Brain aging and cognitive decline Flashcards
Brain aging
The brain shows structural and functional decline with age
Understanding this is critical for understanding pathological pathways
Allows for improvement of healthcare in aging population
Why do we age ?
Evolutionary theories
-passive vs active dying
How do we age ?
Biological theories
- somatic mutations (DNA damage)
-Telomeres
-Mitochondrion
-Altered proteins and waste accumulation
-Caloric restriction
-Sirtuins
Passive aging
no evolutionary benefit of longer life after reproductive maturity has been reached → lifespans evolved relative to reproductive age (fertility)
After reproductive age, deterioration in:
Mechanisms for reproduction
Maintenance and repair functions
Acitve aging
Support:
Several longevity genes (gerontogenes) exist that affect lifespan and have no apparent other function
Single gene mutations can accelerate aging (Hutchinson-Guilford progeria or Werner syndrome)
Against:
In wild, species rarely survive to ages when senescent deterioration becomes relevant
Not in agreement with “survival of the fittest” theory: anti-aging genes offering advantage to species should increase among population
Somatic mutation theory
Accumulation of random unrepaired DNA damage results in cellular senescence
-DNA damage induced aging through cell death may serve to prevent cancer
-Human and mouse mutation in DNA repair enzymes results in accelerated aging phenotypes
Telomere theory
All cells have limited capacity to replicate due to the progressive shortening of their chromosomes telomeres
- mice live short but have long telomeres
- variation in length in mouse strains is not related to lifespan
- inactivation of telomerase does not reduce lifespan in mice
- telomerase considered as an anti-aging medicine but activation may cause cancer
Mitochondrial dysfunction theory
Functionally impaired mitochondria produce reactive oxygen species (ROS) that can damage DNA, proteins and lipids
Superoxide Dismutase (SOD) enzymes reduce ROS (i.e. are antioxidants)
Support
Flies and worms with mutant SOD have reduced lifespans
Against:
Genetic mutations that reduce ROS levels do not seem to prolong lifespan
No evidence yet that antioxidants prolong lifespan in mammals (vitamin E may even cause cancer)
Altered proteins and waste accumulation theory
Accumulation of misfolded and cross-linked proteins impairs normal cell function
Hallmark of neurodegenerative diseases (e.g. Alzheimer, Parkinson)
Support:
Glucose plays important role in cross-linking of proteins (advanced glycosylation end-products)
Link with diet and with diabetes
Collagen = target protein (link with age-related cardiovascular changes and atherosclerosis)
Caloric restriction theory
Reducing food intake by ~30% shifts energy distribution from growth to maintenance → more efficient metabolism + less toxic side products of metabolism (e.g. ROS)
Against:
Demonstrated in unicellular organisms, worms, flies, mice and monkeys, but no clear evidence for humans yet
May have adverse effects on human health (e.g., loss of muscle mass, higher risk of eating disorders, ALS)
CR and longevity
CR is thought to enhance longevity by inhibiting pro-aging genes, such as mTOR
mTOR = mammalian target of rapamycin.
TOR activated by high amino acid concentrations -> promotes RNA translation.
Rapamune: immunosuppressant used in organ transplantations
Metformin: used to treat diabetes type II
CR stimulates protective mechanisms that sense low nutrition:
- FOXO = TF implicated in longevity
- Sirtuins
The sirtuin theory
Sirtuins: proteins involved in the regulation of multiple cellular processes, incl. DNA repair and oxidative stress
Support:
Sirtuins may prolong lifespan, particularly under conditions of cellular adaptation (e.g. caloric restriction),
Sirt KO mice show reduced lifespan
Against:
recently challenged by fly studies
Mechanisms of aging neurons
DNA damage:
In neurons leads primarily to silencing.
Possible protective mechanism because neurons are post-mitotic cells, cannot divide and multiply. Cell death more harmful to system.
Progressive mitochondrial dysfunction: more ROS
(see slide modest vs severe)
ROS damage promoters of neuronal genes -> silencing -> reduced expression
Caloric Restriction reduces mitochondrial dysfunction, inhibits mTOR signaling (autophagy + RNA translation)
Inhibition of mTOR (Rapamycin) mimicks CR state and increases longevity. (many unwanted side-effects)
Sirtuins:
-prevent protein aggregation
-stimulate mitochondrial function and antioxidative response
Functional disconnections - long range disconnectivity
Reduced myelination leading to slower and less efficient traveling of signals between neurons
Axonal damage can lead to weakened or disrupted communication between brain regions
Altered gene activity can reduce expression of proteins for synaptic function. Leading again to weak signals and lack of communication.
Medial temporal lobe
Removing these parts of the brain lead to anterograde and retrograde amnesia
Working memory stayed in contact
