Cellular Aging Process and Mechanisms

Cell Ageing Process

• Cellular aging is a response to damage or stress.
• This response can manifest as cell death (apoptosis) or arrested cell growth (cell senescence).
• Aging is a biological process that transforms a healthy organism into one that is less healthy.
• Cellular aging is important in regulating the cell cycle, including the prevention of cancer.

Objectives

• Understanding the aging process at the molecular and cellular levels, including characteristics.
• Understanding the molecular and physiological aging process, such as IGF and p53 signaling pathways.
• Establishing the association between telomeres and cellular aging.

What Is Aging?

• Aging is a biological process.
• It converts a healthy organism into a less healthy one.

Aging

• Reduced tissue/physiological function.
• Increased susceptibility to disease (age-related diseases).
• Reduced resistance to stress (both physical and psychological).

Changes in the Plasma Membrane

• Structural changes lead to changes in permeability.
• Less fluid due to an increase in saturated fatty acids.

Nuclear Changes

• Chromatin becomes more condensed (increase cross-links, disulfide bonds between histones).
• Implication: DNA damage less likely repaired.
• Cells in culture eventually stop growing (senescence) due to changes in factors regulating the cell cycle.

Cytoplasmic Changes

• Increased volume with age.
• Lipofuscin (age pigment) found in non-dividing cells (e.g., nerve and muscle cells).
• Lipofuscin appears as yellow-brown granules.

Mitochondrial Changes

• Decrease in the number of folds (cristae).
• Decrease in the number of mitochondria.

Lysosomal Changes

• Reduced activity leads to the accumulation of cellular garbage (e.g., lipofuscins).
• Release of enzymes leads to cell death.

Pre-programmed Cell Death (Apoptosis)

• Apoptosis vs. Necrosis

  • Necrosis: external cause (trauma), random DNA breaks
  • Apoptosis: internal cause (cellular suicide), non-random 180 base fragments

• Apoptosis as a natural developmental process (e.g., interdigital tissue, neurons).

Cellular "Aging" Responses: Yin and Yang

• Good news (prevents cancer).
• Bad news (promotes aging).

Evolution of Long-Lived Organisms

• Life span varies between single-celled organisms, multi-cellular organisms with post-mitotic cells, and organisms with renewable tissues.
• Cell division is risky.
• The risk of cancer increases with age.

Cancer

• Cancer risk rises exponentially with age
• Driven by somatic mutations.
• Mutations from endogenous & exogenous DNA damage.

Tumor Suppression & Aging

• Genes protecting from cancer (tumor suppressor genes)
• Damaged cells die or arrest growth (apoptosis or senescence).
• An evolutionary balancing act between cancer protection and cellular aging.

Senescence Morphology

• Senescent cells become flattened, enlarged, and exhibit increased β-galactosidase activity.
• Larger nucleus and nucleoli.
• More multinucleated cells.
• Increased lysosomes, Golgi, and cytoplasmic microfilaments.

Cellular Senescence

• Cellular senescence arrests growth in response to potential cancer-causing events.
  • Chromatin instability
  • DNA damage
  • Short/dysfunctional telomeres
  • Oncogenes
  • Stress/damage signals

Molecules Secreted by Senescent/Aged Cells

• Disrupt normal tissue differentiation; example: milk production by mammary cells.

Molecular and Physiological Mechanisms of Aging

• Dietary restriction after adulthood reduces aging effects and increases lifespan in lab animals.
• Insulin/IGF-1 signaling pathway genes are strongly implicated in aging effects (regulate metabolism & stress responses, influence maintenance functions).

Integrating Molecular Mechanisms with Life History Theory

• Insulin/IGF-1 ('growth' hormones) pathway strongly regulates growth and maintenance trade-offs.
• Poor environment (e.g., dietary restriction) favors maintaining survival and reduces growth and reproduction.
• Conversely, good environment favors growth and reproduction but reduces maintenance.
• Lab animal studies show that lifespan-extending mutations of insulin/IGF-1 pathway mutants perform poorly and do not show evidence of longer lives.

Telomeres and Aging

• Humans have 46 chromosomes and 92 telomeres (one at each end of the chromosome).
• Telomeres are repetitive DNA sequences at the ends of chromosomes.
• Telomeres function in protecting chromosomes
• Separating chromosomes.
• Preventing their fusion, in turn, leading to genomic instability.
• Telomeres act as a "clock".
• The shortening of telomeric sequences is a regulator of a cell's division capacity.
• Healthy human cells are mortal because they can divide a limited number of times; aging occurs from each division.
• Telomere shortening may function as a molecular clock.

Telomerase and Senescence

• In most somatic cells, telomerase expression is low or absent.
• As cells divide, telomeres shorten, which gives signaling to cells to enter senescence.
• Short telomeres signal cells to senesce (stop dividing).

Telomerase and Cancer

• Telomerase is active in cancer cells allowing proliferation, and protecting telomere length.
• Cancer cells often do not age.

Short Telomeres, p53 and Growth Arrest

• Short telomeres trigger growth arrest via a checkpoint signaled by the p53 checkpoint mechanism.
• If cells of a tumor still have p53, this works.
• If tumor cells lose p53, then cell division continues, leading to chromosomal rearrangements.
• Genomic instability can promote tumorigenesis

What do Telomeres do?

• Protecting chromosomes.
• Separating one chromosome from another in DNA sequence
• Without telomeres, chromosome ends would be "repaired," leading to fusion and massive genomic instability.

Telomere Function (cont.)

• Telomeres are a clock that regulates how many times an individual cell can divide.
• Telomeric sequences shorten each time DNA replicates.
• Once telomere shrinks to a certain level, cells stop dividing, slow down metabolism, age and die.

Telomeres & Aging

• Healthy human cells are mortal because of a finite number of cell divisions. Dividing older each time they divide, until they age and die.
• Telomere shortening may be a molecular clock, which counts the number of times a cell has divided and when telomeres are short, cellular senescence occurs.

How Does Telomerase Work?

• Telomerase is active in germ cells, in vitro immortalized cells, a vast majority of cancer cells, and possibly some stem cells.
• High telomerase activity exists in germ cells, stem cells, epidermal skin cells, follicular hair cells, and cancer cells.
• Some cells are immortal due to switched-on telomerase.
• Examples include blood cells and cancer cells.

Human Aging

• The Greek god Zeus granted Tithonus the gift of immortality but not of perpetual youth.
• Tithonus aged but could not die.
• Tennyson's poem "Tithonus" reflects the desire for longer lives, even though it may be without youthful vitality.