SUBJECT: PHYSIOLOGY TOPIC: AGEING LECTURER: DR.

GIGI FRANCISCO DATE: MARCH 2011

PHYSIOLOGY OF AGEING AGING – is actually one of the individual’s physiological processes. Thus it is absolutely NORMAL for one to experience this.

This particular graph shows us the number of deaths occurring on a particular age group. It suggests a high number of deaths at birth. Also, during the first decade of our lives, there is a marked decline in the number of deaths. After this steep decline comes a progressive increase in deaths, which occurs starting the second decade of our lives, until we grow old. Notice that as time goes by, the population is starting to bulk up in the economically productive age, as well as in the elderly age. This is actually due to the numerous medical advancements during this period that helped the entire race extend or improve its longevity. (Same is true here in the Philippines. During the 20s, 30s, most people died due to TB, because there was no cure for it during that time. However, shortly at the latter part of the same period came the advent of antibiotics. From then on, infections were easily cured, thousands of lives were saved and there was an obvious decrease in mortality. This caused us to slowly experience a stable population pyramid, wherein there is a steady mortality rate, indicating that more people are bound to die as they get older. Please check the ppt. The image is not that clear.) PHYSIOLOGY: AGEING Therefore, we are all bound to get old. Hahaha. IS AGEING A DISEASE? SHOULD WE FIGHT AGEING? BEFORE THAT, LET US CLASSIFY AGEING FIRST. o PRIMARY AGEING – intrinsic, physiological changes brought about by TIME. o SECONDARY AGEING – changes that result from the interaction of the natural, physiological ageing (PRIMARY) and stress from the environment, which includes DISEASE. However, the elderly will be more vulnerable to certain disease processes. These disease processes are the main concern of the medical science. Page 1

MECHANISMS OF AGEING o DAMAGE DUE TO OXIDATIVE STRESS AND OTHER MACROMOLECULES  Sources of Oxidative Stress - Reactive Oxygen Species (ROS), which are mainly byproducts of cellular metabolism.

- This reaction produces AGEs, Advanced Glycation End-products. - These AGEs cause damage by altering the structure of various proteins/enzymes, which would eventually lead to the disruption of its function. - In a deeper aspect, AGEs inflict harm through a process called “cross-linking” that causes intracellular damage and apoptosis. - This serves as the basis for the GLYCATION HYPOTHESIS OF AGEING by Anthony Cerami - It states that LEVEL OF GLYCEMIA = EXTENT OF GLYCATION/ PRODUCTION OF AGEs - Eg. (AGEs in proteins) altered structure/function, opacity of lens in diabetics (lead to cataract formation), stiffness of collagen in blood vessels (decrease in arterial compliance and distensibility)  Mitochondrial Damage - Since this is the major source of ROS, this is also the major target of damage. - Basis for the MITOCHONDRIAL THEORY OF AGEING. - It states that oxidative damage to the mtDNA (mitochondrial) reduces its efficiency and capability to generate ATP, which translates to an eventual decline and loss of function and afterwards, ageing.  Somatic Mutations - Damage to (genomic) nuclear DNA and mtDNA, due to constant exposure to radiation, toxic chemicals from the environment, plus oxidative stress. - When DNA is damaged, failure of DNA replication/transcription occurs. This would all boil down to disruption of normal function, which leads to ageing. - Basis for the DNA DAMAGE THEORY OF AGEING - Similarly, it states that accumulation of DNA damage interferes with DNA replication/transcription. This would cause impairment of function and thus, ageing. Although oxidative stress can cause DNA damage, it is not clear whether or not DNA damage is sufficient to cause the functional deterioration that characterizes ageing. o INADEQUACY OF REPAIR  DNA Repair - Every time your cell undergoes replication, there are minor mutations that take place, due to the imperfections in the DNA, but more importantly due to external hazards that affect this process. - However, we do not manifest any form of DNA damage immediately, because our body has its own way of counter-acting these mistakes. (Immune system quickly destroys malfunctioning cells/potentially dangerous proteins resulting from incorrect DNA replication) - As time goes by, these protective mechanisms weaken, thus not all mistakes/malfunctioning cells or proteins are corrected/ eliminated by our defenses. - Basis for the DNA REPAIR THEORY OF AGEING - It states that DNA repair mechanisms decline with age, and as these mechanisms do so, our body allows the proliferation of harmful cells/ proteins that resulted from the minute DNA replication mutations. More harmful cells/proteins = ageing.  Protein Turnover - Proteins constantly participate in various metabolic reactions taking place within the body. Page 2

- The most common source of these ROS is the Mitochondria, where the Electron Transport Chain happens. - As the ETC proceeds, it releases the most common free radical in the body, known as superoxide. However, our body has its own defense against these substances, in the form of an enzyme, Superoxide Dismutase, that will reduce the damage done by this molecule to the body by converting it to hydrogen peroxide.

- After this, the hydrogen peroxide generated will be converted to water and molecular oxygen, by another part of this defense system, the enzyme Catalase.

- An alternative defense mechanism, Glutathione Peroxidase also acts on hydrogen peroxide in a redox reaction, by converting (reducing) it to water, and having an oxidized glutathione as by-product.

- Also, Vitamins C and E help in the detoxifying of these radicals. - What happens is that, as a kid, these defense mechanisms are well-oiled and efficient; therefore they are able to keep up with all the ROS produced by metabolism. Cells are continuously protected and these radicals fail to affect our body. - However as we age, these systems gradually become inefficient and damaged, therefore producing less defensive action towards these harmful radicals. - An imbalance now sets in between the production of ROS (higher), and the processing/detoxification of these radicals (lower). As more of these radicals are produced, our cells receive more damage and start to decline in function. This damage is what we term oxidative stress. More oxidative stress = ageing. (Damage due to various Macromolecules)  Glycation and Glycoxidation - Reaction/interaction of Glucose and Macromolecule (protein/DNA)

PHYSIOLOGY: AGEING

- As they do so repetitively, their 2O structure (certain sub-configurations and motifs, eg. Alpha-helix) and 3O structure (3-D model of protein, stabilized by hydrophobic reactions and salt bridges, S-S/disulfide bonds) could possibly be affected. *biochem review. Haha* - Remember, once protein structure is affected, function comes next. Loss of function of proteins would lead to ageing. - Protein turnover (replacement of new ones), decreases with age. Abnormal proteins accumulate, because they can’t be replaced with new ones.  Membrane Deterioration - Polyunsaturated fatty acids in the membrane are also under oxidative stress, which then produces lipid peroxides. - These Lipid Peroxides change the character and affect the integrity of the cell membrane. - There is an increased amount of Cholesterol, which leads to a higher CHOLESTEROL: PHOSPHOLIPIDS (in membrane) ratio. - More cholesterol in the membrane means the membrane becomes more congested, or rigid (nagsisiksikan sila), thereby decreasing membrane fluidity. - All in all, these changes interfere with membrane function – barrier, transport of substances and cell signalling. Please do remember that all of these defective processes occur frequently in the elderly, compared to the younger ones, where sometimes, some of these defective mechanisms do not even apply. o DYSFUNCTION OF HOMEOSTASIS OF CELL NUMBER  Hyperplasia - An increase in cell number; where hyperplasia occurs, there is an enlargement in organ/tissue. - The prostate gland is normally a hyperplastic organ in an ageing male, although it can still cause problems in urination.  Neoplasia - More common for the elderly - Formation of new and abnormal cells; common cause of cancer in the elderly. (loss of deregulation of mitosis) From these concepts arise a few more mechanisms:  Limitations of Cell Division - Experiment was conducted, wherein they cultured a generation of fibroblastic cells and observed how many generations of cell division can these cells perform, provided with a good nutritional supply. - At the end of the experiment, they found out that cells started to stop undergoing cell division. - Therefore, each cell can only undergo cell division according to its pre-determined amount/level. - Remember, each cell has a pre-determined amount of cell divisions it can perform. - Called the Hayflick Limit of Cell Division - By Leonard Hayflick and Paul Moorehead - Role of Telomeres in cell division, by Calvin Harley - Telomeres are regions of repetitive DNA found at the ends of chromosomes that protect these ends from deterioration. - If not for these telomeres, the ends of the chromosomes would be eliminated upon PHYSIOLOGY: AGEING

continuous replication. It is these telomeres that give an “allowance” at the ends, so that the coding regions of the DNA will be preserved despite replication. As the ends of the telomere get chipped off slowly, the replicating capacity of the cell also decreases, due to its dependency to the telomeres. When these ends become very short already, the cell becomes incapable of cell division. - This major role of the telomere is the reason why it is implicated to be the factor that affects the predetermined amount of cell divisions a cell can undergo. The length of these telomeres can provide a glimpse of the capacity of a particular cell to divide.

- This theory strongly applies to most of the body cells; however there are still minute exemptions to this. (Skin, gametes and germ cells)  Cell Removal - Apoptosis (programmed cell death) - Dysregulation of the process of apoptosis would lead to ageing. - There would be failure to remove damaged cells. (Which are normally removed via apoptosis) - While an abnormal increase in apoptosis, would eventually cause a decrease in cell number. (eg. Brain, starts at the AGE OF 30! O.o) AGEING IN PHYSIOLOGICAL SYSTEMS

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More important than knowing the items, is noting what the trend is. All of the body parameters mentioned, (conduction velocity, basal metabolic rate…) are all set to decline some point in our lives. o LOSS OF HEIGHT  We will all shrink.  Women start to shrink at the age of 20. Peak height at the age of 15-16.  Men start to shrink at the age of 25. Peak height at age 18.  Due to the compression of the cartilaginous disk and eventual loss of integrity of vertebral bones. o DECREASE IN LEAN BODY MASS  Increase in adipose tissue mass, even in active, sporty individuals.  Changes in the metabolism (decline in metabolism), then causes a change in the proportions of adipose tissue in the body.  Redistribution, accumulation of body fat (visceral and abdominal cutaneous tissue) o SKIN  Epidermis thickness decreased; this causes a decrease in melanocytes, which in turn causes decreased protection against UV radiation. (elderly are more prone to skin cancer)  Dermis, decreased collagen and elastin. (loss of skin elasticity)  Treatment via Retinoic Acid simply causes an inflammation reaction, which, after some time will subside and you will return to your original skin again.  Decreased sweat glands and sebaceous glands.  Decreased melanocytes in hair cells. Means more gray hair. o SKELETAL MUSCLE  Decrease in muscle mass, progressive atrophy of muscles  Gross Sarcopenia, a decrease in muscle mass, sets in.  This is all due to inactivity, and the loss of innervation of these muscles (loss of type II motor neurons, which naturally degenerate in time)  Causes decrease in fine motor control  Reduction in overall muscle strength. o BONE  Osteoporosis, wherein bone resorption exceeds bone formation (loss of bone mass)  Increased risk of bone fractures; basic rule: elderly should not fall.  Contrary to popular belief, both BOYS and GIRLS are affected. The more dramatic effect only seen in girls due to the effects of menopausal period.  Even if bone density is improved by medicine, there are still evidences that suggest sustained bone fractures, which usually occur at the head of the femur. o SENSORY FUNCTIONS  Decline in all of your sensory functions.  Decreased touch sensitivity, vibratory sense and twopoint determination  Hearing - Presbycusis, loss of hair cells in the organ of corti  Vision - Presbyopia, decreased lens elasticity and loss in power of accommodation - Possible diseases: cataract and glaucoma  Taste - Deterioration of the ability to discriminate tastes  Olfaction, reduced. PHYSIOLOGY: AGEING

 TASTE and OLFACTION AGEING would result to “blunttasted food”. o MOTOR FUNCTION  Decrease/slowing of reaction time, which is reflective of;  Decrease/slowing of central processing  Posture and balance deteriorates o COGNITIVE FUNCTION  Intelligence, memory and learning - DECLINE IS NOT SIGNIFICANT. - Trouble could be present in recent memory but they do not unlearn things. - Slowing of central processing, but still capable of learning new things. o CARDIOVASCULAR FUNCTION  Decreased arterial compliance, consequent increase in peripheral resistance - Cause an increase in systolic pressure - Therefore, increase in afterload; can cause left ventricular hypertrophy in elderly  Postural hypotension - Blunting of the baroreceptor reflex, where baroreceptors, which are supposed to quickly sense the change in blood pressure upon rising from bed, are not able to do so. - This inhibits the elderly from jolting out of the bed and running towards somewhere upon waking up, unlike us, where we can easily scram and run to school when we are 5 minutes away from the start of our Physio class. O:D o PULMONARY FUNCTION  Decrease in lung volumes  Decline in maximal oxygen intake  Decrease in strength and endurance of respiratory muscles, which lead to a lower response to physical conditioning/ exercise with age.  THIS DOESN’T MEAN YOU CAN’T EXERCISE ALREADY. You simply have to limit yourself even more due to your physical incapability. o RENAL FUNCTION  Less response to Na+ load  Less ability to concentrate/dilute urine  Impaired secretion of K+, Acids  DECREASED BLADDER CAPACITY AND COMPLIANCE; results in premature contraction even if not yet full.  This is the reason behind the main concern of elderlyurine incontinence. o GASTROINTESTINAL FUNCTION  SECOND MOST COMMON cause of hospitalization for the elderly  However, if this stays healthy, it will seem like a GI tract of any young, healthy individual.  Common problems: motility, chewing (due to presence of dentures), swallowing (due to the weakening of the muscles responsible for involuntary swallowing) and constipation (due to the less response of colonic wall to distension, therefore it stacks up so much/naiipon) CAN WE DEFER AGEING? YES! Despite the fact that we will all reach this stage in life, we can somehow do something to delay its onset.

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THEREFORE, AGEING DEPENDS ON YOUR GENES. MAINTAIN A HEALTHY LIFESTYLE, EXERCISE AND DIET. AGEING IS A NORMAL PROCESS. AFTERALL, WE DON’T HAVE TO LOOK YOUNGER TO DO THE THINGS WE ENJOY. -------------------------------------------------------------ENDofTRANX
A research conducted, wherein 2 sets of mice are fed differently, one fed continuously (ad libitum), while the other one was fed in a controlled manner, 60% of the total diet of the ad libitum mice. The research shows that the mice with a controlled diet outlived the mice that had unlimited supply of food. They started to link caloric restriction to an increase in lifespan. o CALORIC RESTRICTION  Retards growth (still unsure though)  Decreases oxidative stress, due to decrease in metabolism, decrease in production of ROS.  Decrease in caloric intake causes decrease in uptake of insulin, decrease in insulin-like growth factors and insulin-like signals, would all boil down to a lower blood sugar, where less glycation/glycosylation reactions happen.  In this case, you are simply decreasing the occurrence of all the harmful reactions we talked about (in the 2 nd page of this handout) o ANTI-AGEING MEDICINE aka MAGIC BULLETS  Vitamins C and E  AAs: Methionine  Hormones: Melatonin, DHEA, Estrogen, Testosterone, GROWTH HORMONE - Researchers conducted an experiment wherein mice were genetically modified, removing the gene for the GH receptor. The mice without GH receptor didn’t react to the hormone, therefore produced less growth yet a longer lifespan.  HOWEVER THERE IS NO CREDIBLE EVIDENCE THAT THESE WORK 100%.  CAUTION! WE ARE NOT AWARE OF THE LONG-TERM EFFECTS OF THESE SUBSTANCES. (Clinical) o PROGERIA  Rapid ageing in young people.  15 year old person that looks like (functions like, works like, body is actually like) a senior citizen.  And they actually die because of the diseases that occur commonly in the elderly. This is not completely modified or affected by the intake of various substances.

Goodluck Batch 2014! HAPPY SUMMER! SUMMMER NAAAAAA! WOOOOOOOOOOO!

PHYSIOLOGY: AGEING

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