Molecular Basis of Aging: Metabolism and Genome Integrity
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Questions and Answers

What effect does abundant food have on insulin signaling in mammals?

  • It leads to dauer formation.
  • It activates DAF-16.
  • It inhibits PTEN.
  • It activates DAF-2. (correct)

    • How does calorie restriction influence the role of DAF-16?

  • It inhibits PI3K signaling.
  • It keeps DAF-16 inactive during starvation.
  • It activates DAF-16, leading to dauer formation. (correct)
  • It turns DAF-16 off, promoting growth.

    • Which protein is directly activated by AGE-1 in the insulin signaling pathway?

  • DAF-2
  • PTEN
  • AKT (correct)
  • FOXO

    • What occurs with complete loss of DAF-16 function?

    <p>It induces dauer larva formation. (C)</p> Signup and view all the answers

    What is the relationship between the age-1 mutant of C.elegans and adult life expectancy?

    <p>It doubles the adult life expectancy from approximately 2 to 4 weeks. (B)</p> Signup and view all the answers

    What is the role of phosphatase and tensin homolog (PTEN) in the context of insulin signaling?

    <p>Inhibits PI3K signaling. (B)</p> Signup and view all the answers

    Which of the following explains the Hayflick limit?

    <p>It describes the maximum lifespan of a cell due to telomere shortening. (D)</p> Signup and view all the answers

    What effect does insulin signaling have on C.elegans and its longevity?

    <p>Insulin signaling contributes to increased longevity through nutrient sensing. (D)</p> Signup and view all the answers

    What is the primary function of DAF-16 when it is active?

    <p>Facilitates normal development. (A)</p> Signup and view all the answers

    What is implied by the statement that aging is developmental biology?

    <p>Aging and development share similar molecular mechanisms. (C)</p> Signup and view all the answers

    How do mutant alleles affecting DAF-16 contribute to longevity in C.elegans?

    <p>They partially inhibit DAF-16 function. (B)</p> Signup and view all the answers

    What is the overall effect of elevated oxidants and free radicals on cellular functions?

    <p>They damage chaperones and cellular structures. (D)</p> Signup and view all the answers

    Which gene mutations are found to be allelic concerning longevity in C.elegans?

    <p>age-1 and daf-23. (D)</p> Signup and view all the answers

    What are the primary common features associated with accelerated aging?

    <p>Disruption in metabolism and genome integrity. (B)</p> Signup and view all the answers

    How does the age-1 mutant influence the formation of dauer larvae in C.elegans?

    <p>It inhibits dauer larvae formation in well-nourished conditions. (A)</p> Signup and view all the answers

    What is the significance of telomere shortening in the context of aging?

    <p>It leads to cellular senescence after a certain number of divisions. (A)</p> Signup and view all the answers

    Which process induces cellular senescence as a defense mechanism?

    <p>DNA damage (A)</p> Signup and view all the answers

    What is the role of P53 in the context of genome integrity?

    <p>To regulate gene expression and induce DNA repair (C)</p> Signup and view all the answers

    What observation has been made regarding dogs and IGF-1 levels?

    <p>Dogs with low IGF-1 levels live longer than others (B)</p> Signup and view all the answers

    Which of the following mutations is common in human cancers concerning P53?

    <p>Mutations in its DNA binding domain (B)</p> Signup and view all the answers

    What effect does moderate genome damage have when P53 is active?

    <p>Induces DNA repair (C)</p> Signup and view all the answers

    Which statement about calorific restriction and longevity in humans is true?

    <p>Much evidence suggests it does not promote longevity (D)</p> Signup and view all the answers

    In the context of diabetes, what represents a complete block of insulin signalling?

    <p>Uncontrolled illness leading to fatality (C)</p> Signup and view all the answers

    What is a significant consequence of cellular senescence?

    <p>It acts as a tumor suppressor mechanism (C)</p> Signup and view all the answers

    What is a primary consequence of telomere shortening in cells?

    <p>Loss of essential genes (A)</p> Signup and view all the answers

    What is the Hayflick limit?

    <p>The number of times a cell can divide before becoming senescent (A)</p> Signup and view all the answers

    Which enzyme is responsible for extending telomeres?

    <p>Telomerase (A)</p> Signup and view all the answers

    Which type of cells are known to possess telomerase activity?

    <p>Embryonic stem cells (A)</p> Signup and view all the answers

    How does the activity of DNA polymerase influence telomere length?

    <p>It cannot replicate the telomere ends (B)</p> Signup and view all the answers

    What role does the P53 protein play in cellular ageing?

    <p>Induces cellular senescence (C)</p> Signup and view all the answers

    What happens to human fibroblasts from an 80-year-old adult compared to those from a fetus in terms of cell division potential?

    <p>They have fewer doublings available (D)</p> Signup and view all the answers

    What initiates the polymerization process in DNA synthesis?

    <p>RNA primers (C)</p> Signup and view all the answers

    Flashcards

    Progeroid syndromes

    Genetic disorders causing premature aging.

    Insulin signaling and longevity

    Changes in insulin signaling pathways can extend lifespan, as seen in some organisms.

    Telomere shortening

    Telomeres, protective caps at chromosome ends, get shorter with each cell division.

    Hayflick limit

    The maximum number of times a normal cell population can divide until cell division stops.

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    Cellular senescence

    A state where cells stop dividing, usually due to shortened telomeres or other factors.

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    Age-1 mutation (C. elegans)

    A mutation that doubles the lifespan of C. elegans by disrupting insulin signaling.

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    daf-23/age-1 gene

    This gene, when mutated, doubles lifespan in C. elegans by controlling the dauer larva stage.

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    Dauer larva

    A developmental stage in C. elegans characterized by dormancy and extreme longevity, often in response to harsh conditions.

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    Chaperones

    Proteins that help other proteins fold correctly and prevent aggregation, promoting cell stability.

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    Proteostasis

    The maintenance of protein homeostasis - a balance between protein synthesis, folding, and degradation.

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    Caloric restriction

    A reduction in calorie intake without malnutrition, often extended lifespan.

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    Insulin signaling pathway

    A network of proteins and molecules involved in controlling glucose metabolism and other cellular functions.

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    P53, The Genome Guardian

    A key protein that acts as a tumor suppressor by regulating gene expression and activating DNA repair mechanisms.

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    Apoptosis

    Programmed cell death, a controlled process that eliminates damaged or unwanted cells.

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    Insulin Signaling & C. elegans

    The insulin signaling pathway in the nematode worm C. elegans is highly conserved, meaning it shares similarities with the human pathway.

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    DAF-2 (Insulin Receptor)

    The insulin receptor in C. elegans, analogous to the insulin receptor (InsR) in mammals. It plays a crucial role in insulin signaling and longevity.

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    DAF-16 (FOXO)

    A transcription factor in C. elegans that regulates genes involved in stress resistance and longevity. It is activated in the absence of insulin signaling.

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    Reduced Insulin Signaling & Longevity

    Reduced insulin signaling, as seen in some mutant worms, can extend lifespan in C. elegans. This indicates a link between insulin regulation and longevity.

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    Partial Loss of Function

    A mutation that reduces the function of a gene, but does not completely eliminate it. It's like turning down the volume on a gene instead of silencing it.

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    Oxidant Damage

    Oxidative stress caused by reactive oxygen species (free radicals) which damage cellular components like DNA and proteins. This damage accumulates over time, contributing to aging.

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    Telomeres

    Repetitive DNA sequences found at the ends of chromosomes, acting as protective caps. They shorten with each cell division.

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    Telomerase

    An enzyme that can extend telomeres by adding repetitive DNA sequences, preventing their shortening and potentially delaying cellular senescence.

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    Germline Stem Cells

    Cells that give rise to gametes (sperm and eggs) and possess telomerase activity, allowing them to maintain telomere length and potentially divide indefinitely.

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    Embryonic Stem Cells

    Undifferentiated cells from early embryos that have telomerase, allowing them to divide indefinitely and potentially differentiate into various cell types.

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    Reverse Transcriptase

    An enzyme component of telomerase that uses telomerase RNA as a template to add DNA repeats to telomeres.

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    Study Notes

    Molecular Basis of Aging: Metabolism and Genome Integrity

    • The lecture covers the molecular mechanisms of aging, focusing on metabolism and genome integrity.
    • Specific aims include appreciating progeroid syndromes' genetic basis and its connection to accelerated aging.
    • Understanding how insulin signaling affects longevity (in Drosophila and C. elegans).
    • Learning about telomere shortening and maintenance.
    • Exploring the Hayflick limit and its relationship to cellular senescence.

    Disruption in Metabolism and Genome Integrity

    • Defects in a small set of cellular functions can cause progeroid syndromes.
    • Examples include Hutchinson-Gilford progeria syndrome, Cockayne syndrome, Werner syndrome, and others.
    • These defects lead to multiple impairments in nuclear integrity, nucleotide excision repair, and metabolism.
    • Environmental influences, along with these cellular defects, contribute to aging processes.

    Aging as Developmental Biology

    • Aging is comparable to developmental biology, where death is the ultimate outcome.
    • Research on model organisms (Drosophila, Mus musculus, and Caenorhabditis elegans) provides insights into molecular mechanisms of development and aging.
    • A C. elegans mutation can double adult lifespan by altering insulin signaling. This is the opposite of a progeroid syndrome.

    Insights from C. Elegans - Dauer Larva

    • C. elegans larvae can enter a dauer stage under specific environmental conditions.
    • This stage enhances survival in harsh conditions.
    • The duration each stage spends can be determined by external factors.

    Age-1: A Gene Promoting C. elegans Longevity

    • 1988 study identified the age-1 gene mutant as having a link to longer lifespan.
    • It increases the post-reproductive adult lifespan by about twofold.
    • The age-1 mutant shows a partial loss of function of the wild-type function.

    Age-1 and Daf-23 are Allelic

    • The age-1 and daf-23 genes code for the same protein, but different alleles.
    • daf-23 constantly produces the dauer larval form, even when ample food is present.
    • Well-fed age-1 mutants are long-lived as adults, in contrast to the wild type.

    Dauer Formation is Regulated by the Insulin Signaling Pathway

    • Insulin stimulates glucose uptake from the blood and converts it to glycogen.
    • It also increases fatty acid synthesis, which results in the lipid esterification and fat production within adipose tissue.
    • Insulin signaling's effects depend on environmental factors such as caloric intake. This path is important for aging processes.

    Insulin Signaling Is Highly Conserved

    • Insulin signaling pathways are conserved between mammals and C. elegans.
    • Mammalian signaling is regulated by Insulin Receptor and IGF-1 Receptor.
    • C. elegans employs DAF-2, AGE-1, DAF-18, AKT, DAF-16.

    Reduced Insulin Signaling and Longevity

    • C. elegans daf-16 mutants and loss-of-function mutations significantly increase lifespan.
    • A complete absence of daf-16 yields constitutive dauer larva formation and a decreased lifespan.

    Downstream Targets of DAF-16

    • DAF-16 has downstream targets crucial for longevity.
    • These targets include antioxidants, small heat-shock proteins (HSPs), antimicrobial peptides, and new genes.

    Summary of Insulin Signaling and Longevity

    • Caloric restriction accelerates dauer formation in C. elegans.
    • Partial caloric restriction extends lifespan.
    • Mutated genes regulating insulin signaling affect lifespan.
    • Similar genes promote lifespan in Drosophila.

    For Humans, Insulin Signaling and Longevity:

    • Complete inhibition of insulin signaling is harmful in humans.
    • Caloric restriction as a human longevity strategy is still uncertain.
    • Obesity correlates with Type 2 Diabetes and higher risk of cancer.

    Genome Integrity and Aging:

    • Progeroid syndromes are characterized by cellular defects in metabolism, nuclear integrity, and nucleotide repair
    • Examining DNA repair mechanisms like P53 and telomere regulation provides insight into aging processes.

    P53: The Guardian of the Genome

    • p53 regulates cellular senescence, a response to cellular stress, and prevents cancerous growth.
    • 50% of human cancers stem from mutations in p53's DNA-binding domain.
    • Moderate damage triggers DNA repair; severe damage causes cellular senescence or apoptosis.

    Cellular Senescence as a Defence Mechanism

    • Cellular senescence is stable cell-cycle arrest, primarily for pre-cancerous cells.
    • Telomere loss triggers cellular senescence.
    • Other reasons such as nuclear integrity and DNA damage can trigger cellular senescence.

    Telomeres

    • Telomeres are repetitive DNA sequences at chromosome ends, acting as protective caps.
    • DNA polymerase can't reach the end, so telomeres shorten with each replication cycle.
    • This shortening contributes to cellular and organismal aging.

    Hayflick Limit

    • The Hayflick limit is a finite number of cell divisions in cell culture.
    • The number of divisions depends on the organism's life expectancy.
    • Loss of telomeres correlates with the Hayflick limit.

    DNA Synthesis

    • DNA polymerase can only carry out synthesis in a 5' to 3' direction.
    • RNA primers are needed, followed by elongation and repair, to ensure genome stability and replication.

    Chromosome End Problem

    • DNA synthesis reaches a limit due to RNA primer-based DNA replication.
    • The 5' end of a chromosome cannot be completely duplicated.
    • This leads to shortening of telomeres.

    Telomerase

    • Telomerase is an enzyme that adds repetitive DNA sequences to telomeres.
    • This elongation compensates for shortening during DNA replication.
    • Telomerase is found in germline and embryonic stem cells, but usually reduced in adult cells.
    • Cancer cells often have upregulated telomerase.

    Telomerase and Aging

    • Telomere loss can lead to reduced cell replication, increased cellular senescence and potentially to the accumulation of senescent cells in the organism.

    • Aging is a complex process driven by a range of factors, including telomere shortening, and incomplete DNA replication, cellular senescence and stress response mechanisms.

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    Molecular Basis of Aging: Metabolism and Genome Integrity (November 2023) PDF

    Description

    This quiz explores the molecular mechanisms of aging, emphasizing metabolism and genome integrity. It covers key topics such as progeroid syndromes, insulin signaling impacts on longevity, telomere dynamics, and cellular senescence. Understand the genetic and environmental influences that contribute to aging processes.

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