Cell AgingThomas Darr, Mark Glassman, Vineeta Nangia, Reina Stillman

Powerpoint for this Wiki:

Cellular aging is caused by the accumulation of damage to different cellular molecules such as proteins, lipids, and nucleic acids. When these molecules deteriorate, a cell’s functioning capabilities decrease and degeneration of organs and tissues occur. The eventual result of cell aging is cell death. (1)

Senescence is derived from the Latin word senex or "old age" and in its most basic definition, means the period of decline that follows an organisms developmental phase. In other words, senescence is a decline in health and functions associated with aging. (3)

Cellular or replicative senescence is when cells lose their ability to divide. This may result from the shortening of one or more critical telomere. Shortened telomeres cause a DNA damage response (DDR) which activates senescence and stops cell growth. Senescence can also be caused by genomic damage at nontelomeric sites. Once again, a DDR response occurs and jumpstarts senescence. One specific example of damage resulting in senescence
Causes and Defining Aspects of a Senescent Cell

is a break in a DNA strand. Strong mitogenic (mitosis triggering) signals may also cause cells to senesce. One example of such a signal is an oncogene (a gene that disposes normal cells to change into cancerous tumor cells). However, senescence can occur without a DDR response. In vitro cells may senesce after “culture stress.” An example of such stress is inappropriate substrata (a surface on which an organism grows or is attached), The equivalent stress in vivo (in a living organism) is unknown. (4)

Senescent cells have a few defining aspects. The first is that grow of the cell is arrested permanently and cannot be reversed. Senescent cells are resistant to apoptosis. Also, senescent cells increase to almost double the size of their nonsenescent counterparts. Also, cells that senesce as a result of DDR signaling secrete growth factors, proteases, cytokines, and other factors with hormonal and paracrine activities. (4)

Eventually, the senescent cells will die. Likewise, one's entire body will eventually begin to decline, a period known as organismal senescence. During this period, the damage to one's body begins to accumulate and interfere with the body's functioning. This interference causes effects associated with aging such as a declination in the ability to respond to stress, increased homeostatic imbalance, and increased risk of aging-associated diseases. Death is the ultimate result of aging. (1)

Many organisms including some cold-blooded animals exhibit negligible senescence. An animal with negligent senescence displays a lack of symptoms of aging. It does not have measurable functional decline or reductions in reproductive capacity with age. Also, unlike senescent organisms, death rates in a negligibly senescent species do not increase with age. Some organisms thought to be negligibly senescent include the Rougheye Rockfish (lifespan of 205 years) and the Aldabra Giant Tortoise (lifespan of 255 years). (2)
Aldabra Giant Tortoise

Different rates of aging correspond to differences in species' maximum life spans (the maximum amount of time one or more members of a population has been observed to survive between life and death). For example, a mouse of 3 years is elderly and a human of 80 years is elderly. Inherited genetic differences account for the differences in the rates of aging. Genetic differences affect many processes such as the efficiency of DNA repair and the rates of free radical (an atom of molecule with a single unpaired electron in an outer shell) production.(2)

external image 16-19b-Telomeres-L.gif

Telomeres (5)

Telomeres are segments of DNA at the end of chromosomes that serve to prevent the ends of important genes from degrading. Telomeres are repeating sequences of nucleotides. On one strand, the sequence is TTAGGG, the other strand exhibits AATCCC. Each time a cell divides and DNA replicates, the end of each DNA strand is damaged. Telomeres prevent genes, DNA that codes for proteins, from being damaged, therefore allowing the daughter cells to function properly and not die. With each cell division, 30 to 200 nucleotides from telomeres are lost. As a cell and its offspring divide, the telomeres get shorter and shorter.

Telomeres can be lengthened by the enzyme telomerase. Telomerase adds base pairs to telomeres. In young cells, the enzyme is abundant, keeping their telomeres from wearing down. However, as cells divide, telomerase presence decreases, leading to shorter telomeres.

When telomeres get too short, the gene begins to be affected by the damage at the ends of the strands. Upon this occurence, the cell dies. A cell with shorter telomeres is older - an aged cell. In multicellular organisms, the data regarding causation (one event is the reason for another) versus correlation (two events occur simultaneously but do not effect one another) is unclear. In humans, telomeres shorten with age. However, it has not been determined that telomere shortening is the cause of the aging process - graying hair, wrinkly skin, etc.

Telomeres also have an effect on cancer. Due to the rapid reproduction of cancer cells, telomeres shorten rapidly, suggesting that the cells should die. However, in successful cancer cells, telomerase is activated, lenghtening the telomeres in the cells after each cell division, creating immortal cancer cells. Scientists believe that blocking telomerase can effectively destroy cancer; however, its effects may carry over into systems that are positive - such as reproduction. This website (http://learn.genetics.utah.edu/content/begin/traits/telomeres/) shows an animation about telomeres and cancer. The
http://www.youtube.com/watch?v=AJNoTmWsE0s animation also does a great job showing how telomeres and telomerase work.

Thieving Oxygen/Free Radicals

Oxygen, of course, is a key component in cell function and existence. Diatomic Oxygen (O2) is a key part in cellular respiration-the conversion from energy in the form of sugar, glucose, to ATP (Adenosine Triphosphate), which is a necessary part of the life and function of all cells. That is to say, without oxygen, cells would be unable to function and quickly die.

However, oxygen is also one of the key components of cell aging, and
Simplified view of a radical Oxygen
eventually to a cell’s death. Diatomic oxygen, among other subatomic particles, can be referred to as a free radical. A free radical is a molecule that has a free electron in it’s outer shell that is not part of a pair, and is characterized as being very unstable. Free radicals are typically the most common source of natural cell aging and death; when a radical comes in contact with essentially anything in a cell, from DNA and RNA to proteins, the radical reacts with and damages the cell. When enough damage from enough radicals is accumulated in the cell, the cell dies. The most common radical in most living systems in oxygen. (1)

Radical oxygen is mostly formed within the mitochondria of a cell, in the Electron Transport Chain that is used to create ATP. Oxygen is the final step in which electrons transport themselves through the chain, and on occasion the electrons transfer incorrectly-this results in the production of an oxygen with an unpaired electron in it’s valence shell, a radical oxygen (2). Naturally, as it’s the spawning point of the radical oxygen, the mitochondria is often the most-damaged target of radical oxygen, particularly the mitochondrial DNA. The mtDNA is difficult to repair, and eventually the mitochondria of a cell shut down, resulting in the aging and eventual death of the cell. However, free radicals are present throughout the cell, reacting with and damaging necessary proteins, and the DNA of a cell located in the nucleus (2).

However, there are enzymes in all cells whose sole purpose is to check and neutralize free radicals, known as anti-oxidant enzymes, or free radical scavengers. These anti-oxidants act can as targets to which the unpaired electrons can attach to easily (3), or can donate an electron to a free radical; either way, antioxidants neutralize the effects of free radicals, and are a key factor in preventing the very rapid decay of all cells.

Gene Loss/DNA Damage Theory

There are many ways in which DNA can be damaged, such as exposure to radiation, the effects of free radicals, and so on. Usually this damage is either repaired by enzymes, or if the damage is too extensive, the cell destroys itself via apoptosis. Typically, if there is cell damage or a mutation and the cell does not catch the mistake and take steps to get rid of the problem, then the cell becomes cancerous, and poses a direct threat to the life of the organism. However, in cells that that do not replicate frequently or at all, such as brain or muscle cells, DNA damage can accumulate and lead to effects typically associated with biological aging. (1)

In the brain, neurons are fairly nonreplicative, and thus DNA damage does not typically lead to cancer. However, damage to the DNA in brain cells, particularly from the free radical 8-hydroxydeoxyguanisine (8-oxo-dG), (1) accumulates with time, leading to a reduction in efficiency in brain function. In particular, transcription in genes that are involved with in synaptic plasticity, vesicular transport and mitochondrial function is reduced dramatically with the passage of time.

Likewise, cardiomuscular cells replicate at a very slow rate, and as an organism ages, the cells in the heart also grow old, accumulating DNA damage with time in the form of 8-OHdG (1). This weakens the cells, weakening the heart as a whole, along with skeletal muscle-thus, as an organism ages, both it’s heart and it’s skeleton begin to weaken.

An animation explaining how DNA can become damaged can be found at:

Apoptosis and Necrosis


Apoptosis is programmed cell death. During apoptosis, a cell shrinks and pulls away from neighboring cells. The surface of the cell also appears to boil; fragments break away during this time. The DNA of the cell also condenses and breaks in to fragments. Eventually, the nucleus and entire cell disintegrates. Apoptosis serves to regulate cell numbers by removing unwanted or damaged cells. All cells are equipped with instructions and the capability to carry out apoptosis; however, whether or not apoptosis occurs depends on many different factors including the cell type, the cell's damage, and the presence of death-promoting signals. (1)

Necrosis is another type of cell death. Unlike apoptosis, however, necrosis is unplanned and can result from a sudden traumatic injury, infection, or exposure to a toxic chemical. During necrosis, the semi-permeable cell membrane loses its ability to control the flow of liquid into and of out the cell. As a result, the cell fills with liquid and swells. Eventually, the cell lyses (bursts) and releases the liquid into surrounding tissue. Inflammation and redness results from the chemicals needed in the body to clean up the liquid. Necrosis occurs in heart attacks, frostbite, and pneumonia. (1)

Apoptosis and Necrosis

A major difference between apoptosis and necrosis is that apoptosis is an active process that requires energy. It is not accompanied by inflammation and is not degenerative in nature; rather, apoptosis only affects specific cells and usually occurs in normal adult tissues. Apoptosis rids the body of unwanted, infected cells and its failure can result in autoimmune diseases and cancer. (2)

There are two main types of apoptotic pathways. One is an activation-induced apoptosis which is initiated by a variety of signals such as the binding of ligands to death--promoting protein receptors on a cell surface. The other is damage-induced apoptosis, triggered by damage to cellular parts. (3)

In senescence, these two pathways are variably affected and can have myriad impacts on the aging process. Any changes to these pathways that occur during aging can cause disease. Scientists today are looking into modulating these two pathways in a manner that causes effects such as prolonged life span or reduced age-related degeneration. (3)

Also, apoptosis may increase with age as there is an increased level of oxidative stress with age. However, evidence also indicates that apoptotic mechanisms become less efficient as one ages. This can lead to the accumulation of errors and phenotypic changes typical of aging. A decrease of apoptosis would cause increased cell survival but also the accumulation of damaged cells and therefore, the accompanying appearance of the aged phenotype. Also, a decrease is apoptosis may increase one's risk of cancer. (4)

As one ages, apoptosis can be both good and bad. In certain tissues and organs, decreased apoptosis may increase the risk of cancer. However, increased apoptosis can cause rapid senescence. For example, during normal aging, a significant loss of cardiac and skeletal muscle cells results from apoptosis. Also, too much apoptosis is linked to neurodegenerative diseases such as Alzheimer's, Parkinson's, and Lou Gehrig's. One's lifespan is largely influenced by both the antitumor and pro-aging affects of apoptosis. (4)

Cancer Cells and Aging

Normal cells do not divide indefinitely as a result of cellular senescence, which may have evolved in order to protect eukaryotes from developing cancer. Studies of human tissue and cancer-prone mice have demonstrated that senesence decreases the likelihood of cancer. Cells may adopt a senescent phenotype in response to inappropriate mitogenic (mitosis triggering) signals that may be oncogenic (tumor causing). Such information indicates that senescence is a mechanism that protects cells from developing tumors. In order for the development of cancer to occur, senescence must be bypassed (cells must expand their growth potential and be able to proliferate while expressing activated oncogenes) and cellular immortalization must occur. During immortalization, cells acquire genetic alterations that override senescence. Moreover, cellular senescence occurs with the help of two tumor suppressor signaling pathways (the p53 and pRB/p16INK4a pathways). Finally, studies have shown that senescent cells are abundant in premalignant tumors but diminished in malignant tumors. (1)


An interesting theory related to senescence and tumor promotion is the antagonistic pleiotropy theory, which states that a biological process such as senescence can be beneficial or harmful depending on the age of the organism. The theory is also based on the assumption that organisms grow in environments that have many fatal extrinsic hazards such as predation, starvation, etc. Because of these hazards, old individuals are not common and there is not a lot of natural selection against processes that promote disability or disease late in life. Therefore, age-related phenotypes such as cancer are not largely affected by natural selection. As a result of selection, senescence may be dominant in young organisms because of its ability to suppress cancer and increase fitness. However, when these organisms become old, senescence becomes damaging and promotes cancer. (2)

It may seem counter intuitive that senescence promotes cancer. However, there are a few ways in which this can happen. First, senescent cells increase with age. The increase commonly occurs in cells that undergo mitosis and are capable of giving rise to cancer.Cancer may be caused when a tissue environment is disrupted with the accumulation of dysfunctional senescent cells with mutations. Also, senescent cells have a secretory phenotype (SASP) that affects the behavior of neighboring cells. Many SASP factors that affect other cells are known to stimulate phenotypes associate with cancer cells. Also, a defect in either of the two pathways on which senescence depends may increase an organism’s susceptibility to cancer or cause cancer. (5)

Moving away from senescence, in a 2011 study conducted at the Kimmel Cancer Center, scientists found that cancer cells cause nearby connective tissue cells to age at a faster rate than normal in order to cause inflammation, resulting in the creation of high-energy nutrients needed to feed cancer cells. (6)

Normally, oxidative stress causes a stress response called autophagy, in which DNA to becomes damaged and the body deteriorates. Near the cancer, cells induce oxidative stress in normal connective tissues in order to gain nutrients. The process by which the cancer cells induce oxidative stress as well as the transferral of nutrients from connective tissues to cancer cells is still unclear. However, scientists believe that a process called a "lactate shuffle" may transfer the nutrients from the connective tissues to the cancer cells. In the "lactate shuffle" one transport protein releases the lactate from the connective tissues cells and another transport protein in the cancer cells takes it up. Scientists believe that fibroblasts in the connective tissues feed cancer cells through two protein pumps or mono-carboxylate transporters called MCT1 and MCT4. MCT4 is also a maker for oxidative stress; therefore, the inhibition of MCT4 may provide a new anti-cancer therapy. Antioxidants can also help to treat cancer through their natural anti-inflammatory action. (6)

Effects of Cellular Aging on the Body

As cells age, and subsequently, in some cases, die, organs’ maximum abilities begin to lower. Atrophy, the loss of tissue mass, affects all tissues in the body, and is caused by cells aging and dying. The heart provides a good example of the effects of atrophy and cell aging. According to the NIH (National Institutes of Health), at age 20, the heart is capable of pumping 10 times the blood required to keep the body alive. As a person (and her heart) ages beyond 30, 1% of this extra capability is lost, slowly eating away at their ability to operate. The loss of extra function, though it does not cause major problems when a person is not demanding of their body, does have an affect on returning to homeostasis. After an exertion, to get enough oxygen back into the cells via the blood, the heart needs to use some of its reserve capacity. As this reserve capacity lowers, the return to homeostasis slows. Often, this reduced reserve capacity is the underlying issue of heart failure, because a high-demand activity triggers the inability of the heart to keep up.

Stress and Aging

When an organism is under stress, the parasympathetic nervous system begins to take effect, releasing many hormones, stress-related and otherwise, neurotransmitters, and oxidants. When someone is under constant stress, the imbalance of all of these generally useful anabolic hormones like DHEA, or insulin-like growth factor, can result in an overconcentration of glucose and insulin in a system. The large amounts of these factors in an organism can lead to the production of oxidants, which themselves damage the cell, in addition to the fact that glucose (and indirectly, insulin) already put plenty of stress of the mitochondria in terms of formation of radical oxygen (see previous section).

Cognitive and physical stress has always been considered bad for the health, but until recently, there has been no genetic link between stress and aging. However, recent studies have shown that long-term stress causes telomeres to shorten and shrivel, resulting in a shortened life span and hastened body deterioration. What is interesting is that people who cope well under stress and prove to be resilient do not suffer the same damaging effects. Therefore, it is extremely important to take steps to either reduce stress or learn coping methods, the first being a positive attitude. Eleven stress reducing techniques are listed below.
1. Meditate
2. Picture Yourself Relaxed
3. Breathe Deeply
4. Look Around You
5. Drink Hot Tea
6. Smile
7. Listen to relaxing music
8. Take a nap
9. Exercise
10. Talk to a friend
11. Imagine yourself with Halle Berry

Ways to Reduce Aging
1. Exercise
Studies have shown that vigorous exercise reduces cellular aging by preventing the shortening of telomeres that results from stress. As little as 42 minutes of exercise in 3 days protects individuals from shortening telomeres. The US Centers for Disease Control and Prevention recommend adults exercise for 75 minutes of vigorous activity or 150 minutes of moderate activity per a week. (5)
2. Eat Foods with Antioxidants
Foods with antioxidants neutralizes the aging effects of free radicals. Foods rich in antioxidants include pecans, legumes, artichokes, berries, and dark chocolate. (4)
3. Eat Foods with Omega-3 Fatty Acids
Studies have shown that Omega-3 fatty acids increase levels of the antioxidant enzymes catalase and superoxide dismutase, thus reducing oxidative stress. Omega-3 increases also levels of the enzyme telomerase, which works to maintain telomere length. Food rich in Omega-3 fatty acids include flax seeds, walnuts, salmon, soybeans, tofu, tuna, and shrimp. (3)
4. Drink green or black tea
Studies have shown that people who drink an average of 3 cups of green or black tea a day have telomeres about 4.6 kilobases longer than those who drink a quarter of a cup of tea day. This difference in length corresponds with about 5 years of life. (6)
5. Meditate
Meditation results in beneficial effects by reducing cognitive stress and increasing positive states of mind and hormonal factors that promote telomere maintenance. (1)
6. Drink Water
When a cell is hydrated, is swells up and triggers a mechanism in the body that functions in healing. Other effects of cellular hydration include a reduction of cell acidity, reduced autoimmune response, increased fat burning, DNA repair, and increased resistance to viruses. When a cell is dehydrated, DNA damage and accelerated aging becomes a problem. The cell is more sensitive to viruses, free radicals, and autoimmune diseases. Therefore, it is important to drink a lot of water. The general recommendation is 8 cups a day. (2)

All Sources:

Sources for Introduction:
1)National Institute of Health An explanation of cell aging and cell death.

Sources for Senescence:
1) Senescence, Healthy Aging and Longevity A description of senescence.
2) Negligible senescence A explanation of why some organisms do not appear to age.
3) Senescence A long, detailed, description of senesence.
4) The Journal of General Physiology An article on the four faces of cellular senescence.


Sources for Telomeres:
5) Learn Genetics, University of Utah. This site has lots of great information about telomeres as well as informative images and animations.

Sources for Oxygen/Free Radicals:
Free Radicals: A Major Cause of Aging and Disease An essay about free radicals.
The free radical theory of aging An essay about the free radical theory of aging.
What are Free Radicals? A short explanation of free radicals

Sources for Gene Loss/DNA Damage Theory
(DNA damage theory of aging) Wikipedia page on the DNA damage theory of aging

Sources for Apoptosis and Necrosis:
1) The Rubins Essay on how apoptosis is involved in cell aging.
2) Cells Alive Short explaination of apoptosis
3) Discovery Medicine An experiment on programmed cell death and apoptosis
4) Journal of Gerontology An essay on mitochondrias' role in cell death and apoptosis
National Institute of Health explanations of cell again and death

Sources for Cancer Cells and Aging:
1) National Institute of Health An experiment on cancer aging, and cell senescence
2) Huffington Post Article about how cancer cells may speed up aging
3) UniProtKB information on DNA
4) Wikipedia wikepedia page on reactive oxygen species
5) National Center for Biotechnology Information experiment: Mitochondrial oxidative stress in cancer-associated fibroblasts drives lactate production, promoting breast cancer tumor growth: understanding the aging and cancer connection.
6) e! science article about how cancer cells accelerate aging and imflammation in the body, to speed up tumor growth
7) Cancer Cell explanation on the connection between scenescence and cancer
Image: http://www.google.com/imgres?um=1&hl=en&sa=N&biw=1639&bih=681&tbm=isch&tbnid=Zakpfvwu_v9PBM:&imgrefurl=http://www.impactaging.com/papers/v3/n2/full/100281.html&docid=2PyqJoYjDIz5dM&imgurl=http://www.impactaging.com/papers/v3/n2/full/100281/Figure4.jpg&w=722&h=606&ei=4NVdT-eBCqHh0wHQwMnKDw&zoom=1

Sources for Effects of Cellular Aging on the Body:
Aging changes in organs - tissue - cells article about how aging affects organs, tissues, and cells

Sources for Stress and Aging:
1) Stress, aging, and brain oxidative damage.Abstract on the effects of stress on aging
2) Can meditation slow rate of cellular aging? Cognitive stress, mindfulness, and telomeres Abstract on the correlation between meditation and the reduction of cellular aging
3) Anticipation of Stressful Situations Accelerates Cellular Aging Article about the correlation between anxiety and the acceleration of cellular aging
4) Stress and aging: Slow it down Article about reducing stress to slow down aging
5) Aging: The Stress Factor Article on stress's affect on aging

Sources for Ways to Reduce Cellular Aging:
1) Hospital Soup Article on 5 ways to reduce aging
2) Medical News Today Article about exercise reducing cellular aging, by reducing stress
3) Fit Sugar An article on fruits high in antioxidants
4) Nutra IngredientsA study on how omega-3 is linked to a younger biological age
5) Health and Lightan article on the importance of cellular hydration
6) New York Times An article on meditation's affect on the brain

Images: http://www.google.com/imgres?num=10&hl=en&gbv=2&biw=1573&bih=723&tbm=isch&tbnid=4hxOHGMTQD6OLM:&imgrefurl=http://www.weddingdietsite.com/2008/09/refresh-yourself-with-ginger-tea-drink.html&docid=ghxQPLqhzz6mvM&imgurl=http://www.thedailygreen.com/cm/thedailygreen/images/lemon-ginger-tea-recipe-lg.jpg&w=460&h=360&ei=lDRdT_DtEYjn0QGewZmnDw&zoom=1

AP Questions and Essay:

  1. What purpose do telomeres serve?
    1. protecting the ends of genes
    2. coding for proteins
    3. maintaining the cell’s general functions
    4. providing a starting point for DNA replication
    5. making the chromosome the right length
  2. As cells age, the affect on the body is:
    1. atrophy
    2. reduced organ functioning
    3. slower return to homeostasis
    4. “a” and “b”
    5. “a”, “b”, and “c”
  3. Which of the following is not a characteristic of radical oxygen?
    1. It are the most common example of free radicals.
    2. It are most typically found in the mitochondria of a cell.
    3. It have an odd number of electrons in the outermost electron shell.
    4. It can be neutralized by products called antioxidants
    5. It leads to an increase in glucose concentration in the cell.
  4. Which of the following does not cause senescence?
    1. telomere shortening
    2. genomic damage at nontelomeric sites
    3. culture stress
    4. strong mitogenic signals
    5. DDR signaling pathway
  5. What does not happen in a cell during apoptosis?
    1. inflammation occurs
    2. the DNA condenses
    3. the nucleus disintegrates
    4. the surface of the cell appears to boil
    5. the cell shrinks
  6. How does senescence cause cancer?
    1. senescent cells increase with age
    2. mutations can occur in senescent cells
    3. senescent cells occur with the help of tumor causing pathwayas
    4. the SASP phenotype stimulates other phenotypes associated with cancer cells
    5. a, b, and d
  7. How does senescence prevent cancer?
    1. senescence occurs in response to inappropriate mitogenic signals
    2. senescence occurs with the help of the p53 and pRB/p16INK4a pathways
    3. senescence prevents cells from multiplying
    4. a and c
    5. a, b, and c
  8. Which of the following is not a proven effect of stress on an organism?
    1. An increase of stress on individual cells
    2. An imbalance of hormones in a system
    3. Shortening of
      the telomeres
    4. An overproduction of Glucose in a system
    5. A decrease in long fatty acid chains in the cell
  9. All of the following are defining aspects of senescent cells, except:
    1. Growth of the cell is permanently stopped and cannot be reverse
    2. The cell division process is slowed
    3. Resistant to Apoptosis
    4. Increase to almost double the size of their nonsenescent counterparts
    5. Secrete grotwh factors, proteases, cytokines, and other factors with hormonal and paracrine activities
  10. An indicator that a cell has aged is:
    1. Its telomeres are shortened
    2. there is a relatively high amount of diatomic oxygen in the cell
    3. The cell's DNA is damaged
    4. Both A and B
    5. A, B, and C
Choose three of the five aging mechanisms listed below, and describe how each one can cause an organism to age.
-free radicals
-damage to DNA (Gene Loss)