Site
map Main
Index Chapter supplements
Copyright
Learning
Objectives Outline
Lecture Notes
Changes/Suggestions
Glossary
Chapter 2 - Molecules, Cells, and
Theories
The importance of understanding body materials and cells
becomes evident when one realizes that the human body has a hierarchy of
structure and functioning, with these materials and cells at its foundation.
This chapter will take a broad view of this hierarchy and then examine major
body substances and cells in greater detail.
Like all physical objects, the body is made of matter
composed of units called atoms. Each atom has at its center a
nucleus that contains one or more small particles called protons
and neutrons. Each atom also has one or more smaller particles
called electrons, which move about in regions some distance away
from the nucleus (Fig. 2.1).
An atom is the smallest unit of an element that has the
properties of that element. For example, all the carbon atoms that make up a
lump of coal can burn and produce carbon dioxide. Most types of atoms lack a
complete set of electrons in their outer regions. Therefore, these atoms may
react chemically with one another in ways that produce complete electrons sets.
Atoms that engage in one type of chemical reaction may lose or gain electrons
and become ions. (Fig. 2.2); atoms
engaged in other chemical reactions end up sharing electrons with neighboring
atoms (Fig. 2.3). Ions
attract each other because they have opposite charges and atoms that share
electrons may be bonded together in specific ratios, thus forming groups called
molecules. Furthermore, fragments of some molecules may lose or
gain electrons. Such molecular fragments are also called ions (Fig. 2.4).
Each type of molecule has its own properties, which may be
very different from those of the atoms composing it. For example, hydrogen
atoms form a gas that can burn explosively and oxygen atoms support combustion,
but when hydrogen atoms are chemically bonded to oxygen atoms in a 2:1 ratio,
they form water molecules, which can extinguish fires. Molecules also undergo
chemical reactions, which may produce still other molecules. For example,
during digestion, water molecules may react with starch molecules and produce
sugar molecules.
Besides producing new substances, each chemical reaction
either releases or absorbs energy. The energy given off by
chemical reactions can be used to power other activities, including other
chemical reactions that absorb energy. For example, the energy given off by
burning fuel can be used to power an automobile. The energy in foods, measured
as calories, is given off when the foods are metabolized. This energy powers
all body functions and keeps us warm.
Many atoms, ions, and molecules in the body are arranged in
combinations that form structures of various shapes, such as sheets, granules,
and tubes. These structures make up components called organelles
(e.g., cell membrane, ribosomes, microtubules) (Fig. 2.5) .
Organelles in turn are in highly complicated and organized structures called cells.
The organelles are like the parts of an automobile in that each organelle can
carry out only a few specialized functions. However, like the parts of an
automobile that is being driven correctly, a complete and properly assembled
set of organelles that has proper guidance can operate on its own.
Cells are the smallest units of the body that can survive on
their own under favorable conditions (i.e., homeostasis) and have
all the characteristics of life. These characteristics include organization,
constant chemical activity, external or internal movement, an active response
to stimulation, and reproduction. By possessing and carrying out the
characteristics of life, cells and the substances they produce constitute all
the larger components in the body and perform all body functions. Though cells
in the body have many features in common, they are also specialized in a
variety of ways and therefore can perform different functions. For example,
muscle cells can contract to provide gross movements, and bone cells can
secrete materials that make hard and rigid bones that provide support and
protection.
Tissues, Organs, Systems, Organism
Cells of the same type plus some materials they secrete are
found together in organized groups called tissues (Fig. 2.5) .
Different tissues are organized in groups called organs, organs
are organized in groups called systems, and systems are found in
an organized group called the organism, a human body. Just as
each cell performs certain functions, so also does each tissue, organ, and
system. When these functions are combined and coordinated, homeostasis can be
maintained and the individual can survive. Combining and coordinating male and
female functions can result in reproduction, which maintains the survival of
the human species. There are additional hierarchical levels beyond the body
(e.g., family, community, nation) which are studied in disciplines other than
biology (e.g., sociology and political science).
The atoms, ions, and molecules contained in the body or
making up its parts are derived from atoms, ions, and molecules in the diet.
However, many dietary substances are modified before entering the body and
becoming integral parts of it. The following discussion focuses on body
chemicals, which are chemicals that are already internal or compose parts of
the body. Dietary chemicals and their relationships to body chemicals are
discussed in Chap. 11.
Approximately 70 percent of the body consists of water
molecules (Fig. 2.6). Water
dissolves and transports materials, lubricates and cushions structures,
regulates temperature, and modulates osmotic pressure and acid/base balance.
The other body chemicals are of myriad variety and complexity. Some of them are
minerals that are present as ions (e.g., sodium ions). The bulk of the
remaining body chemicals are molecules, many of which share common features and
therefore can be grouped into broad categories. These categories are carbohydrates,
lipids, proteins, and nucleic acids.
The smallest and simplest carbohydrate molecules are simple
sugar molecules called monosaccharides. One of the most abundant
monosaccharides is glucose (Fig. 2.7). Other
carbohydrate molecules consist of monosaccharide molecules linked together. A
carbohydrate containing two monosaccharides is called a disaccharide,
and carbohydrates consisting of many monosaccharides are called polysaccharides.
Polysaccharides may contain from dozens to thousands of monosaccharide
molecules, which are arranged to form straight or branched chains (Fig. 2.8). A common
polysaccharide is glycogen, which is made of glucose.
Carbohydrates are used for storing and supplying energy and for building
materials and receptor molecules for communication.
Nucleic acid molecules contain dozens to thousands of small
molecules linked to form chains (Fig. 2.9). The small
molecular units in nucleic acids are called nucleotides. Each
nucleotide contains a sugar molecule with five carbon atoms, a molecular
fragment containing phosphorus (a phosphate group), and a
molecular fragment containing nitrogen (a nitrogen base). There
are five types of nitrogen bases, which can be designated by the initials A, G,
C, U, and T (adenine, guanine, cytosine, uracil, and thymine). Though many
nucleotides are linked to form nucleic acids, others remain separate. These
individual nucleotides often have additional phosphate groups or other
modifications and are used to transfer energy from chemical reactions to other
activities. Two of the most abundant and widely used nucleotides are adenosine
diphosphate (ADP) and adenosine triphosphate (ATP)
(Fig. 2.10)
.
The nucleic acids are divided into two main classes based on
the type of sugar used in their nucleotides. The sugars in nucleic acids called
ribonucleic acid (RNA) have one more oxygen atom
than do the sugars in nucleic acids called deoxyribonucleic acid
(DNA). A second difference between RNA and DNA is that
nucleotides in RNA contain A, G, C, and U, while nucleotides in DNA contain A,
G, C, and T. Most DNA molecules contain two chains of DNA linked side by side
by matching nitrogen bases in complementary pairs. The double strand of DNA is
twisted in the form of a double helix, which resembles a twisted ladder (Fig. 2.9). Other
combinations of DNA, RNA, and individual nucleotides are also made by matching
complementary nitrogen bases.
Though there are only four different nucleotides in RNA and
DNA, nucleic acid molecules in both classes have enormous variety. The reasons
are the same as those permitting the writing of an essentially limitless variety
of sentences using the limited number of letters in the alphabet. That is,
nucleic acid molecules may be of different lengths, and more importantly, the
nucleotides may be arranged in a virtually infinite number of ratios and
sequences. As with the letters in a sentence, the nucleotide sequence in each
nucleic acid molecule contains a message. Also like
letters in sentences, changes in either the nitrogen bases employed or the
sequence of the bases can change the message or make it meaningless (e.g., dog_dig_god_dgo). When complementary nitrogen bases are
matched, the encoded message can be deciphered in
cells and the information it contains
can be used as instructions. Many of these instructions direct the formation of
protein molecules by a process called translation.
Like carbohydrate and nucleic acid molecules, protein
molecules consist of many small molecules linked to form chains (Fig. 2.11)
(a) Two amino acids, each with a short segment of -N-C-C- and side groups of
hydrogen (H), oxygen (O), and R-groups. (b) A chain of amino acids (i.e., a
polypeptide). The small molecular units in proteins are called amino
acids, of which there are 20 types.
Compared with many polysaccharides and nucleic acid
molecules, protein molecules show much more variety in structure and
functioning. This variety exists for five reasons. First, the different amino
acids may be combined in a virtually infinite variety of lengths, ratios, and
sequences. Second, polysaccharides and nucleic acids contain few different
types of units, while each protein molecule may contain all 20 types of amino
acids. Third, the shapes of different amino acids cause protein chains to form
various twists and bends. Fourth, some amino acids link to others in a protein,
causing it to take on and maintain other twists and bends (Fig. 2.12).
Fifth, some amino acids link to amino acids in adjacent protein molecules,
causing additional changes in configurations and positions.
Many twists, bends, and links, and therefore the shape and
position of each protein, are determined by the conditions surrounding it
(e.g., temperature, amount of acid present). When these conditions change, the
shape and position of a protein may shift, and slight changes in these
conditions cause dramatic shifts in some proteins. Furthermore, as with any
tool or device, the shape and position of each protein determine what functions
it can perform and how well it can perform them (Fig. 2.13) .
This is a major reason body structures retain their normal shapes and proper
functioning only under homeostatic conditions. Proteins serve as building
materials; receptor molecules and hormones for communication; enzymes for
regulating reactions; and antibodies for defense.
Lipid molecules are placed into the same category because at
least a large portion of each molecule does not dissolve well in water. We will
mention only a few types of body lipid molecules.
Among the most water‑repellent lipid molecules are the
triglycerides, also called fat. Triglycerides
contain a backbone made of a glycerol molecule with three fatty
acid arms protruding from it (Fig. 2.14)
. Fatty acids contain up to 20 carbon atoms in a row (Fig. 2.15).
The body also contains glycerol combined with only one or two fatty acid
molecules, forming monoglycerides and diglycerides,
respectively. Glycerides store and supply energy.
The carbon atoms in some fatty acids are linked to the
maximum number of hydrogen atoms; such fatty acids are called saturated
fatty acids (Fig. 2.15).
In other fatty acids, additional hydrogen atoms can be linked to the carbon
atoms, and these fatty acids are called unsaturated fatty acids. Monounsaturated
fatty acids have only one location that permits the addition of
hydrogen atoms (Fig. 2.15),
while polyunsaturated fatty acids have more than one such
location (Fig. 2.15c, Fig. 2.25d). Similar terms are applied to triglycerides with fatty
acids able to hold zero, one, or more than one additional hydrogen atom (i.e., saturated
fat, monounsaturated fat, and polyunsaturated fat).
Often, glycerol linked to two fatty acids is also linked to
a molecular fragment containing phosphorus, forming phospholipids
(Fig. 2.14b)
. While the regions of phospholipids containing fatty acids repel water, the
region containing phosphorus attracts water. These properties cause
phospholipids to align and form double‑layered membranes in the watery
internal environment of the body.
A third group of lipid molecules are called steroids.
Their carbon atoms are linked to form rings (Fig. 2.16)
. Well‑known examples of steroids include
cholesterol, which is used as a building material, and sex steroids such as
testosterone, estrogen, and progesterone, which serve as hormones for
communication.
Though many carbohydrate, nucleic
acid, protein, and lipid molecules are not joined to any others in these
categories, many molecules link together and form molecular complexes.
Combinations of carbohydrate and protein are called glycoproteins
or mucopolysaccharides, depending on whether carbohydrate or
protein predominates. Combinations of nucleic acids and proteins are called nucleoproteins,
and combinations of lipids and proteins are called lipoproteins.
The formation of molecular complexes can modify the physical properties (e.g.,
flexibility) and activities (e.g., accessibility) of the molecules involved.
A free radical (*FR) is an atom
or molecule with an unpaired electron (* = an unpaired electron). For example,
an ordinary oxygen molecule is made of two oxygen atoms, and it contains 16
electrons. (Fig. 2.3). If
another electron is added to the molecule, one electron would be unpaired. The
resulting molecule would be a free radical called a superoxide radical.
Some free radicals are made from highly reactive substances that contain
oxygen, and some free radicals produce such highly reactive substances. These
substances, which are not free radicals themselves, are called reactive
oxygen species (ROS).
Small *FRs in the body include the superoxide radical
(*O2-), the hydroxyl radical
(*OH), and the nitric oxide radical (*NO).
Larger free radicals contain an organic molecule, such as a fatty acid,
combined with extra oxygen. Examples include the alkoxyl radical
(*RO) and the peroxyl radical (*ROO),
where the R represents the original organic molecule. Peroxyl radicals
containing a fatty acid are also called lipid peroxides (*LPs).
Reactive oxygen species in the body include hydrogen
peroxide (H2O2), peroxynitrite anion (ONOO-),
organic hydroperoxide (ROOH), plus certain amino
acids (e.g., tryptophan) and other substances produced during cell metabolism.
An organic hydroperoxide containing a fatty acid is also called a lipid
hydroperoxide.
These *FRs and ROS are not equally important. Superoxide
radicals and H2O2 result
in damage only when they fuel reactions that produce hydroxyl radicals (*OH) or
ONOO-, because these latter two substances are among the fastest
acting and most toxic to the body. Free radicals containing fatty acids react
much slower than these.
Importance in aging Free
radicals seem to be implicated in aging. Reasons include the apparent negative
correlations between the following; mean longevities (MLs)
and maximum longevities (XLs) of species and their
rates of forming *FRs and ROS; MLs and XLs and their rates of developing damage
from *FRs; age and the level of *FR defenses in some species; and age and the
rate of repairing damage from *FRs.
Other reasons include the apparent positive correlations
between the following; MLs and XLs of some species and their levels of *FR
defenses; MLs and anti-*FR supplements (i.e., antioxidants); age and the rate
of *FR formation; age and the amount of damage from *FRs; age-related diseases
and *FRs (e.g., atherosclerosis, heart attacks, strokes, Alzheimer's diseases,
parkinsonism, cataracts, kidney failure, cancers).
Formation of *FRs and ROS Some
*FRs and ROS produced by the body are useful. Examples include; *NO for signals
among neurons; *NO to cause blood vessel dilation for blood pressure
regulation; H2O2 to destroy bacteria; and other defense
*FRs and ROS produced during defense processes such as inflammation and immune
responses. Many *FRs and ROS are produced as by-products from other useful
reactions. Examples include cells producing *O2-, H2O2,
and *OH and other *FRs and ROS when cells obtain energy from nutrients;
detoxifying certain plant materials; break down of dopamine (DOPA) and fatty
acids; using iron or copper in reactions; and performing reactions peculiar to
their special functions. Finally, *FRs and ROS result from unwanted conditions
including exposure to ultraviolet light, internal bleeding, reversing unduly
restricted blood flow, and reactions between glucose and proteins (see
Glycation below).
Conditions that increase *FR production include elevated
amounts of O2 in the body; high blood LDLs; high blood glucose
levels; excess vitamin C; very high level of exercise; skin photosensitizers
including certain cosmetics, medications, and air pollutants; menopause; and
smoking; and increasing age. Conditions that decrease *FR production include
reduced intake of polyunsaturated lipids; moderate exercise; increased intake
of cruciferous vegetables (e.g., broccoli, cauliflower, cabbage); reduced
intake of copper, iron, or magnesium; and reduced intake of certain amino acids
(e.g., histidine, lysine).
Common chemical reactions by which *FRs and ROS are formed
include the following, where e- represents an electron, H+
represents a hydrogen ion, and H- represents a hydrogen atom sharing
electrons with another atom or molecule.
O2 + e- → *O2-
*O2- + e- + 2H+ →
H2O2
H2O2+ e- → OH-
+ *OH
These reactions are common when cells use oxygen to derive
energy from nutrients (see Mitochondria below); where iron or copper ions
exist; in skin struck by ultraviolet light; and when enzymes in the brain use
monoamine oxidases (MAOs).
Common reactions with *FRs involving fatty acids are shown
next, where PUFA represents a polyunsaturated fatty acid. These reactions occur
in three processes called initiation, propagation,
and termination. The reactions are chain reactions
because propagation or reinitiation may occur
repeatedly before termination occurs. Each time propagation or reinitiation occurs, another damaged fatty acid is produced
and a new *FR is formed, leaving a wake of oxidized damaged molecules.
Oxidation damage from free radicals spreads though the cell like oxidation
damage from a fire spreads from one house to the next along a street in a
neighborhood. Since free radicals form in many areas in a cell, many molecular
“fires” can be spreading at once through a molecular “neighborhood” such as a
cell membrane (Fig. 2.18).
initiation
H-PUFA1 + *FR → *PUFA1 +
H-R
*PUFA1 molecule rearranges itself
rearranged *PUFA1 + O2 →
*PUFA1-O-O (peroxyl radical = *LP)
propagation
*PUFA1-O-O + H-PUFA2 →
H-PUFA1-O-O (a damaged fatty acid {lipid hydroperoxide}) + *PUFA2
(new *FR)
repeated propagations
*PUFA2 + O2 → *PUFA2-O-O
*PUFA2-O-O + H-PUFA3 →
H-PUFA2-O-O (another damaged fatty acid) + *PUFA3 (new
*FR)
etc., etc. → many H-PUFAx-O-O
(many damaged fatty acids) + another *PUFAn
(another new *FR)
termination
*PUFAn + H-R →
H-PUFAn + R
or
*PUFAn + *PUFAn → R-O-O-O-O-R →
(toxic substances) + O2
reinitiation
R-O-O-O-O-R + iron or copper → *PUFA-O or
*PUFA-O-O
Effects from *FRs Free
radicals damage body molecules by taking electrons from molecules, a process
called oxidation. This process alters the shapes and functions of
the molecules, causing the body to sustain structural damage and malfunctions.
The main types of molecules affected are nucleic acids,
proteins, and lipids. The consequences from even a small alteration in DNA can
be devastating because the effect is multiplied during protein production.
Also, damaged DNA may be unable to be replicated, preventing cells from
reproducing by mitosis. Alternatively, some types of DNA damage promote cancer.
Damage to proteins and lipids causes abnormal cell and body
structures and operations. Protein molecules such as those in tendons and
ligaments become excessively joined together, and the functions of enzymes and
cell membranes become abnormal. Damaged mitochondria are often unable to
produce adequate energy for maximum cell activity. *FR damage can initiate
inflammation, cause excess blood clotting, and promote several diseases,
especially cataracts and atherosclerosis. Some *FR effects on proteins and
lipids compound problems by increasing the rate of *FR production, reducing the
body's ability to eliminate *FRs, and decreasing the ability to repair or
remove damaged molecules.
Clearly, free radicals damage a variety of essential bodily
components and alter body functions. To defend against *FR damage, the body has
mechanisms to eliminate free radicals and to remove and repair molecules
damaged by them. Substances called antioxidants destroy them by
helping to create pairs of electrons. Examples of dietary antioxidants include
vitamin E, vitamin C, beta-carotene (a vitamin A precursor), and substances in
fruits and vegetables. The body also makes many antioxidants (e.g., melatonin, glutathione,
albumin, uric acid), and can even recycle some of these antioxidants after they
have neutralized *FRs.
The body also makes enzymes to divert *FR production and to
speed up *FR elimination. Extremely important examples remove superoxide
radicals (superoxide dismutase) and H2O2 (glutathione
peroxidase, catalase). These enzymes are especially important because they
prevent the formation of *OH, the most reactive and harmful free radical.
Selenium is a vital dietary constituent because it helps an enzyme (glutathione
peroxidase) remove H2O2.
Glucose joins chemically with certain amino acids in
proteins. No enzymes are needed for these reaction, and they usually occur with
the side groups of arginine and lysine (Fig. 2.11)
see R-). The products are altered amino acids attached to glucose (i.e., Amadori products). The amino acid/glucose portion may break
down to form a distorted protein plus an ROS (e.g., H2O2),
and the ROS may form *FRs. Distorting a protein in
this way is like bending and twisting a wire clothes hanger until it is
useless.
Alternatively, the amino acid/glucose portion may join with
others on the same or different protein molecules. This is called a Maillard
reaction. The results are cross-links among the protein strands, and
they then resemble strips of tape that have become stuck and tangled together.
The cross-links are extremely stable and long-lasting, and common ones are
called pentosidine.
The reactions forming glucose cross-links between proteins
are called nonenzymatic glycation because glucose reacts without
the use of enzymes. They are also called glycation, or glycoxydation because *FRs help as oxidizing
substances during the process. The glycated proteins are damaged and distorted,
turn a darker color, and are called advanced glycation end-products
(AGEs). Other sugars in the body perform similar reactions that
produce altered proteins, and AGEs may be formed by other chemical pathways.
Most types of protein in the body are subject to glycation.
Effects Studies
on AGEs began in the 1970s, and studies on their relationship to aging began in
the 1980s. To date, little is known about the exact identity and
characteristics of AGEs formed by glycation. Though they do not seem to cause
aging, they accumulate with aging and seem to contribute to aging and
age-related diseases. For example, the rate of glycation is inversely
correlated with the XL of animals, though the amount
of AGEs formed is not related to XLs. Also, *FRs and glycation are related in
at least four ways; *FRs increase glycation; glycation increases *FRs; both
processes increase the effects from *FRs by damaging defense and repair
enzymes.
There is no known benefit from glycation or from AGEs.
However, glycation adversely affects all body parts and functions directly by
distorting the proteins involved. Other adverse effects from glycation include
indirect damage to DNA and lipids though the *FRs produced from glycation and
by the abnormal operations of damaged proteins; body stiffening; poor movement
of materials between cells, and distorted signaling of cells (see Intercellular
Materials below); reduced ability to control blood vessels and blood pressure;
damage to blood vessel linings and atherosclerosis; increased blood clotting;
increased development of Alzheimer's disease; kidney injury and eye damage from
AGEs in blood vessel walls; amplification of most effects from diabetes
mellitus; and tissue damage and inflammation by activating defense cells. For
example, macrophages and monocytes are activated when AGEs attach to their cell
membrane receptors for AGEs. These receptors are called receptors for
AGES (RAGEs).
Keeping blood glucose levels within normal levels seems to
be a main way to minimize glycation and its adverse effects.
We can now use our understanding of body chemicals to
examine cells in greater detail. In doing so, we will focus on the structures
and corresponding functions in one cell that has the general features found in
most cells (Fig. 2.17).
Specializations in cell structures and age changes in cells are described in
Chaps. 3 through 15, along with the systems in which they are found.
The outer boundary of the cell is called the cell
membrane. It consists of a double layer of phospholipid molecules that
contains other lipid molecules and protein molecules. Some of these proteins
have carbohydrate molecules extending outward from them (Fig. 2.18).
The lipids and some proteins give the membrane strength to
hold the cell contents together and regulate the continuous passage of
substances into and out of the cell through the membrane. Other proteins and
carbohydrates serve as identification markers for the cell, attach the cell to other
cells or neighboring structures, or serve as cell membrane receptors.
Receptors are like antennae that receive messages by binding messenger
molecules. The cell membrane may also engulf particles and take them into the
cell, a process called phagocytosis.
A very soft gel called cytoplasm lies within
the cell membrane. Cytoplasm is mostly water, and it contains a large quantity
and variety of dissolved ions and molecules. Its gel‑like consistency
supports organelles, allowing them to function and interact properly. Cytoplasm
also stores dissolved materials and granular substances. Finally, many chemical
reactions occur in the cytoplasm. Some of them release energy, which may be
transferred by ATP or other modified nucleotides to energy‑consuming
reactions and activities in the cell.
Membranes similar to the cell membrane extend throughout
much of the cytoplasm. These membranes, called endoplasmic reticulum
(ER), partition the cytoplasm much as walls, floors, and ceilings
divide the inside of a building into rooms and corridors. The ER
compartmentalizes the cytoplasm and regulates the movement of materials within
it. Smooth ER also manufactures lipids (e.g., steroids). The
other type of ER is called rough ER because its coating of
granular structures makes it appear like rough sandpaper. The granules are
called attached ribosomes, and they manufacture proteins that
will be secreted from the cell. Other ribosomes, called free ribosomes,
are suspended in the cytoplasm and manufacture proteins for use within the
cell. Proteins destined for secretion are transported between layers of ER to a
packaging area.
The protein‑packaging area is an organelle called the Golgi
apparatus, which consists of stacks of containers made of membranes
arranged like stacks of flattened bags. Like grocery bags being packed at a
checkout counter, Golgi apparatus containers are filled with proteins destined
for secretion. The Golgi apparatus also manufactures carbohydrates, some of
which combine with proteins as they are packaged. Filled Golgi containers are
transported to the cell membrane, where, like bubbles, they burst open and
release their contents from the cell.
Some proteins in the cell are stored in droplets of fluid
surrounded by membranes. Other manufactured materials, as well as dissolved
substances or particles taken in by the cell membrane, may be stored in a
similar way. Such storage containers are called vacuoles.
Vacuoles with special functions may have other names. For example, vacuoles
containing proteins that help digest materials (i.e., digestive enzymes) are
called lysosomes, and vacuoles containing substances that destroy
certain toxins are called peroxisomes.
Each mitochondrion consists of a double layer
of membrane enclosing a small amount of liquid (Fig. 2.19).
Mitochondria are of various shapes and sizes.
Many of the numerous chemical reactions in mitochondria
convert one type of molecule to another. This activity helps provide a balance
of molecules in the cell. Other related chemical reactions release energy.
Mitochondria that receive oxygen release much more energy than is released by
the cytoplasm. However, as in the cytoplasm, most of the energy released in
mitochondria is placed into ATP molecules for transfer to energy‑consuming
activities throughout the cell.
The energy in the ATP molecules originates in nutrient
molecules in food. As the cell breaks down the molecules, carbon dioxide and
other wastes are released. During these processes, electrons and hydrogen ions
removed from the nutrients carry energy from the nutrients into the
mitochondria. Then the electrons and ions are moved by regulated mechanisms
along and through the inner mitochondrial membrane. The mechanisms are called
electron transport and oxidative phosphorylation. At the end of these
mechanisms, the electrons and hydrogen ions are combined with oxygen to form
water while the energy they carried is used to make ATP.
A small percentage of the electrons and ions escape the
ATP-producing mechanisms and combine with oxygen to form free radicals and ROS
(e.g., *O2-, H2O2, *OH). From less
than 1 percent to 5 percent of the oxygen used by mitochondria ends up in *FRs
and ROS. The amount is determined by several factors including the type of
cell, chemical conditions in the cell, and the age and condition of the
mitochondria. Damaged and old mitochondria produce more *FRs and ROS. Though
mitochondria contain antioxidants and enzymes to eliminate them, some ROS and
*FRs escape from the mitochondria and cause damage in other parts of the cell
or the body. The *FRs and ROS also damage the mitochondria, especially their
inner membrane and their DNA. Mitochondrial DNA (mtDNA)
damage is greatest in active non-dividing cells (e.g., heart, muscle, brain).
Damaged mitochondria also produce less ATP. All these changes increase with age
and may be a main cause of aging. (see Mitochondrial
Theory and Mitochondrial DNA Theory below).
Microtubules and Microfilaments
Besides membranous organelles, the cytoplasm has long thin
organelles that consist mainly of protein. Those shaped like tubes are called microtubules,
and those shaped like fibers are called microfilaments. Like tent
poles and ropes, both types of organelles provide internal support for the
cell, forming the cytoskeleton (Fig. 2.20).
They also help the cell change shape and move, and help transport materials
from place to place within the cell.
The cytoplasm and its organelles are separated from an inner
region of the cell by a double layer of membrane called the nuclear
membrane. This membrane and the materials it surrounds
constitute the nucleus. The soft gel in the nucleus (i.e., nucleoplasm)
resembles cytoplasm. The highly convoluted DNA molecules it contains have
several names, including chromosomes, chromatin, hereditary
material, and genetic material. The information encoded
in the DNA directs the construction and activities of the cell. The portion of
the DNA directing the production of ribosomes is called a nucleolus.
The portion of the DNA at one end of each chromosome is called a telomere.
The telomeres are of different lengths on different chromosomes.
Human cells have 46 chromosomes. Like the sentences in each
chapter of a lengthy instruction manual, each chromosome has thousands of
instructions. When an instruction is to be carried out, the nucleus makes an
RNA copy of the instruction contained in the DNA. Accurate transcription is
achieved by complementary base pairing. The RNA copy - messenger RNA
(mRNA) - may be edited in the nucleus before being transported to
the cytoplasm. Using other RNA molecules in ribosomes and in the cytoplasm, the
instruction in the mRNA directs the assembly of amino acids to form a chain
with a specific length, ratio, and sequence. These characteristics help
determine the final shape and functions of the amino acid chain. After
twisting, bending, and possibly combining with other amino acid chains, the
amino acid chain is a finished protein molecule.
The length of DNA used to direct the formation of an amino
acid chain is called a gene. Only some genes are used at any
given time. One way a cell can prevent a gene from operating is by winding the
DNA for that gene tightly. Masses of tightly wound DNA are called heterochromatin.
Other gene activity is controlled by other genes, by messenger substances, and
by conditions in and around the cell.
Some protein molecules are called structural proteins
because they become structural components of the cell. Other protein molecules
(enzymes) control the production of non-protein substances
and regulate cell activities. Therefore, by directing the manufacture of
structural proteins and enzymes, DNA controls all the structures and functions
of the cell.
If a cell continues enlarging, it must eventually divide.
Otherwise, the amount of cytoplasm and organelles it contains will become too
large to be adequately served by its cell membrane and nucleus.
DNA Duplication
In preparation for division, a growing cell makes a copy of its DNA (Fig. 2.21).
Occasional errors occur during this process, but certain enzymes, acting like
proofreaders, identify and correct nearly all these errors before duplication
of the DNA is completed. It is noteworthy that similar enzymes can maintain the
genes in an error‑free condition by repairing the DNA if it is damaged
afterward.
One error that is usually not corrected is the omission of
part of each telomere. As a cell divides repeatedly during life, its telomeres
become ever shorter in an age-related manner. Shortening of telomeres occurs at
different rates among the chromosomes. Once the telomeres reach the minimum
critical length, the cell is unable to divide again because it cannot make a
complete copy of the remaining DNA, which contains essential genes. The reasons
are not clear, but they may involve deleterious effects on chromatin structure
or signals that inactivate genes needed for cell division.
Human telomeres consist of repeated segments made of six
nucleotides (i.e., TTAGGG). Other animals and other organisms have different
sequences and lengths in their telomere repeat units. Telomeres have diverse
functions besides permitting complete replication of the essential DNA in a
chromosome. Examples include attaching chromosomes to the nuclear membrane;
preventing chromosomes from attaching to each other; protecting DNA from
enzymatic attack; and influencing genetic activities.
Some cells can prevent shortening of their telomeres with
each cell division. Examples include embryonic cells, sperm-producing cells,
and cancer cells. Usually, such cells use the enzyme telomerase
to rebuild the telomere during DNA replication. Some cells use mechanisms not
requiring telomerase.
The effects of telomere shortening and telomerase on human
aging are not yet known. Rapid telomere shortening is found in Werner's
syndrome and in Down's syndrome, which are two syndromes that mimic rapid aging.
Persons born with low birth weights who experience growth spurts (i.e., bursts
of cell division) after birth, or people who experience growth spurts for any
reason, may have especially short telomeres in their rapidly growing body parts
because of the decline in telomerase after birth. Results for such individuals
may include increased risk of high blood pressure because their kidneys may
grow faster than normal or increased risk of atherosclerosis due to rapid cell
proliferation in arteries injured by high blood pressure.
Maintaining or reinitiating telomerase production may be a
main cause of cancer. If telomerase activity could be stopped in cancer cells,
the cancer might be curable. Alternatively, if telomerase could be reactivated
in specific cells where injury has occurred, better healing might result.
Mitosis
Once the cell has copied its DNA and has enough cytoplasm and organelles to
divide, it partitions the DNA into two identical sets of genes. The cell then
pinches itself into two cells, each of which contains one set of genes plus
some of all the other cell components. This process, which results in cell
reproduction, is called mitosis (Fig. 2.21).
In the early phase of mitosis, the cell winds its duplicated DNA strands into
tightly coiled chromosomes (Fig. 2.22).
At the end of mitosis, portions of each chromosome are unwound so many
genes become active again.
Besides maintaining efficient cells, the growth and reproduction
of cells allow for growth, replacement, and repair of parts of the body. It is
through these processes that a single microscopic cell (a fertilized egg)
develops into a full‑grown person composed of trillions of cells. Cell
growth and reproduction also allow for the replacement of skin cells and red
blood cells, which are dying continuously, and for the healing of skin that has
been cut or scraped.
Hayflick limit In
1961, Hayflick and Moorhead reported that cells removed from the dermis of human
skin and grown in laboratory vessels divide a certain number of times, stop
dividing, and gradually die. Since then, this characteristic has been observed
in many cell types from humans and other animals. It is now commonly called the
Hayflick limit. Cells in laboratory vessels that stop dividing
and eventually die said to undergo replicative senescence (RS).
The Hayflick limit shows three properties that seem to be
related to aging. First, the number of divisions is negatively correlated with
the XL of the species from which the cells originate (e.g., mice have 10-15
divisions, humans have 60 divisions, Galapagos turtles have 100 divisions or
more). Second, the number of divisions is inversely proportional to the age of
the person from whom the cells were taken. Third, the number of divisions is
lower for cells from people who undergo changes like aging but at an abnormally
young age (i.e., progeroid syndromes). Because of these and other factors, many
scientists believed that the Hayflick limit was the key to age changes.
It has since become evident that aging does not result from
a loss of ability of body cells to divide. Cells from even the oldest humans
can divide 20 or more times when grown in laboratories. Also, many body cells
lose their ability to divide in the process of differentiation (e.g., neurons,
muscle), so loss of ability to divide does not equal old age or the approach of
death of the cells. However, age-related changes occur in cells as they
approach their Hayflick limit. Examples include enlargement, less motion,
altered chromatin and nucleoli, and very short or absent telomeres. Therefore,
aging occurs in cultured cells, and reaching the Hayflick limit is one
indication that the cells are aging.
Scientists continue to debate the importance of the Hayflick
limit to human aging. Some say it is an artificial phenomenon that occurs only
in laboratory vessels. Others state that cells undergoing RS are different from
cells that remain in the body. Also, the proportion of cells in the skin that
have some features like RS cells is not related to the age of the person.
Certain researchers believe that RS-like cells in the skin exist only in
pathological conditions (e.g., arthritis, atherosclerosis, Werner's syndrome),
not in normal aging.
Despite this controversy, the Hayflick limit and the process
of replicative senescence has been studied intensively. Much research has
focused on discovering how RS is controlled. Telomeres and telomerase may be an
important key. Recent research showed that cells do not reach a Hayflick limit
and RS when active genes for telomerase are placed into the cells. Many other
factors, regulators, and possible mechanisms have been scrutinized and seem to
be involved. As a result, this research has been helped by theories of aging
and has contributed to further development and modification of these theories
(see Biological Aging Theories below). These pathways seem to be related to age
changes in the body and to regulating the growth of cancer.
Another cellular process whose study may increase the
understanding of aging is deliberate programmed death of cells, called apoptosis.
The name comes from the Greek meaning "to fall off”. Apoptosis is helpful
in removing unwanted cells or extra cells during development (e.g., unused
neurons, webbing between fingers and toes); removing damaged cells; and
balancing cell reproduction with cell removal to maintain homeostasis. It is a
deliberate energy-requiring process. Apoptosis may be regulated by genes or damaged
organelles within the cells, by signals from other cells, by environmental
factors, or by a combination of such factors. Not all types of cells undergo
apoptosis, and cells reach apoptosis at different rates and at different times
(e.g., prenatal, postmenopause). The significance of
apoptosis to aging is not known.
A third age-related cell process involving cell division is continuous uncontrolled cell reproduction, called neoplasia. Benign neoplasia occurs when neoplastic cells remain in one mass. When neoplastic cells spread to other areas of the body, the disease is called cancer. (Suggestion 38.01.03)
There are age-related increases in incidence rates and
mortality rates for cancer. People over age 65 have 60 percent of all cases of
cancer; have an incidence 11 eleven times greater and have a mortality rate
from cancer 15 times greater than those under age 65. The twelve leading types
of cancer have a mean age at diagnosis of age 63 or greater.
For those 65+, major cancers, in decreasing order of
occurrence, are cancers of the prostate; colon; pancreas; urinary bladder;
stomach; rectum; lungs and bronchi; leukemia; uterus; non-Hodgkin's lymphomas;
breast; and ovary. Except for lung cancer, which has a peak mortality rate in
the 75-79 age group, there is an age-related increase in mortality rates from
most of these cancers. Rates of colon cancer are expected at least to double by
the year 2030 due to the increase in the number and percentage of elders in the
population.
Elders have greater problems from cancer because of having
higher frequency and severity of coexisting diseases plus other age-related
problems. Care and treatment for elderly cancer patients needs to be more
individualized and modified based on age-related changes.
The rate of cancers among the elderly is increasing in
numbers and as a percent of the elder population. This may be due in part to
the decreasing rates of death from heart attacks, resulting in more people
living long enough to develop cancer. Barring significant discoveries about
cancer, or other major changes in society, these trends will continue and will
become worse for the elderly and for the society as whole. Therefore, the need
for research on cancer in the elderly continues to grow. Aging and cancer
should be studied together because many factors believed to underlie aging also
correlate positively with the onset and spread of cancer (e.g., genetic
regulation and damage, *FRs, telomeres, and immune responses).
For a few photos of neoplasia, go to Preserved Specimen Index.
For Internet images of neoplasia, search the Images section of http://www.google.com/ for Neoplasia.
For data about rates of cancer based on age, see https://gis.cdc.gov/Cancer/USCS/DataViz.html.
Use a search engine to search for images on “cancer rates by
age”. One result could be as follows.
Importance Genes play
several significant roles in aging. Many genes seem to influence the very
different lifespans among different species (e.g., flies, mice, humans). Of the
estimated 30,000 genes in humans, scientists estimate that 70 to 7,000 of them
may influence aging itself.
Genes related to aging help determine an organism's ML and
XL. Evidence for this includes differences (e.g., weeks to decades) in ML and
XL among different species; effects from selective breeding; effects from
placing new genes into animals (i.e., transgenic animals); and effects from
specific gene mutations. In humans, genetic impact on ML and XL is also shown
by the similarity in lifespans within families and the even greater similarity
in lifespans among twins. Genes also influence the onset and nature of
age-related diseases plus the effects of lifestyle and environmental factors in
aging processes. In addition, genes undergo significant accumulated alteration
and damage during life, and portions of genes move from place to place within
cells (i.e., transposable elements). These two alterations also seem to
influence aging and diseases.
Though genes have a major role in aging and age-related
diseases, scientists estimate that only 35 percent of the variance among human
lifespans can be accounted for by variation among genes. For identical twins,
the figure is 40-70 percent. The same seems true for many other animals. The
remaining variation between ML and age-related diseases is due to lifestyle,
environmental factors, and occasional incidents (e.g., accidents). For example,
lifespans and age-related diseases are not identical for identical twins, who
have identical genes. For identical twins, the more differences between their
lifestyles, the greater the differences in aging and genetically caused
age-related diseases (e.g., Alzheimer's disease). Finally, the impact of genes
on ML and age-related diseases decreases with advancing age, especially at very
advanced ages.
Nature and nurture Genes influence how the environment affects aging, and the
environment influences how genes affect aging. Environmental factors may have
different effects on genes at different times because age changes make genes
more or less sensitive as time passes. Environmental factors include external
influences and internal ones (e.g., hormones). Genes influencing age-related
diseases may also be affected by environmental factors, and these effects may
be different at different ages (e.g., pre- or postmenopause).
Human ML, health in later years, and perhaps even XL may be increased by
avoiding harmful lifestyle and environment factors while increasing beneficial
ones.
Some disease-promoting genes become active or important only
at older ages (e.g., Alzheimer's disease, certain cancers). These genes may be
time-dependent or may be triggered by lifestyle or environmental factors. When
human ML was low, few people got these diseases. Since human ML is increasing,
these genes will have a growing impact. Some unknown or unnoticed
genetically-induced diseases may become significant. The effect may be to put
additional limitations on the increase in ML. Alternatively, since mortality
rates decrease after age 100, genes that promote high ML may start to overpower
such late-acting detrimental genes.
Methods of study One
way to identify genes affecting human aging involves finding similar genes in
animals. Popular animals for such studies include a small worm found in soil
(C. elegans), fruit flies (D. melanogaster), and laboratory mice. Diverse
techniques are used to study the genetics of aging in these and other animals.
Examples include selective breeding; placing genes from one animal into another
(i.e., transgenic research); and mutating genes.
The genes that control normal aging and human XL are still
unknown, though genes affecting the immune system (e.g., MHC genes), blood
pressure regulators (e.g., ACE), and brain neurons (e.g., APOE) are good
candidates. Genes that influence aging, ML and XL in some nonhuman species
(e.g., C. elegans, D. melanogaster) have been identified.
Age-related abnormalities Genes that influence or cause age-related human disease have been
studied in detail (e.g., cancer, Alzheimer's disease). Controversy exists about
whether such genes should be viewed as normal variations of age-related genes
or as abnormal disease conditions. Among these are genetic conditions that
promote progeroid syndromes. People with these syndromes show changes that
resemble aging but that occur at much earlier ages than normal. Examples
include Down's syndrome and Werner's syndrome.
Down's syndrome occurs in people having an extra chromosome
21. The extra chromosome is present because of abnormal formation of an egg
cell in the ovary. Progeroid symptoms include more rapid shortening of
telomeres; shorter Hayflick limits in skin cells; increased risk of brain
changes resembling Alzheimer's disease; and a shorter ML.
Werner's syndrome (WS) is caused by loss of a region of
chromosome 8. The condition develops only if a person has the mutation on both
copies of chromosome 8 (i.e., autosomal recessive mutation). People with only
one mutation will not show the disease, but they can transmit the disease to
their children.
Indications of WS appear during adolescence. Manifestations
include slow DNA synthesis; rapid telomere shortening; abnormal chromosome
structure; increased DNA damage from *FRs; lower Hayflick limits in skin cells;
premature graying (age 20); hair thinning (age 25); thinning skin; premature
skin aging; atrophy of the subcutaneous tissues of the limbs; loss of fat from
arms and legs; calcification of soft tissues and blood vessels; heart disease;
muscle thinning; osteoporosis; cataracts (age 30); diabetes (age 34); skin
ulcers (age 33); increased cancers; aging voice (age 27); death (age 30-50).
Since higher levels in the hierarchy of body structure are
composed both of cells and of the materials they secrete, we will now examine
the more abundant of these materials. These substances are found between cells
and are therefore called intercellular materials. Some intercellular
materials are amorphous (i.e., lack organized structure) and contain proteins
or carbohydrate/protein complexes dissolved in water; others are fibers. In
many body structures, the substances between cells contain a mixture of
amorphous materials and fibers.
Amorphous materials vary in consistency depending on the
amount and types of materials present in the water. For example, the
intercellular material in blood (plasma) is a liquid because it
contains approximately 90 percent water and its other molecules are not tightly
bound together. Other amorphous intercellular materials are soft slippery gels
because they contain more protein. Much of this type of material is under the
skin. Other amorphous materials, such as that in cartilage, are firm gels
containing much mucopolysaccharide. Finally, amorphous materials that contain
much mineral, such as in bone, may be hard and rigid.
Collagen Fibers
Many fibers in intercellular materials are made of a protein called collagen,
the most abundant protein in the body. The molecules in a collagen fiber are
aligned parallel to each other and are twisted and bound together. The
resulting fiber is thick, flexible, and strong and stretches little when
pulled. Therefore, a collagen fiber is like a string, rope, or cable. Woven
mats of collagen fibers can form tough sheets (e.g., flat tendons), while
bundles of collagen fibers can form strong cable-like connectors (e.g.,
ligaments).
Elastin Fibers
Another common type of fiber is made of a protein called elastin.
As in a collagen fiber, the molecules in an elastin fiber are aligned and
twisted together. Though an elastin fiber is flexible, the nature and
arrangement of the elastin molecules produce a fiber that stretches easily when
pulled. The fiber also snaps back to its original length when the tension is
released. Therefore, an elastin fiber resembles a rubber band. The ability to
be stretched and snap back is called elasticity. Structures
containing many elastin fibers are often resilient (e.g., outer ear, dermis of
skin).
The theories of aging are general statements proposed to
summarize and explain some observations about aging. The theories are tested by
additional research, after which they are modified to include the new
information. While each theory may be valid for some observations about aging,
none of them explain completely all aspects of aging. The theories are actually
hypotheses in the scientific method of inquiry. As with all hypotheses, they
are valuable in giving broad logical perspectives to diverse bits information;
giving direction to additional research; and helping to develop practical
applications of knowledge.
General Characteristics of the Theories
Developing good theories of aging is difficult for diverse
reasons. Examples include the lack of agreement on a definition of aging; the
multitude of possible causes of aging; the complexity of aging within one
organism or species of organisms; the diverse ways aging reveals itself in
different species; the interactions among aging processes, environmental
influences and diseases (i.e., nature versus nurture); the limited information
about aging processes; the diverse expertise or perspectives among people who
develop the theories; and societal, cultural, and economic conditions. As a
result, dozens of theories of aging have been proposed over the
passed 100 years. Their diversity, complexity, and interconnections can
be intimidating and confusing. While realizing this, we will look at some of
them. First we will examine broad groups of theories,
and then look at more specialized ones.
One group of theories, the evolutionary theories,
attempts to explain evolutionary aspects of how and why aging exists in living
things. Another group, the physiological theories, focuses on how
and why aging occurs within present day animals. They explain structural and
functional age changes in animal bodies. Physiological theories may concentrate
on one aspect or one structural level of an animal. Examples include genes and
genetic mechanisms (e.g., senescence genes); molecules and their chemical
reactions (e.g., glycation); activities of cell organelles or entire cells
(e.g., mitochondria, cell division); signaling among cells (e.g.,
interleukins); whole body regulatory and control systems (e.g., immune system,
nervous system, endocrine system); or behavioral and psychological
characteristics. Some physiological theories attempt to explain all age changes
based on only one or a very few phenomena (e.g., free radical theory,
cross-linkage theory). Others use a combination of factors (e.g.,
immuno-neuro-endocrine theory).
A dichotomy between the physiological theories separates programmed
theories from stochastic theories. All programmed
theories maintain that aging occurs because of intrinsic timing mechanisms and
signals. Stochastic theories (i.e., probability theories) maintain that aging
occurs by accidental chance events. Some theories include both aspects. For
example, one theory proposes that aging occurs because timed programmed genetic
signals make an organism more susceptible to accidental events. Another
dichotomy between physiological theories separates universal theories of aging,
which apply to all organisms, from theories that apply to only one type of
organism (e.g., mammals, humans).
Theories of aging are difficult to categorize because many
of them overlap. As examples, evolutionary theories may incorporate aspects of
genetics and behavior; mitochondrial theories may incorporate aspects of free
radicals, energy metabolism, membranes, and mitochondrial genetics. Scientists
who focus on the interrelatedness of body structures and functions have
proposed network theories, which combine physiological theories
from the molecular to the system level of the body.
Here are some popular broad categories of aging theories.
Some of them are discussed next. Genetic theories may emphasize nuclear gene
mutations or damage; mtDNA mutations or damage;
programmed aging genes; senescence genes; decreased DNA repair; error
catastrophe; or dysdifferentiation. Altered molecule
theories may emphasize damaged and abnormal proteins; cross-linkage; glycation;
waste accumulation; or general molecular wear and tear. Free radical theories
may emphasize free radical formation or free radical defense mechanisms. Cell
and cell organelle theories may emphasize the cell membrane; mitochondria;
telomeres; or heterochromatin. Signaling theories may emphasize intercellular
signals or individual hormones. System theories may emphasize the nervous
system, the endocrine system, the immune system, or combinations such as the
immuno-neuro-endocrine theory.
Aging must have evolved because not all species and not all
cells show aging. To understand evolutionary theories of aging, one must be
familiar with the theory of evolution of living things. The theory of evolution
states that early in the Earth's history there were no living things. Over millions
of years and through chance chemical reactions, larger and more complex
molecules were formed. Through continued chance events, some of these molecules
grouped together into organized clusters that could reproduce. These were the
first cells. Some of these cells developed cooperative interactions as they
formed colonies. Over many generations, these multicellular colonies evolved
into today's plants and animals.
As time passed, some molecules, cells, and organisms had
characteristics making them better able to survive environmental problems and
competition from others. They were able to produce more offspring with similar
characteristics. The instructions to produce these characteristics were
contained in their genes. These successful well-adapted offspring were able to
produce the next generation, and so forth. Molecules, cells, and organisms with
characteristics that made them less able to survive and reproduce became less
common and, finally, extinct because their genes were not sustained through continuing
generations. This is the process of natural selection.
During evolution by natural selection, environmental
conditions and interactions among living things changed. At the same time,
chance events caused alterations in genes such as mutations and recombinations. These alterations led to organisms with
different characteristics. Natural selection allowed organisms with beneficial
genetic changes to reproduce more successfully, so their genetic
characteristics became more common. Genes in organisms that allowed less
reproduction became less common but remained among the organisms because as
generations passed, there were fewer of these organisms. Genes that allowed
little or no reproduction gradually decreased and disappeared. These genes were
not passed to future generations. Since these processes occurred in different
environments (e.g., hot, cold; dry, wet; light, dark), different genes and
types of organisms survived in different places.
Thus, chance events, genetic changes, and natural selection
produced the great variety of living things present today. These processes are
still happening. For example, selective breeding produces new varieties of
plants and animals, and altering the environment causes extinction of species.
Natural events and people are part of evolution by natural selection.
One evolutionary theory of aging is based on the disposable
body theory. Once an organism has reproduced successful offspring that
can eventually reproduce, its body is no longer needed, and it ages and dies.
Here is why. Resources are limited. An organism must partition its resources
between survival of its body and reproduction. Resources for survival are used
for defense and repair activities, which would also slow or prevent detrimental
aging. If an organism's genes allocate most of its resources toward its own
survival, and thus limit or prevent aging, the organism could not allocate
enough resources to reproduction. Its genes would not survive by natural
selection. If an organism's genes allocate inadequate resources to survival, it
would not live long enough to produce ample successful offspring. Its genes
would not survive by natural selection. An organism whose genes allocate ample
resources to survive long enough to produce many successful offspring would
have its genes survive by natural selection. However, because genes limited the
resources allocated to defense and repair mechanisms, these mechanisms begin to
fail, aging occurs, and the organism dies. In this theory, genes do not cause
aging, they just do not prevent it after successful reproduction.
A second evolutionary theory, the antagonistic
pleiotropy theory, states that effects from certain genes may be
beneficial early in life but detrimental later in life. These detrimental
effects result in aging. For example, certain genes may promote rapid
metabolism leading to rapid successful reproduction early in life. However,
rapid metabolism may also cause damage to body molecules. The damaged molecules
may accumulate. The continued accumulation of damaged molecules causes aging.
According to this theory, genes actively cause aging.
A third evolutionary theory of aging, the accumulation
of late-acting error theory, states that natural selection has
permitted the evolution of genes that cause aging. During evolution, any
genetic changes that caused detrimental changes prior to successful
reproduction would be eliminated by natural selection. However, new detrimental
genetic changes that do not cause harm until after adequate successful reproduction
would not be eliminated by natural selection. Over evolutionary time, these
late-acting genes have accumulated. The detrimental effects from these genes
are what we know as aging. This theory also concludes that genes actively cause
aging.
Other evolutionary theories of aging try to explain why not
all species seem to have a maximum longevity, why there are such diverse
maximum longevities among species within the same group (e.g., among mammals),
and if aging is advantageous in any way.
Genetic Theories Genetic theories
suggest that aging is heavily influenced by or actually caused by genes (see
Genes and Aging above). Finally, though certain genes that influence
longevities and aging in research animals have been identified, no one has
identified aging genes in humans (see Genes and Aging above).
Genetic Timers One genetic theory of aging states that the genes are used in a
specific sequence, much as a book would be read from the first sentence of the
first chapter through the last sentence of the final chapter. Each section of
this genetic biography would direct the body's activities during
a specific stage of life including fetal development and maturation. The
sections would also contain instructions on how to progress to the next stage.
The sections for later stages in the individual's life would provide
instructions on how to carry out the changes called biological aging. The
person's life ends when aging limits adaptation enough that homeostasis cannot
be maintained and death occurs. Another genetic biography theory, the antagonistic
pleiotropy theory, was described with evolutionary theories of aging.
A modified version of the genetic biography theory, the genetic
clock theory, suggests that some genes keep track of the body's
progress and perhaps the passage of time or number of cell divisions. In this
way, genes can control the age at which certain events occur. For example, when
grown experimentally, some types of cells can reproduce only a certain number
of times, after which they die. Furthermore, the number of times the cells can
divide decreases as the age of the person from whom the cells were extracted
increases.
Another modified version of the genetic biography theory,
the death gene theory, states that the last chapter in the
genetic instruction manual contains genes called death genes that
tell the body to deteriorate and die. Some scientists consider genes that cause
fatal age-related diseases to be death genes.
One way cells seem to keep track of their age is through shortening
of their telomeres as they divide. The telomere theory states
that shortening of the telomeres alters the expression of other genes, perhaps
those closest to the telomeres. This might happen if heterochromatin near the
telomere unwinds, allowing detrimental genes to become active. Different rates
of aging could occur in different cells or parts of the body because the
telomeres in some cells shorten faster than those in other cells. The heterochromatin
loss theory suggests that unwinding of chromosomes happens at many
areas in a cell. This activates detrimental genes that cause aging.
Limited Gene Usage Other genetic theories of aging suggest that genes are used over
and over during adult life rather than being used in a specific sequence. One
of these theories, the limited gene usage theory, suggests that
there is a limited number of times that the instructions in genes can be read.
The reading somehow alters or damages the genes. After many years of being read
and reread, some genes may become unreadable so that instructions are lost.
Other genes may be read poorly, resulting in mistakes by the body. In either
case, the results are the detrimental changes that are biological aging. A
sufficient number of these changes weaken the body so much that it can no
longer maintain itself, and death occurs.
There are two suggested explanations why genes can be read
only a limited number of times. One explanation, the somatic mutation
theory, proposes that harmful factors injure the genes. Possible
environmental factors include radiation, toxic chemicals, and free radicals.
Within the cell, genetic disruption can occur when movable parts of the genetic
material, called transposable elements, shift positions. In humans and other
organisms, transposable elements move between the mitochondrial DNA and the
nuclear DNA. The other explanation for limited gene usage, the faulty DNA
repair theory, states that though genes are being damaged throughout
life, cells also have mechanisms to repair the damage as quickly as it occurs.
At first, then, damage to the genes has little effect. After many years,
though, the repair mechanisms begin to fail. With either of these explanations,
the result is the same. The damage that accumulates over the years reduces the
genes' ability to direct properly the body’s activities, and biological age
changes begin to occur.
Error Catastrophe Theory A related theory, the error catastrophe theory, states that the damage
is not to the genes themselves but to the RNA and protein molecules that read
the genes and carry out their instructions. These damaged molecules spread
increasing numbers of mistakes throughout the cell and the body, causing
biological age changes.
Rate of Living Theory
The rate of living theory of aging states that
aging is determined by the rate of metabolism because metabolism causes damage.
The higher the rate of metabolism, the faster the rate of aging and the shorter
the mean and maximum longevity. The rate of metabolism in animals can be
measured by the rate of oxygen use. This theory proposes that an animal can use
only a certain amount of oxygen per unit of body mass in a lifetime. The animal
can use the oxygen quickly and have rapid aging and a short life, or use it
slowly and have slow aging and a long life.
Most animals follow this rule. Two major exceptions are
mammals and birds, which have life spans longer than their rates of metabolism
would predict. Proposed explanations for these discrepancies suggest that birds
and mammals have more efficient metabolism resulting in less damage or that
these animals have better repair mechanisms.
Free radical theory
In 1956, Harman proposed the free radical theory
following research on how radiation causes damage to organisms. He used the
research on free radicals from radiation to include other sources and effects
of free radicals, including aging. The theory states that free radical damage
is a main reason or the main reason for true aging and for age-related
diseases. No one knows which, if any, of the many types of free radicals are
more important in promoting aging.
This theory is now based on several observations. Main
examples include positive correlations between the following; metabolic rate
and free radical production; age and rate of free radical formation; age and
amount of free radical damage; free radicals and many age-related diseases
(e.g., atherosclerosis, heart attacks, strokes, Alzheimer's disease,
parkinsonism, cataracts, renal failure, and certain cancers); and, sometimes,
mean longevity and antioxidant supplements. Other examples supporting the free
radical theory include negative correlations between longevity and free radical
production; and between age and free radical defenses. Thus, the free radical
theory of aging became the most likely explanation for the former rate of
living theory.
Free radicals seem to contribute to aging and age-related
diseases primarily by damaging DNA, proteins and lipids. The exact effects and
the relative importance of effects from free radicals on DNA, proteins, and
lipids are not known, though the general effects seem to be aging and an
increase in certain age-related diseases. For example, damage to DNA slows DNA
production for cell reproduction; adversely affects cell processes; and
promotes cancer. Damage to proteins disturbs and distorts much bodily
structure; reduces enzyme activity; makes proteins more susceptible to
enzymatic destruction; promotes inflammation; and upsets signaling and control
mechanism for homeostasis. Damage to lipids reduces the effectiveness of
cellular membranes to regulate the movement of substances; reduces energy
production by mitochondria; promotes atherosclerosis and blood clotting; and
promotes additional free radical production.
In spite of all the body's efforts, free radical production
and damage from *FRs occurs. Further, their rate of production, rate of causing
damage, and amount of damage all increase with age. This free radical damage
adversely affects a variety of essential bodily components and alter body
functions. Many scientists believe that years of such damage are a main cause,
if not the most important cause, of what we know as biological aging.
Mitochondrial theory
The mitochondrial theory was proposed by Ozawa
and colleagues in 1989. This theory states that mitochondrial activities and
damage to mitochondria cause aging. The theory developed from the free radical
theory when scientists combined numerous discoveries. As examples, mitochondria
are main sources of free radicals; mitochondria are severely damaged by free
radicals; mitochondria are easily affected by harmful environmental agents
(e.g., radiation, pollutants, medications); damaged mitochondria accumulate
with aging; cells that do not divide (e.g., muscle, neurons) or that divide
slowly (e.g., bone, liver) accumulate many damaged mitochondria; damaged
mitochondria produce greater amounts of free radicals; mitochondria release
substances that produce free radicals in other parts of the cell, other cells,
and the blood; damaged mitochondria have less ability to regulate signaling
substances (e.g., calcium); mitochondrial DNA (mtDNA)
is much more susceptible to free radical damage than is nuclear DNA;
mitochondria cannot repair their DNA; unlike nuclear DNA, cells use virtually
all their mtDNA, so any mtDNA
damage causes problems; mitochondrial transposable elements, including damaged mtDNA, move to the nucleus; and certain mitochondrial
diseases promote specific age-related diseases (e.g., atherosclerosis, types of
neuron degeneration).
Mitochondrial DNA theory Scientists who focus more on genetic mechanisms of aging
have also focused on the age-related changes in mtDNA
to develop the mitochondrial DNA theory. According to this
theory, mtDNA damage occurs much faster than does
damage to nuclear DNA. mtDNA sustains damage 10 to 20
times faster than does nuclear DNA because mtDNA is
not protected by proteins; it is attached to the inner mitochondrial membrane,
where most free radicals are produced; and it cannot repair itself.
Furthermore, damaged mtDNA accumulates in cells because
damaged mitochondria replicate faster than undamaged mitochondria; mitochondria
that replicate retain damaged mtDNA; mitochondria
with damaged mtDNA are eliminated slower than normal
mitochondria; and non-dividing cells or slowly dividing cells accumulate high
percentages of damaged mitochondria. Some scientists believe that the XL for
humans is approximately 130 years because by that age, all mtDNA
in the body would have some type of damage from *FRs.
Death would result soon after that from mitochondrial failure.
The damaged mtDNA leads to more
age changes than does damage to nuclear DNA because each cell uses almost all
its mtDNA genes while using only approximately 7
percent of its nuclear DNA genes. Thus, nearly any adverse change in mtDNA will have adverse effects on the mitochondria. These
effects include less energy production; more free radical formation; reduced
control of other cell processes; and accumulation of damaged harmful molecules.
These changes lead to aging and certain age-related diseases.
Clinker theories Potentially harmful substances are known to accumulate in
the body over a period of years. Because these materials interfere with the
body passively, theories that claim that they cause aging are called clinker
theories. A material first proposed to cause aging is lipofuscin.
It is a mixture of chemical waste products from normal cell activities,
including those in mitochondria. As time passes, lipofuscin becomes more
concentrated inside cells, such as those of the heart and the brain, because
the cells cannot effectively eliminate it. When cells have accumulated a great
deal of lipofuscin, they appear darker in color. Because of the gradual
darkening, lipofuscin has been called age pigment. Though
lipofuscin now seems unimportant in aging, some people believe that it contributes
to aging by interfering with cell activities.
Other materials that accumulate and seem to get in the way
include a protein called amyloid. It is found between cells
within the heart, the brain, and other organs. In some disease conditions,
called amyloidosis, it becomes excessive and severely interferes with the
operation of these organs. For example, amyloid is found in great abundance
between the nerve cells in the brains of people with with
Alzheimer's disease. Accumulation of glucose has also been implicated as
causing age changes. It binds to molecules (e.g., collagen, hemoglobin),
causing them to stick closer together, restricting their movements, and
altering their functions. Collagen with many glucose cross-links also becomes
darker and contributes to age pigments.
Cross-linkage theories
The fact that collagen molecules and other chemicals in the
body become linked together as time passes has led to another group of theories
of aging, the cross-linkage theories. Free radicals, glucose, and
even light seem to promote the formation of bonds between molecules. The
cross-linkage theories maintain that such bonding reduces the movement of
molecules for chemical reactions, the movement of materials through the body,
and the movement of body parts. The result is malfunctioning and aging. In
addition, when glucose cross-links proteins by glycation, free radicals are
produced. These free radicals may also contribute to aging. The glycation
theory proposes that most aging is caused by glycation and the resulting
free radicals.
Hormone theories Some research provides evidence that aging is caused by hormones.
Hormones are chemical messengers produced in the body by structures called
endocrine glands. Hormones are carried by the blood and give instructions to
almost all body cells.
Some hormone theories attribute human aging to only one
hormone. An example is the insulin theory. It proposes that when
cells are subjected to high levels of insulin, they become less sensitive to
insulin. Also, elevated levels of insulin reduce the production of growth
hormone (GH) from the pituitary gland. Combining the proposed effects of high
insulin and low GH resulted in the insulin/growth factor imbalance theory.
It proposes that aging results from excess stimulation of growth by insulin and
other growth-promoting substances including GH and glucocorticoids. The results
are faster cell reproduction, larger cell size, larger body size, and the
decline in physiological reserve that marks aging. This theory is reflected in
the disposable body theory.
The glucocorticoid theory focuses on
glucocorticoid hormones, which are secreted by the adrenal glands. It states
that if glucocorticoid levels are slightly elevated frequently or steadily,
aging is inhibited because such levels keep the body's adaptive mechanisms at
peak performance. The slightly elevated levels of glucocorticoids also prevent
damage from excess inflammatory responses or immune responses. Aging results
from improper levels of glucocorticoids. When levels are low, adaptive
mechanisms become inadequate. When levels are high, damage results from excess
suppression of defense mechanisms (e.g., inflammation, immune function) and
stimulation of high blood glucose levels. In addition, high levels of
glucocorticoids cause damage to certain areas in the brain. Since mild stress
promotes slightly elevated levels of glucocorticoids, proponents of this theory
suggest that life expectancy and perhaps quality of life are maximized in
people with mildly stressful lives. In other words, having realistic challenges
throughout life is beneficial.
Another hormone theory, the reproductive hormone
theory, states that aging results when reproductive hormone levels
decline after reproductive years. With lower sex hormones, genes receive
inadequate or detrimental signals. The result is declining production of
desirable proteins and excess production of deleterious proteins, leading to
aging.
More complex hormone theories combine interactions and
effects from insulin, GH, glucocorticoids, melatonin, and other hormones.
Calcium theory Some scientists have used portions of several theories to
develop the calcium theory. This theory states that abnormal
concentrations and movements of calcium occur from several factors including
free radical damage to membranes in cells; inadequate energy supply from
damaged mitochondria; accumulations of amyloid protein; and elevated levels of
glucocorticoids. Since many of the body's regulatory mechanisms rely on calcium
as a signaling substance, abnormal levels of calcium lead to cell malfunctions
and inadequate regulation of adaptive mechanisms. Examples include the
functions of many enzymes, muscle cells, nerve cells, and blood vessels. The
result is aging.
Immune system theories Other theories of aging focus
on the immune system. The immune system consists of cells found
in many parts of the body. Some of the cells are grouped in structures like the
lymph nodes. The lymph nodes may become noticeable when an ill person has
“swollen glands.” Other immune system cells are concentrated in the outer layer
(i.e., epidermis) of the skin. Many immune system cells are carried from place
to place in the body by the blood and the lymphatic fluid. Most of these mobilized
cells are lymphocytes.
The immune system is one of the major defense systems in the
body. This system operates by identifying many large molecules and all cells in
the body. Those identified as normal parts of the body are left undisturbed.
However, anything identified as not belonging in the body is attacked and
destroyed by the immune cells.
One immune theory of aging is like the error
catastrophe theory in that it focuses on making mistakes. This immune theory
states that as a person gets older, the ability of the immune system to
distinguish normal from foreign materials weakens. The immune cells begin to
attack and destroy important bodily components, thereby causing changes
associated with aging. An example of such changes would be inflammation of the
joints (i.e., arthritis). Because the body's immune system is attacking the
body itself, this theory is called the autoimmune theory.
Other types of immune theories are the immune
deficiency theories. One version resembles the disposable body theory.
It states that an immune system with indefinite capabilities never evolved
because such ability is not needed for reproductive success. The other version
resembles the limited gene usage theory. It states that the immune system
becomes weaker as it is used. With either theory, after many years the immune
system is not able to defend the body against foreign molecules and microbes.
These noxious agents are allowed to injure the cells of the body and to disrupt
their functioning. Detrimental age changes are the result.
Both types of immune theories have been combined into a more
unified immune dysregulation theory. It states that both changes
in the immune system occur and cause aging because regulating signals among
immune system functions become disproportionate. Additional age changes occur
because of imbalanced signals sent by the immune system to other cells.
Wear and tear theory
The wear and tear theory suggests that aging is
nothing more than the accumulation of injuries and damage to parts of the body.
Use, accidents, disease, radiation, toxins, and other detrimental factors
adversely affect parts of the body randomly. The result of years of such abuse
is aging. This theory was once quite popular, but it has fallen into disrepute.
A major reason for its demise is it cannot account for the rather regular and
universal nature of biological age changes in humans. However, as shown above,
more focused forms of this theory have appeared in stochastic theories, such as
the somatic mutation theory, the free radical theory, and the cross-linkage
theory.
Many scientists believe that aging results from
combinations of phenomena like those in the above theories. Scientists who
believe that there are interactions among these phenomena have developed network
theories. Sometimes, these interactions seem to interact in a positive
feedback fashion, producing an expanding spiral of damage and leading to aging.
For example, free radicals from mitochondria damage the mitochondria, cause
somatic mutations, cause leakage of calcium from the mitochondria, and promote
glycation. These changes reduce the production and effectiveness of enzymes
that remove free radicals and that repair molecules damaged by free radicals.
Also, glycation increases free radical production. With more free radicals and
less free radical defenses, the rate of damage to mitochondria increases,
leading to faster free radical production, and so forth. A network theory for
human aging may include all these phenomena plus their effects on the immune,
nervous, and endocrine systems. Damage to these systems leads to disruption in
regulatory and defense systems needed for homeostasis. Some theories of human
aging may also include social and cultural factors. Aging is a result of degeneration
or breakdown in proper integration and regulation among all these levels.
In conclusion, the number and diversity of theories
attempting to explain biological aging can be confusing. Each theory is
supported by some evidence, and each can explain certain aspects of biological
aging. However, none tells the complete story. This may be because aging
results from a combination of causes. Some causes may be more important than
others, and some may act at different times. Others may affect different parts
of the body or may be effects rather than causes. It is also possible that none
of the theories are correct.
However, it is still important to formulate, test, and
revise theories if the cause or causes of aging are to be discovered. Once they
are known, influencing the processes in biological aging might be possible. It
might also be possible to identify undesirable but not inevitable changes that
frequently occur along with aging and to direct more attention to them. Much
progress has already been made in this direction. Many diseases that are not
part of aging but that are associated with aging provide excellent examples.
Some of the more common ones include heart attack, stroke, osteoporosis,
emphysema, and cancer. Numerous others will be mentioned in the following
chapters. Through good nutrition, exercise, timely health care, and avoidance
of the risk factors for these diseases, many cases can be prevented, improved,
or at least have their progress slowed.
We now turn to a detailed examination of biological aging in
humans. We will start on the outside of the body and examine the integumentary
system.
©
Copyright 2020: Augustine G. DiGiovanna, Ph.D.,
Salisbury University, Maryland
The materials on this site are licensed under CC BY-NC-SA
4.0
Attribution-NonCommercial-ShareAlike
This license requires that reusers
give credit to the creator. It allows reusers
to distribute, remix, adapt, and build upon the material in any medium
or format, for noncommercial purposes only. If others modify or adapt
the material, they must license the modified material under identical
terms.
Previous print editions of the text Human Aging: Biological Perspectives
are © Copyright 2000, 1994 by The McGraw-Hill Companies, Inc. and 2020
by Augustine DiGiovanna.
View License Deed |
View Legal Code