• Redness
• Swelling
• Heat
• Pain
• Loss of Function

1. What Is the Main Cause of Inflammation in the Body?

There are many causes of inflammation that is triggered by the body’s immune system:

• Injury such as a splinter, scrapes, trauma, or any damage caused by a foreign object.
• Pathogens, including viruses, bacteria, parasites, or fungi
• Chemicals such as glucose, fatty acids, chemical irritants (e.g., acids), toxins, and alcohol
• Radiation such as sunburns
• Biological such as damaged cells in the body

2. What Happens During Inflammation?

Inflammation involves the contribution of different immune cells which release substances known as inflammatory mediators, including hormones such as histamine and bradykinin [1].

These inflammatory mediators induce vasodilation (dilatation of the vessels) which promotes the blood flow in the injured tissue and the recruitment of inflammatory cells (neutrophils, monocytes, and endothelial cells) to the site of injury.

The vasodilatation and the blood rush into the injured tissue result in redness and heat which are 2 signs of acute inflammation.

The pain associated with inflammation is caused by the irritation of local nerves by the inflammatory mediators.

These inflammatory cells have specific roles during acute inflammation:

• Neutrophils initiate the phagocytosis and killing of pathogens to decontaminate the wound, while also promoting cell proliferation and angiogenesis.
• Monocytes also contribute to the phagocytosis and killing of pathogens, and become macrophages, which remove dead cells, and support cell proliferation and tissue restoration following injury.
• Endothelial cells are the building blocks for vessels, and during wound healing, these cells generate new vessels (angiogenesis) to satisfy the metabolic demands of the highly proliferative healing tissue. 

Depending on the site of injury, a transitory loss of function can be observed due to tissue damage, swelling, or pain during inflammation.

3. How long Does Inflammation Last For?

Inflammation can be acute lasting for a few days (2-3 days) or chronic which lasts for a longer time until the insult is resolved.

What Are the Outcomes of Inflammation?

The resolution of acute inflammation (initial inflammation) depends on the causes and the extent of tissue damage. It is characterized by the following outcomes:

• Complete repair of the injured tissue and without scars
• Resolution of the inflammation with the formation of a scar or fibrosis
• Formation of an abscess
• Chronic inflammation if the initial inflammation persists and remains unresolved

The complete repair of the injured tissue or the formation of scars is mediated by a process known as wound healing.

Wound healing is a natural reaction of our body to tissue damage and involves crosstalk between different cells, cytokines, inflammatory mediators, and the vascular system to repair the damaged tissue.

4. What Are the Most Common Inflammatory Diseases?

The most common inflammatory diseases are associated with chronic mediated inflammation which includes the following diseases [2]:

• Rheumatoid Arthritis
• Cardiovascular diseases
• Inflammatory Bowel Disease (IBD) 
• Allergic Asthma
• Chronic obstructive pulmonary disease (COPD)
• Diabetes
• Chronic Kidney Disease
• Cancer

4.1. Rheumatoid Arthritis

Rheumatoid arthritis is due to a local chronic inflammation that results in the infiltration of immune cells into the joints and the release of inflammatory mediators such as cytokines.

4.2. Cardiovascular diseases

Atherosclerosis is associated with a chronic inflammation that leads to heart diseases such as stroke, and myocardial infarction.

4.3. Inflammatory Bowel Disease (IBD)

Inflammatory Bowel Disease (IBD) is a group of chronic inflammatory disorders affecting the bowels that are caused by ulcerative colitis (inflammation of the colon due to ulcer) or Crohn’s disease.

4.4. Allergic Asthma

Allergic asthma is due to the inflammation of the airways caused by the inhalation of an allergen which results in their swelling and tightening affecting breathing.

4.5. Chronic obstructive pulmonary disease (COPD)

COPD is a chronic inflammatory lung disease due to the exposure of the airways to harmful particles or gases causing inflammation that obstruct airflow in the lung leading to breathing difficulties.

4.6. Diabetes

One of the characteristics of diabetes is the infiltration of immune cells, such as macrophages, into pancreatic tissue, and their release of pro-inflammatory molecules responsible for inflammation.

4.7. Chronic Kidney Disease (CDK)

Chronic kidney disease or chronic kidney failure is a progressive loss of the function of the kidney resulting from the accumulation of body wastes and fluids in the blood.

One of the causes of chronic kidney disease is the inflammation of the glomeruli that filter blood for the elimination of waste and fluids in urine.

4.8. Cancer

Chronic inflammation is one of the characteristics of different types of cancer from various origins (Prostate, hepatic, colorectal, ovarian, pancreatic, and lung cancers).

4.9. Neurodegenerative diseases

Neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease are associated with the production of proinflammatory molecules by the brain resident immune cells and microglia which cause brain damage.

5. What Is the Difference Between Inflammation and Infection?

Infections cause inflammation which is a natural process by which the body’s immune system fights against pathogens, including bacteria, viruses, fungi, or parasites.

6. How Do You Get Rid of Inflammation in the Body?

Unlike acute inflammation, chronic inflammation can last for a longer period, and therefore, requires management and treatment through lifestyle changes or medications [3].

6.1. Lifestyle changes

6.1.1. Diet

A diet rich in glucose and processed food rich in saturated fat and trans fats promotes inflammation leading to cardiovascular diseases and type 2 diabetes. Hence, a low glucose diet and avoiding processed food can prevent inflammation.

A diet rich in vegetables and fish oils, nuts, mung bean, green and black teas, and certain species (e.g., ginger, turmeric) can prevent or reduce inflammation as they contain antioxidants and polyphenols which have anti-inflammatory properties.

6.1.2. Physical Activity

In addition to weight loss associated with exercising, physical activity also results in energy consumption with reduces the levels of proinflammatory molecules in the body.

6.2. Medications

The most used anti-inflammatory medications include nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids. 

Nonsteroidal anti-inflammatory drugs (NSAIDs) such as naproxen, ibuprofen, and aspirin, alleviate pain by inhibiting the function of the enzyme cyclooxygenase (Cox) involved in the synthesis of the proinflammatory molecules, prostaglandins.

Corticosteroids are prescribed for some inflammatory conditions such as arthritis, asthma, systemic lupus, and sarcoidosis.

Conclusion

Acute inflammation is a natural process by which the body’s immune system responds to injuries and infections. Acute inflammation takes a few days to resolve, leading to a complete repair of damaged tissues, fibrosis (scars), formation of an abscess, or chronic inflammation.

Chronic inflammation can be associated with several inflammatory diseases such as rheumatoid arthritis, allergic asthma, cancer, diabetes, cardiovascular diseases, chronic kidney disease, COPD, inflammatory bowel disease, and neurodegenerative diseases.

The treatment of chronic inflammation includes lifestyle changes, physical activity, and medications using anti-inflammatory drugs such as NSAIDs and corticosteroids.

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• Diabetes
• Hyperthyroidism
• Hypothyroidism
• Addison’s Disease
• Cushing’s Disease
• Acromegaly
• Dwarfism
• Gigantism
• Hypogonadism
• Polycystic Ovary Syndrome (PCOS)

1. What Is Diabetes?

Diabetes is a chronic disease characterized by the presence of a high level of glucose in the blood due to the lack of insulin production by the pancreas or the reduced capacity of tissues to use insulin [1].

Diabetes is the 9^th leading cause of death with an estimated 1.5 million deaths just in 2019 [2].

According to the 2020 statistics, it was estimated that 34.2 million Americans have diabetes and 88 million Americans have prediabetes [1].

1.1. What Does Insulin Do in the Body?

Insulin is a hormone produced by the beta cells of the pancreatic islets (islets of Langerhans) which role is to promote the absorption of glucose from the blood into liver, fat, and muscle cells where it is stored as glycogen or fat.

1.2. What Are the Types of Diabetes?

There are 2 types of diabetes, type 1 diabetes, and type 2 diabetes; however, there is another type of diabetes that occurs during pregnancy and is known as gestational diabetes.

• What Is Type 1 Diabetes?

Type I diabetes is an autoimmune disease characterized by reduced or lack of insulin production by the pancreatic islets due to their destruction by the body’s own immune system.

The causes of typ1 diabetes are unknown but may involve genetics and environmental factors.

• What Is Type 2 Diabetes?

Type II diabetes is a chronic disease associated with a decreased production of insulin by the pancreatic islets or the absence of response of the body’s cells to insulin, also known as insulin resistance.

Type II diabetes is caused by genetics and lifestyle factors such as obesity, being overweight, lack of physical activity, and stress.

• What Is Gestational Diabetes?

Gestational diabetes is characterized by increased glucose levels in the blood during pregnancy and which usually disappears after giving birth.

1.3. What Are the Symptoms of Diabetes?

Because insulin is lacking or insufficiently available, or the cells of the body do not respond to it, there is an increased accumulation of glucose in the blood and its reduced absorption by the body’s cells.

The lack of glucose absorption by the body’s cells results in symptoms such as fatigue, blurred vision, increased hunger, slow wound healing, and weight loss.

The accumulation of glucose in the blood results in symptoms such as frequent urination (to eliminate the excess), increased thirst, and complications including diabetic neuropathy, kidney failure, and cardiovascular diseases.

2. What Is Hyperthyroidism?

Hyperthyroidism is a disorder characterized by excessive production of the thyroid hormones by the thyroid gland [3].

2.1. What Are Thyroid Hormones?

The thyroid hormones are thyroxine (T4) and triiodothyronine (T3) involved in the regulation of carbohydrate, fat, and protein metabolisms, and growth.

2.2. What Causes Hyperthyroidism?

Hyperthyroidism is caused by the following disorders:

• Graves’ Disease
• Toxic Adenoma
• Silent or Painless Thyroiditis
• Toxic Multinodular Goiter

2.2.1. What Is Grave’s Disease?

Graves’ disease is an autoimmune disease characterized by the body’s production of autoantibodies against the receptor of the thyroid-stimulating hormone (TSH) found on the surface of the thyroid cells.

The binding of the autoantibodies to the TSH receptor results in excessive production of the thyroid hormones thyroxine (T4) and triiodothyronine (T3).

2.2.2. What Is Toxic Adenoma?

A toxic adenoma is a benign tumor of the thyroid that results in excessive production of thyroid hormones.

2.2.3. What Is Silent or Painless Thyroiditis?

Silent or painless thyroiditis is an inflammation of the thyroid resulting in increased production of thyroid hormones.

2.2.4. Toxic Multinodular Goiter

Toxic multinodular goiter is characterized by the formation of nodules within the thyroid responsible for the increased production of thyroid hormones.

2.2. What Are the Symptoms of Hyperthyroidism?

Hyperthyroidism causes thyrotoxicosis characterized by the following symptoms:

• Nervousness and irritability
• Increased heartbeat
• Hand tremors (uncontrollable shaking)
• Anxiety
• Muscles weakness
• Increased perspiration or trouble tolerating heat
• Repeated bowel movements
• Sleep difficulty
• Enlargement in the neck, also known as goiter

3. What Is Hypothyroidism?

Hypothyroidism is characterized by a reduced production of thyroid hormones by the thyroid [4].

3.1. What Causes Hypothyroidism?

The causes of hypothyroidism can be divided into 3 categories: Primary hypothyroidism, central hypothyroidism, and congenital hypothyroidism.

• What Is Primary Hypothyroidism?

Primary Hypothyroidism is caused by a deficiency in iodine, necessary for the synthesis of thyroid hormones, and thyroiditis.

• What Is Central Hypothyroidism?

Central Hypothyroidism is caused by insufficient stimulation of the thyroid by the thyroid-stimulating hormone (TSH) due to brain tumors (e.g., tumor of the pituitary gland), hematological malignancies, pituitary gland surgery, or post-surgery radiation.

• What Is Congenital Hypothyroidism?

Congenital Hypothyroidism is due to a defect in the development of the thyroid.

3.2. What Are the Symptoms of Hypothyroidism?

The symptoms of hypothyroidism include:

• Fatigue
• Weight gain
• Feeling cold
• Constipation
• Hoarse voice
• Poor appetite
• Shortness of breath
• Impaired memory and concentration
• Depression
• Enlargement in the neck, also known as goiter

4. What is Addison’s Disease?

Addison’s Disease is characterized by insufficient production of steroid hormones (cortisol and aldosterone) by the adrenal gland causing adrenal deficiency [5].

4.1. What Causes Addison’s Disease?

Adrenal deficiency is caused by damage to the adrenal gland (adrenal cortex), developmental defects, or the incapacity of the adrenal gland to produce steroid hormones.

4.2. What Are the Symptoms of Addison’s Disease?

Addison’s Disease manifests with the following symptoms:

• Hyperpigmentation of the skin
• Vitiligo
• Nausea and vomiting
• Weight loss
• Abdominal pain
• Extreme fatigue
• Muscle or joint pain
• Anxiety
• Depression
• Irritability
• Poor concentration
• Body hair loss or sexual dysfunction in women
• Low blood pressure

A severe state of Addison’s disease known as adrenal crisis or Addisonian crisis manifests with severe symptoms such as hypoglycemia, hypotension, legs, and lower back pain, nausea and vomiting, abdominal pain, confusion and delirium, and severe weakness.

5. What Is Cushing’s Disease?

Cushing’s Disease is characterized by increased production of cortisol by the adrenal glands [6].

5.1. What Causes Cushing’s Disease?

The increased production of cortisol by the adrenal glands is due to the overproduction of the hormone adrenocorticotropic hormone (ACTH) by the pituitary gland due to the presence of a tumor.

This increased production of ACTH increases the stimulation of the adrenal glands to secrete excess cortisol.

Cushing’s Disease can also be caused by tumors in the adrenal glands resulting in the excess production of cortisol.

5.2. What Are the Symptoms of Cushing’s Disease?

The most common symptoms of Cushing’s disease are:

• Weight gain
• Round face
• Hypertension
• Bone weakness
• Lack of strength in the upper arms and thighs
• Fatigue
• Purple stretch marks
• Irregular menstruation
• Excessive bruising
• Irritability
• Short-term memory deficit
• Lack of concentration
• Facial hair growth (Women)
• Depression

6. What Is Acromegaly?

Acromegaly is a condition characterized by the excess production of the growth hormone (GH) by the pituitary gland [7].

6.1. What Causes Acromegaly?

Acromegaly is mainly caused by a tumor in the pituitary gland known as pituitary adenoma resulting in increased secretion of growth hormone (GH).

6.2. What Are the Symptoms of Acromegaly?

Growth hormone (GH) controls the growth of the body, and its excess may result in the following symptoms:

• Enlargement of the forehead, nose, jaw, and tongue
• Deep voice
• Thick skin
• Increased sweating and skin odor
• Swollen hands and feet
• Headaches
• Join pain
• Vision problem

7. What Is Dwarfism?

Dwarfism is a condition characterized by short stature of 4’10” or shorter [8].

7.1. What Causes Dwarfism?

They are many causes of dwarfism; however, the most common cause is achondroplasia which is a disorder that affects bone growth due to a deficit in the production of bone from cartilage [9].

8. What Is Gigantism?

Gigantism is a condition characterized by the excess production of the growth hormone (GH) during childhood resulting in excessive growth in height, muscles, and organs, compared to other children at the same age. 

8.1. What Causes Gigantism?

The increase in the production of growth hormone (GH) during childhood is mainly due to benign tumors in the pituitary gland.

9. What Is Hypogonadism?

Hypogonadism is a disorder characterized by a reduced function of the ovaries or testes resulting in decreased production of sex hormones such as estrogen for females and testosterone for males [10][11].

9.1. What Causes Hypogonadism?

Hypogonadism can be due to primary or secondary causes:

9.1.1. What Is Primary Hypogonadism?

Primary hypogonadism is due to the incapacity of the gonads (ovaries or testes) to produce sex hormones even after stimulation by the pituitary gland.

Primary hypogonadism can be associated with the following causes:

• Genetic diseases such as Noonan syndrome, Turner syndrome or Klinefelter syndrome
• Undescended testicles
• Mumps orchitis
• Hemochromatosis
• Normal aging
• Cancer treatment
• Injury to testicles

9.1.2. What Is Secondary Hypogonadism?

Secondary hypogonadism is due to alterations in the hypothalamus or pituitary glands resulting in absence of stimulation of the gonads (ovaries or testes) to produce sex hormones.

Secondary hypogonadism can be associated with the following causes:

• Kallmann syndrome (abnormal development of the hypothalamus)
• Pituitary disorders
• Inflammatory diseases
• Obesity
• Stress-induced hypogonadism
• HIV/AIDS
• Medications (e.g., opiate based medications or some hormones)

9.2. What Are the Symptoms of Hypogonadism?

In females, hypogonadism manifests with the absence of menstruation which may affect their growth, breast development, and libido.

In males, hypogonadism manifests with abnormal enlargement of the breasts (gynecomastia), impairment of the development of hair and muscles, reduced height, and sexual difficulties (e.g., erectile dysfunction).

10. What Is Polycystic Ovary Syndrome (PCOS)?

PCOS is a hormonal disorder characterized by the presence of cysts on the ovaries which affects their normal function resulting in infrequent or prolonged menstrual periods or excess male hormone levels [12].

10.1. What Causes Polycystic Ovary Syndrome (PCOS)?

The causes are not well known and may involve genetics and environmental factors (e.g., obesity, epigenetic factors, or endocrine disruptors such as bisphenol).

9.2. What Are the Symptoms of Polycystic Ovary Syndrome (PCOS)?

PCOS can manifest with the following symptoms:

• Irregular periods
• Hair growth on the face and body
• Acne
• Pelvic pain

Conclusion

Due to the importance of the endocrine system for body function, any anomalies in the control, regulation, production, secretion, and activity of hormones can lead to conditions or disorders that affect development, growth, and reproduction.

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• Stress and Anxiety
• Depression
• Premenstrual syndrome
• Diabetes
• Hypoglycemia
• Hyperthyroidism
• Bulimia
• Graves’ disease
• Medication
• Social factors

I. Hunger and Mental Disorders

1- Hunger, Stress, and Anxiety

The link between appetite, stress, and anxiety is associated with the “Fight-or-Flight” mechanism that involves hormonal communications between parts of the brain, including the hypothalamus and the pituitary gland, and the adrenal glands found on top of the kidneys.

Generally, in temporary stressful situations, the hypothalamus secretes CRH (corticotropin-releasing hormone) to stimulate the secretion of ACTH (Adrenocorticotropic hormone) by the pituitary gland leading to the secretion of the hormone noradrenaline (norepinephrine) by the adrenal glands which suppress appetite [1].

Epinephrine prevents appetite by inducing an increase in glucose blood level which signals to the brain that there is enough glucose available for the body cells to generate energy.

In the event of prolonged stress and anxiety, the hypothalamus secretes CRH to stimulate the secretion of ACTH by the pituitary gland leading to the secretion of a glucocorticoid known as cortisol by the adrenal glands that increase appetite, and therefore, hunger [2].

Cortisol indirectly increases appetite by stimulating appetite-promoting factors such as leptin, neuropeptide Y, or cytokines [3].

2- Hunger and Depression

Depression can either increase or decrease appetite depending on the activation or suppression of the activity of certain parts of the nervous system.

In case of increased appetite, there is a hyperactivation of the nervous system reward circuitry which contains pleasure centers.  This circuitry includes a pathway known as the dopamine reward pathway (mesolimbic pathway) responsible for the release of dopamine that promotes motivation and desire for reward stimulus such as an increase in appetite.

3- Hunger and Bulimia nervosa

Bulimia or bulimia nervosa is an eating disorder characterized by excessive eating followed by purging (vomiting) due to feelings of shame or guilt, associated with a potential weight gain. Bulimia is often associated with anxiety and depression.

Binge eating, purging, and the feeling of hunger appear to be associated with hedonic processes that involve motivation for pleasure, such as binge eating, and avoidance of pain such as potential weight gain. Therefore, purging is associated with preventing potential weight gain resulting in a vicious circle of binge eating, purging, and hunger [4].

II. Hunger and Pregnancy

During pregnancy, feeling hungry is natural and common, particularly during the second semester due to cravings, morning sickness, and the necessity to feed the growing baby. For this, a pregnant woman requires an additional supply of energy that triggers hunger and the need to consume more food.

II. Hunger and Premenstrual Syndrome

Physical and emotional changes take place before the start of the menstrual period and are known as premenstrual syndrome (PMS). During this period symptoms, such as stress, anxiety, sleeping difficulty, headache, mood swings, and increased hormonal levels, are common.

The level of hormones such as estrogens, serotonin, and cortisol are significantly increased resulting in metabolic surges and enhanced appetite.

III. Hunger and Chronic Diseases

1- Hunger and Diabetes

During diabetes, there is an increase in glucose levels in the blood known as hyperglycemia. However, the glucose is not being delivered to the cells to produce the energy necessary for their function.

Insulin resistance or lack of it results in a reduction of glucose absorption by the cells resulting in excessive hunger known as polyphagia.

2- Hunger and Hyperthyroidism

Hyperthyroidism is a disorder characterized by increased production by the thyroid of the thyroid hormones thyroxine (T4), and triiodothyronine (T3) that leads to an increase of the body metabolism and energy production.

This excessive metabolic demand is associated with increased glucose consumption by the cells which lowers the level of glucose in the blood causing hunger.

3- Hunger and Graves’ Disease

Graves’ disease is an autoimmune disease that affects the thyroid and causes hyperthyroidism. The increased metabolic demand for glucose and energy production results in hunger attacks.

4- Hunger and Hypoglycemia

Hypoglycemia is associated with a reduction in glucose level in the blood reaching a level of under 4 mmol/L due to several causes such as diabetic treatment using insulin and sulfonylureas, tumors, infections, organ failure, autoimmune diseases, and endocrine diseases [5]. This reduction reduces the level of glucose available for the cells’ function which triggers hunger.

For instance, insulinoma, a small tumor of the pancreas, results in increased secretion of insulin which increases glucose intake by the body cells.

IV. Hunger and Medication

Appetite suppressants or diet pills are used to help individuals lose weight by reducing the brain urge to consume food. Withdrawing from using these medications can trigger hunger and the need to consume more food and energy.

As mentioned above, diabetic medications, such as insulin and sulfonylureas, also reduce the level of glucose in the blood which triggers the need for more energy, and therefore, hunger.

V. Hunger and Social Factors

Several societal factors can promote hunger and weight loss over a healthier diet that provides quality nutrients to our bodies. For instance, the need to lose weight in a short period of time can be dictated by certain cultures that are concerned with body aesthetics.

Another factor is associated with a type of food. A diet rich in carbohydrates increases appetite due to the fast release of glucose in the blood and its rapid use by the cells of the body which results in increased appetite and hunger.

Conclusion

In general, feeling hungry is normal and common in healthy individuals due to physical and mental activities. However, hunger can also be due to more mental disorders and chronic diseases that require treatment. In the case of mental disorders such as anxiety and depression, antidepressants, anxiolytics, and cognitive-behavioral therapies are required to reduce appetite and prevent weight.

For hunger related to chronic diseases, such as diabetes, hyperthyroidism, and Graves’ disease, a follow-up by professionals is essential to monitor both treatment and excessive hunger known to be associated with these diseases.

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• Sympathetic activation
• Intrathoracic pressure changes
• Oxidative stress
• Abnormalities in coagulation factors
• Endothelial damage
• Inflammatory mediators

Approximately 34% of middle-aged men and 17% of middle-aged women are diagnosed with OSA [1]. The prevalence of OSA is estimated at 40% to 80% in patients with hypertension, coronary artery disease, heart failure (HF), atrial fibrillation (AF), pulmonary hypertension (PH), and stroke [2].

What Is Sleep Apnea?

Sleep apnea is a sleep disorder that is characterized by pauses in breathing or shallow breaths during sleep. These pauses can last for several seconds to minutes and can occur 30 times or more per hour.

Each pause in breathing reduces the amount of oxygen that reaches the brain, which can lead to snoring, interrupted sleep, and excessive daytime sleepiness. Sleep apnea is a serious medical condition that can significantly impact the quality of life.

1- Sympathetic activation

The sympathetic nervous system is a part of the autonomous nervous system responsible for the fight-or-flight response. Its repetitive activation by apnea results in increased systolic blood pressure that leads to hypertension and its complication with time [3]. Repetitive apnea may also lead to an autonomic imbalance and reduced heart rate variability [4].

Treatment with nasal continuous positive airway pressure (CPAP) has been shown to reduce blood pressure during the day and night. CPAP treatment of patients with sleep apnea and heart failure or congestive heart failure resulted in the reduction of systolic blood pressure and an improvement of the left ventricular systolic function [5]

2- Intrathoracic pressure changes

Due to the anatomical location of the heart and lungs in the thoracic cage, the interactions between the two are frequent.

Although both heart and lungs occupy limited spaces within the thoracic cage, the breathing dynamic of the lungs results in changes in the space it occupies, and therefore, affects the space occupied by the heart.

These breathing dynamics result in changes in the external constraint of the heart function, blood volume redistribution, direct systolic ventricular interaction (increased pressure by the pericardium), and afterload of the left ventricular.

An increased intrathoracic pressure limits the ventricular diastolic loading resulting in increased direct ventricular interaction, which may limit the filling of the left ventricle [6]. This interaction between the heart and the lungs may explain the association between sleep apnea and cardiovascular morbidity.

3- Oxidative Stress, Inflammatory Mediators, and Endothelial Damage

Hypoxia is a condition associated with a decrease in the level of oxygen available to the body’s tissues. This condition is commonly observed in patients with sleep apnea [7].

Hypoxia triggers an inflammatory response and an increase in innate immune cells such as neutrophils. These cells secrete reactive oxygen species (ROS) or destructive proteinases that are responsible for tissue damage, including damage to the tissues of the cardiovascular system [8].

Neutrophils also activate the transcription factor HIF-1 (Hypoxia Inducible Factor 1) which promotes the activation of endothelial cells, which are essential for the formation of the blood vessels. However, during hypoxia, endothelial cells express adhesion molecules and proinflammatory cytokines that result in endothelial damage leading to defects in vascular formation [9].

4- Abnormalities in coagulation factors

Blood platelets play an essential role in coagulation, thrombosis, and wound healing. During hypoxia, HIF-1 can promote the activation of platelets, and therefore, increase their blood content [9].

Several studies have shown a strong correlation between the increase in platelets, thromboembolic complications, and worse outcomes of cardiovascular events. It was also reported that blood viscosity due to platelet reactivity is increased in patients with OSA in the morning [10].

5- Potential Factors Influencing the Relationship Between Sleep Apnea and Cardiovascular Diseases

Metabolic syndrome comprises related diseases such as obesity, hypertension, diabetes, and dyslipidemia (abnormal cholesterol or triglyceride levels). Having one of these conditions significantly increases the risk of serious disease, including cardiovascular morbidity and mortality from coronary heart disease and stroke.

Several studies investigated the relationship between sleep apnea and diseases related to metabolic syndrome [5].

A study investigated the correlation between obesity and apnea and found that 60% of obese men had sleep-disordered breathing and 27% had obstructive sleep apnea. Another study reported that 60% to 90% of patients with sleep apnea are obese.

Regarding the relationship between sleep apnea and hypertension, a study found that about 40% of patients with sleep apnea suffer from hypertension.

An association between diabetes and sleep apnea was investigated by a study that found that patients with sleep apnea have increased glucose levels and increased insulin resistance.

Although dyslipidemia is a known factor contributing to cardiovascular diseases, a relationship between sleep apnea and dyslipidemia has not yet been established and future studies will certainly investigate a potential association.

Conclusion

Due to the complexity of the factors involved in the relationship between sleep apnea and cardiovascular diseases, the management of patients with OSA requires the involvement of several healthcare professionals including a sleep specialist, cardiologist, primary provider, otolaryngologist, dietitian, neurologist, and pulmonologist. 

Treatments also exist and include CPAP, auto-titrating PAP, bilevel PAP, adaptive servo-ventilation, positional therapy, lifestyle intervention (e.g., weight loss), upper airway surgery, upper airway neurostimulation, oral appliances, and bariatric surgery. Unfortunately, these treatments may prevent OSA but cannot treat some of the underlying causes that require other types of treatments.

References

[1] Peppard, P.E., Young, T., Barnet, J.H., Palta, M., Hagen, E.W. and Hla, K.M., 2013. Increased prevalence of sleep-disordered breathing in adults. American journal of epidemiology, 177(9), pp.1006-1014.

[2] Javaheri, S., Barbe, F., Campos-Rodriguez, F., Dempsey, J.A., Khayat, R., Javaheri, S., Malhotra, A., Martinez-Garcia, M.A., Mehra, R., Pack, A.I. and Polotsky, V.Y., 2017. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. Journal of the American College of Cardiology, 69(7), pp.841-858.

[3] Fletcher, E.C., 2003. Sympathetic over activity in the etiology of hypertension of obstructive sleep apnea. Sleep, 26(1), pp.15-19.

[4] Guzzetti, S., Piccaluga, E., Casati, R., Cerutti, S., Lombardi, F., Pagani, M. and Malliani, A., 1988. Sympathetic predominance in essential hypertension: a study employing spectral analysis of heart rate variability. Journal of hypertension, 6(9), pp.711-717.

[5] Jean-Louis, G., Zizi, F., Clark, L.T., Brown, C.D. and McFarlane, S.I., 2008. Obstructive sleep apnea and cardiovascular disease: role of the metabolic syndrome and its components. Journal of Clinical Sleep Medicine, 4(3), pp.261-272.

[6] Verhoeff, K. and Mitchell, J.R., 2017. Cardiopulmonary physiology: why the heart and lungs are inextricably linked. Advances in physiology education, 41(3), pp.348-353.

[7] Friedman, M., Landsberg, R. and Ascher-Landsberg, J., 2001. Treatment of hypoxemia in obstructive sleep apnea. American journal of rhinology, 15(5), pp.311-313.

[8] Williams, A.E. and Chambers, R.C., 2016. Neutrophils and tissue damage: is hypoxia the key to excessive degranulation?.

[9] Lavie, L., 2003. Obstructive sleep apnoea syndrome–an oxidative stress disorder. Sleep medicine reviews, 7(1), pp.35-51.

[10] Toraldo, D.M., Peverini, F., De Benedetto, M. and De Nuccio, F., 2013. Obstructive sleep apnea syndrome: blood viscosity, blood coagulation abnormalities, and early atherosclerosis. Lung, 191(1), pp.1-7.

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Although energy drinks may enhance alertness and improve reaction time, there is a growing body of scientific evidence showing that energy drinks can have serious health effects on children, teenagers, and young adults. These effects include seizures, diabetes, cardiac abnormalities, and mood and behavioral disorders [1]. 

What Are the Effects of Energy Drinks on Health?

1- Effects of Energy Drinks on Mental Health

Many studies investigated the link between energy drinks and mental health problems such as stress, anxiety, and depression; however, further studies are required to confirm this relationship.

Effects of Energy Drinks on Stress

Although several studies reported a positive correlation between energy drinks and stress, most of them were inconclusive due to the statistical methods used and the measuring factors included in the studies.

A study that investigated the relationship between perceived stress, consumption of energy drinks, and academic performance among 136 college students found positive correlations between the student’ perceived stress and energy drinks consumption. [2]. However, several studies provided no significant correlations between the consumption of energy drinks, stress, and PTSD (Post-Traumatic Stress Syndrome) [1].

Effects of Energy Drinks on Anxiety

A positive correlation between energy drinks and anxiety was reported by some studies, while others lacked statistical significance to back up their results. Two studies reported a positive correlation between the consumption of energy drinks and anxiety scores.

One study that included 107 young adults consisting of college student-athletes, Reserve Officers Training Corps cadets, and psychology students, found that 29% of the participants who consumed energy drinks had anxiety [3]. The other study reported a similar result; however, the effect was only significant in male participants [4].

On the other hand, a study reported a positive correlation between caffeine consumption and anxiety in secondary school children; however, no statistically significant correlation between caffeine consumption from energy drinks and anxiety was observed [5].

Effects of Energy Drinks on Depression

A very large study of Canadian schoolchildren (N = 8210) reported a correlation between depression and the consumption of energy drinks at least once per month or more [6]. A similar result was also reported by another study that reported a correlation between anxiety and consumption of ≥100 mL/day of energy drinks [7].

Interestingly, a study reported a correlation between the consumption of energy drinks and depression, self-harming behavior, and suicidal thoughts in 10th-grade students from Turkey [8].

However, other studies that investigated the association between the consumption of energy drinks and depression in British secondary school children and fourth-year US undergraduate students, have found no positive association [5][9].

2- Effects of Energy Drinks on the Cardiovascular System

Energy drinks have a high content of caffeine that has been associated with multiple cardiac comorbidities including palpitations and arrhythmias such as atrial fibrillation and supraventricular and ventricular ectopy due to the increase in blood pressure [10]. Additionally, symptoms of caffeine overdose also include irritability, insomnia, tremors, and seizures.

3- Effects of Energy Drinks on Sleep

Sleep is controlled by the brain through the suprachiasmatic nucleus of the hypothalamus. The sleep pattern occurs through repetition of a cycle that comprises 5 phases, including light sleep, slow-wave sleep, delta sleep, deep sleep, and REM.

Several studies in adults have found that drinking high amounts of caffeine reduces the percentage of time spent in slow-wave or deep sleep in a dose-related manner and leads to insomnia. They also found that it alters the temporal organization of rapid eye movement (REM)/non-REM sleep [11]. In teens, caffeine intake has also been associated with shorter sleep duration [11].

5- Energy Drinks and Diabetes

The consumption of high amounts of sugar for a prolonged period can result in obesity due to an unbalance in energy consumption. Energy drinks contain large amounts of sugar which result in excessive consumption of energy leading to its storage in the form of fat. Obesity has been reported as one of the major risks of diabetes type 2.

Conclusion

Although energy drinks are widely commercialized as products that increase energy, mental alertness, and physical performance, some studies highlighted their potential negative effects on mental health, cardiovascular system, and risk of diabetes. Therefore, reducing or stopping their consumption may be a good way of preventing any potential health issue. Additionally, the high content of sugar in energy drinks is also a sufficient alarm that should raise awareness about their consumption, particularly by young individuals.

References

[1] Richards, G. and Smith, A.P., 2016. A review of energy drinks and mental health, with a focus on stress, anxiety, and depression. Journal of caffeine research, 6(2), pp.49-63.

[2] Pettit, M.L. and DeBarr, K.A., 2011. Perceived stress, energy drink consumption, and academic performance among college students. Journal of American college health, 59(5), pp.335-341.

[3] Stasio, M.J., Curry, K.I.M., Wagener, A.L. and Glassman, D.M., 2011. Revving up and staying up: energy drink use associated with anxiety and sleep quality in a college sample. College Student Journal, 45(4), pp.738-749.

[4] Trapp, G.S., Allen, K., O’Sullivan, T.A., Robinson, M., Jacoby, P. and Oddy, W.H., 2014. Energy drink consumption is associated with anxiety in Australian young adult males. Depression and anxiety, 31(5), pp.420-428.

[5] Richards, G. and Smith, A., 2015. Caffeine consumption and self-assessed stress, anxiety, and depression in secondary school children. Journal of psychopharmacology, 29(12), pp.1236-1247.

[6] Azagba, S., Langille, D. and Asbridge, M., 2014. An emerging adolescent health risk: Caffeinated energy drink consumption patterns among high school students. Preventive Medicine, 62, pp.54-59.

[7] Trapp, G.S., Allen, K., O’Sullivan, T.A., Robinson, M., Jacoby, P. and Oddy, W.H., 2014. Energy drink consumption is associated with anxiety in Australian young adult males. Depression and anxiety, 31(5), pp.420-428.

[8] Evren, C. and Evren, B., 2015. Energy-drink consumption and its relationship with substance use and sensation seeking among 10th grade students in Istanbul. Asian journal of psychiatry, 15, pp.44-50.

[9] Arria, A.M., Caldeira, K.M., Kasperski, S.J., Vincent, K.B., Griffiths, R.R. and O’Grady, K.E., 2011. Energy drink consumption and increased risk for alcohol dependence. Alcoholism: Clinical and Experimental Research, 35(2), pp.365-375.

[10] Wassef, B., Kohansieh, M. and Makaryus, A.N., 2017. Effects of energy drinks on the cardiovascular system. World journal of cardiology, 9(11), p.796.

[11] Roehrs, T. and Roth, T., 2008. Caffeine: sleep and daytime sleepiness. Sleep medicine reviews, 12(2), pp.153-162.

[15] Bray, G.A., 2004. Medical consequences of obesity. The Journal of Clinical Endocrinology & Metabolism, 89(6), pp.2583-2589.

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What Are the Causes of Dizziness?

The common causes of dizziness are labyrinthitis, stress and anxiety, headache and migraine, hypoglycemia, vertebrobasilar insufficiency, and dehydration. Less common causes are associated with excessive alcohol consumption (binge drinking), Illness, and Carbon Monoxide Poisoning.

1- Labyrinthitis

Labyrinthitis is an inflammation of the inner ear and specifically of the membranous labyrinth that leads to its irritation and swelling. This ear structure is made of a network of passages full of liquid which play an essential role in the control of sound detection and balance by the inner ear. Labyrinthitis is usually caused by a bacterial or viral infection (e.g., cold or flu).

2- Stress and Anxiety

Dizziness has been associated with panic symptoms in stressed and anxious individuals due to central-neurologic links between the vestibular system which controls the sense of balance and spatial orientation and the autonomous nervous system controls the nervous system’s unconscious activity [2].

3- Migraine

Dizziness is one of the symptoms of vestibular migraine whose causes are unknown. However, one possible explanation is a potential link between pain and swelling during inner ear inflammation and migraine and dizziness.

4- Hypoglycaemia

To function the brain requires energy that is produced from glucose that is supplied by the blood. Normally, glucose is maintained in the range of 3.9 to 6.1 millimoles per liter (mmol/L) of blood; however, diabetes patients receiving a diabetic treatment can periodically experience hypoglycemia (Low glucose level) which causes dizziness, fatigue, and weakness.

5- Hypotension

The normal blood pressure in a healthy adult is between 90/60 and 120/80 mmHg. A blood pressure of less than 90/60 mmHg can lead to dizziness. This is commonly observed in individuals with diabetes or cardiovascular diseases.

6- Vertebrobasilar Insufficiency

Vertebrobasilar Insufficiency is transitory ischemia of the vertebrobasilar circulation associated with decreased blood flow in the posterior circulation of the brain that is provided by the basilar artery. Diseases such as atherosclerosis can block or narrow this artery causing a reduced blood supply to several parts of the brain leading to dizziness and imbalance [3].

7- Dehydration

Dehydration prevents a sufficient supply of water and electrolytes to the body resulting in blood dehydration and a decrease in blood flow leading to an insufficient supply of nutrients to tissues and organs, including the brain.

8- Excessive Alcohol Consumption

Excessive alcohol consumption leads to alcohol intoxication and alcoholic ketoacidosis reduces the secretion of insulin by the pancreas which affects glucose usage by the cells in tissue and organs of the body. Diabetes can also lead to ketoacidosis, known as diabetic ketoacidosis.

9- Medication

Discontinuation of antidepressant medication, such as selective serotonin reuptake inhibitors (e.g., Prozac) results in a high frequency of dizziness that may be due to their role in improving balance control and cognitive functioning [4]. Blood pressure medication can also induce hypotension leading to dizziness.

10- Illness

Disorders such as vestibular neuritis or diseases such as Ménière’s Disease comprise dizziness as one of the main symptoms.

• Vestibular neuritis

This disorder affects the vestibulocochlear nerve within the inner ear that sends balance and head position information from the inner ear to the brain. Damage to this nerve (e.g., viral infections) disturbs the function of the nerve which results in dizziness and unbalance [5].

• Ménière’s Disease

Although the causes are not well known, this disease affects the inner ear, and its symptoms include tinnitus (Perception of internal sounds), loss of hearing, and vertigo.

11- Carbon Monoxide Poisoning

The blood transport oxygen to tissues and organs of the body to produce the energy necessary for their functions. Following, carbon monoxide exposure, blood oxygen is replaced by carbon monoxide which results in cellular toxicity.

What Is the Difference Between Dizziness and Vertigo?

Although dizziness and vertigo have been interchangeably used, dizziness is a perception associated with feeling light-headed and unsteady, while vertigo is the perception of being in movement or that your surrounding is in movement. Vertigo is also characterized by symptoms such as nausea, vomiting, sweating, and walking difficulty.

How to Prevent or Treat Dizziness?

The prevention or treatment of dizziness is focused on dealing with its causes. For instance, labyrinthitis and Vestibular neuritis, are treated with antihistamines or motion-sickness tablets. Vestibular rehabilitation through physiotherapeutic exercises is also recommended to help restore balance. Changes in lifestyle, staying hydrated, avoiding binge drinking, and reducing stress levels can prevent dizziness.

Conclusion

Dizziness is not generally associated with a serious condition; however, in certain cases, it can be due to chronic conditions such as diabetes and cardiovascular diseases which require specific treatments. It can also be related to mental disorders such as migraines, and anxiety, which also rely on anti-depressant treatments.

Unfortunately, the causes of Ménière’s disease are not well-known and the potential involvement of hereditary transmission has been proposed. In this case, the treatment relies on the use of medications that reduce nausea and diuretics to reduce liquid build-up in the inner ear.

Finally, dizziness is a symptom that is shared by several disorders such as vertigo, and therefore, it is confusing to differentiate between the two if the right questions are not asked during the diagnostic stage.

References

[1] Neuhauser, H.K., 2016. The epidemiology of dizziness and vertigo. Handbook of clinical neurology, 137, pp.67-82.

[2] Balaban, C.D. and Thayer, J.F., 2001. Neurological bases for balance–anxiety links. Journal of anxiety disorders, 15(1-2), pp.53-79.

[3] Lima, A.C., Bittar, R., Gattas, G.S., Bor-Seng-Shu, E., Oliveira, M.D.L., Monsanto, R.D.C. and Bittar, L.F., 2017. Pathophysiology and diagnosis of vertebrobasilar insufficiency: a review of the literature. International archives of otorhinolaryngology, 21, pp.302-307.

[4] Ramos, R.T., 2006. Antidepressants and dizziness. Journal of Psychopharmacology, 20(5), pp.708-713.

[5] Jeong, S.H., Kim, H.J. and Kim, J.S., 2013, July. Vestibular neuritis. In Seminars in neurology (Vol. 33, No. 03, pp. 185-194). Thieme Medical Publishers.

[6] Harcourt, J., Barraclough, K. and Bronstein, A.M., 2014. Meniere’s disease. Bmj, 349.

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GDF11 has been proposed as a rejuvenating factor as it was reported that it restores skeletal muscle stem cell function and enhances muscle repair after injury.

In this blog, scientific literature on GDF11 is explored to clarify the potential role of this factor in tissue regeneration and longevity.

I. What Is the Function of GDF11 in the Body?

Before discussing the role of GDF11 in the body, it is important to provide information on its expression in adults and during embryogenesis.

1. Where Is GDF11 Expressed in Humans?

A. Where is GDF11 Expressed in Human Adults?

GDF11In humans, the GDF11 protein is highly expressed in the brain, testis, soft tissue, breast, placenta, prostate, stomach, epididymis, and gallbladder. It is mildly expressed in the intestines, salivary glands, the thyroid, the parathyroid, the adrenal gland, the liver, and the tonsils.

However, it appears that there is no protein expression in the other organs and tissues such as the heart, the skin, skeletal and smooth muscles, or the bone marrow [2].

B. Where is GDF11 Expressed During Human Embryogenesis?

Although based on RNA studies in mice, Gdf11 is mostly expressed in the primitive streak and tailbud regions. The primitive streak is a structure that generates new mesodermal progenitors (stem cells) that migrate and differentiate into the mesoderm germ layer that generates future cells such as cardiac muscle cells, skeletal muscle cells, tubule cells of the kidney, red blood cells, and smooth muscle cells (in the gut).

The Tail bud or caudal cell mass is the embryonic structure that is later responsible for the generation of the lower end of the spinal cord [3].

2. How does GDF11 Function?

As a member of the superfamily of the Transforming Growth Factor beta (TGF-β) and the subfamily of the BMP, GDF11 induces cellular signaling through the canonical (classical) signal transduction pathways involving R-SMADS and SMAD4.

However, GDF11 also induces cellular signaling through non-canonical pathways such as the MAPK (Mitogen-Activated Protein Kinase) pathway. Both signalings require the binding of GDF11 to the activin receptors type II A or B [4].

The activation of the canonical and non-canonical pathways results in the transcriptional induction of the expression of genes that control cell proliferation and differentiation, wound healing, and the immune system [5].

3. How Is GDF11 Activated?

Although little is known about the mechanisms that induce the expression of GDF11, a study showed that histone deacetylase 3 (HDAC3), might be involved. The inhibition of HDAC3 using the drug trichostatin A (TSA) promoted the expression of GDF11 [6].

4. What Is the Role of GDF11 in Regeneration?

Although performed in mice, several studies reported that GDF11 can reverse age-related cardiac hypertrophy, and dysfunction of skeletal muscles, accelerate skin wound healing, improve the neuronal activity in the hippocampus, and enhance angiogenesis by promoting the therapeutic functions of mesenchymal stem cells.

A. Does GDF11 Improve Age-Related Vascular and Neuronal Activity in the Hippocampus?

A study reported that bloodstream delivery of GDF11 to older mice improves vasculature and promotes neurogenesis in the hippocampus. The authors suggest that GDF11 could be used to improve the central nervous system function [7].  

B. Does GDF11 Reverse Age-Related Dysfunction of the Skeletal Muscle?

A study reported that the systemic delivery of GDF11 in older mice reverses functional deficiencies and restores the genomic integrity of muscle stem cells. The authors suggest that systemic delivery of GDF11 could be therapeutically used to reverse age-related skeletal muscle and stem cell dysfunction [8].

C. Does GDF11 Reverse Age-Related Cardiac Hypertrophy?

In aged individuals, heart hypertrophy is frequently associated with heart failure. Using a technique called parabiosis which consists of sharing circulation between younger and older mice with cardiac hypertrophy, a study reported that the hypertrophy was completely reversed in the older mice.

The authors identified GDF11 as the factor responsible and suggested that it could be used in therapy to reverse age-related cardiac hypertrophy [9].

D. Does GDF11 Accelerate Skin Wound Healing?

A study investigated the effects of topically applying truncated GDF11 on wound healing of diabetes mellitus (DM) mice models and reported that truncated GDF11 promotes skin wound healing by stimulating dermal fibrosis. They suggest truncated GDF11 could be used as a potential agent for treating skin wounds in the diabetic population [10].

E. Does GDF11 enhance Angiogenesis?

A study investigated the potential use of GDF11 capacity in inducing proangiogenic activities of mesenchymal stem cells (MSCs) for angiogenic therapy. They found that GDF11 promotes the therapeutic functions of MSCs that could be used for ischemic diseases [11].

II. Frequently Asked Questions about Is GDF11 a Rejuvenating Factor?

What is GDF11?

GDF11, or Growth Differentiation Factor 11, is a protein that belongs to the TGF-β superfamily and plays a role in various cellular processes, including cell growth, differentiation, and regeneration.

How does GDF11 relate to rejuvenation?

Studies have suggested that GDF11 levels decrease with age, and replenishing GDF11 levels in older animals has shown promising results in reversing age-related declines in various tissues and organs, suggesting a potential role in rejuvenation.

What evidence supports the rejuvenating effects of GDF11?

Research conducted on animal models, particularly mice, has demonstrated that restoring GDF11 levels can improve cardiac function, enhance muscle regeneration, and even reverse age-related cognitive decline.

Can GDF11 supplementation reverse aging in humans?

While animal studies have shown promising results, the effectiveness and safety of GDF11 supplementation in humans are still being investigated. Clinical trials are needed to determine its potential as a rejuvenating therapy in humans.

Are there any risks associated with GDF11 supplementation?

The long-term effects and potential risks of GDF11 supplementation in humans are not yet fully understood. Some studies have raised concerns about potential adverse effects, such as promoting tumor growth or exacerbating certain age-related conditions.

How is GDF11 administered for rejuvenation purposes?

In animal studies, GDF11 has been administered via injections or infusion directly into the bloodstream. However, the optimal dosage, frequency, and mode of administration for humans have yet to be determined.

What other factors contribute to aging besides GDF11 levels?

Aging is a complex process influenced by various genetic, environmental, and lifestyle factors. While GDF11 may play a role in certain aspects of aging, addressing other factors such as diet, exercise, and stress management is also important for overall health and longevity.

Is there ongoing research on GDF11 and rejuvenation?

Yes, research on GDF11 and its potential as a rejuvenating factor is ongoing. Scientists continue to investigate its mechanisms of action, potential benefits, and safety profile in both animal models and human clinical trials.

Conclusion

A rejuvenating function of GDF11 has been reported by several studies that involved different organs and tissues. However, all these investigations were performed in mice which may not result in similar outcomes in humans. Therefore, clinical trials using GDF11 would certainly determine if this factor is the “Mythical Fountain of Youth”.

References

[1] Morikawa, M., Derynck, R. and Miyazono, K., 2016. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harbor Perspectives in Biology, 8(5), p.a021873.

[2] https://www.proteinatlas.org/ENSG00000135414-GDF11/tissue

[3] Suh, J., Eom, J.H., Kim, N.K., Woo, K.M., Baek, J.H., Ryoo, H.M., Lee, S.J. and Lee, Y.S., 2019. Growth differentiation factor 11 locally controls anterior–posterior patterning of the axial skeleton. Journal of cellular physiology, 234(12), pp.23360-23368.

[4] Simoni-Nieves, A., Gerardo-Ramírez, M., Pedraza-Vázquez, G., Chávez-Rodríguez, L., Bucio, L., Souza, V., Miranda-Labra, R.U., Gomez-Quiroz, L.E. and Gutiérrez-Ruiz, M.C., 2019. GDF11 implications in cancer biology and metabolism. Facts and controversies. Frontiers in oncology, 9, p.1039.

[5] Morikawa, M., Derynck, R. and Miyazono, K., 2016. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology. Cold Spring Harbor Perspectives in Biology, 8(5), p.a021873.

[6] Zhang, X., Wharton, W., Yuan, Z., Tsai, S.C., Olashaw, N. and Seto, E., 2004. Activation of the growth-differentiation factor 11 gene by the histone deacetylase (HDAC) inhibitor trichostatin A and repression by HDAC3. Molecular and cellular biology, 24(12), pp.5106-5118.

[7] Ozek, C., Krolewski, R.C., Buchanan, S.M. and Rubin, L.L., 2018. Growth Differentiation Factor 11 treatment leads to neuronal and vascular improvements in the hippocampus of aged mice. Scientific reports, 8(1), pp.1-13.

[8] Sinha, M., Jang, Y.C., Oh, J., Khong, D., Wu, E.Y., Manohar, R., Miller, C., Regalado, S.G., Loffredo, F.S., Pancoast, J.R. and Hirshman, M.F., 2014. Restoring systemic GDF11 levels reverses age-related dysfunction in mouse skeletal muscle. Science, 344(6184), pp.649-652.

[9] Loffredo, F.S., Steinhauser, M.L., Jay, S.M., Gannon, J., Pancoast, J.R., Yalamanchi, P., Sinha, M., Dall’Osso, C., Khong, D., Shadrach, J.L. and Miller, C.M., 2013. Growth differentiation factor 11 is a circulating factor that reverses age-related cardiac hypertrophy. Cell, 153(4), pp.828-839.

[10] Li, Q., Jiao, L., Shao, Y., Li, M., Gong, M., Zhang, Y., Tan, Z., Wang, Y., Yang, X., Wang, Z. and Zhang, Y., 2020. Topical GDF11 accelerates skin wound healing in both type 1 and 2 diabetic mouse models. Biochemical and biophysical research communications, 529(1), pp.7-14.

[11] Zhang, C., Lin, Y., Zhang, K., Meng, L., Hu, X., Chen, J., Zhu, W. and Yu, H., 2021. GDF11 enhances therapeutic functions of mesenchymal stem cells for angiogenesis. Stem Cell Research & Therapy, 12(1), pp.1-17.

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