By Ron Teeguarden
Telomeres are generally credited with maintaining the integrity of DNA by securing the ends of chromosomes. Telomeres are responsible for maintaining chromosomal stability and for mitigating excessive undue mistakes during replication. They do this by protecting the chromosome extremities from fusion and degradation.
Telomeres consist of a specific repetitive DNA sequence and a set of proteins known as the shelterin complex. As we age, with each replication of a cell, the telomeres become shorter, until eventually they no longer are functional and the cell enters into a phase known as cellular senescence. It is hypothesized by many people that by preventing this shortening, life can be extended. There is considerable compelling evidence to support this theory. But there appears to be an inherent problem in the theory. The problem is, the same telomeric functions that control life expectancy and longevity also play a direct role in the development of cancer under certain circumstances when telomere functions become dysfunctional. In fact, the function responsible for the shortening of telomeres, which results in aging, also dramatically reduces the risk of cancer. This process is as ancient as life on this planet and is very complex and subtle. It is a prime example of Yin-Yang theoretics.
[Note: This article does mention the word “cancer” a number of times, because under some circumstances the functions of telomeres and the processes of aging are inextricably connected to the processes that cause cancer. This article is NOT about how to treat, cure, or prevent cancer – it is about longevity and the promotion of radiant health. Do not construe anything in this article to suggest that any herbs can or should be used to treat, cure or prevent cancer, as this would be a misinterpretation of my point. Cancer is a medical issue to be handled by physicians. (Of course, I do suggest you all eat very well and avoid toxins.)The issue is brought up in this article because it is a common (almost ubiquitous) topic of conversation among those people discoursing the merits of telomerase inhibitors and activators, and of telomere shortening and telomere lengthening. This article is about longevity.]
Telomeres are an essential key to cellular replication, and a shortening of telomeres is involved in the cell’s inability to replicate. Leonard Hayflick first defined “finite proliferative capacity,” and “replicative senescence,” as the cell’s inability to divide beyond a certain limit (Hayflick, 1965). Hayflick noted that cells in culture ceased to proliferate after a certain number of cell divisions. The “Hayflick limit” is defined as the point when normal cells stop proliferating. Senescent cells continue to live, but no longer can they replicate. Because they can no longer replicate, damage accumulates and they simply become old. As our cells become senescent, we age noticeably.
Telomeres help maintain DNA integrity and help with damage response
Telomeres maintain the integrity of the chromosome ends. Our cells maintain a DNA damage response mechanism, a network of processes that (1) sense, signal and repair DNA damage, and (2) regulate cell cycle progression and cell turnover through apoptosis. Without telomeres, the unraveling of chromosomes after replication would appear to our DNA repair machinery as “damage.” Telomeres serve to camouflage chromosome ends from the DNA damage response machinery.
Telomere maintenance is an integral part of DNA damage response. Telomeres interact with many DNA damage response proteins. When telomeres become dysfunctional either as a result of the physiological loss of telomeric sequences (shortening), due to cell senescence or genetic abnormalities affecting the shelterin protein complex, the DNA damage machinery becomes activated. On the other hand, functional telomeres are not subject to these DNA damage control mechanisms.
Telomeres shortens as a result of DNA damage, especially that caused by oxidative stress. Oxidation accelerates the telomere shortening rate and induces premature senescence in cells. For this reason, innate, dietary and supplemental antioxidants are of great importance in maintaining the integrity of our DNA, chromosomes, telomeres and general health.
When telomeres lose their capping function, the DNA damage response is induced. This leads to an accumulation of unrepaired DNA damage during aging, which causes cellular growth arrest, or other cellular complications.
Chromosomal maintenance and repair
Chromosomes, which of course are long strands of DNA, cannot replicate properly without telomeres. There is a process known as chromosomal repair, which differs slightly from DNA damage response and/or DNA repair. DNA repair can be described as the restoration of DNA sequence integrity, while chromosomal repair restores chromosomal function. Chromosomes even have the capacity to acquire new telomeres at chromosomal breakage sites, a process known as “chromosomal healing.” Chromosomal repair is believed to be involved in telomere length regulation and telomere inactivation.
Telomerase to the rescue?
The Telomere Theory of Aging, first posed by the Russian scientist Alexey Olovnikov, postulates that the key mechanism that drives cellular aging is the loss of telomeric DNA, which eventually causes chromosomal instability, and cell senescence and cell apoptosis (death).
Telomerase is the an enzyme that is able to elongate the end of telomeres. However, telomerase is not present, or is present in only very small amounts, in most somatic cells. It is only present (at low levels) in stem cells, and in immune cells during clonal expansion, which contributes to the higher proliferation capacity of these types of cells. Because there is little or no telomerase in most somatic cells, telomeres shorten with age in almost all cells of the body. The end result is generalized aging and ultimately death due to the complications of aging. And thus we have the Telomere Theory of Cell Senescence and Aging.
Telomerase was discovered by Carol Greider and Elizabeth Blackburn in 1984, and together with Jack Szostak, they won the Nobel Prize in Physiology or Medicine in 2009 for their discovery.
The primary consequence of telomere dysfunction is cellular senescence, a permanent growth arrest state, but this telomere shortening can be stopped by telomerase. Telomerase activity is required to maintain telomeres. And there are key regulators of telomerase and telomere function that can directly lead to or prevent cellular senescence.
The Telomere Paradox
Very importantly, and paradoxically, there is a direct link between the telomere maintenance process with longevity, aging and the risk of cancer. There is evidence that supports the concept that senescence itself, induced by short telomeres, is a potent tumor suppressor pathway. In fact, the link between cellular senescence and tumor regression is now fairly well established.
Though the same genes and processes are involved, the telomeric process works differently in normal, healthy somatic cells and in cancer cells. Cells with very short telomeres are prone to many mutations. As a result, very short telomeres can result in some cells becoming cancerous. Cancer cells are able to turn on telomerase, which is able to restore telomere length and maintain it in the cancer cell. As a result, the telomeres of most cancer cells are never shortened, giving these cells endless replicative potential. They become “immortalized.”
So that’s the paradox. While cancer cells can turn on telomerase for their purpose of achieving immortality, normal cells are able to use telomerase activators for repairing or perhaps even extending the telomeres of normal cells, thus extending or even eliminating the Hayflick limit of healthy cells. Telomerase activators might even strengthen the telomeres of immune system cells enough to prevent cancerous cells from developing from cells with very short telomeres
A treatment for cancer proposed by many researchers is a telomerase inhibitor that would prevent the restoration of the telomeres in the cancer cells, allowing the cancer cells to die like other body cells. Identifying telomere inhibitors that only target cancer cells but not healthy cells could be a holy grail of cancer research. In fact, many natural substances seem to be able to do exactly that, but nothing is proven yet.
On the other side of the coin, identifying telomerase activators that only activate the telomerase in healthy somatic cells without causing cancer in those cells, and simultaneously NOT activating telomerase in cancer cells, or even depressing that action, would be the holy grail of longevity seekers.
[Note: Please accept this important message right here: I am not suggesting in any way that any herb can or should be used as a treatment, cure or preventative for cancer. The interest we have here is in understanding the cellular structures and functions associated with the maintenance, promotion and support of radiant health for an extended period of time, thus reducing the likelihood of disease, degeneration and premature death and for increasing the prospects of a very long, healthy and happy life.]
Telomere length – link to aging, health and lifespan
A recent study found that longevity is associated with longer telomeric length in individuals aged 70 years of age or older. These researchers speculate that individuals with longer telomeres have an increased likelihood of resisting cancer and neurodegenerative diseases. That, of course, is their speculation, not mine. My speculation is that these individuals maintain more robust immune functions for longer than most people, probably as a result of better antioxidant functions in and around cells and cell nuclei. Increased telomere length probably prevents some DNA damage over time.
Another study also observed a correlation between telomere length in people of different neurological status. Significant telomere shortening in peripheral blood cells from Alzheimer’s disease patients versus healthy people was observed, and it turned out that healthy people have longer telomere length than those with neurological dysfunction.
People with healthy arteries were found to have longer telomeres in endothelial cells of the surface of coronary arteries in comparison to those with coronary artery disease.
Immune memory, an essential immune capacity, appears to become limited as a result of telomere erosion and telomerase downregulation. Thus, improved telomere function may have a positive impact on immune memory.
Genetics may play a key role in telomere length and homeostasis. Researchers have reported a positive correlation between offspring telomere length and paternal lifespan. They concluded that telomere length is paternally inherited, though this has not been fully confirmed and many other factors could be involved, including epigenetic forces (diet and stress being major potential epigenetic factors).
The effects of psychological stress on telomere length are also being investigated. Researchers have studied the implications of psychological stress, telomerase activity and telomere length of blood cells by examining healthy women who cared for either healthy or chronically ill children. They concluded that both perceived and real chronic stress are associated with significantly higher oxidative stress, lower telomerase activity and shorter telomere length. How stress, and stress management, influences telomeres and longevity will surely be an area of major research and discovery in the future. I think we all know how that research will turn out. (Please meditate and do your yoga every day!)
Obesity and smoking are clear risk factors for age-related diseases. The telomeres of obese women and smokers were significantly shorter than those of the controls who were lean and did not smoke. No surprise here. I would assume many pharmaceutical “drugs” (the kind people take excessively and abusively to get high) are not too good for telomere length either.
These studies demonstrate that telomere length and possibly lifespan can be affected by
environmental factors, and specifically by oxidative stress. There are a lot of sources of oxidative stress. Antioxidants definitely would help here.
Manipulating telomere length
Evidence of a relationship between telomere length and aging has fueled many people’s quest for a “fountain of youth.” Can enhanced telomerase expression stall aging and lead to a longer, healthier life?
A lot of evidence leads to the answer: “Probably.” But only, in my opinion, if pursued from a homeostasis-enhancing perspective. It is critical to ALWAYS remember that balance is the key, not pushing the limits, when it comes to life and health maintenance. Everything ultimately comes down to Yin and Yang, the Law of Cycles, and the Three Treasures.
Balance is the key
Telomere maintenance and length-homeostasis are likely of fundamental importance for enhanced human longevity. Just the right telomeric length for the cells in question, and the cells can flourish. Too short or too long, telomeres can cause problems. Extending the period of years that homeostasis can be maintained, where the telomeres can maintain optimal length, seems to be a key idea when it comes to telomeres.
Mitigating oxidative stress may play a key role in maintaining telomere length-homeostasis for an extended period. Oxidative stress is an ever present reality in all cells, and the body has many mechanisms to deal with oxidative radicals, many of them quite effective. There are a multitude of environmental sources of oxidative stress as well. Modern living offers an abundance of potential oxidants that can cause significant toxicity and oxidative stress at the cellular level. Smoking, drugs, environmental toxins, non-living food, and even our emotions can produce sufficient oxidants to harm our DNA in profound ways that result in accelerated aging. Our diet and our dietary supplements can provide free radical scavengers that neutralize oxidation. That is one reason that eating a beautiful, natural, clean, live diet is so important. It is also a reason to consume dietary supplements that provide a super-abundance of antioxidants.
The introduction of telomerase has been proposed as a method to combat aging and a possible method to regenerate tissue, while telomerase inhibition and telomere shortening is suggested as a possible therapy to defeat cancers. Researchers thus face the challenge of understanding the complex processes that regulate the potential benefits of both telomerase activation and inhibition.
In order to achieve radiant health and super longevity, one must avoid the degenerative conditions generally associated with aging, including cancer. Cellular senescence is closely associated with most of the degenerative conditions associated with aging and is closely related to telomere shortening. Cancer may result from telomere shortening, and once the cancer is established the telomeres can become lengthened due to enhanced telomerase and telomerase activity.
The goal of those seeking radiant health and great longevity is to establish and maintain a “bidirectional” approach that can help maintain homeostasis for a longer period of time, perhaps for decades (some would hope for longer). Homeostasis is the basis of life. Loss of homeostasis is the root of all disease and of aging. Cancer, for example, is a disease in which telomerase regulation ultimately fails. Regulation is the key word for maintaining health and for achieving great longevity. But I believe it is impossible to micromanage our telomeres. The body is too complex. Our lives are too complex. There are too many changes in the environment from minute-to-minute, day-to-day and year-to-year as we age. But “macro-management” is certainly a very real possibility.
Telomere lengths in humans are largely genetically determined and contained within upper and lower limits. Telomeres that are too short lead to premature aging and increased risk of aging-associated diseases. Telomeres that are too long may have negative impacts through an increased risk of proliferative-related disorders. Both situations would increase vulnerability and reduce the chances of living a very long life. Many people are now hoping to establish some control over telomerase activity and telomere length through the use of dietary supplements. (Chart by D. Kappei, J.A. Londono-Vallejo / Mechanisms of Ageing and Development 129 (2008) 17–26)
Adaptogenic herbs provide regulation
Adaptogenic herbs are by nature, generalized regulating promoters of homeostasis. They are bidirectional by their very nature. They activate functions that need to be activated, and deactivate functions that need to be deactivated on a timely basis. To date, there is no evidence that these anti-aging nutraceuticals cause telomere shortening in normal cells – only cancer cells. That is an extraordinary ability of the adaptogens.
If a telomerase “activator” can mildly stimulate telomere repair on a continuous basis over many years or decades, so as to prevent telomere shortening, there is a likelihood that there would be less cellular senescence and slower aging of the tissues, systems and functions of the body.
On the other hand, there is also some possibility that a unidirectional telomerase “activator” could result in an increased possibility of activating cancer. Most cancer cells have enhanced telomerase activity that help assure their “immortality.”
By combining the possible telomerase activator Astragaloside IV with the anti-aging nutraceuticals Resveratrol, Total Astragalosides and Total Gypenosides, along with the full spectrum extracts of five established adaptogenic herbs – Ginseng root, Astragalus root, Gynostemma leaf, He Shou Wu root, and Himalayan Rhodiola root – I believe it is possible to extend life with reduced risk of disease by maintaining telomeric homeostasis.
The miracle of life lies in its ability to maintain balance. Adaptogenic herbs are consumed to promote that ability. There is plenty of evidence that the adaptogenic herbs promote healthy functioning without causing side effects (such as cancer or premature aging). And there is plenty of evidence that adaptogenic herbs can help the body and its cells restore balance even after it has been lost.
It is unlikely that a single, unidirectional chemical will regulate the entire telomere process, throughout the body. In my opinion, the unidirectional approach falls into the realm of medicine, not the realm of health maintenance and dietary supplementation to promote radiant health. Drugs are unidirectional and have both inherent danger and benefit. That is why they are so carefully studied, regulated and controlled. Dietary supplements need to perform as nourishment, to enhance normal, balanced life functions, and to promote health.
The body’s cells are at all times rich in chemicals that push and pull in opposite directions. That is how life works. That is how regulation occurs. That is how homeostasis (dynamic balance) is maintained. Adaptogenic herbs that have bidirectional activity are likely to provide the kind of safety net required when a potential telomerase activator is introduced into the body, and perhaps the power to enhance that activity is a balanced way. Optimal functioning is a concept that must be flexible and adaptable, since the world in which a person lives will always be changing. The ability for the body itself to regulate functions, especially at the cellular level, is critical to longevity and health. Establishing dynamic homeostasis is the key. And thus, adaptogens are central to my health promotion philosophy.
A moment of Zen – How ginseng works as a homeostatic regulator at the deep cellular level
Schematic overview of ginsenosides-mediated genomic and non-genomic pathways.
[Click on diagram to enlarge] Ginseng is the quintessential adaptogenic tonic herb. The primary active constituents of ginseng are saponins known as ginsenosides. Ginsenosides possess a steroid-like skeleton. They are amphipathic in nature and can exhibit their actions at different cellular locations; such as the plasma membrane, cytosol and nucleus. Through the non-genomic pathway (indicated by red arrows), (i) they can initiate their actions by binding with the trans-membrane receptors (e.g. ATPase pump, ion transporters and channels, voltage-gated channels and G-proteins) and subsequently activating the associated downstream signaling cascades. Moreover, they can intercalate into the plasma membrane resulting in an alteration of membrane fluidity and a trigger of a series of cellular responses. (ii) binding with steroid hormone receptors (SHRs) including glucocorticoid receptor (GR), estrogen receptor (ER), progesterone receptor (PR), androgen receptor (AR) and mineralocorticoid receptor (MR) present inside or outside the nucleus by using their hydrophobic backbone is another alternative to trigger downstream cellular responses. Those activated (phosphorylated) SHRs can activate the target molecules through a signaling cascade that brings about various cellular responses. (iii) the ligand-bound SHRs can translocate into the nucleus, where they regulate gene transcription by binding with the specific Response Elements (XRE). This is the so called ‘genomic pathway’ (indicated by blue arrows). Consequently, the altered gene products can affect the final cellular responses.
Yue et al. Chinese Medicine 2007 2:6 doi:10.1186/1749-8546-2-6