial as it is highly probable that dyslipidemia in older people is a

result of metabolic changes that have begun much earlier in life. According to the current

clinical evidence, there are several hormones that offer the possibility of improving CVD risk

prediction. These candidates also offer potential therapeutic avenues in the near future. A

goal of aging research in general, is to prolong healthy life-span by identifying strategies that

could prevent or delay CVD. Finding the appropriate regime for each individual, based on

their circumstances is critical to achieving a long life spent in good health. Prevention is the

key to healthy living: starting life healthy, staying healthy and maintaining the lowest risk

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throughout life. Health promotion programs should target people of all ages, since the risk of

CVD starts early in life and increases with age. With an aging global population, identifying

CVD risk earlier in life or developing novel therapeutic avenues that help prevent the onset of

dyslipidemia in older people would have significant benefits for society as a whole.

Five-year view

There is little doubt life expectancy will continue to increase in the next five years

both globally and in the UK.

With an aging population and increases in the prevalence of obesity/metabolic

syndrome, it is highly probable that significant numbers of older people will have

either diagnosed or undiagnosed CV morbidity.

CV morbidity in older people will inevitably continue to be underpinned by

dysregulated lipid metabolism.

It is likely that novel indicators and risk factors for dyslipidemia and/or CVD will be

used to predict the onset of CV morbidity with aging. It is possible based on current

evidence that they will center on hormonal interplay with lipid metabolism.

How successful we are at developing interventions will ultimately be an important

determinant of quality of life in older people.

Key issues

Developed populations are aging gradually and this presents a number of problems.

CVD mortality rates have halved in the last two decades, but morbidity among older

people persists.

Dysregulation of lipid metabolism has historically been used as a risk for CVD.

The mechanisms that underpin age-related dyslipidemia are incompletely understood.

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CVD is not a pathology caused by one single biological change; instead, it is more

likely the result of a combination of several factors.

Exploring the hormonal interplay with lipid metabolism is one such factor that could

help to further elucidate the mechanisms. This will lead to novel risk factors for

CVD/cardio metabolic risk.

For stress hormones to be used as a risk factor, an improved understanding of the

effects of stress hormones on the regulation of adipose tissue metabolism is

fundamental in order to establish the clinical connection between psychological stress

and the dysregulation of lipid metabolism.

Recent evidence points at several other hormonal candidates that could be used, for

instance leptin levels could be utilized due to its ability to predict IR and other cardio-

metabolic risk factors independent of obesity.

GH measurement in older people could also have an important role to play in

reducing CVD risk.

Dietary intervention could help to normalize the dyslipidemia in middle age.

Careful monitoring of estrogen or hormonal intervention might improve

postmenopausal dyslipidemia in females.

References

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110. Manson, J.E., et al., Menopausal hormone therapy and health outcomes during the intervention and extended poststopping phases of the Women's Health Initiative randomized trials. JAMA, 2013. 310(13): p. 1353-68.

111. Sumino, H. and M. Murakami, [Investigation of atherosclerosis in postmenopausal women: alteration of atherosclerosis-associated factors and vascular atherosclerosis by oral and transdermal estrogen replacement]. Rinsho Byori, 2013. 61(3): p. 256-62.

112. Rossouw, J.E., et al., Postmenopausal hormone therapy and risk of cardiovascular disease by age and years since menopause. JAMA, 2007. 297(13): p. 1465-77.

113. Izzicupo, P., et al., Effects of ACE I/D polymorphism and aerobic training on the immune-endocrine network and cardiovascular parameters of postmenopausal women. J Clin Endocrinol Metab, 2013. 98(10): p. 4187-94.

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Annotated references

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Mc Auley, M.T., et al., A whole-body mathematical model of cholesterol metabolism and its age-associated dysregulation. BMC Syst Biol, 2012. 6(1): p. 130.

Interesting mathematical model that demonstrates that a better understanding of lipid metabolism and aging can only be achieved by studying its many mechanistic interactions

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Chin, K.Y., et al., The relationships between thyroid hormones and thyroid-stimulating hormone with lipid profile in euthyroid men. Int J Med Sci, 2014. 11(4): p. 349-55.

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Worthwhile paper that demonstrates the potential of TSH has a therapeutic means of acting on both TG and LDL-C

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Goldberg, I.J., et al., Thyroid hormone reduces cholesterol via a non-LDL receptor-mediated pathway. Endocrinology, 2012. 153(11): p. 5143-9.

Worthwhile paper that investigates a potential hormonal centered means for lowering LDL-C

List of Figures

Figure 1: The aging UK demographic. By the year 2031 it is predicted that almost 12% of the UK population will 75 years of age or older. Despite this demographic shift, this does not mean that these extra years will be spent as healthy ones (Source of data: Reference 3)

Figure 2: The overall prevalence of selected chronic conditions, as a function of age for the UK population for 2008. CHD and stroke; the principle clinical manifestations of CVD are the most common conditions in older people. Data source: Public Health England (Reference 101)

Figure 3: Schematic representation of lipolysis and lipogenesis and their interplay with a variety of hormones. These interactions are discussed in detail in the main body of the paper. T shaped arrows

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represent inhibition, round headed arrows represent effectors while arrow heads represent synthesis or conversion of a metabolite/hormone.

List of Abbreviations

adipose tissue blood flow(ATBF), adrenocorticotropic hormone (ACTH), caloric restriction (CR), cardiovascular disease (CVD), cholesteryl ester transfer protein (CETP)Comprehensive Assessment of Long- Term Effects of Reducing Calorie Intake (CALORIE) conjugated equine estrogen (CEE), corticotrophin-releasing hormone (CRH)free fatty acids ( FFAs), Growth hormone deficiency (GHD), glucocorticoid (GC) ) growth hormone (GH), glucocorticoid receptor (GR), glucocorticoid receptors (GRs) high density lipoprotein cholesterol(HDL-C) ,hormone sensitive lipase (HSL), hypothalamic-pituitary-adrenal (HPA) axis, IGF-binding proteins (IGFBPs), insulin resistance (IR) lecithin:cholesterol acyltransferase (LCAT),lipoprotein lipase (LPL), low density lipoprotein cholesterol (LDL-C), low-calorie diet (LCD) (WM), protein kinase B(Akt) reverse cholesterol transport (RCT), scavenger receptor of the B class (SR-BI), steroid converting (sc) ,Subcutaneous adipose tissue(SCAT) ,The rate of appearance (Ra), ,transdermal estradiol (E2) ,triacylglycerol’s (TGs), triglyceride-rich lipoproteins (TRLs), Triglycerides(TG), upper body obesity(UBO) , very low-calorie diet (VLCD), very low-density lipoproteins (VLDL), 11β-hydroxysteroid dehydrogenase 1 (11β-HSD1)

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