Longevity: The Biology
April Barnado
The Biology of Longevity |
Image used from Microsoft Word Clip Art, Windows XP Professional.
Theories of Aging
The field of biology, particularly the areas of genetics and cell biology, has proposed major theories trying to explain how we age. These theories include the accumulation of DNA mutations, the free radical theory, the telomere theory, and cell cycle and cell senescence. In furthering knowledge on these theories, scientists hope to better understand how genes and one’s environment work to influence how we age. Even though there is the cultural pressure for science to develop therapies to extend the average life span, much longevity research seeks to understand the aging process in order to explain why conditions such as Alzheimer’s Disease, cardiovascular disease, and cancer often accompany aging. There is the hope that eventually this knowledge can be used to develop therapies to alleviate debilitating diseases common at the end of life instead of developing therapies that focus solely on extending the average life span.
DNA Mutations:
Mutations are errors in the DNA that can be induced or spontaneous. Note that mutations do not necessarily implicate something that will cause cancer; each person has some degree of mutations in his or her DNA that are harmless.
However, mutations in DNA can be detrimental if these mutations result in defected protein products. For example, a defected protein product can be truncated or shorter than normal and thus lose its normal function in the cell. Defected protein products can also result in proteins that do not fold properly, preventing them from either interacting effectively or not interacting at all with another protein or enzyme. These nonfunctional protein products can severely affect pathways or metabolism in the cell, possibly resulting in tissues and ultimately the body that cannot perform a vital function. This theory of aging explains that as cells age, they are more likely to accumulate mutations that affect major cellular processes, such as the three R’s (DNA reading, replication, and repair).
DNA Mutations and the three R’s-
As we age, we are exposed to more and more mutagens in our environment from sources such as x-rays and UV radiation from the sun. The accumulation of these mutations causes damage to DNA and the cell. This damage to the DNA can affect three main processes in the cell, referred to as the three R’s: DNA reading or transcription, DNA replication, and DNA repair. All of these processes are very vital in maintaining the blueprint for the cell, the DNA, and ensuring that each new dividing cell receives an intact copy of the cell’s genetic material.
Mutations in genes that affect the reading, replication, and repair of DNA can cause serious damage to the cell. When the cell suffers such damage, it can be activated to “commit suicide” or undergo programmed cell death, also known as apoptosis. A cell would want to undergo apoptosis in order to protect the integrity of the organism as a whole. One cell that has damage and mutations could divide to give rise to more cells that also have mutations, thus compromising the tissue the cells are located in and ultimately compromising the function of the body.
Before the three R’s of DNA reading, replication, and repair are explained, it is important to review the basic structures of both DNA and RNA. Please refer to the text and diagrams below.
Structure of DNA-
Both DNA and RNA are composed of the same three components: a phosphate group, a sugar (ribose for RNA and deoxyribose for DNA), and a nitrogenous base. The four bases are Adenine (A), Thymine (T), Cytosine (C) and Guanine (G). The bases pair up as shown below according to Chargaff’s Rule:
Adenine (A) always pairs with Thymine (T).
Cytosine (C) always pairs with Guanine (G).
Note that DNA is made up of nucleotides, which consist of a phosphate group, a nitrogenous base, and a sugar.
Created by Dr. Karen Hales, Davidson College.
Permission for use approved by Dr. Karen Hales, Davidson College.
Note that the overall structure of DNA forms a right-handed double helix. The structure can be compared to a spiral staircase as the two strands of DNA wind about an internal, central axis, depicted in the picture below with a black pole. The picture below shows a ball and stick model of DNA.
Image used from Microsoft Word Clip Art, Windows XP Professional.
Structure of RNA-
RNA is similar to DNA in that it contains a phosphate, a sugar, and nitrogenous base. However, RNA does not have the base Thymine (T) but instead has Uracil (U). Therefore, Adenine (A) pairs with Uracil (U) in RNA. RNA also contains a different sugar than DNA, specifically RNA contains ribose. Note that RNA is single-stranded while DNA is double-stranded.
Created by Dr. Karen Hales, Davidson College.
Permission for use approved by Dr. Karen Hales, Davidson College.
Cell Senescence and Cell Death
1) Reading or Transcription
The DNA in each individual cell can be compared to a blueprint. The blueprint gives the instructions for the cell to make a specific protein. Specifically, a gene or genes in the DNA encode for a specific protein. In order to make a protein, the DNA or blueprint must be copied because DNA does not leave its storage place in the nucleus of the cell. In order to get the information to make the protein from the DNA without the DNA leaving the nucleus, the DNA is copied in the form of RNA. This RNA is modified to create mRNA, messenger RNA.
The process of transcription copies DNA to make RNA and eventually mRNA. The process starts with the DNA unwinding in a short, specific region next to a gene of interest, leaving a single strand exposed. This one strand serves as a template to make the RNA. RNA polymerase then comes in to copy the strand of DNA that is serving as template. However, recall that this newly made RNA is not an exact copy of the DNA for RNA contains one different base than DNA. Once the RNA is made, it modified with an added cap and tail to make it more stable so it can exit the cell; it is now called mRNA (messenger RNA).
Transcription is important because it is the first step in making proteins. If there is a mutation that affects one of the enzymes in the transcription process described above, the whole process could be disrupted resulting in mRNA not being made or shipped out of the nucleus properly. Thus, without mRNA being properly made and/or shipped out of the nucleus, important proteins in the cell are not being made. The cell will not function properly and could undergo apoptosis.
Translation and Protein Synthesis
In making proteins, there is a second process called translation. Like the name suggests, the genetic code or the information copied to the mRNA from the DNA is “translated” into a protein code that signals what amino acids (building blocks of proteins) to add to make the protein of interest. Specifically, the genetic code involves three base sequences called codons that code for a specific amino acid that make up the protein. For example, the codon UCA (a codon made up of Uracil, Cytosine, and Adenine) signals for the amino acid serine to be incorporated into a protein that is being made.
Translation occurs on ribosomes, outside the nucleus of the cell in a fluid-filled environment called the cytoplasm. A ribosome is a cellular particle made up of a type of RNA called ribosomal RNA and proteins. There are a variety of enzymes that are key to making translation function, namely enzymes that enable the correct amino acid that corresponds to the codon in the RNA to be incorporated into the new protein. Similar to transcription, if any of the enzymes or the structures involved in transcription are damaged or suffer mutations, the cell can no longer function properly because it cannot make needed proteins. Thus, the cell can be activated to undergo apoptosis.
Here is a simplified scheme that summarizes the processes discussed above. The first arrow symbolizes transcription while the second arrow symbolizes translation. This scheme is known as the central dogma of biology.
DNA RNA protein
2) Replication
The second R or cellular process that mutations can affect is replication. Replication is a process where the DNA of the cell is copied. In this process, the double helical DNA is unwound by an enzyme called helicase. A place in the DNA where the helicase and other enzymes work to unwind the DNA and start DNA replication is called the replication fork. Other enzymes are also at work to keep the DNA from winding back to its original helical shape. A parental strand is unwound, and an enzyme called DNA polymerase will add nucleotides (The building blocks of DNA that consist of a sugar, phosphate, and nitrogenous base.) to the parental strand resulting in a “new” daughter strand.
Replication is an important process in the cell similar to transcription. It is very important that the cell makes an accurate copy of its DNA so that cell can pass the copied DNA to its daughter cell. In order for the cell to make an accurate copy of its DNA, it is dependent on the enzymes that are involved in each step of the replication process, such as the helicases that unwind the parental DNA and the DNA polymerase that makes the new DNA. (Note that these are just a few of the key enzymes involved in DNA replication.)
If one of the genes is mutated that encodes for an enzyme in replication, the enzyme product could be defective rendering DNA replication ineffective. If the cell cannot replicate its DNA accurately to pass on to a daughter cell once it divides, the cell will undergo apoptosis. Apoptosis or programmed cell death ensures that this “defected” cell does not interfere with the functioning of other nearby cells or more globally does not interfere with the functioning of the organism.
3) Repair
The third R or cellular process that mutations can affect is repair. Repair refers to the cell’s ability to detect when DNA has not been replicated correctly and its ability to fix the incorrect DNA that has been added. In replication, the wrong nucleotide can be added to the parental strand. For example, a Cytosine (C) can be mistakenly added to an Adenine (A) instead of Guanine (G) being added. (Recall that Cytosine (C) always pairs with Guanine (G); Adenine (A) always pairs with Thymine (T).) This event is called a mismatch in base pairing. When this mismatch happens, enzymes called endonucleases make a cut in the DNA. Then, another enzyme called an exonuclease comes and excises the damaged DNA of interest. Finally, a polymerase enzyme makes a new DNA nucleotide to insert, and a ligase then functions like “DNA glue” allowing this new DNA nucleotide to be incorporated into the DNA. The cell’s ability to repair and replace nucleotides is very important because if the DNA contains the “wrong” nucleotide this may result in a mutation or change in the sequence of nucleotides in the DNA. With this mutated or changed DNA sequence, proteins cannot be made properly resulting in a cell that also may not function properly.
Summary on the Three R’s and Mutations
The processes of transcription, translation, DNA replication, and DNA repair are all essential processes to every cell in the body. Each of these processes includes a group of key enzymes, each of which serve a very specific function to ensure that these processes proceed efficiently. If one enzyme suffers damage or is encoded by a gene that is mutated, the whole process could be severely affected. The cell may not make an essential protein, make a dysfunctional protein, pass copied, inaccurate DNA to a daughter cell, or not recognize and repair damaged or mutated DNA.
Any of these problems can prove detrimental to the cell’s function and can jeopardize the stability of neighboring cells, the tissues that the cell belong to, and the organism as a whole. As a result, the cell can be signaled to undergo apoptosis or programmed cell death, a process not completely understood by scientists.
As we age, our cells have been exposed to more and more environmental mutations and have faced the normal “wear and tear” of undergoing normal cellular processes. As a result, cells face the risk of their DNA suffering mutations that may affect key enzymes in the important processes of DNA reading, replication, and repair. With mutated and damaged enzymes, these cells are signaled for death. As more and more cells die, tissues start to lose their function resulting in many of the debilitating symptoms observed in aging.
This theory proposes that aging is due to the accumulation of damage to cells and tissues from free radicals. Free radicals are highly reactive molecules that normally contain nitrogen or oxygen with unpaired electrons. Free radicals react with parts of the cell and its membranes to cause damage to the cell, its membranes, and the DNA housed in the cell’s nucleus. This damage is referred to as oxidative stress. Free radicals can occur “naturally” in the body as products from metabolic processes, processes of breaking down food for energy. Free radicals can also be generated due to external agents such as ultraviolet light, ionizing radiation such as x-rays, chemotherapy agents, and environmental toxins (Finkel and Holbrook, 2000).
Some examples of free radicals:
Note all of these free radicals contain unpaired electrons either on the O (oxygen) or N (nitrogen), shown by the star symbol *. These unpaired electrons make free radicals highly reactive with other compounds.
O 2* *NO 2 *OH *NO
Fortunately, our bodies have “natural” enzyme scavengers and defenses against free radicals. In fact, some oxidative stress if kept in check is normal for cells. However, when oxidative stress goes unchecked, it can cause both random cellular damage and damage to specific cellular pathways (Finkel and Holbrook, 2000). There is a delicate balance where the cell must either resist the oxidative stress by removing the free radicals or adapt by repairing the damage that has already been done. The way the cell either resists or adapts to the oxidative stress and damage will determine its survival. As cells are damaged, they can be activated to undergo apoptosis, ultimately resulting in tissue death and negative effects on the function of the organism as a whole.
Telomeres
As DNA is replicated with each cell division, the ends of the chromosomes shorten. The chromosomal ends are shortened because DNA replication cannot take place at these ends. Specifically, the polymerases, enzymes responsible for adding nucleotides to the parental strand of DNA in replication, cannot add nucleotides to the ends of the DNA. These polymerase enzymes work in only one direction; the polymerase cannot move in this particular direction in replicating the chromosomal ends.
Cells solve this problem of end chromosomal replication by having telomeres. Telomeres are structures at the end of chromosomes composed of repetitive DNA sequences and associated proteins that cap the ends of the chromosomes. By capping the ends of chromosomes, telomeres protect the cell’s DNA from being degraded (Kim et al., 2002). Telomeres can be compared to the protective coverings on the end of shoe laces, as explained in a BBC Health News article from 2003. Please see the following link (http://news.bbc.co.uk/1/hi/health/2676735.stm).
Telomerase
It is very important to maintain the cell’s telomeres. When the telomeres get too short, the cell detects that it’s DNA may be unstable and is being degraded. When the telomeres are shortened to a certain length, the cell can be activated to stop growing or stop dividing ( cell senescence) or signaled to undergo cell death or apoptosis. Thus, it is important for the cell to maintain its telomeres on the end of its chromosomes.
The telomere theory proposes that the senescence and death of cells due to shortened telomeres may be behind the aging process. For example, scientists have noted that telomerase that maintains telomere activity and length is limited to immortal or tumor cells in mammals. However, some human cells such as germ and early embryonic cells can express telomerase to help prevent the telomeres from becoming too short. However, most somatic (body) cells do not express telomerase. Thus, the absence of telomerase in most of our somatic cells results in the progressive shortening of telomeres following each cell division. Once these telomeres become too short, the DNA can no longer be replicated, and the cell can no longer divide. Thus, the cell has a limited number of cell divisions before it dies. This limit on the number of cell divisions may be behind the aging process since over time cells essentially “age” and die resulting in tissues degrading the body “aging.” However, this limit on the number of cell divisions further implies questions of whether science can push or even destroy this limit to allow cells to divide indefinitely to “defeat” the aging process and increase human longevity. However, without cells having a limited number of divisions, there is the risk of uncontrolled cell growth, resulting in tumor formation and cancer.
In order to maintain normal telomere lengths to protect the chromosomal ends, the enzyme telomerase adds repeats of the same nucleotides to the chromosomal ends. However, telomerase does not function like the other enzymes involved with DNA replication. Telomerase is not only made up of protein but also RNA. Telomere length is not identical from cell to cell or from human to human. However, telomere length is regulated to an average length, dependent on the cell type and organism. Studies with yeast and other model organisms have established that telomere length is regulated genetically (Russell, 2002).
Telomeres and Cancer
As we age, we accumulate more damage and mutation to our DNA as well as our telomeres being shortened after each cell division. Thus, more and more cells become senescent or inactive as we age, and these cells’ influence on the body may only become significant as their numbers increase as we age. There is also the probability that not only is there more senescent cells but also an increase in the probability that these cells are close in proximity to one another. This close proximity can result in senescent cells creating a “microenvironment that promotes the proliferation…and progression of mutant cells,” resulting in tumors or growths (Kim et al., 2002). Although cell senescence driven by telomere shortening and dysfunction can help protect the organism in early years from defected cells, the accumulation of senescent cells could promote the progression of cancer in aging (Kim et al., 2002).
In order for a cell to divide, it goes through a highly regulated pathway called the cell cycle. The cell cycle occurs in most of our somatic cells. In the cell cycle, it is very important that the all the chromosomes of the cell’s DNA are duplicated and distributed to the daughter cell. The cell cycle is made up of four stages and is summarized below:
Permission pending from The Biology Project, University of Arizona.
(http://www.biology.arizona.edu/cell_bio/tutorials/cell_cycle/cells2.html)
M (Mitosis or the division phase): This stage refers to the division of a mother cell that results in a daughter cell that is identical to the mother cell. In order to have a successful division, the mother cell’s DNA must be accurately replicated and distributed to the resulting daughter cell.
G1 (Growth Phase 1): In this stage, the cell prepares for the DNA to be replicated in the S (Synthesis) phase.
Note that cells can cease division or undergo cell senescence and exit the cell cycle at this phase before proceeding and committing to the S (Synthesis) phase.
S (Synthesis): This stage refers to the actual replication or copying of the mother cell’s DNA. This replication results in two exact copies of the cell’s DNA and chromosomes. This phase is important in the cell cycle because the cell will only proceed to this phase to replicate its DNA only if it is going to divide. It would be wasteful for the cell to copy its DNA and then not divide.
G2 (Growth Phase 2): In this stage, the cell prepares for its division into the daughter cell.
Regulation in the Cell Cycle:
There are important checkpoints in the cell cycle. The cell cycle’s purpose is to make one copy of its DNA for the daughter cell. In order to accomplish this purpose, once the cell cycle has started, the cell needs to be committed to finish the cycle. Also, once the cell cycle has started, the cell does not need to go backward in the phases, i.e. going from the S phase back to the G1 phase. During the cell cycle, it is important that the cell respond to environmental signals to help regulate it. If cell division is not needed or is especially needed in a certain tissue, the cells in that certain tissue need to respond accordingly.
Cyclin dependent kinases and Cyclins
Two of the key players that work as switches to help the cell proceed from one phase to the next are cyclin dependent kinases and cyclins. Cyclin dependent kinases are enzymes that add a phosphate group to cyclins to activate them. Cyclins trigger the progression of the cell cycle from one phase to the next. The cyclins and cyclin dependent kinases that regulate and activate the cyclins occur at major checkpoints in the cell cycle.
Major Checkpoints
One major checkpoint is after the G1 phase. At this checkpoint, the cell prepares for DNA replication in the S phase. The cell “check s its environment” to see if it has enough nutrients or if there are environmental signals signaling it to not undergo cell division. Also, during this important checkpoint, the cell must assess whether there is DNA damage. If the DNA is damaged, it would not be beneficial for the cell to replicate or copy this DNA and incorporate it into a daughter cell. This checkpoint is so important because once the cell passes this checkpoint it passes the point of no return. For once the cell starts synthesizing or copying its DNA in the S phase, it is committed to finish the cell cycle and divide.
There is also a major checkpoint after the G2 phase. At this checkpoint, the cell must double-check to make sure that the DNA has in fact been copied. If the DNA is only partially copied, then it would not be beneficial for the cell to go to the M (Mitosis) phase to divide and create a new daughter cell. Further, the cell checks its size to make sure that it can feasibly divide to make a new daughter cell.
Note that if the cell cycle is not regulated, then cell growth is not regulated. Uncontrolled cell growth can result in tumor formation and cancer. Uncontrolled cell growth can result from possibly the cell passing through the major checkpoints, discussed above, with damaged or only partially copied DNA. Also, the cell could be receiving signals “telling” it to continually undergo the cell cycle, resulting in unregulated cell growth and cancer.
Cell senescence and cell death (apoptosis)
As shown above, a cell can exit the cell cycle and stop division and growth. Cell senescence refers to this exiting of the cell from the cell cycle. Cell senescence also refers to the limit of cell divisions a normal somatic (body) cell can undergo. Cells, after a finite number of divisions, are growth-arrested and do not undergo cell division, even if stimulated to do so by environmental factors.
“Cells have a time to live and a time to die” (Kimball’s Biology Pages, 2004). A cell can die due to injury from mechanical damage or by exposure to toxic chemicals. A cell can also die by suicide, referred to as programmed cell death or apoptosis. Why would a cell want to commit suicide? The cell would want to undergo programmed cell death or apoptosis in order to ensure the proper development of the organism. For example, in fetuses, in order for the formation of fingers and toes to be done correctly, tissue between fingers and toes must be removed. Apoptosis of cells results in this tissue being removed. Apoptosis also occurs to protect the organism as a whole, protecting the organism from one “bad cell” that maybe has damaged DNA or mutations and that could affect other cells in its surrounding tissue. Apoptosis can be signaled by the withdrawal of signals that tell the cell to keep going through the cell cycle or keep dividing. The cell can also receive signals to stop the cell cycle.
For an overview on apoptosis, please see the following link: (http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Apoptosis.html)
As we age, cells continue to divide but also suffer damage from environmental triggers such as UV from the sun, radiation, toxins and from the normal wear and tear of undergoing the cell cycle and normal cell processes. Thus, the cell reaches the point where it is damaged and no longer can divide and grow. When the cell reaches this limit, the cell stops dividing and enters into a senescence phase and eventually dies. Scientists do not understand when the limit occurs when cell becomes senescent or at what point the senescent cell dies.
With cell death, tissues are damaged and eventually die resulting in the debilitating processes seen in aging, such as atrophy of the skin, damaged heart vessels and muscle, and damaged supporting cells in the brain. Specifically, cell senescence is associated with many degenerating diseases common in aging such as atherosclerosis (hardening and damage to the arteries), osteoarthritis, Alzheimer’s dementia, and cancer. The tissues implicated in these diseases simply wear down affecting the normal function of the organism.
Questions or Comments: Email Dr. Verna Case
Davidson College Biology Department
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