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Chapter 2 - Molecules, Cells, and Theories

 Hierarchy of the body


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.


Atoms, Ions, and Molecules


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.


Organelles and Cells


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 Acids


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.


Molecular Complexes


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.


Free radicals


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).




H-PUFA1 + *FR *PUFA1 + H-R


*PUFA1 molecule rearranges itself


rearranged *PUFA1 + O2 *PUFA1-O-O (peroxyl radical = *LP)




*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)




*PUFAn + H-R H-PUFAn + R




*PUFAn + *PUFAn R-O-O-O-O-R (toxic substances) + O2




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.


Cell Membrane


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.


Endoplasmic Reticulum


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.


Golgi Apparatus


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.


Genetic Control


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.


Cell Division


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 for Neoplasia.


For data about rates of cancer based on age, see

Use a search engine to search for images on “cancer rates by age”. One result could be as follows.



Genes and Aging


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).


Intercellular Materials


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


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).




Reasons for Theories of aging


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.


Evolutionary Theories


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.


Physiological Theories


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.


Network theories

 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
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