PSIO 487 Exam 1 Flashcards
Theory
a scientifically
acceptable general principle or
body of principles offered to
explain phenomena
Evaluate recent trends in human life expectancy and mortality rates.
life expectancy is increasing overall in the world
-modern tech and medicine
the age of death has increased in the US
can the rate of aging impact human longevity
yes
Differentiate between aging and longevity.
aging = The progressive, event-dependent decline in the ability to
maintain biochemical/physiological function
*influenced during development (environmental factors)
longevity = The length of the lifespan, independent of the biological
aging process
*genetically determined
Mutation accumulation theory (Medawar)
deleterious ‘late life’
genes/mutations will still be passed onto future generations
Explain the field of geroscience to someone without a science background.
geroscience = the intersection between basic, biology, aging, and health
Describe some of the current NIA objectives for advancing
knowledge related to the process of aging
Goal a:
Identify factors associated with successful aging and resilience against disease and dysfunction
because some people are super agers they can preform cognitively or physically better than people decades younger than them so the NIA will work to understand the factors that can be associated with resilience and be able to determine whether those factors can be harnessed to increase resilience more broadly across population
Goal B:
Consider the role of place in aging processes, taking into account geography in studies of late-life disability and mortality trends.
Health and mortality can vary dramatically across geographic regions, localities, census tracts, and even ZIP codes. We will continue to support and conduct research to identify the drivers behind these differences as well as policies and interventions that may close gaps between health and mortality in diverse locales.
Discuss the concept of ‘successful aging.’
Successful Aging: little or no age-related decline in function
1. Avoidance of disease
2. Maintenance of physical and cognitive function
3. Active engagement with life (maintenance of autonomy and social
support)
Explain the advantages and the limitations of categorizing aging
as ‘successful’ and ’usual.
advantages = we know what will work and what does not
diets
disadvatages = what does it mean to live successfully?
social aspect
avoidance of disease
still being able to move
Describe and give specific examples of the three major age-
associated physiological changes.
-Physiological rhythms
-Loss of complexity
-Homeostenosis
stenosis
narrowing
the range of physiological limits and the amount of physiological reserve is narrowed with age
frailty
a clinically recognizable state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple physiologic systems such that the ability to cope with everyday or acute stressors is comprised
-homeostenosis contributes to frailty
homeostenosis
a decreased ability to maintain homeostasis under stress
What are the age-associated physiological changes?
physiological rhythms = many circadian rhythms shift or become less prevalent with age
loss of complexity = many networks of control systems and feedback loops help maintain homeostasis
homeostenosis = a decreased ability to maintain homeostasis under stress
what are the three components of successful aging
- avoidance of disease
- maintenance of physical and cognitive function
- active engagement with life (maintenance of autonomy and social support)
Antagonistic pleiotropy theory aka “pay later theory” (Williams)
genes that increase the odds of successful reproduction in early life may
be harmful later in life
successful aging
little or no age - related decline in function
usual aging
normal decline in physical, social, and cognitive functioning with age
Disposable soma theory (Kirkwood)
hazardous environments favor
early reproduction and a short lifespan; allocation of all resources to
reproduction when necessary (even if it leads to death)
Three Psychosocial Theories of Aging
§ Disengagement Theory
§ Activity Theory
§ Continuity Theory
Disengagement Theory
Describes a natural, acceptable withdrawal of older adults from society as they age
Activity Theory of Aging
Argues that successful aging is more likely when older adults remain physically active and socially active
Continuity Theory of Aging
Argues that older adults will maintain relatively similar levels of activity and socialization as they did in their younger years
Progeroid syndrome
a condition in which physiological aging is
mimicked in an accelerated fashion
- ‘Progeroid’ indicates anything that resembles premature aging
Unimodal progeroid syndromes
demonstrate accelerated aging of one tissue only
* Alzheimer’s and Parkinson’s are unimodal progeroid syndromes
Segmental progeroid syndromes
affect many tissues and organ systems
Hutchinson-Gilford Progeria Syndrome (HGPS)
-Most prevalent and widely studied progeroid syndrome
-LMNA gene mutation leads to buildup of progerin protein
− Progerin = mutated, truncated lamin A protein
− Build up of progerin destroys the nuclear envelope
-Clinical features: alopecia, atherosclerosis, lipodystrophy,
myocardial infarction, death
− Average age of death for HGPS is 13.5 years
Classifying Progeroid Syndromes
Classification based on number of tissues affected
Classification based on type of mutation
-Mutations affecting proteins of the nuclear envelope
- Mutations that affect DNA repair pathways
Farnesyl transferase inhibitor (FTI)
Prevents farnesylation of lamin A and progerin proteins
Farnesyl in HGPS
− Farnesylated lamin A builds up at the nuclear
envelope
− Induces nuclear ‘blebbing’
The Nuclear Envelope
Two lipid bilayers
− Inner layer associated
with nuclear lamina
Nuclear lamina
− Contains intermediate
filaments and proteins
− Functions to:
* provide structural support
* organize chromatin
* regulate DNA replication
* anchor nuclear pore complexes
Cellular senescence
the process
through which cells undergo permanent
cell cycle arrest in response to
certain stressors
Why is cellular senescence good?
A protective mechanism that allows
cells to respond to potentially
tumorigenic events, including:
− DNA damage
− Activation/expression of oncogenes
− Increased signals for growth (mitogens)
− Oxidative stress
G2
the cell double checks the duplicated chromosomes for error making needed repairs
S phase
each of the 46b chromosomes is duplicated by the cell
G1 phase
cellular contents excluding the chromosomes are duplicated
G0 phase
cell cycle arrested
Senescent cells have a distinct phenotype, which includes
- Irreversible arrest of cell proliferation
− Cells exit the cell cycle - Resistance to apoptosis
− Stem cells - Altered cell function
− Cells no longer divide, but remain metabolically active
− Changes in function are specific to each cell type
− Typically includes chromatin rearrangement, altered secretory function,
and activation of tumor-suppressor genes
The Hayflick Limit
after ~50 divisions, cells entered a ‘resting’ phase
- Most cells undergo a finite number of divisions
− Telomeres shorten with each cellular division
− Most cells eventually reach the end of their ‘replicative lifespan’
-expect cancer, stem, gametes
The Senescent Phenotype
senescene initiation = senescene including signals and cell exists cell cycle
early senescence = progressive chromatin remodeling implementation or senescene program
late senescene = triggered by aging or long term unscheduled damage
A hallmark of a senescent phenotype:
altered cell function
senescene Associated Secretory Phenotype (SASP)
Senescent cells secrete growth
factors, inflammatory cytokines,
ECM-degrading enzymes, etc.
− Leads to a decline in tissue and organ
function
− Ultimately contributes to aging &
age-related pathologies
Telomeres
-Nucleoproteins that cap the
end of each chromosome
− Non-coding
− Consist of proteins and repetitive
hexameric nucleotide sequences
(TTAGGG in humans)
- Protect against degradation,
rearrangement, and fusion
- Shortened with each somatic
cell division due to the
end replication problem
Telomerase
-Telomerase is a reverse
transcriptase enzyme that adds
more hexameric sequences to
elongate the 3’ end of telomeres
- Solves the end replication problem
- Active in:
− Stem cells
− Gametes
− Cancer cells
- Mostly absent from somatic cells
Oncogenesis
the process through which normal cells are transformed
into cancer cells
hTERT
-Encodes for the catalytic subunit of telomerase
-Expression is upregulated in stem cells
-no hayflick limit
Explain how shortened telomeres and hTERT mutations
contribute to oncogenesis.
Short telomeres are found
in most cancers
− Promote chromosomal
instability (fusions and/or
rearrangements)
mutations in p53 lead to oncogenesis
Describe the components of the telomerase enzyme complex.
Two essential components:
− Telomerase reverse transcriptase (hTERT) – catalytic subunit
− Telomerase RNA component (hTR or hTERC) – provides RNA template
Define ‘telomere syndrome.’ Explain why most of these syndromes have
hematologic manifestations and discuss the most common cause of death
in affected individuals
telomere syndrome = mutation in five components
most have hematological manifestations = aplastic anemia because the telomere shortening starts at the haematopoeitic stem cell which is the red blood cell progenitor
Dyskeratosis Congenita (DC)
Results from mutations in Dyskerin complex genes (hTR, hTERT, DKC1) or Shelterin complex genes
Oral leukoplakia
− Skin hyperpigmentation
− Nail dystrophy and ridging
Discuss the current evidence related to maternal exposures/experiences
and telomere length in offspring
Shelterin
protein complex
− Protects ends of telomeres
from DNA repair mechanisms
− Regulates telomerase activity
Hoyeraal-Hreiderasson Syndrome (HHS)
Results from homozygous hTERT mutations or DKC1 mutations
Idiopathic Pulmonary Fibrosis (IPF)
hTERT and hTR mutations have been identified in
many IPF patients
Progressive lung scarring leading to respiratory failure
List the biochemical pathways that are currently believed to be central to
the process of aging (from AFAR reading)
Mammalian Target of Rapamycin (mTOR)
- A nutrient sensor that also
responds to cellular stress - Regulates cell growth,
proliferation, and survival - Activated by:
− Nutrient abundance - Inhibited by:
− Nutrient depletion
− Exercise
− DNA damage and cellular stress
mTOR & Aging
Hypothalamic mTOR activity
increases with age
− Associated with late-life
obesity
- Lower mTOR activity
correlates with longer lifespan
in worms, flies, mice
− Acute mTOR inhibition also
impairs healing and leads to
insulin resistance
Rapamycin
mTOR inhibitor
AMP-Activated Protein Kinase (AMPK)
- An energy sensor that regulates many cellular
metabolic processes - Activated by:
− Increased AMP:ATP ratio (energy depletion)
− Exercise - Stimulates catabolic pathways:
− Fatty acid oxidation
− Glucose uptake via GLUT4 (insulin not required)
− Autophagy - Inhibits anabolic pathways:
− Protein synthesis (via inhibition of mTOR)
− Glycogen, cholesterol, and fatty acid synthesis - AMPK activity decreases with age
Metformin
-Antidiabetic drug
− Lowers blood glucose
− Acts (in part) by activating AMPK
Hormesis
a process that exhibits a biphasic dose response
- Within the hormetic zone, there is a favorable response to a stressor or toxin
Sirtuins
are nutrient sensors; mediate
responses within the hormetic zone
Compare and contrast caloric restriction and intermittent fasting. Briefly
summarize the available data related to these approaches
Monkeys were fed a 30% calorie restricted diet for 20 years
− Reduced age-related disease (cancer, diabetes, heart disease)
− Two studies, but only one study reported increased lifespan
Improved sleep, mood, sexual function, and overall life quality
mitophagy
Damaged/stressed mitochondria are removed
Increased release of ROS & DAMPs
=Increased release of ROS & DAMPs = Age-related disease
