Download 3) Cellular Aging - Cal State LA

Biology of Human Aging
“Cellular Aging”
Chapter 3
Outline
• Cell Components
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Plasma membrane
Nucleus
Endoplasmic reticulum
Ribosomes
Golgi Apparatus
Lysosomes
Mitochondria
Centrioles
Cytoskeleton
• Validity of Cell-Culture Findings
• Specific Cellular Changes during Aging
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Membrane Changes
Nuclear Changes
Cytoplasmic Changes
Robisomal Changes
Mitochondrial Changes
Lysosomal Changes
Central concept: many of the aspects of aging seen at the organ
level are the results of changes that occur with age at the
cellular level
– Loss of immune competency
– Age-related senility
• Focus of the chapter: understand cellular changes that occur
with aging even in the absence of disease
• Cellular changes that might influence aging are expected to:
– Be progressive
– Be deleterious
– Be irreversible
Cells are highly organized units and contain:
1. Various types of structures called organelles
2. Chemical substances: inclusions (glycogen granules and lipid droplets)
3. Nucleus: controls cellular functioning
4. Cytoplasm: semi-fluid substance that surrounds the nucleus
5. Plasma membrane (cell membrane): surrounds the cytoplasm;
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Forms the cell’s outer boundary
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Provides point of attachment for cell components
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Acts as barrier, regulates movement of material into and out of cell
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Selectively permeable
Plasma Membrane
• Composed primarily of Phospholipids
• Associated proteins & lipids are either embedded in the lipid or
loosely bound to the membrane surface
• Some proteins extend completely through the membrane forming
channels that connect cytoplasm with intercellular space
• Carbohydrates often attached to the outer surface of plasma
membrane
• All the material that enter a cell must pass through plasma
membrane; the ease of the passage depends largely on the
permeability
Fluid Mosaic Model
Figure 3.3
Nucleus
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Most cells contain a single nucleus
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Cells lacking nucleus: incapable of protein synthesis &/or cell division (RBC)
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Nuclear membrane separates the nucleus from the rest of the cell
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Contain genetic material
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Chromatin, nucleosome, Codes messages that direct synthesis of certain
proteins  confers specific functions to each specific cell type
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Central dogma of molecular biology: DNA RNA Proteins
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Most proteins act as enzymes or structural proteins
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All cells in an individual contain full genetic complement of DNA (except
reproductive cells)
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Proteins are produced at different times due to various control mechanisms
• DNA unable to pass through nuclear pores:
• Central dogma of molecular biology: DNA RNA Proteins
• RNA carries the DNA instructions to ribosomes in the cytoplasm 
protein synethesis
• Transcription: DNA mRNA
• Translation: mRNA Proteins
• Different types of RNA:
• mRNA (messenger): contains codes from DNA that specify the exact aa
(amino acid) sequence
• tRNA (transfer): combine with free aa in the cytoplasm and carry them to
ribosomes
• rRNA (ribosomal): join w/ proteins in the cytoplasm to form ribosomes
From DNA to Protein
Figure 3.34
Cytoplasm
• mRNA is being translated to protein
• rRNA and tRNA play a role in protein synthesis
• There are other important organelles within the cytoplasm
– Endoplasmic reticulum
– Ribosomes
– Golgi Apparatus
– Lysosomes
– Mitochondria
– Centrioles
– Cytoskeleton
Structure of a Generalized Cell
Figure 3.2
Endoplasmic Reticulum (ER)
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Network of membranous tubules that form channels extending throughout
the cytoplasm of the cell
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Contains enzymes involved in the synthesis of substances (fatty acids and
steroids)
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Rough vs. smooth ER
Ribosomes
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Small cytoplasmic organelles
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Free floating or attached to ribosomes
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Sites of protein synthesis (aa assemble to protein) in response to the
instructions from DNA
Ribosome travels along an mRNA molecule and “reads” its message tRNA
delivers the aa, and ribosome assembles them in the sequence directed by
mRNA
Golgi Apparatus
• Cytoplasmic organelles consisting of flattened, membranous sacs
• Enzymes; add carbohydrates to proteins (glycoprotein) or add fatty
acids or other groups to proteins
• Eventually become membranous  pinch off from the sac  vesicle
 move to surface  fuse w/plasma membrane  release their
content into exterior of the cell
• Golgi apparatus most evident in secretory cells
Lysosome
• Appear granular when inactive, but form vesicles when active
• Surrounded by membrane and contain strong digestive enzymes
capable of breaking down proteins, carbohydrate, DNA, RNA
• Particularly abundant in phagocytic cells (macrophages)
• Assist in the removal of dead or dying cells and foreign material
Mitochondria
• Oval structures, double membrane
• Outer membrane which forms the boundary is smooth
• Inner membrane, filled w/ a semi-fluid matrix, has folds and
extend into the central portion of the mitochondrion
• Inner membrane contains enzymes capable of sequential break
down of lipids, carbohydrates, and proteins  energy, carbon
dioxide, and water
Generates metabolic energy for cellular activities
• Contains it own supply of DNA, ribosomes and capable of selfduplication
• Metabolically active cells contain more mitochondria than less
active cells
• Major role in programmed cell death (PCD or apoptosis)
Centrioles
• Cylinder-shaped structures, mostly located close to the nucleus
• Involved in cell division
• Consist of parallel microtubules that are capable of self-duplication
• During division: centrioles divide  form two pairs  one pair move
to each end of the cell
• A network of microtubules, spindle fibers, develop b/w the two pair,
involved in the redistribution of chromosomes into daughter cells
Cytoskeleton
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Three dimensional network of tiny fibrils (microfilaments) and tubules
(microtubules)
Cytoskeleton components maintain shape & organization of the cells
Involved in the transport of substances with the cell, cell division, movement
Validity of cell-culture findings
• Some of the cells in older organism don’t function as effectively as
they used to.
• Functional alterations occur at different rates as not all functional
capacities decline at the same rate during aging
• Whether the changes observed in individual cells are the direct result
of a programmed series of events occurring inside the cells or indirect
effects due to random changes that occur outside the cells
• Growing cells in culture (in vitro vs. in vivo)
– How valid are the data?
– Do the data coincide closely enough w/ growth patterns of cells in vivo?
Evidence: cultured cells behave similarly to the cells in the body.
• Cell division; specific to each cell type
• Post-mitotic state in culture resembles senescent changes in the body
• Cultured cells can be kept frozen in liquid nitrogen
• Though mitotic activity is halted by freezing, it can be resumed by
thawing the cells
• Total number of divisions the cells will undergo remains the same
• Test: whether limitation of mitotic activity is due to culture medium:
• Old + young cells , controls: 1) old cells 2) young cells
• Measure the time it took each type of cell cease dividing and die
The medium is not the limiting factors; in the same medium old cells
stopped dividing while young cells still divide (same rate as controls)
Validity of cell-culture findings
Limited capacity and intrinsic regulation of the cell to divide
• Skin transplanted from young animals survive longer
Progeria
• People undergo changes that somewhat resemble accelerated
aging
• Begins during 1st year of life and median age at death is 13 years
• Slower than normal growth rate, loss and graying of hair
• Skin & blood vessel calcification, skeletal deformities (expanded
skull)
• Fibroblasts have shorter life span in culture media
Age-related changes in body cells may be reflected in cell
culture, thus, cultured cells can provide a valid
comparison for in vivo cellular aging
Both in vivo & in vitro studies indicate that the capacity of a cell to undergo
division generally exceed the number of divisions the cells undergo during
a normal lifetime.
Thus, aging changes occurring in vivo that are affected by cell division are
associated more w/ the rate of division than w/ actual cessation of division
Q: What causes the limitation/restriction on cell division?
•Progressive imbalance in normal cellular compartments may limit division
•Formation of certain cellular organelles does not occur at the same rate, in succeeding
generations these become less abundant; unable to support cell division
• Progressive generation of organelles during cell division  imbalance that becomes
lethal to cell (cellular senescence in fungi assoc. w/ proliferation of abnormal mito. DNA)
• changes in certain nuclear DNA sequences occur w/ aging in vertebrates
Specific Cellular Changes During Aging
Cellular aging is influenced by complex cellular functions that cause
changes in protein synthesis and turnover, and reduce the efficiency
of DNA repair and enzymatic activity
Membrane Changes
Plasma membrane regulates transport of molecules into & out of cell.
Functional changes:
Alterations in transport of ions, nutrients, aa, & protein across membrane
Structural changes affect cell membrane permeability (e.g., less fluid in
ER of old animals) due to increase in saturated fatty acids in membrane
Nuclear Changes
• Cellular machinery that synthesizes RNA from DNA is potentially unstable (changes initially occur in nucleus, eventually seen in cytoplasm)
• An increase of error in protein synthesis has secondary effects including
formation of faulty DNA, defects in plasma membrane, transport of
material, decline in mitochondria production, etc.
• Increased in DNA damage during aging & decreased DNA repair
• More condensed chromatin (cross-links b/w sulfur atoms)
• Production of an inhibitor substance in the cytoplasm of aging cells and
diffusion into the nucleus (nuclei of young cells no longer synthesize
DNA when transplanted into senescent cell)
Cytoplasmic changes
• Dramatic increase in volume with age
• Decrease rate of DNA synthesis
• Gradual buildup of lipofuscin (age-pigment)
Ribosomal changes
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Amount of rRNA decreases with aging
Decrease in the number of free and attached ribosomes
Decline in protein synthesis
Decrease in the rate of elongation of the amino acid chains
Mitochondrial changes
• Production of lipofuscin (indirectly)
• Apparent disorganization of the membrane
• Structural changes
• Decrease in number of mitochondria in post-mitotic cells
• Decrease in energy and contribute to functional changes
• Sequential chemical reactions  free radicals  oxidation
reactions w/ lipids  destructive molecular changes
• Role of anti-oxidants in diet
Lysosomal changes
• Collection of enzymes surrounded by a membrane
• Play an important role in intracellular digestion and breaking down
foreign substances, waste removal
• With aging the action of the lysosomes is less efficient in older cells
• Accumulation of indigestible and non-degradable residues
• Changes in membrane
• Changes in number
• Changes in activity of enzymes