Nepveu Lectures (Aging) Flashcards
What criteria should the hallmarks of aging fulfill?
(1) it should manifest during normal aging;
(2) its experimental aggravation should accelerate aging; and
(3) its experimental amelioration should retard the normal aging process and hence increase healthy lifespan.
What are the 9 hallmarks of aging?
(1)
Cellular senescence
(2)
Mitochondrial dysfunction
- genetic manipulations (PolgA) that impair mitochondrial function but do not increase ROS accelerate aging.
(3)
Deregulated nutrient sensing.
(4)
Loss of proteostasus
- cochaperone deficiency accelarates aging;
- overexpression of chaperones extends lifespan (worms, flies);
- Rapamycin (mTOR inhibitor) extends lifespan through induction of autophagy (yeast, worm, flies);
- Spermidine extends lifespan (macroautophagy inducer);
(5)
Epigenetic alterations
- SIRT1 improves health but not longevity.
- SIRT6 extends longevity (through IGF-1)
- HP1a inactivation shortens, wherease overexpression extends, longevity in flies.
(6)
Telomere attrition.
- associated with aging.
- telomerase inactivation causes a decrease in lifespand;
- premature aging is rescued by telomerase expression.
(7)
Genomic Instability
- Cells accumulate mutations and DNA lesions with age;
- Deficiencies in DNA repair cause progeroid syndromes;
- BubR1 transgenic mice exhibit extended lifespan.
(8)
Altered intercellular communication.
- Dysfunctional immune system
- Chronic inflammation
Contagious aging (or bystander effects)
- Circulating rejuvenating and aging factors
(9)
Stem cell exhaustion.
What is the evidence linking Cellular Senescence and Aging?
(1)
Links between replicative senescence and species life span: Cells from short-lived species tend to senesce after fewer population doublings than cells from long-lived species.
(2)
Donor age: Cells cultured from old donors tend to senesce after fewer population doublings than cells from young donors.
(3)
Premature aging syndromes:
Patients suffering from Werner syndrome (WS) age prematurely. Fibroblastic cells isolated from WS patients senesce in vitro much faster than age-matched controls.
(4) Physiological and molecular correlates:
Using markers of senescence, like senescence-associated β-galactosidase and p16INK4a expression, we can observe that the number of senescent cells in human tissues increases with age.
(5) Experimental evidence:
The INK-ATTAC Mouse model.
In the INK-ATTAC model, the p16INK4a promoter activates a caspase 8 fusion protein in response to the drug AP20187, inducing apoptosis in senescent cells. When crossed with progeroid mice, treatment with AP20187 did not extend lifespan, but it significantly protected against age-related pathologies such as cataracts, sarcopenia, and fat loss.
How does cellular senescence acts as a protective barrier against cancer progression? (Tumour Suppressive Mechanism)
(1)
Senescence is triggered by DNA damage: DNA damage can occur at telomeres or elsewhere in the genome, and this damage drives cells into senescence (a state where they stop dividing).
(2)
Oncogenes can cause senescence: Oncogenes, like RAS, may induce senescence rather than transformation (conversion to a cancerous state). This happens because:
(3)
Oncogenes can lead to replication stress.
Oncogenes can increase the production of reactive oxygen species (ROS), which damage DNA.
Senescence prevents malignant transformation: In mouse and human tissues, precancerous growths (adenomas) often contain many senescent cells. This suggests that senescence serves as a defense mechanism, halting the progression to full-blown cancer.
(4)
Key players in senescence: Tumor suppressor pathways (like p53/p21 and p16INK4a/pRB) are central to enforcing the senescence response, further preventing uncontrolled cell growth.
Findings forced a re-evaluation of the role of ROS in aging. What were these findings?
(1)
lack of correlation between the level of ROS production and longevity in various species;
(2)
the existence of long-lived mutants and species with high ROS production and high levels of oxidative damage.
(3)
deleterious rather than beneficial effects on lifespan from the administration of antioxidants in various species from invertebrates to humans;
(4)
the inactivation or over-expression of antioxidant activities in several genetically engineered organisms fails to produce outcomes that support the theory;
What can use to prevent Age-related diseases?
- TOR drives aging diseases
- Rapamycin- Based prevention can be used
What are side effects of inhibition of TOR activity?
- impaired wound healing
- insulin resistance
- cataracts
- testicular degeneration in mice
All mouse models of premature aging involve a mutation in a DNA damage response gene. What are some examples of where this mutation would be?
(1) Signalling (ATM)
(2) Checkpoint control
(3) DNA repair
(4) DNA replication (mitochondria)
(5) Telomere maintenance
The Study of Aging Using Heterochronic Parabiosis
- Heterochronic parabiosis is a surgical technique in which the circulatory systems of a young and an old mouse are connected to study the effects of young blood on aging.
- In the 1950s, scientists discovered that heterochronic parabiosis appeared to rejuvenate older animals.
- Young blood improved the proliferation and regenerative ability of muscle stem cells in old mice.
- In 2013, GDF11 (Growth Differentiation Factor 11) was found to mimic the effects of young blood by significantly reversing cardiac hypertrophy (age-related heart enlargement) in old mice.
- In 2014, raising GDF11 to youthful levels was shown to rejuvenate muscle stem cells, improving muscle strength and endurance.
When performing Heterochronic Parabiosis, what were the morphologic changes and functional changes that took place?
(1)
Morphologic changes:
- Neurogenesis
- Synaptic plasticity
- Mitochondrial patterning in muscle satellite cells
- Macroautophagy
- Cardiac hypertrophy
(2)
Functional changes:
- olfaction
- cognitive function
- exercise endurance
- grip strength
What are the effects of young blood?
- circulating factors are key in reversing several-age related pathologies
- aging is associated with “pro-aging” factors and the decline of “pro-youthful” factors,
-some rejuvenating effects do not involve stem cells.
Effects of old blood:
- skeletal muscle: inhibits repair and promoters fibrosis
- liver: suppresses cell proliferation
- brain: inhibits neurogenesis
Effects of young blood:
- Heart: reduces wall thickening
- Skeletal muscle: increases repair and improves structure
- pancreas: reverses B-cell decline
- spinal cord: enhances re-myelination following injury
- brain: improves blood flow and function
- neurons: increases number of dendritic spines
What are various strategies for the rejuvenation of the brain? (make less aged)
(1) Exercise:
Enhances neurogenesis (✔).
Enhances synaptic plasticity (✔).
Enhances cognitive function (✔).
(2) Caloric Restriction:
Enhances neurogenesis (✔?).
Enhances synaptic plasticity (✔?).
Enhances cognitive function (✔?).
(3)
Heterochronic Parabiosis:
Enhances neurogenesis (✔).
Enhances synaptic plasticity (✔).
Enhances cognitive function (✔?).
(4) Young Plasma Administration:
Enhances neurogenesis (?).
Enhances synaptic plasticity (✔).
Enhances cognitive function (✔).
Endurance Exercise and Aging in PolG Mice
PolGA refers to a mutant version of the polymerase gamma (PolG) gene, which encodes the catalytic subunit of mitochondrial DNA polymerase. This enzyme is essential for mitochondrial DNA replication and repair.
- PolG Mutant (Exercised):
Lacked visible aging signs (no alopecia or graying hair).
Appeared similar to WT littermates. - PolG Mutants (Sedentary):
Displayed accelerated aging features. - WT Mouse:
Normal appearance and aging. - Conclusion:
Endurance exercise reduces early mortality and slows down aging-related decline in PolG mutant mice.
Exercised PolG mutants showed significantly improved body condition compared to sedentary mutants.
