Rewinding the Age Clock: Anti-Aging Research
As we blow out the candles on birthday cakes year after year, we may not be completely aware of the changes that are accumulating in our bodies with the passing of time. The mind and body gradually degrade with age, losing their former vigor and resulting in a wide range of effects. Memory is weakened, motor skills decline, bones become brittle, and skin loses elasticity (News in Health; Agency for Healthcare Research and Quality; A.D.A.M., Inc.). Aging is also marked by an increased susceptibility to infection and disease partly because of the decline of the immune system in its effectiveness in fighting pathogens (Gardner, 1980).
Every year, countless attempts are made to reverse aging and recapture youth. A great amount of money is spent on cosmetic procedures and substances such as creams and lotions in attempts to restore youthful appearances. The number of surgeries in senior citizens has greatly increased over the past twenty years as more people over the age of 90 have been seeking operations to prolong and improve their lives (Lucadamo). While the search for the elusive fountain of youth is no new phenomenon, recent research has yielded findings that could potentially bring us closer to the end of this search. In experiments performed on mice, it was found that TA-65, a telomerase activator extracted from a Chinese medicinal plant called Astragalus membranaceus, increased the lifespan of adult mice without increasing cancer risk (De Jesus et al., 2011). Raising both excitement and controversy, the company T.A Sciences has incorporated TA-65 into a nutraceutical capsule that is meant to prolong the human lifespan when ingested over a period of time (Telomerase Activation Sciences).
U.S. Department of Energy Human Genome Program/Wikimedia Commons
The Scientific Process of Aging
Aging is linked to the shortening of telomeres (shown in Figure 1), which are repeated DNA sequences found at the end of chromosomes. Characterized by TTAGGG repeats and protected by a protein complex called shelterin, mammalian telomeric DNA ensures the stability and proper replication of DNA, thereby maintaining cellular health (de Lange, 2005; Harley et al., 1990). Because they function as the protective tips of chromosomes, telomeres prevent degradation of the chromosome by undergoing degradation themselves during DNA replication and cell division (Harley et al., 1990; Hayflick and Moorhead, 1961). In 1961, Lenhard Hayflick discovered that this degradation of telomeric DNA causes a stage at which the cell can no longer divide (Hayflick and Moorhead, 1961). In other words, as the cell divides, telomeres shorten until they become too short. At this point, cells achieve replicative senescence and are unable to divide further, thereby leading to the various changes that are associated with aging (Telomerase Activation Sciences).
Studies have been illustrating the association between telomere shortening and the various changes related to advancing age. Some researchers have used fibroblast cells as a tool to explore this relationship. Fibroblasts are ideal for aging studies since they are characterized by four stages of development and have finite replicative capacity. In the first two stages, growth, development, and proliferation of cells occurs. In the third stage, the ability of the cells to replicate declines and many cells begin to undergo death, or apoptosis. By the fourth stage, the cells, now resembling aged cells, have completely lost their ability to replicate and do not even respond to growth factors (Cristofalo and Pignolo, 1993). A study conducted with human fibroblasts from donors of varying ages demonstrated a relationship between age and telomere length. In this study, which was published in Nature, Southern blotting analysis was used to measure the length of telomeric DNA in fibroblasts obtained from donors of various ages. A statistically significant inverse relationship was observed between the donor age and telomere length: as age increased, the length of telomeric DNA decreased (Harley et al., 1990). In other words, telomere shortening appears to occur in an age-dependent fashion.
Degradation of telomeric DNA is not only linked to aging but also plays a role in a myriad of diseases. Telomere degradation can result from some genetic diseases, such as Down's Syndrome and aplastic anemia, or from genetic mutations affecting telomere structure and replication. Chronic stress and infections can also lead to telomere shortening, which then causes premature aging syndromes and other age-associated diseases (Harley, 2005). For example, studies have found that people with shorter than average telomeres are more susceptible to heart disease and stroke; this corresponds with past findings that older people, who have shorter telomeres than their younger counterparts, are more likely to develop these conditions (von Zglinicki et al., 2000). Dyskeratosis congenita is a disease characterized by shortened telomeres due to mutation (Cawthon et al., 2003). Individuals with this condition are born with degraded telomeric DNA, which causes abnormal nail formation, pigmentation of the skin, and sores within the mouth (Savage and Alter, 2009). By stopping cell division, telomere shortening can cause damage of proliferative tissue, or tissue that typically may have high levels of cell division. For example, telomere shortening can prevent renewal of tissue in the lungs, causing an increased risk of pulmonary fibrosis, or scarring of fibrous connective tissue in the lungs, leading to breathing problems. Shortening of telomeres leads to a wide range of negative effects; therefore, it has been proposed that pharmacological elongation of telomeric DNA would be able to counter these issues (Harley, 2005).
Elongation of Telomeres with Telomerase
Telomere terminal transferase – more commonly known as telomerase – is an enzyme that elongates telomeric DNA by attaching TTAGGG sequences to the ends of chromosomes (Shay/Wright Laboratory). Consisting of protein and RNA subunits, telomerase is capable of replacing telomeric DNA that has been lost due to cell replication. This enzyme is found in high levels in fetal and embryonic cells because these cells are growing and developing and since cell division is extremely important at this stage. On the other hand, the extremely low levels of telomerase in cells of the adult body lead to telomere shortening causing aging to occur (Ulaner and Giudice, 1997; Wright et al., 1996). Experiments performed with human cells in culture have revealed that while normal cells that have not been treated with telomerase undergo shortening of their telomeres and thereby age, cells that have been treated with this enzyme function more effectively and retain the ability to divide for a longer period of time (Harley, 2005). Furthermore, even under stress, cells in the presence of telomerase do not lose their ability to divide and grow. Ultimately, cells treated with this enzyme retain the characteristics of young and healthy cells.
Telomerase's Potential Link to Cancer
While administering telomerase to human cells may reverse aging and treat degenerative diseases by allowing replenishment of cells and proliferative tissues, this pharmacological intervention also poses the threat of causing cancer. Degradation of telomeres causes apoptosis of cells that proliferate excessively, thereby preventing formation of tumors (Folini et al, 2011; Harley, 2005). Therefore, even if cells are able to divide excessively, they will still be induced to undergo apoptosis, thereby averting formation of a tumor. However, the presence of telomerase tampers with this mechanism by preventing the degradation of telomeric DNA and allowing somatic cells to break the cycle of aging and become immortal. Telomerase-induced elongation of DNA has been shown to occur in most human cancers probably since high or unregulated levels of telomerase allow cells to divide without limit (Harley et al, 1990). For example, high levels of telomerase were found in HeLa cells, the famous immortal cells taken from an African American cervical cancer patient named Henrietta Lacks in 1951 and cultured for research (Liu et al, 2011). Therefore, rendering human somatic cells immortal may cause them to become cancerous.
Telomerase Activator TA-65: The Elixir of Youth?
Published on April 14, 2011 in the journal Aging Cell, a recent study indicated that a telomerase activator known as TA-65 elongates telomeric DNA without increasing cancer risk. In this study, which was conducted at the Spanish National Cancer Centre in Madrid, Spain, TA-65 was obtained from a traditional Chinese medicinal plant known by its scientific name as Astragalus membranaceous (shown in Figure 2). Two groups of mice were used, with each consisting of middle-aged and old mice; while one group was given food containing the telomerase activator, the other group was given regular food as a control. The researchers found that in mice who had a copy of the Terc gene needed to make telomerase, TA-65 activated telomerase resulting in elongation of very short telomeres and reversal of DNA damage. In addition to this, in female adult mice, this molecule also increased overall glucose tolerance, improved skin health of female, and decreased osteoporosis risk. Even though the mice that were given TA-65 had an increased incidence of liver cancer in comparison to the mice in the control group, this difference was statistically insignificant and therefore dismissed (De Jesus et al, 2011). Thus, the researchers have concluded that TA-65 is able to elongate telomere length and allow tissue replenishment without increasing cancer risk.
The Controversy: Pharmacological Interventions Incorporating TA-65
To capitalize on the telomere-elongating capabilities of this molecule, the company T.A. Sciences has developed a nutraceutical capsule named TA-65 that delivers the anti-aging benefits of this telomerase activator to people. Physicians are collaborating with the company and becoming licensed to distribute TA-65 to patients. Priced at a staggering $10,280, T.A. Sciences' six month Patton Protocol provides the customer with a 1000 unit dosage of TA-65. People who enroll on this protocol will consume four capsules per day; expected results are longer telomeres, a stronger immune system, increased bone density, and a decline in other age-related degenerative effects. Possible effects that are not guaranteed by T.A Sciences include increased energy, increased endurance, sexual enhancement, and a general sense of well being (Telomerase Activation Sciences).
Courtesy of Nutrition.Diet News
The creation and marketing of a pill that claims to reverse aging has raised a great amount of controversy. Carol Greider, Ph.D. who was awarded the Nobel Prize for her work with telomeres and telomerase, voiced her concern that there is no overall elongation of all telomeres in studies concerning TA-65. While extremely short telomeres elongate in response to the activator, the same cannot be said about the others since an increase in telomeres of average length does not take place. Therefore, according to Dr. Greider, the TA-65 supplement may not function in exact accordance with the claims of T.A. Sciences (Singer). Dave Woynarowski, M.D. has countered this argument by pointing out that the 2011 Spanish study on TA-65 was done with mice as subjects. The mechanism of aging in mice is different than that in humans; aging in mice is more complex and does not consist of only telomere shortening (Woynarowski).
Other professionals in the field of age research bring up another potential issue associated with TA-65: the use of telomerase. Judith Campisi, Ph.D., a scientist at California's Buck Institute for Research on Aging, has brought up the topic of cancer and its link to telomerase. According to her, it cannot be overlooked that the mice given TA-65 did develop liver cancer, even though the incidences did not reach statistical significance (Singer). William Andrews, Ph.D., chief executive officer of Sierra Sciences, LLC shares Campisi's concerns, noting that telomere elongation could possibly extend the life of cancerous cells that would typically die in the absence of TA-65. However, Andrews has also pointed out that telomerase activation by TA-65 could maintain immune cells and allow them to fight cancerous cells (Kendrick).
According to Andrews, deciding whether to take TA-65 or not is a gut decision rather than one concerning the mind. He believes that the positive outcomes promised by the pill far outweigh the negative effects that it might cause (Kendrick). However, research has found that making a comprehensive lifestyle change in terms of diet, exercise, and stress reduction habits leads to increased telomerase activity in a more natural manner and thereby produces similar results. In a study conducted by researchers at the University of California, San Francisco, a group of 30 men with low-risk prostate cancer were enrolled in a comprehensive lifestyle modification program. For 3 months, they consumed a low fat diet rich in fruits, vegetables, unrefined grains, and legumes, participated in moderate aerobic exercise and practiced relaxation techniques such as yoga, stretching, and meditation. At the end of the program, their telomerase activity was measured. The results of this comprehensive lifestyle change included a significant increase in telomerase activity, a drop in low density lipoprotein (LDL) cholesterol levels, and a decrease in psychological distress (Ornish et al, 2008). As a result of this program, the subjects of the study emerged as healthier, more relaxed individuals. Therefore, TA-65 is not the only method of increasing telomerase activity and improving overall health; natural lifestyle modifications have a similar effect and are significantly less expensive.
Despite the controversy surrounding TA-65, it must be acknowledged that its discovery denotes a great stride in the field of aging research. Future research and clinical trials concerning this anti-aging compound have the ability to elucidate its properties and implementations. Therefore, TA-65 promises to be of great use in the future.