Ageing

Defining Ageing

Chronological age \ne Functional age 

Primary aging 

  • Decline in biological function - affects us all

  • Occurs in the context of overall good health i.e. “normal” ageing process

Secondary ageing 

  • Decline in function die to hereditary defects and negative environmental influences

    • disease, poor lifestyle choices, environmental pollution and psychological stress

Biological Ageing 

  • Biological ageing or senescence = impact of time on the body

  • Changes range from those affecting its cells and their function to those affecting the whole organism

  • Linked to shortening of telomeres

  • Telomeres are repeated sequences of nucleotides on DNA

  • 6 base pairs, TTAGGG on one strand bound to AATCCC on the other strand (repeated many times)

  • Cells age based on the number of times they have replicated

  • More damage to your cells the more your cells need to replicate (i.e. tumours/cancers)

  • Cells may self-destruct if the damage cannot be easily repaired

  • Normal diploid cell can replicate

  • ~50 times before genetic material no longer able to be copied

  • Neurons are different; don’t replicate – have to be protected from damage (by glial cells)

Neurodegeneration 

  • The gradual loss of neural structure or function 

  • Neurodegenerative conditions → chronic and progressive loss 

Many things kill neurons 

  • Oxidative stress 

  • Lifestyle

  • Neuroinflammation 

  • Glutamate 

Many proteins can have toxic effects

  • Prions (misfolded proteins)

  • Beta-amyloid (plaques) 

  • Hyperphosphorylated tau (tangles)

  • Alpha-synuclein (Lewy bodies) 

Neurons may die as a result of 

  • Necrosis

    • toxins, products of metabolism, cause direct damage to the cells

  • Apoptosis 

    • programmed cell death, may be initiated due to presence of certain agents

  • One of main systems involved in cellular aging is the cholinergic system (NT - acetylcholine: ACh) (See Cholinergic system overview in additional materials). (Lee & kim., 2022)

  • Cholinergic neurons in the basal forebrain = 1st cells to be affected in degenerative disorders, followed by other subcortical regions

    • e.g. PD, Down-syndrome, progressive supranuclear palsy, CJD,

  • Korsakoff's syndrome, TBI. (Schliebs & Arendt, 2011)

  • loss of ACh in the hippocampus contributes to memory decline with ageing

  • Cortisol (stress) interferes with hippocampal morphology, suppresses proliferation and reduces volume (Kim, Pellman & Kim, 2015)

Autonomic nervous system changes 

  • Increases in blood pressure

  • Increases in cortisol release

  • More inflammation responses in the peripheral areas.

  • Weakening muscular strength (neuromuscular junction changes)

  • Sympathetic nerve activation decreases

Autonomic symptoms in older adults explains about 20% of Health-Related Quality of Life measures and 32% of depressive mood states. (Renno-Busch et al., 2021. Front. Neurol.)

Structural changes

  • Sulci and gyri become more pronounced

  • Ventricle space increases

  • Grey and white matter reductions (cell death or myelin destruction or integrity reduction).

    • Lifetime loss approx. 100grams or 7%

  • Reductions efficiency

Degradation in Grey and white matter* shows that those that demonstrate poor cognitive and/or motor functions show largest degradation

* measured via diffusor tensor imaging via DTI and FA techniques

Alzheimer’s Disease (AD) Dementia

  • Slow & progressive disease of the brain

    • Initially manifests as impairment of memory

    • Leading to problems with reasoning, planning, language, perception & emotion (e.g. depression)

  • Characterized by cerebral atrophy

    • i.e., loss of brain cells and important brain systems like the cholinergic system

  • At autopsy, AD brains contain:

    • Neurofibrillary tangles (intracellular)

    • Senile plaques (extracellular)

Demographics:

  • Increasing age = increasing prevalence of AD

  • ≈50% of people aged 85+ have disease

    • 4.4% % of those with AD were age 65+ yrs in Europe,

    • 7.7% over 70yrs have AD

    • 3.9% worldwide prevalence when 60+ yrs old

  • Declines in death rates after age 65 mean that more people will survive to the oldest ages, where risk of AD is greatest.

Diagnosis:

  • No certainty till post-mortem when brain tissue can be examined

  • During life, a patient can be diagnosed with “probable AD”

    • Neuroimaging (e.g., CT Scan, MRI, FDG-PET)

    • Medical and psychiatric history

    • Physical examination

    • Psychometrics/cognitive function assessments

    • Mini mental state exam (MMSE)

PET Scan

Stages:

Is AD typical of old age?

Amyloid Cascade hypothesis

  • Plaques composed of a protein called beta- amyloid (Abeta, Aβ), extremely toxic to brain cells in high levels

  • Failure in the metabolism of Amyloid precursor protein (APP) leads to the formation of Aβ and their aggregation as senile plaques

Amyloid precursor protein (APP)

  • Integral membrane glycoprotein expressed in many tissues

  • Concentrated in the synapses of neurons

  • Thought to have a role in synapse formation and neural plasticity

  • Precursor protein of Aβ peptide

  • Proteolysis (degradation of proteins by protease enzymes) of APP produces Aβ

  • Synthesized by the cleavage of APP by enzymes

  • β-secretase and γ-secretase

Aβ Peptide

  • The Aβ peptide is hydrophobic and self-aggregating

  • Aβ accumulates to form amyloid plaques (senile plaques)

  • Plaques interfere with neurotransmission e.g. Russell et al., (2012)

  • Aβ encourages tau proteins to form tangles inside neurons, although the mechanism is unclear

  • Aβ also directly toxic: dimers cause damage at synaptic clefts

  • Strategies to decrease the production of Aβ, stimulate the clearance of Aβ formed or prevent the aggregation of Aβ into amyloid plaques are being pursue

Tau and NFTs

  • In AD, tau undergoes hyperphosphorylation causing microtubules to collapse

  • Tau proteins clump together to form neurofibrillary tangles (NFTs)

  • AD is a true tauopathy

Genetics - ApoE

  • ApoE (Apolipoprotein E) gene

  • ApoE has a role in cellular repair and carrying cholesterol

  • Three variants:

    • E2 – 7%, linked to atherosclerosis & Parkinson’s

    • E3 – 79%, “neutral” type

    • E4 – 14%, linked to AD and other unfavourable outcomes

  • E4 variant is largest genetic risk factor for late- onset sporadic AD

  • ApoE enhances proteolytic break-down of Aβ

  • ApoE-ε4 is not as effective at catalyzing these reactions

Genetics

  • The accumulation of Aβ1–42 is dependent upon the cleavage of the β-secretase and the γ-secretase enzymes

  • Presenilin genes (PS1 and PS2) are involved in γ- secretase enzyme activity, and mutations in presenilins often lead to Aβ1-42 accumulation as found in AD patients

  • Transgenic mouse models used to study potential gene therapy for AD – “knockout” mice that inhibit γ-secretase

  • But mice showed reduced Aβ - still showed neurodegeneration suggesting that γ-secretase does have important normal function

Treating AD

  • No cure

  • Preventative actions 

Developing treatments:

  • Memantine

    • Acts on glutamatergic system

    • Blocks NMDA-type glutamate receptors

    • Reduces excitotoxicity

  • Brand names:

    • Axura, Akatinol, Abixa, Memox Namenda

  • Modest effect in moderate-to-severe AD

Cholinesterase inhibitors

  • Significant treatment effects

  • Consistently better than placebo

  • Disease eventually continues to progress

  • Average effect size is modest

  • Global changes in cognition, behaviour, and functioning have been detected by both physicians and caregivers

  • Critical targets for the effective management of AD by an increase in the availability of acetylcholine in the brain regions and decrease in the Ab deposition

Potential protective agents

  • Higher education (Cognitive reserve)

  • Ongoing intellectual stimulation

  • Brain training games e.g. Lumosity, Nintendo DS, not yet proven to be effective (Owen et al., 2010)

  • Physical and leisure/social activities

  • Physical exercise (in Tg mice) inhibits levels of Aβ ≈ benefit the brain by making it more resistant to stress- induced neuron cell damage (Um et al., 2008)