Aging is the progressive accumulation of damage to an organism over time leading to disease and death. Aging research has been very intensive in the last years aiming at characterizing the Pathophysiology of aging and finding possibilities to fight age-related diseases. Various theories of aging have been proposed. In the last years advanced glycation end products (AGEs) have received particular attention in this context. AGEs are formed in high amounts in diabetes but also in the physiological organism during aging. Higher levels of diabetic complications are due to poor glycemic control. The incidence and prevalence of diabetes mellitus is rising. About 50% of people with diabetes mellitus are unaware of their condition. Pharmacotherapy and Therapeutic lifestyle change (Diet, Regular exercises, Sunshine, Vitamin D and Calcium normal levels) should be the cornerstone of diabetes management.

1. Advanced
Glycation
End products
(AGEs)
Dr. Fathi Neana, MD
Chief of Orthopaedics
Dr. Fakhry & Dr. A. Al-Garzaie Hospital
January, 15 - 2021

3. what is the macromolecular composition
of the cell?

4. 1- Water, 70% or more of total cell mass
2- Inorganic ions, 1% or less of the cell mass (sodium (Na+), potassium (K+), magnesium (Mg2+),
calcium (Ca2+), phosphate (HPO4
2-), chloride (Cl-), and bicarbonate (HCO3
-))
3- Carbon-containing (organic) molecules 80 to 90% of the dry weight of most cells
Carbohydrates, Lipids, Nucleic Acids and Proteins
The Molecular Composition of Cells
Nucleic Acids
DNA and RNA—are the principal
informational molecules of the cell.
(DNA) has a unique role as the genetic
material, located in the nucleus.
Messenger RNA (mRNA) carries
information from DNA to the ribosomes,
where it serves as a template for protein
synthesis. Two other types of RNA
(ribosomal RNA and transfer RNA) are
involved in protein synthesis.

5. Proteins
While nucleic acids carry the genetic information of the cell,
The primary responsibility of proteins is to execute the tasks directed
by that information.
Proteins are the most diverse of all macromolecules
Each cell contains several thousand different proteins, which perform
a wide variety of functions.
The roles of proteins include:
1- Serving as structural components of cells and tissues (Collagen
and connective tissues)
2- Acting in the transport and storage of small molecules (e.g., the
transport of oxygen by hemoglobin – Lipoproteins carrying
cholesterol)
3- Transmitting information between cells (e.g., protein hormones)
4- Providing a defense against infection (e.g., antibodies)
5- The most fundamental property of proteins, however, is their
ability to act as enzymes, which, catalyze nearly all the chemical
reactions in biological systems.
6- Thus, proteins direct virtually all activities of the cell.
The Molecular Composition of Cells

6. 1. Loose (areolar) connective tissue (delicate thin
layers between tissues; present in all mucous
membranes)
2. Adipose tissue (fat)
3. Dense connective tissue (tendons/ligaments)
4. Hyaline cartilage (nose/ends of long bones/ribs)
5. Elastic cartilage (outer ear/epiglottis)
6. Fibro cartilage (between vertebrae/knee joints/pubic
joint)
7. Bone (skeletal system)
8 Blood (blood stream)
Types of connective tissues

7. Collagen fibers
A type of protein fiber found abundantly
throughout our body.
It provides strength and cushioning to
many different areas of the body, including
the skin.
Collagen fibers
Found in our various types of connective
tissue such as cartilage, tendons, bones,
and ligaments (musculoskeletal system)
Connective
tissue fibers
Purpose Components
Collagenous
fibers
Bind bones
and other
tissues to each
other
Alpha
polypeptide
chains
Elastic fibers
Allow organs
like arteries
and lungs to
recoil
Elastic micro
fibril and
elastin
Reticular
fibers
Form a
scaffolding for
other cells
Type III
collagen
Types of connective tissue fibers
Types of connective tissue fibers

8. Effects of
Hyperglycemia
Pathogenesis

9. Effects of Hyperglycemia
Pathogenesis
1- Chronic inflammation
2- Metabolic changes (> DM 1)
3- Glycation of Collagen

10. Effects of Hyperglycemia
Pathogenesis Chronic inflammation
1- Chronic inflammation
2- Metabolic changes (> DM 1)
3- Glycation of Collagen

11. Blood sugar and inflammation
the vicious cycle
Anatomy of the Vicious Cycle
Dr. Richard K. Bernstein,
the following equation is the vicious cycle of blood sugar
and inflammation:
Inheritance + inflammation + fat in the blood feeding the
liver = insulin resistance = elevated serum insulin levels =
fat cells to build even more abdominal fat = rise in
triglycerides in the liver’s blood supply = enhanced
inflammation = increased insulin levels due to increased
resistance to insulin
Researcher Mario Kratz, PhD,
a chronic low-grade inflammation plays a role in ALL major diseases:
Heart disease, diabetes, autoimmune disorders, arthritis, fibromyalgia, generalized
inflammation, and certain cancers.
Additionally, he confirms from his findings that inflammation causes insulin resistance
the main cause of type 2 diabetes.
SALIX ALBA

12. Obesity
Free fatty acids (NEFA)
Triglycerides
Hyperinsulinemia
Systemic Insulin
resistance
Systemic Insulin
resistance
Kidney
Musculoskeletal
Vessels
DM 2
Metabolic disorders
Metabolic syndrome
Triggering adipose
tissue inflammation
Local insulin
resistance
Adipose tissue
Macrophages Liver
Local insulin
resistance
Lipogenesis
Diabetes & Inflammation—the Vicious Cycle
Anatomy of the Vicious Cycle Dr. Richard K. Bernstein
Chronic low-grade inflammation plays a role in all major diseases including musculoskeletal manifestations
Phagocytosis + Pro inflammatory
mediators
Adipokines
1- Leptin (pro-inflammatory)
2- Adiponectin (anti-inflammatory).
Hyperglycemia
Blood sugar and inflammation - the vicious cycle

13. Galectin-3 blood levels are elevated in human and rodent obesity
Galectin-3 directly impairs insulin action in myocytes, adipocytes, and hepatocytes
Galectin-3 treatment causes systemic insulin resistance in vivo
Galectin-3 loss of function improves insulin sensitivity in obesity

14. Sedentary Lifestyle
Caloric overload, High Carb-Sugar, Inactivity, Stress, Sleep, Obesity, Drugs, etc
5- 83% Type 2 diabetes
Insulin, Not Cholesterol, Is the True Culprit in Heart Disease
February 18, 2017 | 6,928 views - Dr. Joseph Mercola
Reaven GM. Physiol Rev. 1995;75:473-486
Clauser, et al. Horm Res. 1992;38:5-12.
10- polycystic Ovary
Syndrome
(PCOS)
Insulin Resistance syndrome
Hyper insulinemia - Insulin toxicity
1- Direct damage blood vessels
Intima –neoangiogenesis –plaque -
3- High blood pressure
Mg loss in urine –> spasm of blood
vessels – salt water retention
Sympathetic nervous system
4- Heart disease & failure
Endothelial dysfunction, coagulopathy,
Hypertension , coronary heart disease.
6- Obesity (abdominal),
Lipogenesis - Dyslipidemia
9- Osteoporosis
8- Certain types of cancer
as colon, breast & prostate
INSULIN
RESISTANCE
(Toxicity)
12- Ch. Inflammation
Glucose - NEFA -Triglycerides
7- Insulin-Leptin-Ghrelin
(Hunger pain)2- Coagulation & fibrinolysis
disorders
11- Higher risk of Alz.D,
Nephropathy, etc

15. Signs and symptoms of
chronically elevated insulin:
1- Fatty liver
2- Unexplained Weight Gain
abdominal obesity
3- Hunger and cravings
4- Elevated blood sugar
5- Acne and pores on the face
testosterone
6- Menstrual Irregularities
7- Polycystic ovarian syndrome
8- Hirsutism , scalp hair loss in
women
as in male pattern
9- Acanthosis nigricans
10- Skin tags
11- Increased risk of gout.
fructose convert too uric acid
12- High blood pressure
13- Puffy swollen ankles
sodium and water
Vascular & heart disease
Fatty liver
Polycystic ovarian disease (PCOS)
Acanthosis nigricans -
Acne - large pores - faceSkin tags
Do You Know Your Insulin Level ?
October 23, 2013 by David Spero, BSN, RN
Hirsutism
Abdominal obesity
Elevated blood sugar

16. Origin of Inflammation:
There are many unknowns in medicine but what causes Inflammation we do know is:
Sugar, Omega 6, Lack of exercise
1- Environmental chemicals
2- Excessive chronic stress
3- Infections, allergies (food and environmental)
4- High glucose levels
5- Excessive abdominal fat
6- High carbohydrate and sugar foods
7- High Omega 6
8- Unhealthy unnatural processed food.
9- Too little or too much physical activity (everything in life needs to be in balance in
order to achieve and maintain wellness)
The question still perplexing scientists is, which came first, the fat or the
inflammation?
Effects of Hyperglycemia
Pathogenesis Chronic inflammation

17. 1- Chronic inflammation
2- Metabolic changes (> DM 1)
3- Glycation of Collagen
Effects of Hyperglycemia
Pathogenesis Metabolic changes

18. 1- Glycosylation (Glycation) of proteins
2- Micro vascular abnormality
(Blindness, Renal failure, and Neuropathy),
3- Macro vascular abnormality
(risk for myocardial infarction, stroke, and lower limb amputation )
4- Accumulation of extracellular matrix (ECM) and soft tissue
More seen in longstanding type I
Some complications have direct association
Effects of Hyperglycemia
Pathogenesis Metabolic changes

19. Glycosylation (Glycation) of proteins

20. Glycosylation (Glycation) of proteins

21. Effects of Hyperglycemia
Pathogenesis Glycation of Collagen
1- Chronic inflammation
2- Metabolic changes (> DM 1)
3- Glycation of Collagen

22. GLUCOSE and other reducing sugars
React with proteins by a non-
enzymatic, post-translational
modification process called (non-
enzymatic glycosylation or
Glycation).
Non-enzymatic glycosylation or Glycation
Advanced-Glycation end-products (AGEs) :
The sugar-derived carbonyl group adds to a free amine, forming a reversible
adduct which over time rearranges to produce a class of products termed
advanced-Glycation end-products (AGEs)

23. Hyperglycemia
Advanced Glycosylation
End product (AGEs)
Micro & Macro vascular
damage
Collagen Dysfunction
(Glycated protein - Collagen - LDL –
LDH - Etc…)
AGEs inhibitor
Amino guanidine
Effects of Hyperglycemia
Pathogenesis Glycation of Collagen
->> dysfunction + micro-macro vascular insult
Glycation

24. 1- AGEs causes micro and macro vascular complications
-Increased vascular permeability.
- Increased arterial stiffness
- Inhibition of vascular dilation by interfering with nitric oxide.
2- Oxidizing LDL.
3- Binding cells — including macrophage, endothelial,
and mesangial — to induce the secretion of a variety of cytokines.
4- Enhanced oxidative stress. — cell dysfunction
Advanced Glycosylation End product (AGEs)
pathological effects
AGEs result from early Glycolysation - Accumulate in tissue - Damage extra and intra
cellular proteins -There are receptors on cell surface for AGEs belong to IG receptors
- Signaling lead to cell dysfunction

27. Glycolysation of collagen
fiber
Increase collagen crosslink
Increase in hydration
Increased formation
Advanced Glycosylation
End product (AGEs)
Effects of Hyperglycemia
Pathogenesis Glycation of Collagen
->> dysfunction + micro-macro vascular insult

29. How to control
Hyperglycemia
and
Diabetes mellitus

30. How to control Hyperglycemia and Diabetes mellitus
Lifestyle diseases can be reversed and cured
Therapeutic lifestyle change Rather than
treating risk factors by drugs for life
Prevent rather than treating Risk factors

31. How to control Hyperglycemia and Diabetes mellitus
Therapeutic lifestyle change
Stimulate insulin production :
1- Sunlight ->> circadian rhythm (Melatonin- Insulin)
2- Vitamin D ->> immunosuppressive (B cells)
(type 1 diabetes + 17% type 2 diabetes)
3- Drugs ->> Insulin
Improve insulin sensitivity :
1- Calcium ->> VGCC (Voltage gated calcium channel)
2- Exercise ->> Depletion of stores
3- Diet ->> LCHF vs. IF (Intermittent fasting)
(83% type 2 diabetes)
4- Drugs ->> Glucobay – Glucophage
Sunlight +Vitamin D + Calcium + Exercise + Diet
= Drugs for diabetes - its side effects

32. Rule of diet - LCHF vs. Intermittent fasting

33. The link between chronic hyperglycemia and vascular damage
has been established by four independent biochemical
abnormalities:
1- Increased polyol pathway flux,
2- Increased formation of advanced glycation end-
products (AGEs),
3- Activation of protein kinase C(PKC),
4- Increased hexosamine pathway flux.
These seemingly unrelated pathways have an
underlying common denominator: Overproduction
of superoxide by the mitochondrial electron transport
chain.
Mitochondrial reactive oxygen species (ROS) partially inhibit
the glycolytic enzymes glyceraldehyde-3-phosphate
dehydrogenase, which diverts increased substrate flux from
glycolysis to pathways of glucose over utilization. Preliminary
experimental evidence in vivo suggests that this new
paradigm provides a novel basis for research and drug
development.
Pathophysiological mechanisms of diabetic angiopathy
Author links open overlay pane lHans-PeterHammes
https://doi.org/10.1016/S1056-8727(02)00275-1Get rights and content
The sequelae of chronic hyperglycemia in diabetes of all phenotypes are divided into microvascular and
macrovascular complications.
Microvascular disease causes blindness, renal failure, and neuropathy, and diabetes-accelerated
Macrovascular disease causes excessive risk for myocardial infarction, stroke, and lower limb
amputation.

34. Figure 3. Oxidative defense strategies. CAT:
catalase; GPx: glutathione peroxidase; SOD:
superoxide dismutases.
How to reduce diabetic angiopathy

35. How to reduce diabetic angiopathy