StemCell Therapy

Ever since the cellular clock called telomerase was discovered, it was hailed as the next big thing in anti-aging research. And the science world has been divided in two. One side evoked unlimited cell regeneration that might make degenerative diseases a memory of the past. The other side cautioned us that cancer cells unlock telomerase to make themselves immortal while hastening our own death. So where lies the truth? This is exactly what youll find out in these 8 frequently asked questions on telomeres, telomerase and aging. Read on.

Q: What exactly is telomerase?

A: Lets start with what telomeres are: repeated units ending linear(eukaryotic) chromosomes. They are normally deleted with each cell division. Once the cell reaches the maximum number of divisions (also called the Hayflick limit), it remains in this state for some time and then dies.

Some cells do not like being limited and they add back their telomere units with the help of an enzyme called telomerase. This way, telomere length stays the same despite repeated cell divisions. Which brings us to the next question.

Q: Do all cells express telomerase?

A: No, they dont. When it comes to humans, telomerase is expressed in cells that are needed for development germ cells during replication and embryo cells or regeneration stem cells. Cancer cells use telomerase as well. All the other cells are inhibited from expressing it.

Before we move even further, lets stop for a moment and clear something up: not all cells normal or not use telomerase expression to keep on dividing. More to the point, some cells are able to add back telomeric units with the help of ALT or the alternative lengthening of telomeres.

Telomerase is not equally expressed during the life cycle of an organism, of its tissues or of its cells. Telomerase peaks in proliferative tissues and it is downregulated in postmitotic ones. Even in colonial animals like the Botryllus schlosseri golden star tunicate, telomerase peaks in bud rudiments and further decreases in its zooids. In other words, telomerase activity peaks in progenitor and stem cells and it is downregulated during differentiation. Telomerase is highly expressed in cells which actively divide and it is downregulated during quiescence.

Telomerase differences exist between growth patterns as well. Mammals grow only during the embryonic and juvenile stages. They exhibit determinate growth. On the other hand, species with indeterminate growth often express telomerase in their somatic cells. They grow throughout their lives and often exhibit very slow senescence.

And when it comes to plants, the latter have two types of tissues:

Q: But do all species inhibit telomerase in their adult somatic cells?

A: The short answer is no.

Poikilotherms or cold-blooded animals like invertebrates, fish, amphibians and reptiles persistently express telomerase in adult somatic tissues. This could have an impact on their regeneration abilities. Temperature increases metabolism, hence it may increase cancer mutation rates and endotherms do have higher metabolic rates than poikilotherms. This could be the reason for which endotherms or warm-blooded animals like birds and mammals supress telomerase in their adult somatic tissues as a cancer-protection mechanism.

Q: Which are the telomeric parameters that modulate long lifespans?

A:There are a set of important parameters to study in long-lived species:

Q: How does absolute telomere length influence lifespan?

A: Generally speaking, telomere length is indirectly proportional to lifespan. In other words, short telomeres are associated with long lifespans and viceversa.

Well start by examining the telomere length of humans, then rodents, sea urchins and turtles. The first two examples are gradual senescence species while the latter display negligible senescence signs.

The length of human telomeres is 10-15 kb.

Unlike humans, rodents have extremely long telomeres of 25-150 kb which dont decrease with age. Rodents have a much higher cancer rate than humans. Rodents usually have telomeres that are longer than 30kb and telomerase activity seems to inversely correlate with body mass. In other words, larger rodents express less telomerase. And when it comes to rodents, there is no correlation between telomere length with size or lifespan. But lets go further to negligible senescence species and how they fare about telomere length.

In sea urchins at least, long-lived species like Strongylocentrotus franciscanus and medium-lived ones like Strongylocentrotus purpuratus have short telomere lengths of around 5 kb, while short-lived species like Lytechinus variegatus have long telomeres of around 20 kb. Nevertheless, no telomere shortening takes place in any of these three examples.

And the telomere length of the Chrysemys picta painted turtle is over 60 kb. Apparently, this length and its subsequent growth rate is maintained with age. The related Emys orbicularis European freshwater turtle doesnt show any signs of senescence according to current knowledge. The latter maintains its 20 kb telomeres constant with age.

Q: Does the precise telomeric sequence vary among species?

A: Yes, major groups of animal species contain different telomeric sequences as follows.

The vertebrate (TTAGGG)n telomeric repeat sequence is common in most multicellular organisms, including:

Exceptions include roundworms and arthropods. The nematode telomere motif is (TTAGGC)n, while the arthropod telomere motif is (TTAGG)n. Beetles lost the arthropod telomere motif and likely employ alternative lengthening of telomere elongation.

Q: Does telomerase cause cancer?

A: According to the telomere loss theory, telomere shortening leads to the aging of cells and that of the whole organism and presumably, this phenomenon evolved to protect us from cells replicating to their hearts content and giving us cancer in exchange.

Telomeres shorten with age and that leads to replicative senescence. Making these somatic cells express telomerase is desirable for allaying many degenerative processes, but the greatest fear is that such a process may lead to the onset of cancer.

Here are two reasons for which this is an unfounded fear:

Q: Does telomerase increase lifespan?

A: Not exactly. Telomerase expression seems to correlate with the regenerative potential of a species or at least that of its germ and stem cells and not so much with its maximum lifespan.

In one experiment, telomerase was inserted in adult and old mice with the help of a viral vector. A life extension of 24 % in the adults and 13 % in the elderly was achieved. And compared to controls, the treated mice did not develop cancer at a higher rate.

But several species express telomerase in their somatic cells when indeterminate growth and/or vegetative reproduction is at play and yet, several cases of aging can be encountered in there as well.

In another experiment previously cited as well 3 species of sea urchins express telomerase in their cells and yet, their wildly differing lifespans include:

Telomerase is present in the early and adult stages of all these sea urchins and their telomere lengths show no age-related shortening. So telomere length is not the mechanism underlying their lifespan differences. And there is no difference in oxidative damage between them. All of the previously mentioned sea urchins maintain regeneration abilities with age. Go figure. Can you solve this puzzle? Can you explain why do these types of urchins have wildly different lifespans when they start out with all the cards in their favor? Id love to hear from you in a comment!

To wrap things up, I view telomerase insertion in somatic cells as paving the way for regenerative medicine to do wonders in acute and chronic diseases of the aged, but I doubt it could impact human lifespan other than by alleviating what cant be alleviated today.

Cited studies include:

Francis, N., T. Gregg, R. Owen, T. Ebert, and A. Bodnar. Lack of Age-associated Telomere Shortening in Long- and Short-lived Species of Sea Urchins. FEBS Letters580, no. 19 (August 2006): 4713-7. doi:10.1016/j.febslet.2006.07.049

Gomes, N.M., J.W. Shay, and W.E. Wright. Telomere Biology in Metazoa. FEBS Lett 584, no. 17 (September 2010): 3741-3751. doi:10.1016/j.febslet.2010.07.031.

De Jesus, B., E. Vera, K. Schneeberger, AM Tejera, E. Ayuso, F. Bosch, and MA Blasco. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 4, no. 8 (August 2012): 691-704. doi:10.1002/emmm.201200245.

Note: this blog post includes excerpts from The aging gap between species book.

Anca Iovi is the author of Eat Less Live Longer: Your Practical Guide to Calorie Restriction with Optimal Nutrition ,The Aging Gap Between Species and What Is Your Legacy? 101Ways on Getting Started to Create and Build One available on Amazon and several other places. If you enjoyed this article, dont forget to sign up to receive updates on longevity news and novel book projects!

Dont miss out on the Pinterest board on calorie restriction with optimal nutrition where she uploads new recipes every day. https://www.pinterest.com/longevityletter/eat-less-live-longer/Or the Comparative Gerontology Facebook Group where you can join the discussions on how species rate at different speeds and what could be the mechanisms underlining these differences! https://www.facebook.com/groups/683953735071847/

The dose makes the poison.

In large doses, a stressor can kill you. In low doses, it can make you stronger. The specific adaptation that a cell derives from being exposed to a low dose of some stressor is called hormesis. And this concept is central to understanding aging.

Because if cells for whatever reason lack what they need, autophagy sets in and they often survive. Autophagy or self-eating is the process through which a cell recycles its own intercellular junk and damaged organelles in order to get the building blocks it needs to continue living. Unfortunately, the ability of a cell to undergo autophagy in response to stress declines with age. That is why you must avoid the buildup of intracellular junk as much as possible and if possible, train the ability to undergo autophagy.And this is exactly what you will learn from this blog post.

Here are 3 simple things you must do to initiate autophagy and stop the aging clock:

I admit I am not a sports buff. Worse than this, I hated sport during my school years because it took me away from reading books and frankly, I found it boring and useless. Things only began to change once I learned how to swim at the mathusalemic age of 25. I now swim 1-2 times per week and I still view it as the best sport ever. I used to ride a bike during my college years, but Bucharest is not a bike-friendly place so I ended up giving away my bike and renting one out when Im in the mood for it.

But after reading Stop the clock the optimal anti-aging strategy by P.D. Mangan, I realized that I was doing it all wrong. When compared to aerobic exercise, weightlifting and high-intensity exercise training are better options to stress the body and induce autophagy. Of course, this wont make me give up swimming, but now I wont hesitate to catch the subway if the situation calls for it. And the subway always seems to be arriving when its too late for me to catch it. Murphys law.

I wish all mothers of grown-up kids would read this. Skipping eating for more than the usual 8-hour night fast is not the end of the world. It wont kill you. Better still, fasting will activate autophagy. As your cells sense they lack nutrients, they will start recycling whatever intracellular junk you accumulated. In Stop the clock the optimal anti-aging strategy, the author recommends fasts of 12-16 hours including the 8-hour fast. That could be achieved by skipping breakfast and dinner from time to time. And in my case, thats often what I do during hectic days.

Plants are literally rooted in the ground, so the only way they can protect themselves from being eaten is chemical warfare. They cant shade themselves from the sun and they cant run away to save their lives like animals do so they synthesize all sorts of toxins and pigments. This may be the reason for their purported health benefits. Personally, I never really liked meat until I discovered sushi during college , but Ive always loved colors; a plate full of veggies and/or fruits looks so beautiful. Its nice to know that having an eye for color turns out to be another simple way to initiate autophagy. And many phytochemicals like anthocyanins, resveratrol, curcumin can be ingested from veggies, fruits, herbs, tea, coffee, chocolate (the real one!) and/or dietary supplements.

And while I wholeheartedly agree with most of the advice given inStop the clock the optimal anti-aging strategy, I dont condone the low-carb paleo diet as being efficient on the long term. The moment youll lower your carbs, you will by default ingest more fats and more protein. And the body can definitely use fats and proteins to get you some energy, but it takes time to mostly complete your glycogen stores. Not to mention that half of the effect of calorie restriction is protein or more exactly methionine restriction. Paleo diets with no sugar, grains or oils sound very good in theory, but in practice people will replace them with lots of daily animal products. I personally find the paleo diet slows me down both mentally and physically. I need carbs to move fast and think fast. But if you found success by trying paleo, good for you!

Summing up, the dose makes the poison. And this is true for the 3 simple steps mentioned above too.

Most life extension animal studies stressed those animals at a bearable limit by using all sorts of stressors: calorie restriction, cold, toxins and many others. And the common denominator in all these studies is the inhibition of growth which is a positive thing after the maturity stage has been achieved.

Nevertheless, species in the wild often adapt to nutrient-poor, water-poor and oxygen-poor environments by varying the age at which maturation takes place and by varying the degree of necessary maturation. In other words, such species may either delay their maturation age (the tiny Arctica islandica clam needs 10 years to become an adult) or they may undergo reproductive system maturation only. The latter is the case of neotenic amphibians that forgo the costly metamorphosis and preserve their youthful appearance (the Proteus anguinus olm). These are evolutionarily conserved mechanisms that inhibit growth and cell division stimulating hormones like insulin and thyroid hormones.

But since most of you reading this post already finished growing up, the lesson is simple: comfort is your enemy.

(Hint: if you want to read this book, you can check it out on Amazon)

Anca Iovi is the author of Eat Less Live Longer: Your Practical Guide to Calorie Restriction with Optimal Nutrition ,The Aging Gap Between Species and What Is Your Legacy? 101Ways on Getting Started to Create and Build One available on Amazon and several other places. If you enjoyed this article, dont forget to sign up to receive updates on longevity news and novel book projects!

Dont miss out on the Pinterest board on calorie restriction with optimal nutrition where she uploads new recipes every day. https://www.pinterest.com/longevityletter/eat-less-live-longer/ Or the Comparative Gerontology Facebook Group where you can join the discussions on how species rate at different speeds and what could be the mechanisms underlining these differences! https://www.facebook.com/groups/683953735071847/

Books

Although physicians have better technologies today to uproot cancer from the human body, receiving a diagnosis of cancer is still a very stressful ordeal, even when it is cured in the end or even when the tumor is not proved to be malignant in the first place!

Lifestyle is important in preventing cancer, but at the end of the day, there is only so much you can do. I mean, humans still have a 33% chance of developing cancer during their lifespan just because they are humans.

But thats not the case in all animal species. Unfortunately, when it comes to oncology research, very few types of animals are studied to help us find treatments. Mice have an 80% rate of developing cancer if raised in a lab. They live about 2 years in the wild, so they dont need to worry about the possibility of developing cancer. But nature develops all sorts of evolutionary experiments and when it comes to cancer, here are 10 of them:

1 The naked mole rat is a rodent species where no individual was ever found of developing tumors. Even if tumors are discovered in the near future, its rarity is a mystery for a rodent the size of an average mouse. One mechanism supporting this increased cell contact inhibition of the average naked mole rat is their constituent hyaluronan, which has a molecular weight 5 times larger than ours. It sure helps that growth is expensive in their environment and they developed an uncanny ability to survive prolonged periods of starvation and intermittent oxygen restriction.

2 The smaller and shorter-lived the animal, the easier and cheaper it is to study it in the lab. The problem with this approach is that the more cells an animal has and the longer one lives, thereby surviving more cell divisions, the higher the chance of an animal should be to develop cancer, right? Only that its wrong! Known as the Petos paradox, larger animals actually have a decreased rate of cancer throughout their lifespan. One such interesting animal is the bowhead whale which is the longest-lived mammal surviving up to 2 centuries. Although hunted by humans for food apart from rivaling killer whales cancer is almost never found in these giant sea lords who are just as accustomed to prolonged starvation and intermittent oxygen restriction (during diving for feeding) as naked mole rats.

3 Another animal of considerable size with very few cases of cancer is the elephant. Now bigger animals have cells with bigger cell diameters as well. But when it comes to weighing several tonnes, the elephant living around 70 years in the wild must be an evolutionary experiment as well since cancers are so rare. One recent explanation could be the sheer number of copies of the p53 gene compared to healthy humans who have only 2 or cancer-prone Li-Fraumeni syndrome who have only 1 copy.

4 One of the mechanisms larger animals learned to keep cancer at bay was to turn off telomerase in their somatic cells. Certainly, telomerase is an enzyme present in most human cancer cells that allows them to escape normal limits on growth and become immortal. But although telomerase suppression is present in many longer-lived species, I doubt it does them any good as it stops regeneration in its tracks and it increases genomic instability. In other words, somatic telomerase repression could be a side effect and not necessarily a desired effect. And the way to check for that is to study species that dont bother with it what are their usual cancer rates? Youd expect that an animal with indeterminate growth that avoid somatic telomerase suppression to have at least an average if not higher cancer rate, right? Well the red sea urchin certainly does not. Although living close to a century, its cancer rate is close to zero.

5 You may think that the red sea urchin and many of its sea urchin relatives are rarely studied, so thats why its cancer rate is so low. But take lobsters these are commercially important species that cater to most peoples plates. The average lobster leads a benthic lifestyle as well, living at the bottom of the water and being exposed to many carcinogens. And the average lobster goes on growing for the rest of its life. And yet its cancer rate is extremely low.

6 Decapod crustaceans in general are useful biological models in oncology research because they display indeterminate growth and rarely get cancer. Apart from lobsters, these include crabs, shrimp and crayfish.

7 One small rodent that displays abundant telomerase in its tissues is the gray squirrel and yet when it comes to placing its cells in a culture dish, their spontaneous proliferation is extremely slow. Go figure.

8 The axolotl is a frequently used animal in regenerative medicine studies, but rarely used in oncology research even if its cancer rate is low.

9 A group of species in which the cancer rate is surprisingly low is formed of long-lived seabirds.

10 Another rodent with cancer-proofing strategies is the blind mole rat. Living underground just like the naked mole rat, this rodent has a double set of interferon genes which may kill cancer cells in the first place.

Classical cancer studies were extremely helpful in developing chemoterapy, novel cancer surgery techniques, radiotherapy and hormone blockers, but whats the next step? Can we do better than this? Can we adopt genetic strategies from animal species that learned how to prevent cancer in the first place?

References

Most references were taken from the Cancer chapter in The aging gap between species.

Dang, CV. A metabolic perspective of Petos paradox and cancer. Philos Trans R Soc Lond B Biol Sci 370, no. 1673 (July 2015). doi:10.1098/rstb.2014.0223.

Gomes, N.M., J.W. Shay, and W.E. Wright. Telomere Biology in Metazoa. FEBS Lett 584, no. 17 (September 2010): 3741-3751. doi:10.1016/j.febslet.2010.07.031.

Gorbunova, V., A. Seluanov, Z. Zhang, VN Gladyshev, and J. Vijg. Comparative genetics of longevity and cancer: insights from long-lived rodents. Nat Rev Genet 15, no. 8 (August 2014): 531-40. doi:10.1038/nrg3728.

Maciak, S., and P. Michalak. Cell size and cancer: a new solution to Petos paradox? Evolutionary applications 8, no. 1 (January 2015): 2-8. doi:10.1111/eva.12228.

Nagy, J.D., E.M. Victor, and J.H. Cropper. Why dont all whales have cancer? A novel hypothesis resolving Petos paradox. Integrative and Comparative Biology 47, no. 2 (August 2007): 317-28. doi:10.1093/icb/icm062.

Prokopov, A.F. Theoretical paper: exploring overlooked natural mitochondria-rejuvenative intervention: the puzzle of bowhead whales and naked mole rats. Rejuvenation Research 10, no. 4 (December 2007): 543-60. doi:10.1089/rej.2007.0546.

Roy, S., and S. Gatien. Regeneration in Axolotls: a Model to Aim For! Exp Gerontol 43, no. 11 (November 2008): 968-973. doi:10.1016/j.exger.2008.09.003.

Abegglen LM, Caulin AF, Chan A, et al. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA. 2015;314(17):1850-1860. doi:10.1001/jama.2015.13134.

Anca Iovi is the author of Eat Less Live Longer: Your Practical Guide to Calorie Restriction with Optimal Nutrition ,The Aging Gap Between Species and What Is Your Legacy? 101Ways on Getting Started to Create and Build One available on Amazon and several other places. If you enjoyed this article, dont forget to sign up to receive updates on longevity news and novel book projects!

Dont miss out on the Pinterest board on calorie restriction with optimal nutrition where she uploads new recipes every day. https://www.pinterest.com/longevityletter/eat-less-live-longer/ Or the Comparative Gerontology Facebook Group where you can join the discussions on how species rate at different speeds and what could be the mechanisms underlining these differences! https://www.facebook.com/groups/683953735071847/

Publication Year: 2015 ISBN: 9781517484811

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