Biology of Human Aging

“Cellular Aging”Chapter 3

Outline

• Cell Components• Plasma membrane• Nucleus• Endoplasmic reticulum• Ribosomes• Golgi Apparatus• Lysosomes• Mitochondria• Centrioles• Cytoskeleton

• Validity of Cell-Culture Findings

• Specific Cellular Changes during Aging• 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;

• Forms the cell’s outer boundary

• Provides point of attachment for cell components

• Acts as barrier, regulates movement of material into and out of cell

• 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• Most cells contain a single nucleus

• Cells lacking nucleus: incapable of protein synthesis &/or cell division (RBC)

• Nuclear membrane separates the nucleus from the rest of the cell

• Contain genetic material

• Chromatin, nucleosome, Codes messages that direct synthesis of certain proteins confers specific functions to each specific cell type

• Central dogma of molecular biology: DNA RNA Proteins

• Most proteins act as enzymes or structural proteins

• All cells in an individual contain full genetic complement of DNA (except reproductive cells)

• 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)

• Network of membranous tubules that form channels extending throughout the cytoplasm of the cell

• Contains enzymes involved in the synthesis of substances (fatty acids and steroids)

• Rough vs. smooth ER

Ribosomes

• Small cytoplasmic organelles

• Free floating or attached to ribosomes

• 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 activitiesGenerates metabolic energy for cellular activities

• Contains it own supply of DNA, ribosomes and capable of self-duplication

• 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

• 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

• 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

Validity of cell-culture findings

• 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

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

Membrane Changes

Nuclear Changes

• Cellular machinery that synthesizes RNA from DNA is potentially un-un-stablestable (changes initially occur in nucleus, eventually seen in cytoplasm)

• An increase of error in protein synthesisincrease 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 damageDNA damage during aging & decreased DNA repairdecreased DNA repair

• More condensed chromatincondensed chromatin (cross-links b/w sulfur atoms)

• Production of an inhibitor substanceinhibitor 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

• 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 lipofuscinlipofuscin (indirectly)

• Apparent disorganization of the membranedisorganization of the membrane

• Structural changesStructural changes

• Decrease in number of mitochondrianumber of mitochondria in post-mitotic cells

• Decrease in energyenergy and contribute to functional changes

• Sequential chemical reactionschemical reactions free radicalsfree radicals oxidation

reactions w/ lipids destructive molecular changesmolecular changes

• Role of anti-oxidantsanti-oxidants in diet

Lysosomal changes

• Collection of enzymesenzymes surrounded by a membrane

• Play an important role in intracellular digestionintracellular digestion and breaking down foreign substances, waste removal

• With aging the action of the lysosomes is less efficientless efficient in older cells

• Accumulation of indigestible and non-degradableindigestible and non-degradable residues

• Changes in membranemembrane

• Changes in numbernumber

• Changes in activity of enzymesactivity of enzymes