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
Genes Regulating Somatic Maintenance and RepairGenes Regulating Somatic Maintenance and Repair
Genes Regulating Somatic Maintenance and RepairGenes Regulating Somatic Maintenance and Repair
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
Normal Aging and Brain Normal Aging and Brain –– Loss of Neurons and SynapsesLoss of Neurons and Synapses
These structural changes affect connectivity and functional responsiveness of the aging brain
Normal Aging and Brain Normal Aging and Brain –– Loss of Neurons and SynapsesLoss of Neurons and Synapses
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
Normal Aging and Brain Normal Aging and Brain
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
Normal Aging and Brain Normal Aging and Brain
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
Normal Aging and Brain Normal Aging and Brain
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