Telomere shortening has been linked to aging for quite a while. In recent years, new data, particularly regarding the influence of senescent cells and the role of "stem cell depletion" in aging, have shed new light on the role of the telomere countdown timer. I recommend reading my last post about the top five telomere myths before you continue here because I will build on the terminology I developed there.
Michael Pietroforte
Latest posts by Michael Pietroforte (see all)

Biological age as an emergent property

An old cell behaves differently than a young cell. The proteome, the entire set of proteins produced by the cells of an organism, changes over time. This change can be measured in proteomics studies, and gene expression profiling studies prove that gene expression signatures change with age.

Experiments with shared circulatory systems (heterochronic parabiosis) of young and old mice indicate that substances exist in the blood plasma that influence systemic aging. Because everything that happens at the systemic level ultimately originates at the cellular level, cells must have the ability to reverse their biological age.

In heterochronic parabiosis experiments, mice share circulatory systems

In heterochronic parabiosis experiments, mice share circulatory systems.

Indeed, we now know that transcription factors exist that can turn back the biological clock in old cells. In 2012, Shinya Yamanaka received the Nobel Prize for his discovery that somatic cells can be transformed into embryonic-like stem cells, so-called induced pluripotent stem (iPS) cells, something that cell biologists believed to be impossible until recently. These iPS cells also reset their age to zero, which can be measured with various biomarkers, including the Horvath clock. It has been shown that this not only works in vitro. Scientists used this technology to reverse the age of mice.

The pictures show two mice of the same chronological age. the expression of yamanaka factors reversed the biological age of the left mouse. what did the rejuvenated mouse do with all the accumulated damage?

The pictures show two mice of the same chronological age. The expression of Yamanaka factors reversed the biological age of the left mouse. What did the rejuvenated mouse do with all the accumulated damage?

New research has revealed that the rejuvenation effect can be decoupled from the pluripotency gain, which indicates that transcription factors exist only for the purpose of controlling the age-dependent behavior of a cell.

These two insights—that is, that the proteome is age-dependent and that transcription factors exist that reverse cellular age—explain how old tissue can be rejuvenated when connected to young tissue. When cells receive signals from their neighbors about the tissue’s current age, they start to express rejuvenating factors, allowing them to adapt their gene expression patterns accordingly.

But how do the neighbors know the current time, that is, the biological age of their resident tissue? Well, they know from their neighbors; in other words, the biological age of an organism must be an emergent property constructed by the complex time signals of all cells.

Imagine musicians playing together. All the musicians try to keep the time of the other musicians. However, each musician also contributes to the tempo. The actual tempo is an emergent property that cannot be determined until the musicians start to play. The best you can do is give a range for the tempo, depending on the title the musicians agree to play. If you know that aged musicians are going to perform, you might predict a slower rhythm.

Cells in a multicellular organism must play to the tempo of all their fellow cells. Cells communicate heavily with each other to be able to adapt their behavior to the changing situation of the organism (availability of food, mating partners, etc.). One of these changing parameters is the biological age of the organism. Cells in an old body must play to a different tempo than the cells in a young body. Just as musicians listen to the rhythm of the band, the cells listen to the time signals they receive from other cells.

As telomere length probably has little effect on the configuration of the cell’s epigenome, and because the epigenome determines the signals a cell sends, the initiating source of these signals most likely does not come from dividing cells (mitotic cells).

Senescent cells

Researchers seem to have identified this initiating timing source. The master clocks of the aging organism are probably the so-called senescent cells. That senescent cells play a crucial role in aging is now beyond any doubt. Many companies are trying to find new ways to remove senescent cells from tissue because the rejuvenation effects of local and systemic senolysis are well known.

When the telomere countdown timer of the mitotic clock goes off, most cells commit programmed suicide. However, a fraction of cells stays alive, despite cell cycle rest. These are the senescent cells, sometimes wrongly called zombie cells. Neurons also don’t divide, and nobody calls them zombie cells.

Obviously, senescent cells are very much alive and have crucial biological functions. Interestingly, like neurons, they have a memory function, and their only job is to send this information to other cells. Despite their role during embryogenesis and wound healing, they also send signals to normal tissue through the so-called senescence-associated secretory phenotype (SASP) and, as recently discovered, through senescent-cell adhesion fragments (SCAFs). These biologically essential signals have many functions, one of which seems to be to control the biological age of a senescent cell’s resident tissue. Of course, the time is not explicitly encoded in those messages, just as musicians don’t peek at their neighbors’ watches to find the right beat.

The age of the tissue or the organism is an emergent property determined by all time signals. Thus, the more senescent cells contribute their signals, the older the tissue. Sometimes, senescent cells induce senescence in mitotic cells long before their time, which accelerates the systemic aging process. As the Hayflick limit programmatically creates more and more senescent cells, the behavior of local (probably mostly via SCAF) and, to a certain degree, remote (via SASP) cells change, their epigenome adapts to the age of the tissue and the organism.

My guess is that this is essentially what the Horvath clock measures. The epigenome of cells reflects the age of their tissue because gene expression must be age-dependent. New so-called transcriptomic aging clocks measure these age-dependent changes in cell behavior. It is important to note that these changes are not the result of transcriptional noise caused by the loss of epigenetic information and cell identity.

As mentioned above, the biological age at the systemic level is determined through intercellular signaling, which has been known since the heterochronic parabiosis experiments of the Conboys. Many scientists are currently trying to identify the molecules that carry these time signals. The most well-known researcher in this field is perhaps Harold Katcher, who made the geroscience community marvel about the composition of his miraculous lifespan-extending E5 substance. His book, despite having a bizarre title for a geroscience topic, is certainly worth reading.

Tampering with these signals in the blood plasma significantly extended the lifespan of Katchers’ rats. I’ll bet that senescent cells are the major source of pro-geronic factors. If anti-aging signals really exist, they must come from young, undamaged cells, most likely with long telomeres.

However, it is also clear that clearing pro-aging signals from the blood plasma can only extend the life of an organism for a limited time because senescent cells will continue to influence mitotic cells in their neighborhood through the SASP and SCAFs. Thus, even if pro-aging signals are continuously filtered from the blood plasma, the organism will continue to age, although at a slower pace.

The modification of cell behavior with age—that is, the programmed change in age-dependent cell identity—has fundamental consequences. Cells start to downregulate internal damage repair and external repair of the extracellular matrix, which explains why damage accumulates with age. However, this is only one effect of many.

Essentially, every hallmark of aging results from the change in gene expression over time: deregulated nutrition sensing, downregulation of mitochondrial activity, and an impaired immune system. Every process that keeps the organism alive is slowly downregulated in aging. Thus, aging can be defined as a gradual and programmed downregulation of life as such.

The remaining question is why only a fraction of cells becomes senescent, whereas the majority commit programmed suicide once the telomere countdown timer goes off. The answer is that telomeres have two major biological functions. One function of the telomere countdown is to differentiate mitotic cells into senescent cells; the other is programmed stem cell elimination.

Stem cell elimination

Stem cell depletion is recognized as a major cause of aging by most geroscientists. I don’t like the term because it implies that stem cells somehow get used up as we age. Even worse is the term “stem exhaustion.” The theoretically correct expression is programmed stem cell elimination.

Stem cells also make use of the telomere countdown timer, although their timer ticks a bit slower because human stem cells express small amounts of telomerase (the enzyme that extends telomeres). Once a local stem cell pool is emptied, damaged and suicidal somatic cells can no longer be replaced with new cells, and tissue can no longer be regenerated. Centenarians often suffer from a significant shortage of stem cells, which explains why any kind of damage is poorly repaired in elderly individuals.

As the telomere countdown timer eliminates more and more somatic cells, and fewer stem cells are available to produce replacements, tissue homeostasis is increasingly compromised, and the balance in the entire organism becomes gradually disrupted.

The Hayflick limit explains why multicellular organisms literally run out of cells. This is a very simple equation. If you programmatically restrict the number of cell divisions, thereby limiting the lifespan of individual cells, it is only a matter of time until organs run short of cells. It is no coincidence that long-lived animals have a more generous Hayflick limit. It simply gives them a larger reservoir of cells for their long lives (read my previous article for details).

At first, the effect of programmed stem cell elimination is hardly noticeable, but the more the creation of new somatic cells is downregulated through the Hayflick limit, the more organs begin to feel the shortage, causing a gradual loss of organ function. Once an essential organ reaches a critical point at which it can no longer perform its tasks, the organism dies of old age.

At the microbiological level, the telomere countdown programmatically limits the lifespan of cells. At the macrobiological level, the second major biological function of the telomere countdown timer is to programmatically set an upper limit for the organism’s maximum lifespan.

Telomeres and rejuvenation

If you understand the new telomere theory of aging, you should be able to explain why telomere extension does not result in rejuvenation, even though the telomere countdown is the major driver of aging. You can’t reverse time by turning your clock back, and you therefore can’t rejuvenate a senescent cell by resetting the telomere timer.

The stem cells that are lost because their telomere countdown timer went off won’t come back if you extend the telomeres of the remaining stem cells. Senescent cells, in which you extend the telomeres, will not dedifferentiate and become mitotic cells again. Remember that the function of the telomere countdown timer is only to flip the p53 switch.

Does this mean that there is no cure for aging? Of course not! The telomere theory of aging predicts that the removal of senescent cells (senolysis) with the help of senolytics is one way to reverse the age of an organism. Somatic cells that no longer receive pro-geronic time signals from senescent cells adapt their epigenome by expressing rejuvenation factors and start to behave like young cells.

Plasmapheresis (the dilution of blood plasma) that removes the pro-geronic factors from the blood is another promising approach that the telomere theory of aging predicts.

Partial reprogramming is probably just a shortcut. Most likely, the same rejuvenating transcription factors that are used for reprogramming are activated when cells don’t receive pro-aging signals from their neighbors.

Stem cell therapies, using rejuvenated iPS cells, are another promising strategy for finding a cure for aging. If you replenish old tissue with young stem cells, accumulated systemic damage will be repaired.

Even though it is obvious that telomere extension cannot rejuvenate cells and tissue, it is also clear that preventing the telomere countdown timer from going off in the first place by continuously maintaining telomere length with the help of telomerase expression in mitotic cells will significantly slow aging.

However, this might not prevent aging altogether, since many cells become senescent for other reasons, such as unrepairable DNA double-strand breaks or other damage caused by the wear and tear of metabolism. Future research will reveal how efficiently organisms with a disabled telomere countdown timer are able to clear damaged cells and repair damaged tissue entirely if the number of stem cells is preserved.

Conclusion

If you have read many scientific papers about aging, you’ll have noticed that I used somewhat unusual language in this article. Where most scientists talk of dysfunctions when describing the effects of senescent cells, I speak of functions, and where scientists talk of stem depletion and I prefer the term stem cell elimination. One of the reasons is that most research in this field is motivated by medical objectives. Everything that causes unpleasant effects from our perspective is identified as a pathological condition and is thus considered a failure of the underlying biology.

The fact that the telomere countdown, with its effects on aging, is an evolved trait and must therefore be seen as a programmed function of life is detested by many researchers who assume that benevolent Mother Nature must have failed somehow if something goes wrong from the point of view of a medical doctor.

This view is consistent with the false premise that evolution only tries to optimize the reproduction fitness of individuals. The fact that many geroscientists hold on to this outdated theory of evolution is perhaps the number one reason why many scientists in this field still cling to the wear and tear theory of aging even though the evidence contradicting the paradigm is increasing by the hour.

In my next post, I will discuss one major objection to the telomere theory of aging, namely, that programmed aging as an evolved trait contradicts Darwinism. Subscribe to the newsletter if you want to be informed when I publish the next article in my telomere series.

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10 Comments
  1. Mike Best 1 year ago

    An interesting look at why we age. I dont know too much on this subject except some pretty basic stuff.

    What is your guess on what killed most of Katcher’s rats at the end? Just running out of good stem cells basically? Is there a limit on stem cells late in life even if the signalling is reset to a younger state?

  2. Author
    Michael Pietroforte 1 year ago

    Mike, thanks!

    Katcher’s rats simply died because of old age. It is not entirely clear what E5 is, but I guess he is only filtering pro-geronic signals from the blood plasma. However, local signaling does not require blood. For instance, senescent cells can directly reprogram mitotic cells via SCAFs. And yes, you are right. The Hayflick limit continues to eliminate stem cells. Thus, filtering blood plasma can only slow aging.

  3. Mike Best 1 year ago

    I am curious ehat E5 is myself or at least what he was after when he filtered the blood for the factors. He did say in an interview that they were using things from young blood but in even higher concentrations than would be present in young blood normally and Akshay I think made a comment they didnt need to dilute the old blood first because the amounts upregulated their targets enough without having to do that.

    It appears we are close to getting humans where they can age more like something like a crocodile with a short period of majore decline at the end but getting most people past like 95-100 is a whole bigger issue. Getting 80 year olds looking like in shape 50 year olds would be a major thing though.

  4. Author
    Michael Pietroforte 1 year ago

    Do you have a link to the interview?

    I concur that a significant advancement in geroscience is within reach, and it may occur suddenly, just like the advent of AI. Moreover, the crucial discovery may originate from an individual who was not previously recognized.

  5. Mike Best 1 year ago

    Not off hand but I will try and find a link in the morning. My guess is they had identified a few things they really wanted and filtered by size to get them in addition to the rest of the factors that came with them.

  6. Author
    Michael Pietroforte 1 year ago

    I just read a relatively new paper from Steve Horvath who measured the epigenetic age of Katcher’s rats. The authors of the paper seem to suggest the existence of anti-aging factors, as they attribute the rejuvenation effects to factors found in young rat plasma:

    It has been reported that plasma dilution improves cognition and attenuates neuroinflammation in old mice, which suggests that dilution of putative circulating deleterious factors in old mice may be beneficial (33), although there is no documented evidence that plasma dilution increases lifespan in mice or any other mammals. It seems unlikely that the blood dilution that took place in our rats after i.p. plasma injection every other week, may have played a role in the changes reported here. Besides, after 30 months of age, the treated rats began to die in spite of the fact that we continued injecting plasma until their natural death.

    The Conboys appear to have a differing view , as they believe that the dilution effects are crucial and, therefore the removal of pro-aging factors.

    Our data demonstrate that a single NBE suffices to meet or exceed the rejuvenative effects of enhancing muscle repair, reducing liver adiposity and fibrosis, and increasing hippocampal neurogenesis in old mice, all the key outcomes seen after blood heterochronicity.

    NBE stands for “neutral” age blood exchange.

  7. Mike Best 1 year ago

    Havent found that specific interview yet but my view is both things can work to an extent. Katcher seems to think no dilution is needed for e5 to work effectively though. I think the Conboys are maybe a little hard headed thinking dilution alone can be just as effective as adding things from young blood. They wont say what they are making sure they get for e5 from the young pigs blood but looking at some things mentioned in the process patent I would think Klotho is possibly one of the proteins they are after.

    Do you think stem cell therapy combined with something like e5 treatments could possibly produce a mouse/rat that has a lifespan quite a bit longer than the top lifespans so far with calorie restriction and things like Rapamycin?

  8. Author
    Michael Pietroforte 1 year ago

    The primary issue is that Horvath and the Conboys are utilizing different biomarkers. Horvath primarily concentrates on his epigenetic clocks and lifespan, while the Conboys focus on tissue-dependent metrics such as muscle repair, fibrosis reduction, and myogenic proliferation. I can’t recall reading a Conboy paper that discusses epigenetic clocks, which is unfortunate.

    In my opinion, E5 or plasma replacement may not be the optimal solution. The improvements in lifespan and healthspan that can be achieved are moderate at most. It is likely that stem cell therapies have more potent effects, but their execution can be more challenging.

    Senolysis appears to be the most favorable option in the short term. Potential solutions for the long term could be provided by gene therapies and partial reprogramming.

  9. Mike Best 1 year ago

    Someone on redditt says the Conboys are doing a study now that will include Horvath clock measurements. My prediction is the change wont be as large as the e5 change there.

    I tend to agree about senescent cell removal maybe being the best current strategy. That seems to reset a lot of things associated with aging back to more youthful levels.

  10. Author
    Michael Pietroforte 1 year ago

    My prediction is the change wont be as large as the e5 change there.

    That’s quite possible. I’ve to add the Conboys do not rule out that anti-aging factors in young blood exist and Horvath does not rule out that pro-aging factors exist in old blood.

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