Neuro Week 9

What is ageing

Progressive biological changes that decrease physiological function and resilience over time

At what levels do ageing changes occur

Molecular

Cellular

Tissue

Whole organism

what are examples of molecular changes

DNA damage, altered gene regulation, damaged proteins

what are examples of cellular changes

mitochondrial dysfunction, senescence, impaired recycling

what are examples of tissue changes

reduced regeneration + altered cell communication

what are examples of whole organism changes

reduced physiological reserve + increased disease vulnerability

What is the alternative definition of ageing given

Ageing = progressive decrease in ability to maintain and restore biological homeostasis

What is chronological age

Time since birth

What is biological age

Molecular/cellular/functional state of an organism

What influences biological age

Genetics, lifestyle, environment, disease, accumulated cellular damage

Can people of the same chronological age have different brain ageing trajectories

Yes – people of the same chronological age can follow very different trajectories of brain ageing

Is ageing simply a collection of diseases

No – ageing is a major risk factor for many chronic diseases, but ageing itself is not simply a collection of diseases

What is the greatest risk factor for many neurodegenerative diseases

age

Is normal brain ageing the same as neurodegenerative disease

no

What is normal ageing

Gradual molecular, cellular and functional changes. Many functions remain preserved through adaptation and compensation

What is neurodegeneration

Additional pathological processes. Progressive dysfunction and/or loss of vulnerable neuronal populations

What is the key point about ageing and neurodegeneration

Ageing increases vulnerability to neurodegeneration, but ageing itself is not neurodegenerative disease

What unique challenges does the brain present

Many neurons must survive for decades and are post-mitotic;

neurons have extremely high energy requirements;

neural function requires precise protein and organelle trafficking;

synapses require continuous remodelling and maintenance;

the CNS has relatively limited regenerative capacity;

function depends on coordinated interactions between neurons, glia and vasculature

What makes the brain particularly vulnerable to accumulated cellular damage

The long lifespan, high energy demand and limited replacement of neurons

What are the three categories of ageing hallmarks

Primary, Antagonistic, Integrative

What are primary hallmarks

Processes contributing to the initiation and accumulation of cellular damage

What are antagonistic hallmarks

Responses to damage that may initially be protective, but become harmful when chronic or dysregulated

What are integrative hallmarks

Cellular changes that converge on loss of tissue-level and network resilience

What are the primary hallmarks

Genomic instability

Telomere attrition

Epigenetic alterations

Loss of proteostasis

Disabled macroautophagy

What are the antagonistic hallmarks

Deregulated nutrient-sensing

Mitochondrial dysfunction

Cellular senescence

What are the integrative hallmarks

Stem cell exhaustion

Altered intercellular communication

Chronic inflammation

Dysbiosis

What do primary hallmarks involve

Accumulation of molecular and cellular damage that initiates ageing

What do primary hallmarks represent

Processes through which molecular damage progressively accumulates

How does DNA damage occur continuously

from endogenous and exogenous sources

what are examples of endogenous sources

reactive oxygen species, metabolic by-products, spontaneous chemical reactions, replication errors in dividing cells

what are examples of exogenous sources

UV/ionising radiation, environmental chemicals, toxins

What normally happens to DNA damage

Normally DNA damage → detection → repair

Is DNA repair always perfect

no

What happens over decades with damage and imperfect repair

Accumulated genomic abnormalities

What does genomic integrity require

Continuous maintenance throughout life

why do Neurons face a particular genomic challenge

Survive for decades without genome replacement through cell division (they cant just divide and replace)

what does high metabolic activity do

generates oxidative stress

Neurons are also highly transcriptionally active, why can that be a problem

Frequently transcribed neuronal genes can become hotspots for DNA lesions / mutations

what does Some neuronal activity even induce

DNA doublestrand breaks (ddsb) to enable expression of immediate-early genes

What makes effective DNA repair critical for neuronal survival

Long-lived neurons must maintain the same genome for decades

What cellular responses can persistent DNA damage trigger

Successful repair → function maintained

Persistent damage → altered transcription + cellular dysfunction

Severe/irreparable damage → cell death

In proliferative cells → persistent cell-cycle arrest/senescence

What is the fate of a damaged cell dependent on

Whether the damage can be successfully repaired

What are the possible fates of a damaged cell

DNA repair; Apoptosis; Cellular senescence; Necrotic cell death; Efferocytosis; Immune cell-mediated clearance

What are senolytics

Drugs that selectively kill senescent cells

What happens in neurons with apoptosis

Loss of a largely irreplaceable cell → disruption of neural circuits

What happens in microglia/astrocytes with senescence

Dysfunctional cells persist → inflammation + reduced neuronal support

What happens in endothelial cells with senescence

Impaired vascular function + blood-brain barrier dysfunction

What does the impact of accumulated DNA damage in the brain depend on

Which cell population is affected

What are telomeres

Repetitive DNA sequences protecting chromosome ends

what is telomere attrition

progressive shortening

What happens to telomeres with repeated cell division (4 things)

1. Telomeres progressively shorten

2. Critically short/dysfunctional telomeres are recognised as DNA damage

3. Persistent DNA-damage signalling

4. Senescence or apoptosis

What can progressive telomere shortening limit

The ability of dividing cells to continue proliferating

Do mature neurons divide

No – mature neurons rarely divide, so telomere length is not a simple neuronal "age clock."

Where does telomere dysfunction remain relevant

Neural stem/progenitor cells, microglia, astrocytes, vascular/endothelial cells, peripheral immune cells

What do these cells influence

The environment in which neurons function

How may telomere attrition influence brain ageing

Predominantly through dividing neural and non-neuronal cell populations rather than mature neurons themselves

What determines cell identity

Cells largely contain the same genome, but identity depends on which genes are accessible and expressed

What mechanisms regulate gene expression

DNA methylation, histone modifications, chromatin organisation

Do these mechanisms change the DNA sequence

No – they regulate gene expression without changing the DNA sequence

What is gene regulation essential for in neurons

Synaptic plasticity, learning and memory, stress responses

What can ageing disrupt

The epigenetic programmes that maintain neuronal identity and function

What are epigenetic clocks

Algorithms estimating biological age from DNA methylation

When is epigenetic age considered accelerated

When epigenetic age > chronological age = accelerated epigenetic ageing

What are the caveats about epigenetic clocks

Different clocks measure different features; they are biomarkers, not literal clocks controlling ageing; changing the biomarker does not necessarily change ageing itself

What is the key point about epigenetic clocks

Epigenetic clocks can estimate aspects of biological ageing, but they should not be mistaken for the mechanism causing ageing

What systems do cells use to maintain a healthy and functional proteome

Molecular chaperones (protein folding/refolding)

Ubiquitin-proteasome system (degradation of unwanted proteins)

Autophagy-lysosomal system (removal of larger aggregates and cellular components)

What happens to these processes with ageing

All of these processes decline

What accumulates with ageing

Misfolded/aggregated proteins – e.g., amyloid-β and tau (AD); α-synuclein (PD)

What does accumulation of misfolded proteins lead to

Increased cellular stress + impaired neuronal function

What must neurons maintain

Protein quality across enormous cellular distances, for decades, while continuously remodelling synapses

What is the proteostasis burden in dendrites

Increased local translation (monosomes); increased stress-responsive chaperones; local signal integration and plasticity

What is the proteostasis burden in axon shafts

Long-range transport; local translation (variable); increased degeneration vulnerability

What is the proteostasis burden in the soma

Transcription hub; central degradation site (autophagy); transport origin

What is the proteostasis burden in the pre-synapse

Increased proteostasis burden; vesicle trafficking; short-term signalling

What is the proteostasis burden in the post-synapse

Increased proteostasis burden; increased protein turnover; UPS-driven plasticity

What is autophagy

Lysosome-dependent cellular degradation and recycling

What are the three major forms of autophagy

Macroautophagy (cargo enclosed in an autophagosome → lysosome)

Chaperone-mediated autophagy (selected proteins transported directly into lysosome)

Microautophagy (lysosome directly engulfs cellular material)

what does autophagy do

Autophagy removes and recycles damaged or unwanted cellular material

What can macroautophagy remove

Large cellular cargo

What can an autophagosome engulf

Protein aggregates, damaged cellular components, entire organelles e.g., damaged mitochondria (mitophagy)

What are the steps of macroautophagy

1. Phagophore initiation

2. Autophagosome formation

3. Autophagosome and lysosome fusion

4. Autolysosome

5. Degradation and recycling

What is the result of macroautophagy

Recycled nutrients (amino acids, fatty acids, sugars, and nucleotides) for cellular reuse

What must neurons maintain across very large distances

Cellular quality

Where can damaged proteins and organelles accumulate

In distal axons and synapses

Where do autophagosomes form

Locally, but effective clearance depends on long-distance transport along the axon, autophagosome maturation, and access to functional lysosomes

Why does this matter with ageing

Autophagosome transport and maturation become less efficient

damaged cargo may remain in distal neuronal compartments

this places particular stress on axons and synapses

What is the key point about macroautophagy in neurons

For neurons, macroautophagy is not just a degradation problem. It is also a transport problem

What are antagonistic hallmarks

Responses to damage/stress that are initially adaptive but become harmful

How do cells respond to damage (antagonistic hallmarks)

By altering nutrient sensing (balance growth vs maintenance)

mitochondrial function (adapt energy production and stress signalling)

cellular state (senescence prevents damaged cells from dividing)

When do antagonistic hallmarks become harmful

When chronically activated or dysregulated

What do cells continuously monitor

Nutrient and energy availability to determine whether cellular resources are invested in growth or maintenance

What happens when nutrients are abundant

mTOR (i.e., build) – promotes protein synthesis and cellular growth

supports anabolic processes

suppresses autophagy

What happens when cellular energy is low

AMPK (i.e., conserve/repair) – suppresses energy-consuming processes

promotes autophagy and cellular recycling; supports mitochondrial maintenance

What does nutrient sensing balance

Cellular growth with maintenance and repair according to energy availability

What happens to cells with ageing

Cells become less able to switch appropriately between growth and maintenance

What happens to AMPK responsiveness

Decreased AMPK responsiveness = poorer adaptation to energetic stress

What happens to mTOR signalling

Persistent/inappropriate mTOR signalling = continued anabolic signalling and decreased autophagy and cellular recycling

What does this affect in neurons

Synaptic plasticity, protein turnover, mitochondrial maintenance, cellular stress responses

What is the key point about nutrient sensing and ageing

Ageing disrupts the ability to shift resources from growth toward maintenance and repair

What percentage of body mass is the brain

~2% of body mass