ByP.B.TIRUPATHI PICHIAH M.Sc., Ph.D.,

OVERVIEW5.6.10.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 aging5.6.11.2. Male Reproductive aging

5.6.12.METABOLIC AND HORMONAL CHANGES5.6.12.1. Energy Metabolism5.6.12.2. Fuel Utilization and Storage5.6.12.3 Hormonal Changes associated with aging

a) Diabetesb) Metabolic Syndrome

5.6.12.4. Pharmacological Changes associated with aging

5.7.INTERACTION BETWEEN AGING AND DISEASE5.7.1. Cardiovascular interaction5.7.2.Skeletal System Interaction

IMMUNITY & AGING

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.

5.6.10.CHANGES IN THE IMMUNE SYSTEM

Signals

Signals

Sig

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Signals

Signals

Immune System Translation

and Detection of Right Signal

Attack or

Withdraw

Young age (High)

Old age Low

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5.6.10.1 Normal Structure & Function

B-Cells are responsible for Humoralimmunity., and they transforms intoPlasma cells and produces antibodies That is immunoglobulin.

Ig

T-Cells are responsible for cell mediatedImmunity additionally they play role inGrowth and development of B-Cells.

T-Cells are responsible for graft rejectionIn organ transplantation.

Bacteria Bacterial Cell lyses

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.

Function of immunity

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

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 NK1.1+ 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 cellproliferation than macrophages from young mice

Vaccines are poorly effects the elderly peoples comparing with youngers.

Cytokine Production

Production of IL-8 was found to be significantly lower in elderly men compared to either elderly women or the young of either sex.

IL6 and TNF production requires greater quantity of LPS of pathogen in elderly.

B cells Of The Innate System

B1 cells express CD5 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:

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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 TelomereTelomere

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Loss of Functional GenesNo 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 lifeTime. 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.

GnRH Hypothalamus Pituitary

FSH Ovary (Stimulate Follicle development)

Estrogen

LH

Signal for release of LH

ovulation.

Estrogen level drops

Follicle released

Corpus luteum LH

progesterone (High)

Stop GnRH

Develop the endometrium Fertilized egg if

Pregnancy

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 2.7min 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 the 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 [Nr5a1 (steroidogenic factor-1) and Nr5a2 (liverreceptor homologue-1)], 3) pituitary-derived polypeptides (activin, inhibin, and follistatin), as well as 4) Gonadotropin subunits and 5) GnRH receptors.

Animal: Young (Y) 3-mo-old and Middle aged (MA) 9-12month old females

Experiment: Overectomized + progesterone

The mRNA levels for the gonadotropin subunits and GnRH receptors were decreased in middle-aged females relative to young animals.Nr5a1 and follistatin, Nr5a2, Inhba, and Inhbb transcripts mRNA levels were significantly greater in Y versus MA animals

To induce the LH surge

no significant differences in the mRNA levels of Esr or Pgr family members between age groups at any time point.

Nr5a1 mRNA expression was greater in Y than MA animals and was significantly decreased by GnRH pulses in both age groups. Follistatin mRNA levels increased significantly with GnRH treatment in Y animals but were not significantly changed in the MA females.

Conclusion: Suppress in pituitary gene expression postovariectomy and during the steroid-induced 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 500m 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 18hrs 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 levelIn 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 modificationsin 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 ageHuman.

There is no age related decline in overall resting metabolic activity of the body’sCells 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 variousSpecies, 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

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

Pancreases Glucagons Adipocytes Energy MetabolismIn Young

In old

Pancreases Glucagons Adipocytes No response

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Accumulation of Fat

Increase in Body Mass

5.6.12.3 Hormonal Changes associated with aging

Endocrine Organs

In Young Animal In Old Animal

Loss of WeightLoss of Structure

Secretion level of Hormone Decreases

Normal WeightNormal Structure

Secretion level of Hormone not changed

Example:

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Requires Normal amount of Insulin

Requires more amount of Insulin

a) DiabetesWith 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 insulinFor 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

Diabetic people Low level of NRF-1 Down regulation of antioxidantDefense gene

Many transcriptional factor levelGet decrease

Old People

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.

Brain Hormone Communication with other body part

In Young

In old Brain or endocrine aging and Degeneration of tissues

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

Aorta with Atherosclerosis

Leptin Brain Stop Feeding

Fat Cells Apoptosis

Mutation Mitochondria tRNA 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 lessHence the water soluble drugs will get concentrated in blood.

This may lead to stress in the liver and canCause the decrease in liver mass.

The drug and receptor binding also becomesVery 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 administrationOf 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 fibrosis3.Reduced blood flow4.Enhanced endothelial injury5.Defective endothelial repair6.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 isAlso one of them.

5.7.2.Skeletal System Interaction

The skeletal system also undergoes wide stress as the age progress, some of theEffects 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 weStudy 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 impairsthe body’s Response to various drugs.

Aging occurs only due to loss of the genetic information residing in our genes. If weCan conserve the copies of the genes then its possible to slow down aging progression.

Thank You