Telomere theory of aging

Originally considered to be simple counters of cell division, telomeres as well as protecting the chromosome from damage also affect the gene expression of all the genes on that chromosome through a mechanism known as the telomere position effect (TPE). Wright and Shay and a number of other leading scientists have demonstrated how the telomeres affect this gene expression throughout life. These changes in gene expression in effect reprogram the cell as the telomeres shorten and contribute to the dysfunctional changes associated with aging.

This programmed change of gene expression and resulting dysfunction is different to changes in gene expression through DNA Methylation and histone acetylation patterns called epigenetic drift although they share similarities. Both processes are influenced by genotype, both appear to result in stem cell dysfunction, both occur independently of tissue and finally both are linked to disease risk factors. It is likely that Epigenetic drift constitutes a second aging “clock” within the cell and should be the focus of life extension therapies in conjunction with telomere restoration to potentially restore youthful cell function.

Regarding telomeres, Dr Michael Fossel one of the foremost advocates of the telomere or epigenetic theory of aging, explains that it is not the absolute length of telomeres which control this, but it is the level of erosion relative from the time the egg was fertilized. As he explains, “Telomere length is irrelevant, telomere loss is critical”. In summary, the rate of telomere shortening appears to depend on the telomeres original length. People starting out with the longest telomeres experience the fastest rate of telomere shortening and vice versa. This also explains how mice, which have significantly longer telomeres compared to ours still have shorter life spans. So it is the restoration of telomere loss to the it’s initial length that is the goal here rather than simply extending them as much as possible.

This shortening eventually causes the cell to enter senescence not because the chromosomes are not properly capped, but because the gene expression has altered to the point that the cell ceases to be functional. The question over whether some older people have enough senescent cells to explain their aged tissue is resolved by the fact that cell senescence is only part of the picture. Gene expression patterns are causing all the cells in an older person to be less functional and express a phenotype of an older cell.

Coupled with changes in gene expression, senescent cells play their part as well as a significant number of these exhausted cells refuse to die (known as Apoptosis) and they remain in place and send out damaging signals known as the senescence-associated secretory phenotype (SASP). They are a part of the larger picture and aside from cancer are some of the most dangerous and dysfunctional cells, being incapable of division and are in fact toxic to neighboring cells via SASP. This means that a relatively small number of such cells create a far greater problem and this is why the area of senolytic agents capable of removing them has been of considerable interest recently.

To elaborate, neuron cells, heart cells and muscle cells for the most do not divide and this is a common objection to the theory, but this is because these cells need support from their neighboring cells which do divide. Each neuron, for example, is surrounded by Glial cells, which do divide and whose telomeres do shorten. With old age these cells are lost and the neurons lose their support. With advancing age the blood supply to the brain is significantly compromised as the cells of the arteries begin aging due to the gene expression changes caused by telomere erosion. For every non dividing tissue type this loss of support from their neighboring dividing cells is consistent with the pathology that we observe in the non-dividing tissues as they age.

In conclusion this makes the targeting of telomeres of primary importance in mitigating the effects of aging and reversing the changes in gene expression and why we believe this is the most suitable point of intervention to reverse the changes in gene expression and revert cells to a younger healthier pattern of expression. It has been demonstrated in numerous experiments that restoring relative telomere less rejuvenates cells and tissue in both animal and human cells tested. This is why after decades of testing and research it is finally time to develop this as a restorative therapy with the potential to address a myriad of age associated conditions and to potentially extend lifespan considerably.


Misconceptions about the telomere theory of aging

by Dr Michael Fossel from "The Telomerase Revolution" Benbella Books


Misconception #1: The most common misconception about the telomere theory is that telomere length defines or causes aging. The truth is, an organism’s telomere length has almost nothing to do with how long they live or how fast they age. As many researchers point out, some animals, such as mice, have long telomeres but short lifetimes, while other animals, such as humans, have much shorter telomeres but longer lifetimes.

Telomere theory doesn’t suggest that telomere length controls aging: telomere length is irrelevant to aging. Rather, changes in telomere length control cell aging. The data consistently supports this observation. The key question isn't how long your telomeres were at birth, but how much your telomeres have shortened. It's the shortening that alters gene expression.

Observations of the change in telomere lengths from birth to senility in mice and other organisms show clearly that telomere shortening – or rather, the way in which shortening telomeres cause changes in gene expression – is the driving force in the aging of the whole organism.

This is part of the reason why measurement of telomere length has limited predictive clinical value. Only if you know the average telomere lengths for a particular type of cell in a particular species can a single telomere length be used to help assess body function and pathology. For example, if I know that teenaged humans have an average telomere length of 8.5 kbp in their circulating white cells but that this usually falls to 7.0 kbp by age eighty, then finding that your white-cell telomeres have a length of 6 kbp tells me you’re in trouble. The length, 6 kbp, is irrelevant unless we know the context. It's not the length, it's the change in length.

Misconception #2: Despite what you might have seen on television health programs, telomeres do not unravel. This common misconception derives from the usual analogy of telomeres as aglets, the plastic end caps on shoestrings. The implication of this metaphor is that when you get older, the plastic aglet of the telomere wears away and all the strands that make up the DNA unravel, causing your chromosomes to come apart, killing the aging cell.

But this isn’t what happens, In fact chromosomes never unravel, because deterioration never gets that far. Cellular dysfunction reaches a tipping point long before the telomere is used up. Only in the most extreme cases, such as the fifth generation of “telomere knockout” mice (which cannot express telomerase) do cells ever lose all their telomeres. It simply doesn’t happen in normal aging.

In real life, your chromosomes actually remain in pretty good shape, even if you live to be 120. The only time they actually fray is during decomposition.

Likewise, the idea that telomere shortening is what kills the cell is usually inaccurate. Cells with short telomeres certainly don’t work very well, but that doesn’t mean they’re dead.

Misconception #3: Almost invariably, someone will argue that telomeres couldn’t possibly cause heart disease or Alzheimer’s dementia. Usually, this argument comes from a perfectly rational academic scientist whose grasp of biology is magisterial, but whose grasp of clinical pathology is much less so.

In the case of heart disease, they point out that heart muscle cells, cardiomyocytes, almost never divide, and so heart disease can’t possibly result from telomere shortening.

But the pathology is more complex. Saying that telomere loss can’t cause heart attacks because heart muscle cells don’t lose telomeres is like saying cholesterol can’t cause heart attacks because heart muscle cells don’t accumulate cholesterol.

It’s not changes to the cardiomyocytes that lead to heart disease, but changes in the coronary arteries – the vascular endothelial cells – which lose telomeres and accumulate cholesterol. The underlying pathology lies in the arteries, not in the muscle. The fact that cardiomyocytes don’t divide is irrelevant to the pathology of heart disease.

The same criticism – with a similar misunderstanding of pathology – is used in regard to Alzheimer’s dementia: neurons almost never divide, so Alzheimer’s dementia can’t possibly be due to telomere shortening.

While it is roughly accurate to say that adult neurons don’t divide, the microglial cells that surround and support those neurons divide continually, and their telomeres certainly do shorten with age. Microglial telomere shortening correlates with Alzheimer’s disease and appears to precede the onset of several hallmarks of dementia, including beta amyloid deposition and the formation of Tau protein tangles.

It is useful to make a rough distinction here between direct age-related pathology and indirect age-related pathology. Alzheimer’s and heart disease, are examples of indirect pathology, where neurons and the cardiomyocytes are “innocent bystanders.” Direct aging means that aging cells cause pathology in their own tissue; indirect aging means that aging cells cause pathology in a different tissue, or different cell type.

Telomerase and cancer

This is a common concern, however telomerase does not cause cancer, but is a necessary requirement for cancer cells to divide. Most Cancer cells express telomerase allowing them to divide indefinitely, which is partly why they are so dangerous. This has led to some people expressing concern that activating telomerase will lead to cancer, this however is not the case.

Since it's discovery in 1984 there has been no substantial proof that activation of telomerase causes cancer and in fact the opposite seems to be the case, with optimal telomere length leading to healthy gene expression, cellular stability and a level of protection from cancer. This makes sense as just like young people whose cells express youthful genes and resist cancer, cells rejuvenated with telomerase would do likewise.

For a more in depth analysis of telomerase and cancer see the excellent article by Josh Mitteldorf here.

Other Aging Theories

Wear and tear theory: Cells and tissues have parts that like components in a car, eventually wear out from repeated use, leading to organ failure and death. This popular theory as it sounds perfectly reasonable to many people as this is what happens to most familiar things around them.

Rate of living theory: According to this theory the greater an organism’s rate of oxygen basal metabolism, the shorter its lifespan. The rate of living theory of aging is not completely adequate in explaining the maximum life span.

Cross-linking theory: According to this theory, an accumulation of cross-linked proteins damages cells and tissues, slowing down bodily processes resulting in aging.

Free radicals theory: This theory proposes that super-oxide and other free radicals cause damage to the cell, this accumulated damage then causes cells, and eventually organs, to stop functioning.

Somatic damage theory: DNA damage occurs continuously in the cells of living organisms. While most of this damage is repaired, some damage accumulates, as the repair mechanisms cannot correct defects as fast as they occur. Genetic mutations occur and accumulate with advancing age, leading to cellular dysfunction. Damage to mitochondrial DNA may contribute to mitochondrial dysfunction as part of this process. This theory therefore suggests that aging results from damage to the genetic integrity of cells.