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Aging & Degenerative Diseases
Terms in this set (28)
-the process of aging is something we are all familiar with, but the biological process is still largely a mystery
-lots of disease manifests with age
-do cells show signs of age like an organism?
Discuss how aging manifests as a physiological decline.
-there have been may proposed Hallmarks of Aging, including:
1. genomic instability
2. telomere shortening
3. cellular senescence
4. stem cell exhaustion
5. collapse in proteostasis
6. mitochondrial dysfunction
Discuss how age-related physiological decline has its root at the level of the cell.
-remember, CA is an age-related disease, characterized by an increase in genetic/genomic instability
-damage can either occur spontaneously, or be induced through chemical damage or errors in DNA replication
-CA is not the only condition caused by age-related DNA damage
-artificial induction of genomic damage can provoke accelerated aging
-the mouse that have a mutant/dysfunctional helicase is unable to carry out DNA replication and repair efficiently
-note the gray hair and general frailty (also has osteoporosis, muscle wasting, infertility, and curvature of the spine)
-aging goes across species and they are identifiable in all species
Discuss genomic instability.
-some somatic cells do not have an active telomerase, or their telomerase becomes less functional with age
-telomerase lengthens telomere ends
-telomerase-deficient mice live shorten than wildtype animals
-germ cells have hyperactive telomerase which leads to a sort of unlimited lineage
-not the same for somatic lineage
-each generation lives progressively shorter
-shortening telomeres can age
Discuss telomere shortening.
-Hayflick limit: the number of times a normal cell population will divide before cell division stops
-originally observed in human fetal cells (~50 division)
-suggests that cells are not inherently immortal, but will enter senescence (irreversible cell cycle arrest) at some rate
-linked to telomere length (serves as timer)
-largely attributed to telomere shortening
-in young, cellular senescence prevents proliferation of damaged cells, thus serving a protective role
-in old, pervasive damage and senescence overwhelm regenerative capacity, and cause a number of detrimental effects when not cleared (see to the right
-senescence becomes a problem in old cells
-these cells can impact other cells
Discuss cellular senescence.
-SASP: senescence-associated secretory pehnotype
-associated with hyper-secretion of pro-inflammatory molecules (such as chemokines)
-SASP secretion allows senescent cells to affect their host tissues out of proportion of their numbers
-senolytics (which selectively target and lyse senescent cells) are thus being developed as anti-aging therapies
-target senescent cells and kill them which can take away the bad side effect
-stem cells typically allow for the regenerative capacity of tissues
-but, with age, regenerative capacity goes down, due to loss or dysfunction of stem cells
-thus, it becomes harder and harder to make new cells
-when there are no longer self-renewing (or activatable) stem cells, tissues can longer regenerate following injury or cell death
-stem cell dysfunction can be linked to defects in proteostasis and mitochondria
Discuss stem cell exhaustion.
-achieved through a balance of protein folding and protein degradation (via chaperones, lysosomes, proteasomes)
-protein aggregates are composed of proteins that have hydrophobic patches exposed to the outside environment (typically, hydrophobic patches are on the inside of a protein, away from the aqueous environment)
-these exposed hydrophobic patches can interact with other cellular components, bringing them into the aggregates or damaging them in other ways
Discuss collapse in proteostasisl
-mitochondria have their own DNA, which can be damaged with age (similar to nuclear DNA)
-mtDNA damage can lead to oxidative stress (via increased production of reactive oxygen species aka ROS)
-this leads to a vicious cycle of more mitochondrial damage, and an eventual decline in energy production
Discuss mitochondrial dysfunction.
-often, bioenergetic dysfunction of mitochondria is linked to their own fragmentation
-mito are small and fragmented
-takes mito and pushes them to be fragmented
-fragmentation should aid mitophagy, but there are defects in the mitophagy system
-so, dysfunctional mitochondria remain around, causing more stress
Discuss how mitochondrial dysfunction is linked to fragmentation.
many degenerative diseases become more common with increasing age, and show a variety of cellular hallmarks of aging
Discuss how hallmarks of aging are often associated with disease.
-most common type of dementia (a decline in mental ability that makes it difficult for you to complete daily tasks)
-often manifests with changes in memory, but some people develop problems with language, mood, and thinking
-estimated 10-30% of the population >65 years old has this disease
-currently incurable (and very poorly understood)
Discuss Alzheimer's disease.
-unknown but proposed to be linked to the accumulation of beta-amyloid in plaques and aggregation of microtubule-binding protein tau
-plaques are between nerve cells
-tangles of tau are within the nerve cells
-clumps of amyloid-beta may block cell-to-cell signaling at the synapse
Discuss the major mechanism of action of Alzheimer's disease.
amyloid precursor protein (APP) is concentrated at synapses of neurons; its abnormal cleavage (by beta and gamma secretase) produces an amyloid-beta peptide, which tends to self-assemble into oligomeric plaques in extracellular space
Discuss amyloid precursor protein (APP).
-when hyperphosphorylated, tau will associate into fibrillar tangles
-these tau tangles are unable to associate with microtubules correctly, so the microtubules will start to depolymerize
-this will destroy the supporting system (and traffic route) along dendrites and axons
Discuss what occurs as a result of tau being hyperphosphorylated.
-amyotrophic lateral sclerosis
-characterized by the progressive degeneration of motor neurons in the brain and spinal cord
-age of onset typically ~55 years old, though individuals can present with symptoms as early as in their first or second decades of life
-starts focally and then spreads: muscle cramping and weakness leads to ultimate paralysis
-common presenting phenotype: cytoplasmic mislocalization and aggregation of TDP-43 (a nuclear, DNA-binding protein)
-expansion of 6 nculeotides (GGGGCC) in a non-coding, intronic region of a gene called C9orf72
-normal person: <25 hexameric repeats
-affected individuals: 100-1000 hexameric repeats
Discuss the major molecular mechanism of ALS.
-an unconvential type of translation that does not depend on an AUG start codon but may rely on secondary structures formed from repeat-expanded RNA
-results in dipeptide repeat proteins
-repeat many times in this spot
-these dipeptide repeat proteins will then exert abnormal functions that cause disease
Discuss how repeat-associated non-AUG (RAN) translation relates to ALS.
-bind to NPC and block things
-dipeptide repeat proteins can bind to and inhibit RanGAP, or interact with FG repeats at the nuclear pore to block transport
-defects in nucleocytoplasmic transport can in turn lead to cytoplasmic mislocalization and aggregation of nuclear proteins, such as TDP-43
Discuss how there are different mechanisms that appear to converge on nucleocytoplasmic transport in regards to ALS.
-estimated 2-3% of the population >65 years old has this disease
-characterized by tremors, slow movements, and impaired gait and balance
-pathologically, linked to degeneration of the substantia nigra
-unclear what the molecular cause is...but it is known that mitochondria toxins also induce degeneration of neurons of the substantia nigra
Discuss Parkinson's disease.
-in normal cells, PINK1 is stabilized on dysfunctional mitochondria, which helps to recruit Parkin and trigger mitophagy
-Parkinson's disease patients show many mutations in PINK1 and Parkin genes
-increased mitochondrial damage with age (sporadic forms of the disease) or improper function of PINK1/Parkin (familial/hereditary) can result in an accumulation of dysfunctional mitochondria
-retaining more dysfunctional mitochondria means more oxidative damage, which harms the neurons of the substantia nigra
-interestingly, defects in proteostasis overlap with defects in mitochondria in Parkinson's disease
-alpha-synuclein: a protein that form intracytoplasmic inclusions called Lewy bodies (unclear what its normal role is)
-binds in and inhibits the electron transport chain
-aggregated alpha-synuclein will associate with mitochondria and inhibit activity of complex I in the electron transport chain and this will further increase mitochondrial stress, especially since these mitochondria will not be able to be cleared due to Parkin/PINK1 deficiency
Discuss the major molecular mechanism of Parkinson's disease.
-aging is the predominant risk factor for a variety of diseases (CA, Alzheimer's, etc)
-so, if we can treat aging, we may be able to treat a multitude of diseases at once
Discuss aging as a disease.
-caloric restriction (CR) in mice
-25%, 55%, 65%-less caloric intake increases lifespan in mice (and other animals)
-modify things in gene to modify lifespan
-mutate daf2 for slight loss of function/they live 2 x as long
-daf2 is the C. elegans insulin receptor
Discuss how interventions can help animals live longer, healthier lives.
aging is something that is controlled at the level of genes, like other biological processes
Discuss how their appears to be conservation of "longevity genes."
-N2 is wild-type
-e1368 is a mutation in the C. elegans insulin receptor
-daf-2 RNAi allows for RNAi knockdown of the C. elegans insulin receptor
-"gonad ablated" (use a laster to get rid of the gonad at an early stage of development)
-use RNAi and daf-2 KO and KO gonad
-amazingly, these animals live nearly 6x as long as their wild-type counterparts
Discuss how "super long-lived" animals can be achieved by a combinatorial approach.
-long-lived animals (caused by genetic mutation, caloric restriction, other intervention) show delayed onset of age-related phenotypes (such as protein aggregation, mitochondrial dysfunction, loss of stem cells)
-thus, therapies that oppose these cellular changes may be applicable to treating aging
Discuss hallmarks of aging that are prevented by anti-aging interventions.
-rapamycin works by inhibiting mTOR kinase (remember, mTOR is a kinase that triggers growth)
-rapamycin mimics caloric restriction
-caloric restriction activates reduced levels of insulin and IGF-1 which inhibits mTOR which is also inhibited by rapamycin (can directly inhibit mTOR)
-it would be difficult to assess (in a few years) the effect of rapamycin an human aging/longevity because humans live a few decades
-thus, researchers have started to test whether rapamycin affects aging of large dogs (which live shorter than small dogs)
-based out of University of Washington
-readouts: lifespan, cognitive function, heart function, immunity, and cancer incidence
Discuss one potential anti-aging drug.
-old mice receiving "young blood: show more youthful tissues, and better cognition
-parabiotic mice have joined circulatory systems, so they share systemic factors
-old mice gains young characteristics
-young mice gain old characterstics
Discuss how parabiotic mice suggest there may be a natural competence for rejuvenation.
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