normal aging and environment normal …endocrine system central nervous system alzheimer’s disease...

NEUROBIOLOGY OF NORMAL AGINGNEUROBIOLOGY OF NORMAL AGING

INTRODUCTION INTRODUCTION

AGEAGE--RELATED CHANGESRELATED CHANGES

NORMAL AGING AND GENESNORMAL AGING AND GENES

NORMAL AGING AND TELOMERESNORMAL AGING AND TELOMERES

NORMAL AGING AND BRAINNORMAL AGING AND BRAIN

A) Aging genes regulating somatic maintenance and repairB) Longevity assurance gene

NORMAL AGING AND ENVIRONMENTNORMAL AGING AND ENVIRONMENT

Projected Growth in Population by Age GroupProjected Growth in Population by Age Group

Immune system: Increased natural killer cell activity, increased susceptibility to infection

Cardiovascular system: Increase in size and wt of heart, increased collagen in blood vessels, altered homeostasis of blood pressure

Respiratory system: Decreased vital activity

Musculoskeletal system: Reduction in muscle mass and muscle strength, loss of bone matrix

Gastrointestinal system: Decreased blood flow to gut and liver, altered absorption from GI tract

Integument: Graying of hair, wrinkling of skin, decrease in melanin

Special senses: Reduced peripheral vision, thickening of optic lens, reduced acuity of taste, smell and touch

Biological Changes Associated with Normal AgingBiological Changes Associated with Normal Aging

1. Gross brain atrophy

2. Ventricular enlargement

3. Selective, regional neuronal loss

4. Selective deterioration of axons and dendrites

5. Appearance of senile plaques and neurofibrillary tangles

6. Selective and regional decrease in neurotransmitters/modulators

7. Regional decline in cerebral blood flow

8. Regional decline in cerebral metabolic rate

AgeAge--related Changes in the related Changes in the

Endocrine system Central Nervous SystemEndocrine system Central Nervous System

ALZHEIMER’S DISEASE

NORMAL

Aging BrainAging Brain

Three lines of evidence indicate that aging is governed by genetThree lines of evidence indicate that aging is governed by genetic factors: ic factors:

lifelife--span differences between different inbred strains of laboratory span differences between different inbred strains of laboratory animals animals

lifelife--spans of human monozygotic twin pairs are similar to each other spans of human monozygotic twin pairs are similar to each other than that than that of of dizygoticdizygotic twins twins

identification of genes in fruit flies, nematode worms and identification of genes in fruit flies, nematode worms and yeast that affect yeast that affect duration of life. duration of life.

No specific gene has so far been identified which can abolish thNo specific gene has so far been identified which can abolish the aging processe aging process

Aging genes that have been identified in organisms like fruit flAging genes that have been identified in organisms like fruit fly (y (D. D. melanogastermelanogaster), ), nematode worms (nematode worms (C. C. eleganselegans) and mammals are shown to increase life span ) and mammals are shown to increase life span by regulating by regulating

a) somatic maintenance and repair a) somatic maintenance and repair

b) longevity assurance. b) longevity assurance.

Normal Aging and GenesNormal Aging and Genes

Most of the experiments have been performed in invertebrates C. elegansand D. melanogaster - because of their short, highly plastic life-span

C. Elegans whose average life-span is about three weeks proceeds through 4 larval stages to reach adulthood

Under adverse conditions such as starvation, it diverts from normal moultsinto long-living dispersal form called the dauer larva

Dauers show resistance to stress and can survive about 6 months and then complete development on favorable conditions

Genes Regulating Somatic Maintenance and RepairGenes Regulating Somatic Maintenance and Repair

Mutagenesis studies suggest that a group of genes such as dauer formation (daf) genes (i.e., daf-2, daf-12, daf-16, daf-18and daf-23) and age-1 are involved in the transition from larval into the dauer state

Mutations in daf-2, daf-23 or age-1 genes increase adult life span by turning on gene expression that transduces dauer features

daf-2 encodes nematode IGF-I receptor whereas age-1 codes for the mammalian homologue of phosphatidylinositol-3 kinase

Mutants which involve clk genes display extended life-span

Longest live C. elegans are daf-2/clk-1 double mutants – 5 fold increase in life-span



A mutation of the gene involved in insulin signaling pathway has been shown to increase life-span of D. melanogaster

Other genes involved in increasing life-span of D. melanogaster are:Methuselah (mth) – encodes a secretin-like receptorI’m not dead yet (Indy) – a gene homologous to Krebs cycle intermediate

Overexpression of SOD and catalase can increase the life-span of D. Melanogaster

Transcriptome studies indicate - 1,264 genes exhibit age-dependent changes

The multigene major histocompatibility system (HLA in human and MHC in mice) is considered to be a source of longevity enhancing alleles

APOE2 and ACE loci have been associated with human longevity in a French centenarians study

Some human inheritable diseases, termed as Segmental Progeroid Syndrome, display few but not all signs of normal aging – caused by mutation in a gene

Longevity Assurance GenesLongevity Assurance Genes

Werner syndrome which is similar to normal aging is caused by a defect inWS gene. It encodes a DNA helicase (RecQ) that regulates genome stability

Mutation of this gene leads to impair DNA replication, DNA repair and in resolving DNA secondary structures

Longevity Assurance Genes Longevity Assurance Genes –– Werner syndromeWerner syndrome

In many species such as rodents, nematodes, spiders and fish dietary restriction is found to increase the life span.

In rodents, dietary restriction leads to 50%increase in longevity.

It is unclear whether dietary restriction affects aging rate in humans

Dietary restriction increases longevity byprotecting cells against damage

Environmental enrichment including social housing, exercise wheels, toys and activity stimuli has been documented to reduce the effects of brain aging on plasticity and cognition

Normal Aging and EnvironmentNormal Aging and Environment

In many human somatic tissues aging is marked by the loss of telomeres –located at the ends of DNA strands

Telomeres are critical in maintaining chromosomal integrity

Telomeres undergo gradual shortening by about 100 bp/cell division and when the telomeres reaches below a critical length the cells stop dividing and undergo cellular senescence

Normal Aging and TelomeresNormal Aging and Telomeres

Telomerase is an enzyme which prevents shortening of a cromosome by extending telomeric repeat sequences

The role of telomeres in cellular aging is supported by finding from cancer cells and immortalized cultured cells that have activated telomerase which enable them to divide indefinitely

Normal Aging and TelomeresNormal Aging and Telomeres

Normal aging is associated with a mild decline in cognitive functions - short-term memory, - increase in forgetfulness, - increase in time in learning new information,

- slowing in speed of response and solving problems

Brain weight and volume decrease in individuals over 60 yrs accompanied by an increase in ventricular volume.

Volume losses in age 30-90 yrs – 14% in the cerebral cortex, 35% in the hippocampus 26% in the cerebral white matter

Normal Aging and Brain Normal Aging and Brain –– Loss of Neurons and SynapsesLoss of Neurons and Synapses

Neurons are lost in certain brain regions whereas other regions are spared

In the cerebral cortex, frontal and temporal regions show loss of neurons. This could be attributed to partly shrinkage of neurons

The number of dendrites and synapses are reduced up to 20% in certain regions

In the hippocampus – neurons are lost 37% in CA4 and 43% in subiculum

In brainstem, substantia nigra and locus coeruleus exhibit loss of neurons whereas other regions such as ventral cochlear and nucleus abducens show no loss of neurons. In the cerebellum, the number of Purkinje cells decline with age


These structural changes affect connectivity and functional responsiveness of the aging brain


Most physical properties of neurons are not significantly altered:resting membrane potential, input resistance and height of action potential

LTP – a cellular basis of learning and memory - more difficult to achieve in older animals

Neurons from young animals contain a large number of small mitochondria, whereas in aged neurons there are a small number of large mitochondria

Aged neurons have a decreased functional reserve of ATP comparedto young neurons

Present in smaller number in normal aging brain particularly in the hippocampus, entorhinalcortex and amygdala

PHF tau - destabilizes cytoskeleton - death of neurons

Tangles do contain phosphorylated neurofilaments, MAP-2 and other proteins

The neurofibrillary tangles are cytoplasmic lesions made of hyperphosphorylated form of tau - a microtubule associated protein

Normal Aging and Brain Normal Aging and Brain -- NeurofibrillaryNeurofibrillary tanglestangles

Spherical, multicellular lesions containing Aβ peptides surrounded by dystrophic neurites, activated microglia and reactive astrocytes

Neuritic plaques do contain a number of other proteins including APOE, lysosomalproteases, proteoglycans, heparin sulfate and complement cascade

Aβ peptides deposited as diffuse plaques - primitive plaques - senile plaques –burned out plaques

Diffuse Αβ deposits are present in large number in normal aging brain

Diffuseplaques

Primitive plaque

Senile plaque

Burned out plaque

MicrogliaNeurite

AstrocyteAβ peptide

Normal Aging and Brain Normal Aging and Brain -- NeuriticNeuritic plaquesplaques

Normal Aging and Brain Normal Aging and Brain

LipofuscinA mixture of lipids and proteins that accumulate as brown pigment in some neurons with age. This represents failure of neurons to eliminate the products of peroxidation-induced cell damage

Lipofuscin appears as membrane bound aggregates of granular osmiophilic materials and pale homogenous droplets. Lipofuscins are found in various neuronal populations including cerebral cortex and hippocampus

Lewy bodiesFound in normal elderly individuals particularly in the substantia nigra, locus coeruleus and in the cortex

Lewy bodies are composed of a core of osmiophilic granular and filamentous materials and a peripheral halo of radially oriented filamentous materials

Granulovacular degenerationThese intracytoplasmic vacuoles which represent degenerative process are found in the hippocampal neurons

It contains proteins such as ubiquitin, tau, tubulin and neurofilament

Hirano bodiesRod shaped structures found primarily in the hippocampal pyramidal neurons.

They are composed of microfilament proteins such as actin, tropomyosin and vinculin


Marinesco bodiesIntranuclear inclusions found in substantianigra and locus coeruleus.

They appear as unbound aggregates of fine osmiophilic granular materials. Their number but not size increase with age.

Neuropil threadsThese are thread-like structure in the neuropil of the grey matter that contain PHF-tau protein.

They are restricted to the entorhinal cortex, hippocampus and amygdala


Amyloid angiopathyThis represents extracellular deposition of Aβ peptides in the arteries and arterioles of the cerebral blood vessels located primarily in the cortex

Glial changesAstrocytes and microglia are activated in aging. Their number show modest increase.

Oligodendrocytes develop swelling along their processes which possibly contain broken myelin sheaths


Factors influencing whether aging will be successful or lead to impairment.

From: Reuter-Lorenz PA and Lustig C (2005) Curr. Opi. Neurobiol. 15:245-251

normal aging and environment normal …endocrine system central nervous system alzheimer’s disease...

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