By P B TIRUPATHI PICHIAH M Sc Ph

By P. B. TIRUPATHI PICHIAH M. Sc. , Ph. D. ,

OVERVIEW 5. 6. 10. CHANGES IN THE IMMUNE SYSTEM, 5. 6. 10. 1 Normal Structure & Function a) Humoral b) Cell Mediated 5. 6. 10. 2 Age related Changes 5. 6. 11. CHANGES IN REPRODUCTIVE SYSTEM 5. 6. 11. 1. Female Reproductive aging 5. 6. 11. 2. Male Reproductive aging 5. 6. 12. METABOLIC AND HORMONAL CHANGES 5. 6. 12. 1. Energy Metabolism 5. 6. 12. 2. Fuel Utilization and Storage 5. 6. 12. 3 Hormonal Changes associated with aging a) Diabetes b) Metabolic Syndrome 5. 6. 12. 4. Pharmacological Changes associated with aging 5. 7. INTERACTION BETWEEN AGING AND DISEASE 5. 7. 1. Cardiovascular interaction 5. 7. 2. Skeletal System Interaction

IMMUNITY & AGING

5. 6. 10. CHANGES IN THE IMMUNE SYSTEM Introduction Immune System or Immunity is a medical term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. The fundamental feature of immune system is in distinguishing self and non self. Signals Pathogens Signals Immune System Signals Food Medicine Young age (High) Translation and Detection of Right Signal Old age Low Attack or Withdraw

5. 6. 10. 1 Normal Structure & Function B-Cells are responsible for Humoral immunity. , and they transforms into Plasma cells and produces antibodies That is immunoglobulin. Ig Bacterial Cell lyses T-Cells are responsible for cell mediated Immunity additionally they play role in Growth and development of B-Cells. T-Cells are responsible for graft rejection In organ transplantation.

Function of immunity Age related Changes The size of the thymus decreases with age this results in less area for the production of T cells as well as for the interaction between antigen and antibodies. There is a large immature T cells in Thymus as age proceeds and their differentiation get slower. The different sub population of T cells changes with age. With age the antibody concentration in Blood decreases.

Macrophages and poly-morpho-nuclear cells NK cells secrete factors like interferon-g (IFN-g), which activate macrophages which then eliminate the parasites. Stimulation of macrophages from old mice directly with IFN-g as well as lipopolysaccharide (LPS) was not sufficient to increase tumor lysis and nitric oxide synthase levels to those of cells from young animals NK cells cytolytic activity per cell was in fact decreased in the aged Decrease ability of signal transduction as age progress

T cells expressing NK differentiation markers in aging Aged mice express elevated percentages of NK 1. 1+ T cells in their secondary lymphoid organs, peripheral blood, and liver Age-associated Alterations In Antigen Presenting Cell To initiate an adaptive immune response, T cells must be activated by functional APCs. Antigen-pulsed macrophages from old mice stimulated lower levels of T cell proliferation than macrophages from young mice Vaccines are poorly effects the elderly peoples comparing with youngers. Cytokine Production of IL-8 was found to be significantly lower in elderly men compared to either elderly women or the young of either sex. IL 6 and TNF production requires greater quantity of LPS of pathogen in elderly. B cells Of The Innate System B 1 cells express CD 5 and are a minor subpopulation that are more abundant in the neonate and decrease in the adults.

Differentiation and Maturation of T and B Cells:

% of Degeneration of Thymus

AGING & REPRODUCTION

5. 6. 11. CHANGES IN REPRODUCTIVE SYSTEM Fertility is a capacity to give birth to a progeny. Fertility decreases with aging. One Question ? ? Why bacteria do not show aging and they can reproduce indefinitely ? ? Functional Gene Telomere Eukaryotic Replication Prokaryotic Replication Telomere Loss of Functional Genes No Loss of Functional Genes

Theories of Reproductive aging: Three Theories Proposed 1. Hypothalamic mechanism holds gonadotropin mechanism in check until Puberty 2. Gonadal Steroid inhibit hypothalamic production of gonadotropin that activate the System and Puberty comes when brain decreased the sensitivity to this inhibition. 3. Puberty arise due to removal of a local inhibitory effect of gonadal activity

5. 6. 11. 1. Female Reproductive aging Normal Structure and Function The new born female infant has 733, 000 eggs in the ovaries, which in later years Undergoes artesia and only 500 or fewer eggs are ovulated in the woman’s life Time. The most fast growing oocytes are chosen for ovulation The functional status of ovary is proportional to the follicular storage, the follicular Destruction is mediated by apoptosis.

FSH Gn. RH Hypothalamus Stop Gn. RH Ovary (Stimulate Follicle development) Pituitary Si gn al for re lea se of LH Estrogen LH ovulation. Pregnancy Follicle released Estrogen level drops LH Corpus luteum Fertilized egg if Develop the endometrium progesterone (High)

Age Related Changes: -Cessation of menstrual cycle is the major age related change in a female life span. -The ovary use to have follicle but fails to produce ovarian hormone. -Decrease in estradiol in turn become the reason for higher FSH and LH -It also cause changes in other tissues like uterus, Vagina, breast and external genital even the skin and skeleton system. Hot Flash Hypothesis: Increase in Skin temp in every 2. 7 min by average of 7. 5 ˚ F and raise in pulse rate. Hot Flash is due to release of LH and abolishes on Estrogen Therapy. Reason: The neuron for thermoregulation lie near to the hypothalamus region which is involve in LH release. It is suggested that the juxtaposition of thermoregulatory neuron and the LH regulatory hypothalamic region may be a reason

The aim of this study was to characterize age-related changes in pituitary gene expression for factors with known importance for gonadotroph function, including 1). steroid hormone receptors (Esr and Pgr), (Estrogen Receptor and Progesterone Receptor) 2) orphan nuclear receptors [Nr 5 a 1 (steroidogenic factor-1) and Nr 5 a 2 (liver receptor homologue-1)], 3) pituitary-derived polypeptides (activin, inhibin, and follistatin), as well as 4) Gonadotropin subunits and 5) Gn. RH receptors. Animal: Young (Y) 3 -mo-old and Middle aged (MA) 9 -12 month old females Experiment: Overectomized + progesterone To induce the LH surge The m. RNA levels for the gonadotropin subunits and Gn. RH receptors were decreased in middle -aged females relative to young animals. Nr 5 a 1 and follistatin, Nr 5 a 2, Inhba, and Inhbb transcripts m. RNA levels were significantly greater in Y versus MA animals

no significant differences in the m. RNA levels of Esr or Pgr family members between age groups at any time point. Nr 5 a 1 m. RNA expression was greater in Y than MA animals and was significantly decreased by Gn. RH pulses in both age groups. Follistatin m. RNA levels increased significantly with Gn. RH treatment in Y animals but were not significantly changed in the MA females. Conclusion: Suppress in pituitary gene expression postovariectomy and during the steroidinduced surge in middle-aged rats. It is proposed that age-related changes in pituitary physiology may contribute to reproductive senescence.

5. 6. 11. 2. Male Reproductive aging Sperms are produced in testis and each testis has 250 compartment. This compartment are tightly packed with a coiled structure called seminiferous tubule. The length of the semniferous tubule together of two testis is 500 m or 1640 feet. Sperm is highly specialized cell in delevering the haploid genome to the egg. Sperm matures and activated inside the vagina and this process is called Capacitation. Sperm become fully motile after 18 hrs it spends in epididymis. Sperms are stored in duct deferns. Seminal fluid consist of the secretion of seminal vesicle, the prostrate, and the bulbourethral glands. Each ejaculation contains 300 -400 million sperms

Male reproductive system is less under control to neuroendocrine comparing to female. Testosterone is produced by leydig cells in testis under the influence of LH and if FSH is present this Enhances the testosterone production. Human Males exhibit a daily, not monthly, rhythmicity in their testosterone level. This variability in gonadal hormone secretion is parallel by the finding that LH level in young men vary is pulsating manner. Sleeping and waking states show a difference in interpulse interval. Age related Changes: Mean testosterone level decrease with age, the circadian rhythm of testosterone level In young man is absent in old man. Later age the leydig cell do not response to LH and the amount of Testosterone. The motility % of sperm also decreases with age. The DNA damage is also observed in sperm of aged males. Erectile dysfunction is not correlated with age as the vascular system and signal transductions are responsible

Serum Testosterone level with time

AIM : We hypothesized that formation of spermatozoa in the testis and maturation of spermatozoa in the epididymis (ie, acquisition of motility and loss of the cytoplasmic droplet) may be altered during aging

These results clearly demonstrate that there are numerous clear changes that occur in spermatozoa during aging. Furthermore they support the hypothesis that modifications in male germ cells during aging are due to altered functions at both the levels of the testis and the epididymis

METABOLIC AND HORMONAL CHANGES

5. 6. 12. 1. Energy Metabolism Basal Metabolic Rate decline with advancing age. But these was later contradicted by The analyzing the Oxygen consumption per lit of body water is constant. The observed Decline in the BMR unadjusted for water content is due to muscles mass loss with age Human. There is no age related decline in overall resting metabolic activity of the body’s Cells and tissues.

Age related decrement in the body’s ability to produce energy above the resting level reflect by BMR at least between the age of 28 -60 year. With age the decrease ability to energy production correlates in males among various Species, the number of mitochondria have fewer in old males comparing to young.

Life Span is inversely proportional to amount of Calorie intake. Increasing metabolic rate is decreases the life span. 5. 6. 12. 2. Fuel Utilization and Storage Low Blood Glucose Energy is stored as triglyceride and 1% is stored as glycogen in muscles. Aging has less effect on glycogen is stored and utilization , but there is a protein loss muscles mass starts to decline In Young Pancreases In old Glucagons Adipocytes Energy Metabolism Accumulation of Fat Increase in Body Mass No response

5. 6. 12. 3 Hormonal Changes associated with aging Endocrine Organs In Old Animal In Young Animal Normal Weight Normal Structure Secretion level of Hormone not changed Loss of Weight Loss of Structure Secretion level of Hormone Decreases Old After 2 Hours Glucose tolerance Test Young Sweet Drink Low Blood Glucose Example: Normal Requires Normal amount of Insulin impaired Requires more amount of Insulin

a) Diabetes With age the changes of diabetes increases, it may be due to serum insulin level falls with age. More cases are with NIDD, The level of insulin is not affected but the response of target cells gets decrease. After exposure to sweet food the elderly people shows marked higher level of insulin For longer time comparing with younger people it is because of delayed insulin Clearance due to decrease uptake of insulin by the target tissues. Evolutionary theories says that thrifty genes are responsible for diabetes (Van Neel) This genes allow our ancestor to store fat Old People Diabetic people Low level of NRF-1 Many transcriptional factor level Get decrease Down regulation of antioxidant Defense gene Decrease oxidative metabolism, lipid oxidation, hyperlipidemia and insulin resistance characteristic of diabetes.

Due to Age associated NIDD There is a decrease in several hormones that include growth hormone, dehydro epiandrosterone, Sexual steroid hormone, ADH. In Young Brain Hormone In old Brain or endocrine aging and Degeneration of tissues Communication with other body part Less or no Hormone secretion impaired Communication with other body part b) Metabolic Syndrome Metabolic syndrome is a combination of medical disorders that increase the risk of developing cardiovascular disease , diabetes, Hypertension, myocardial infraction and even death. It affects one in five people, and prevalence increases with age. The term introduced by Camus (1966) and its importance is understand by Morley 2004

Age related factors includes : Diabetes, Hypertension, Hyperuricemia, lipid abnormalities, and increase probability of atherosclerosis Normal Healthy Aorta with Atherosclerosis

Leptin Brain Stop Feeding Fat Cells Apoptosis

Mutation Mitochondria t. RNA lle anticodon Diabetes, Hypertension, Hypecholesteromia, Hypomagsesemia, Diabetes and Insulin resistance 5. 6. 12. 4. Pharmacological Changes associated with aging In elderly people the volume of water is less Hence the water soluble drugs will get concentrated in blood. This may lead to stress in the liver and can Cause the decrease in liver mass. The drug and receptor binding also becomes Very poor with aging. In elderly the drug propranolol exhibit a 28% Longer half life than the youngers. And clearance rate is only 76% with youngers

5. 7. INTERACTION BETWEEN AGING AND DISEASE With aging the immune system weakens, the organs degenerates, endocrine control, Lowers, body communication system weakens, waste removal system diminishes, Drug metabolism decreases, drug receptor binding deceases, hence administration Of drug also not show very good improvement in diseased elderly people. 5. 7. 1. Cardiovascular interaction 1. The structure of heart also undergoes many changes like loss of elasticity of aorta. 2. Arterio capillaries fibrosis 3. Reduced blood flow 4. Enhanced endothelial injury 5. Defective endothelial repair 6. Elevated blood lipid. Recent reports says that with age there is a mutation in cardiac cells genome. Mitochondrial mutations also involved with several metabolic disease and the CVD is Also one of them.

5. 7. 2. Skeletal System Interaction The skeletal system also undergoes wide stress as the age progress, some of the Effects are loss of muscles mass, loss of calcium from bones which leads to osteoporosis In women Estrogen is a hormone that helps prevent calcium loss and bone breakdown. But as we Study that with age the level of estrogen lowers and this is corelated with the loss of calcium from the bones.

Conclusion Aging effects all the systems in the body from endocrine to skeletal system, Aging impairs immunity, it decreases the reproductive capacity, the body energy Production Also lowers, the hormones are less secreted which alters the metabolic pathway. Aging causes many diseases but all are indirectly associated. Aging impairs the body’s Response to various drugs. Aging occurs only due to loss of the genetic information residing in our genes. If we Can conserve the copies of the genes then its possible to slow down aging progression.

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