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

What is a primary characteristic of senescent cells during ageing?

  • Depletion of stem cells (correct)
  • Increased telomere length
  • Enhanced DNA replication
  • Improved cell function

    • What is the Hayflick limit?

  • The total number of divisions a cell can undergo before senescence (correct)
  • The length of telomeres in human cells
  • The maximum lifespan of stem cells in culture
  • The age at which most cells become senescent

    • Which enzyme is primarily responsible for elongating telomeres?

  • Reverse Transcriptase
  • RNA polymerase
  • DNA ligase
  • Telomerase (correct)

    • What typically happens when cells lose their telomeres?

    <p>Cells undergo senescence (D)</p> Signup and view all the answers

    Which of the following statements regarding telomere length and ageing is correct?

    <p>There is a positive correlation between organismal life expectancy and cell culture doublings. (A)</p> Signup and view all the answers

    What role does P53 play in cellular senescence?

    <p>It induces senescence in cells. (A)</p> Signup and view all the answers

    What are the components of telomerase?

    <p>Reverse transcriptase and Telomerase RNA (C)</p> Signup and view all the answers

    How does telomerase allow embryonic stem cells to be cultured indefinitely?

    <p>By maintaining and elongating telomeres (D)</p> Signup and view all the answers

    How does calorific restriction affect the lifespan of organisms according to the study presented?

    <p>It promotes dauer formation and longevity in model organisms. (D)</p> Signup and view all the answers

    What is the role of p53 in cellular senescence?

    <p>It regulates gene expression to induce DNA repair or senescence. (D)</p> Signup and view all the answers

    What is the primary reason large mammals have shorter lifespans compared to smaller mammals?

    <p>Higher levels of IGF-1. (B)</p> Signup and view all the answers

    What is a potential consequence of complete block of insulin signaling in humans?

    <p>Development of diabetes, which can be fatal if untreated. (D)</p> Signup and view all the answers

    What effect does telomere dysfunction have in cells?

    <p>Triggers cellular senescence as a defensive response. (C)</p> Signup and view all the answers

    What is the Hayflick limit in relation to cellular aging?

    <p>The number of times a normal somatic human cell can divide before cell division stops. (B)</p> Signup and view all the answers

    How does the use of telomerase relate to aging in stem cells?

    <p>It allows stem cells to maintain telomere length, thereby prolonging their regenerative capacity. (B)</p> Signup and view all the answers

    What is the relationship between obesity and type 2 diabetes (T2D)?

    <p>There is a strong correlation between obesity and the increased risk of T2D and associated diseases. (D)</p> Signup and view all the answers

    What is implied by the term 'Hayflick limit' in cellular biology?

    <p>The maximum number of cell divisions before senescence occurs (A)</p> Signup and view all the answers

    How does telomere shortening affect cellular senescence?

    <p>It triggers a DNA damage response leading to cell cycle arrest (D)</p> Signup and view all the answers

    What role does telomerase play in aging?

    <p>It maintains telomere length, potentially prolonging cell lifespan (B)</p> Signup and view all the answers

    Which of the following statements is true regarding stem cells and aging?

    <p>Aging leads to a decline in the regenerative capacity of stem cells (A)</p> Signup and view all the answers

    What is the primary function of the insulin signaling pathway in the context of aging and longevity?

    <p>To enhance glucose uptake and support cellular functions (D)</p> Signup and view all the answers

    Which of the following best describes cellular senescence?

    <p>A state of irreversible cell cycle arrest triggered by various stressors (B)</p> Signup and view all the answers

    What process is directly linked with telomere shortening?

    <p>Cellular aging and eventual senescence (C)</p> Signup and view all the answers

    Which of the following is true regarding progeroid syndromes?

    <p>They exhibit characteristics similar to accelerated aging (A)</p> Signup and view all the answers

    Flashcards

    Telomeres

    Repetitive DNA sequences at the ends of chromosomes.

    Hayflick Limit

    The finite number of cell divisions a cell can undergo in culture before senescence.

    Senescence

    A state of cellular aging or a cell's death that cannot divide.

    Telomerase

    An enzyme that adds telomere sequences to chromosome ends.

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    DNA Polymerase

    Enzyme that synthesizes DNA.

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    Chromosome End Problem

    The inability of DNA polymerase to completely replicate linear chromosomes.

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    Germline Stem Cells

    Cells responsible for producing gametes (sperm and eggs).

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    Embryonic Stem Cells

    Cells that can differentiate into all cell types in the body.

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    Progeroid Syndromes

    Rare genetic disorders that cause premature aging and accelerated aging symptoms, affecting a limited set of cellular functions.

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    Insulin Signaling

    A pathway that senses nutrients and regulates metabolism, impacting lifespan in organisms like Drosophila and C. elegans.

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    Telomere Shortening

    The process where the protective caps at the ends of chromosomes get shorter with each cell division.

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    Cellular Senescence

    A state where cells cease dividing and undergo aging, often associated with the Hayflick limit.

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    Age-1 Gene (daf-23)

    A gene in C. elegans that regulates lifespan and dauer larva formation, with mutations extending lifespan.

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    Dauer Larva

    A long-lived, stress-resistant larval stage in C. elegans, associated with nutrient sensing and insulin signaling.

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    Nutrient Sensing

    The ability of cells to detect and respond to nutrient availability, influencing processes like aging.

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    Insulin Signaling & Longevity

    Lowering insulin signaling extends lifespan in C. elegans, Drosophila, and some mammals. This suggests a link between insulin signaling and aging.

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    Caloric Restriction & Longevity

    Restricting calorie intake extends lifespan in some animals. However, extreme restriction can be harmful in mammals and humans.

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    IGF-1 and Lifespan

    Lower levels of Insulin-like Growth Factor-1 (IGF-1) in animals correlate with longer lifespan. Higher resting metabolic rates often correlate with larger mammals.

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    P53 and DNA Damage

    P53 protein plays a role in reacting to moderate DNA damage (repairing it) or severe damage (senescence or apoptosis).

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    Telomere Function

    Telomere dysfunction is a type of severe damage that can trigger cellular senescence, a protective mechanism.

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    Genome Integrity

    Processes like P53 and telomere maintenance ensure genome stability. Maintaining a well-functioning genome is crucial for preventing cancer and promoting longer life.

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    P53-cancer correlation

    Mutations in P53 deactivate this guardian, affecting damaged DNA repair leading to increased cancer risk.

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    Study Notes

    Molecular Basis of Aging: Metabolism and Genome Integrity

    • This lecture explores the molecular mechanisms of aging and the role of metabolism and genome integrity in this process.
    • Aims to understand the genetic landscape of progeroid syndromes related to accelerated aging.
    • Also aims to describe how changes in insulin signaling affect longevity (specifically in Drosophila and C. elegans).
    • Also aims to understand telomere shortening during cell cycles and their growth processes.
    • Aims to discuss the Hayflick limit and its link to cellular senescence.

    Disruption in Metabolism and Genome Integrity

    • Defects in a limited set of cellular functions can cause progeroid syndromes (a group of genetic disorders causing premature aging).
    • These defects often affect key biological pathways crucial for maintaining cellular and organismal health.
    • The diagram illustrates these various cellular functions and their interactions.

    Aging is Developmental Biology

    • Aging is fundamentally a part of developmental biology, where the processes of growing and developing in an organism are mirrored as a form of aging.

    • Model organisms like Drosophila melanogaster, Mus musculus, and Caenorhabditis elegans are studied to understand the molecular mechanisms of aging.

    • A C. elegans mutation (age-1) can double post-reproductive adult lifespan by perturbing insulin signaling. This highlights a possible link between insulin signaling and aging.

    Insights from C. Elegans - Dauer Larva

    • C. elegans's dauer larvae demonstrate a correlation between environmental conditions (like food availability) and life expectancy.

    • The lifecycle of the dauer larva (the different larval stages) is displayed, showing how these stages can vary depending on food and environmental variables.

    Age-1: A Mutated Gene

    • A mutated C. elegans gene (age-1) which is found to promote longevity in the organism.

    • The age-1 mutant doubles the post-reproductive adult lifespan of C. elegans from approximately 2 to 4 weeks.

    • This gene is recessive to the wild-type allele and demonstrates a partial loss of function, as one of its normal functions is to reduce lifespan by roughly 50%.

    Age-1 and daf-23

    • The age-1 mutation is allelic to daf-23 genes, meaning some of their functions overlap.

    • daf-23 genes are connected with dauer larva formation (a state of suspended development in C. elegans, often triggered by unfavorable conditions).

    • Well-fed age-1 mutants do not enter the dauer stage but live twice as long as wild type worms as adults, suggesting a link between dauer development and aging.

    • This connection implies a function in nutrient sensing (age-1/daf-23) related to aging.

    Dauer Formation & Insulin Signaling

    • Dauer formation in C. elegans is regulated by the insulin signaling pathway.

    • Insulin promotes glucose uptake and conversion to glycogen (an energy storage form), as well as increased fatty acid synthesis.

    • This pathway regulates nutrient storage in tissues including adipose tissue, leading to the production of fats.

    Insulin Signaling is Highly Conserved

    • Insulin signaling pathways share similarities in mammals and C.elegans

    • These similarities demonstrate the evolutionary conservation of these pathways, implying an essential role in diverse biological processes including aging.

    Does Reduced Insulin Signaling Cause Longevity?

    • C. elegans mutations that reduce insulin signaling often increase longevity but complete loss leads to constitutive dauer formation.

    • Reduced signaling allows normal development, while reduced insulin plus dauer larva can extend lifespan.

    • DAF-16, a key transcriptional regulator, plays a pivotal role in these effects.

    Downstream Targets of DAF-16

    • DAF-16 affects various downstream targets critical for longevity, including metabolism (apolipoproteins, and cytochrome P450).

    • It influences the development process and antioxidants (superoxide dismutase, metals and catalase)

    • Oxidants (free radicals) damage DNA, causing mutations, which is targeted down-regulating the damage to prevent mutations from occurring.

    Summary of Insulin Signaling and Longevity

    • In C. elegans, restricting calories early in life promotes dauer larva formation and longevity.

    • Partial calorific restriction also enhances longevity.

    • Drosophila studies show similar genetic pathways influencing longevity as found in C. elegans.

    • Similar pathways have been identified in mammals (dogs, mice) relating low IGF levels with lifespans.

    For Humans

    • Complete insulin signaling blockade can cause fatal diabetes.

    • Very little direct evidence suggests that calorie restriction promotes longevity in humans.

    • Obesity correlates with type 2 diabetes and increased cancer risk, highlighting the importance of maintaining a healthy weight.

    • In humans, a fine balance with nutrition is important to avoid anorexia type tissue damage.

    Genome Integrity & Aging

    • This section examines the processes like DNA repair, nucleotide excision repair, and replication maintenance, crucial for maintaining genome stability.

    P53: The Guardian of the Genome

    • Cellular senescence, a cessation of cell division, is regulated by the transcription factor p53, activated by cellular stress like DNA damage.

    • p53 is critical in preventing cancer and maintaining cellular integrity through regulating cell cycle arrest.

    • 50% of human cancers involve p53 mutations, often in its DNA binding domains.

    P53- The Genome Guardian

    • Moderate genome damage can induce DNA repair mechanisms for return to normal function.

    • Severe genome damage can lead to senescence and in exceptional cases, apoptosis.

    Cellular Senescence as a Defense Mechanism

    • Cellular senescence is a stable cell cycle arrest mechanism, acting as a defense against potentially dangerous cells.

    • Senescence is linked to DNA damage, telomere loss, and nuclear integrity.

    • Accumulation of senescent cells is a potential factor in aging, and possibly a major driver in the biological process.

    Telomeres

    • Telomeres are repetitive DNA sequences at the ends of chromosomes.

    • DNA polymerase cannot replicate full chromosomal lengths.

    • Telomere shortening happens with each replication cycle.

    • Repeated loss can lead to chromosome damage, cell cycle arrest, and eventually cell death.

    What Happens When Cells Lose Telomeres?

    • Healthy cells, when grown in cultures divide a finite number of times, in correlation with organismal life expectancy, with telomeres being limiting.

    The Hayflick Limit

    • The Hayflick limit is the maximum number of cell divisions observed in cell cultures from different organisms.

    • Cells that reach the Hayflick limit have severe telomere shortening.

    • Cells then undergo senescence, a terminal cell cycle arrest, as a result of the P53 signaling pathway.

    DNA Synthesis

    • DNA polymerase catalyzes in the 5' to 3' direction, necessitating DNA primers during synthesis

    • RNA primer assists during replication

    • RNA primers need to be removed to allow accurate replication.

    The Chromosome End Problem

    • Synthesis of DNA ends causes a problem with the integrity of chromosomes, affecting the 5' end in various ways.

    Telomerase - An Enzyme that Grows Telomeres

    • Telomerase is a reverse transcriptase that extends chromosomes.

    • It adds repetitive sequences to telomeres.

    • It allows for continued chromosome replication.

    • Preserving telomere length is crucial for normal cellular function and can affect the entire lifespan of the organism.

    Telomerase - Grows New Telomeres

    • Germline stem cells maintain telomerase and indefinite telomere growth

    • Some adult stem cells have reduced telomerase levels

    • Cancer cells, a notable exception, retain telomerase expression.

    Is Aging Caused by Cells Reaching the Hayflick Limit?

    • Multiple factors in cells contribute to aging, including telomere shortening, P53 signaling, inflammation, and many other components.

    • Accumulation of senescent cells as a result of this aging process, which will further affect the metabolism and DNA integrity of the organism.

    • Ageing can therefore be a multifaceted process driven by various cellular and systemic factors.

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    Related Documents

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

    Description

    This quiz explores the molecular mechanisms involved in aging, focusing on metabolism and genome integrity. It covers the genetic aspects of progeroid syndromes, the impact of insulin signaling on longevity, and telomere shortening. Additionally, it discusses the Hayflick limit and its connection to cellular senescence.

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