Telomeres, Aging & fountain of youth Espanol video de telomeros [ 1:17 mns ]: Telomeros, Envejecimiento Celular - Maria Blasco Telomeres: Telomeres are the protective physical caps or ends of the chromosomes and consist of repeated blocks of the DNA sequence, TTAGGG. The telomere protective cap [ shown in red in the right illustration ] is at the end of each of the 24 chromosomes [ light blue in the illustration ]. Telomere function: Telomeres protect the chromosome from fusing with another and also preventing mutations in DNA. Dr. Bill Andrews 69 has evolved an animation to help us understand how telomeres and aging work. His analogy is to "think of a DNA as a long row of bricks, and of DNA replication as a bricklayer walking backwards on top of a brick wall laying a new layer on top of that row. When the end of the wall is reached, the bricklayer finds himself standing on top of the brick he's supposed to replicate. Since he can't put down a brick where his feet are, he steps back and falls off the wall ---- leaving the very end of the wall bare.

As a result, the new copy of the wall is shorter." Just like this brick wall was copied imperfectly, our DNA in a telomere is unable to perfectly copy itself; when a strand is replicated, the new strand is shorter than the old strand. If we lost portions of the information encoded in our DNA every time it replicated, human life would be impossible. Our cells couldn't even divide enough times to allow us to be born. Fortunately, we are born with long, repetitive sequences of DNA at the end of each of our chromosomes, which later shorten during the normal DNA replication process." 69 These repetitive sequences are called "telomeres." Telomeres function by preventing chromosomes from losing base pair sequences [ TTAGGG ] at their ends. Telomeres protect the chromosome from fusing with another and also preventing mutations in DNA. Telomeres become shorter each time cells divide. When we are first conceived, the telomeres in our reproductive single-cell embryos are approximately 15,000 nucleotides long. Our cells divide rapidly in the womb, and by the time we are born, our telomeres have decreased in length to approximately 10,000 nucleotides.

Each time a cell divides, some of the telomere is lost ( [ usually 25-200 base pairs per division ]. They shorten throughout our lifetime. When the telomere becomes too short, the chromosome reaches a "critical length" and can no longer replicate. This means that a cell becomes "old" and dies. 3 This wearing out with age process was discovered by DNA researcher, Leonard Hayflick in the 1960s, as the number of times a normal cell population will divide before it stops. Hayflick discovered that non-stem [ i.e. non-telomerase active ] cells in a dish can only divide about 60 times before the telomeres become too short to survive. The limit on a cellâs maximum lifespan is known as its " Hayflick Limit .â When the telomere is depleted, the cell dies. 4 However, telomere life may be extended by an enzyme telomerase. Unfortunately, the part of the DNA that produces telomerase is asleep in our bodies, i.e. the âswitchâ is turned off.

We now have the ability to turn the âswitchâ back on to produce telomerase, which can then restore and repair the lengths of the ends of your DNA. The result is a healthier DNA and potentially a reversal of the aging process. Telomerase adds repetitive DNA TTAGGG sequences to telomeres. Instead of gradually getting older and dying, the cells continue living indefinitely. The video below summarizes how telomerase works: [ Flash Player may be required to view the animations.] Source: Telomerase function Telomerase prevents DNA strands from shortening, allowing perfect cells to replicate again and again. Telomerase does this by adding repetitive sequences [nucleotides] to the ends of our chromosomes, thus lengthening our telomeres. Telomerase works by filling the "gap" left by DNA replication thereby lengthening telomeres. This is illustrated [ below left ] by the animation created by Bill Andrews. Bill Andrews previously evolved an analogy animation comparing a telomere to the brick of a bricklayer. But instead of the bricklayer being unable to lay the last brick on the brick wall and falling off, an angel takes the bricklayer's place and flies in with telomerase instead of a brick.

69 The angel is the telomerase that adds an extra DNA sequence and lengthens the telomere. 69 Most of the somatic cells have telomerase turned "off" after birth. The exception is in the fetus, where telomerase is turned on. [ the fetus enjoys abundant telomerase until birth ] Human cells have their longest telomeres at birth, then making fewer and fewer telomeres. [ the Hayflick Limit ] There are some specialized cells that continue to produce telomerase after birth. Tissues like the lining of your mouth, your digestive and immune system need to make many copies to repair the daily natural assault from the environment. There is also another kind of cell that manages to turn "on" the telomerase production, so much so that it becomes virtually immortal -- cancer. This lengthening gives cancer cells the ability to continuously multiply [ uncontrolled growth ]. On the other hand, telomerase activators might repair or extend the telomeres of healthy cells, thus extending their Hayflick Limit. Telomerase activation might also lengthen the telomeres of immune system cells enough to prevent cancerous cells from developing from cells with very short telomeres.

4 Telomerase and longevity: In normal cells that are not germ [ reproductive ] cells, telomerase is switched off at an early stage of development. This results in normal cells having shorter telomeres, losing their ability to divide and slowing down in growth. Scientists have found that introducing a telomerase gene into normal cells by genetic manipulation can extend a cell's life span. 5 Telomere size affects how long we will live and our predisposition to diseases. The mouse study below illustrates longevity: 6 7 Short telomeres 41 42 43 44 Telomere length in animals: Animals with relatively longer telomeres for their age live longer or had higher lifetime reproductive success, suggesting that telomere length may be used as an index of individual quality. Each organism has a different DNA identification or fingerprint. For a select few organisms, immortality is a reality. In hydra [ tiny creatures found in most freshwater lakes, ponds, and streams ], telomeres never get shorter. The immortal jellyfish, Turritopsis nutricula, has the ability to, at any stage of its life, to completely reverse its aging process .

65 Other animals living long lives include the sea anemone [indefinitely], the lobster [140+ years], Aldabra giant tortoises [140+], and rougheye rockfish [160 years ]. 70 There are also numerous plants, like the California Giant Sequoia redwood, the aspen [birch] colony in Utah known as Pando or the Trembling Giant tree [ on right ] estimated to be about 80,000 years old, that appear to live forever. 71 72 These plants and animals hold the secret of long life! Telomere length linked to life style: According to research led by Dr. Dean Ornish, telomere length is linked with the degree to which the men made healthy lifestyle changes; with those making more changes experiencing greater lengthening of their telomeres. 45 46 Poor lifestyle habits, as reflected in lack of physical activity, obesity, depression, accumulated stress, poor diet, inflammation and stress, speed up the shortening of telomeres.

Ornish 47 and colleagues 73 determined that dietary improvements and increased exercise "significantly increase telomerase activity and consequently telomere maintenance capacity in human immune system cells." Examples of links between telomere length and diseases: Heart Attack: The blue bar represents the average telomere length of people who didnât have a heart attack. The red bar shows the much shorter telomere length of the people who did. The average telomere length of those who had a heart attack was significantly shorter than that of the people who had no heart incidents. This information is provided by Al Sears, M.D., Power For Healthy Living. An example of telomere length and incidence of cancer on the left and telomere length to incidence of stroke on the right graph. Fig. 2 Relation of telomere length to incidence of cancer (Data adapted from Willeit et al.) Fig. 3 Relation of telomere length to incidence of stroke (Data adapted from Willeit et al.) Telomere length [ TL ] is a measure of cumulative DNA damage from multiple environmental risk factors over an individualâs lifespan.

48 TL is likely a better predictor of Coronary Artery Disease [CAD] than the currently available risk markers, which are single, point measurements in time. Although the development and progression of atherosclerosis occurs over decades, the process is clinically silent until the manifestation of full-blown disease. The rate of telomere shortening is accelerated prior to the onset of clinical disease, so longitudinal assessments of telomere length should be a good predictor of CVD. Expect your doctor in the future to measure the length of your telomeres to help you with your health problems. HOW TO LENGTHEN YOUR TELOMERES: A ticket to a healthier and live longer future 49 50 A. Vigorous exercise 51 13. Zinc A lack of zinc in elderly people is associated with excessive numbers of short telomeres. 60 14. Vitamin C has been shown to slow the loss of telomeres in human vascular endothelial cells. 61 15. Chinese green tea 62 16. Selenium 18. Anti-oxidants 63 [ The following has also been shown to lengthen telomere length ]: H.

TA-65: an extract from a Chinese herbal medicine that appears to turn the âswitchâ on to make your cells produce telomerase. TA-65 is highly purified through a proprietary extraction process from the CChinese plant Astragalus Root. Measuring Telomere Lengths: Two blood test techniques are available to measure telomere length: 1. Telme Health by Calvin Harley & Elizabeth Blackburn [ ] 2. Life Length by Maria Blaco [ ] These biomarkers are based on the belief that telomere lengths may serve as an appropriate biomarker for aging and for age-related diseases and that this knowledge may have significant implications for clinical medicine. 64 68 More helpful information about telomeres may be viewed: [ Flash Player may be required to view the animations.] Video: Bill Andrews at Independent Research Conference 2/12/2012 Length = 1:44 hr. Andrews: Fountain of youth Video by Elizabeth Blackburn: what are telomeres? length = 43mns. Blackburn:Telomeres Video Bill Andrews Telomeres Reversing the aging process: length = 60 mns.

Andrews: Telomeres Summary: This article summarized basic information about telomeres. Chromosome DNA identify who we are, telomeres are the flames that gives us life, and telomerase ignites the spark to keep the flame alive! Scientists, since Hayflick's demonstration, have been aware of being able to reverse aging and control diseases with telomerase for over 50 years. Unfortunately, the world appears to have suppressed such medical application. In general, markers of poor health status are associated with relatively shorter telomeres, while markers of better health status are associated with longer telomeres Research about telomeres has exploded since 2000. Although researchers have gained a lot of understanding about the nature of telomeres, a great deal still remains unknown. Although we do not really know the secret of some plants and animals that appear to live forever, scientists suspect that telomeres probably hold the secret of their long lives. The future of the human race is headed in the direction of longer and healthier life spans. Telomerase gene therapy is a feasible and generally safe approach to improve health span and to treat disorders associated with short telomeres.

Telomeres = Biological Clock source: TA-65 doctor bioclock Today, telomeres can help you look younger, live longer and be healthier. Positive changes to the way we eat, exercise and relax may keep our telomeres healthy, slow cellular aging and the pop-up of chronic diseases. Today, medical science can raise menâs life expectancy to about 86-106 years, and womenâs 92-112 years based the current life expectancies at this time. Looking at other factors besides telomere shortening, oxidative stress and disease also contribute to human aging. Looking retrospectively at this century, the lifespan of both males and females has continued to increase dramatically over the years, and this would suggest that it will continue to move in an upward fashion. If the lifespan can be extended due to telomerase activity, as well as the absence of other factors it is hypothesized by Cawthon that the human lifespan could eventually reach 1,000 years. 67 Such future possibilities would create new problems like what to do with all the aging population! But this is an issue for another day.

Scientist Kaku discusses adopting telomere research to clinical medicine in the video below. Video Michio Kaku explains how to reverse aging Length = 4:37 mns 2 Wikipedia, Elizabeth Blackburn." Wiki: Blackburn 3 Southwestern University, "Facts about telomeres and telomerase," 2008. SWU: Teleform info 4 Wikipedia, "Hayflick limit." Wiki: Hayflick limit 5 Serrano, Antonio L. Vicente AndrÃ©s, "Review Telomeres and Cardiovascular Disease, Does Size Matter?" Circulation Research, February 4, 2004. Serrano: review CVD & telomeres 2004 6 Jaskelhoff Mariela, and others, "Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice," Nature, January 6, 2011;469(7328):102-6.

Jaskelhoff: Telomere reverses aging 2011 7 Willeit Peter and others, "Longitudinal Changes in Leukocyte Telomere Length and Mortality in Humans," J Gerontol A Biol Sci Med Sci, 2014: 69A (2): 231-239, first published online October 22, 2013. Willeit: telomere length & mortality 2014 8 Okereke OI, Prescott J, Wong JYY, Han J, Rexrode KM, et al., "High Phobic Anxiety Is Related to Lower Leukocyte Telomere Length in Women," PLoS ONE, 2012,7(7): e40516. doi:10.1371. Okereke: Anxiety lin telomeres 2012 9 Jaskelhoff Mariela, and others, "Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice," Nature, January 6, 2011;469(7328):102-6.

Jaskelhoff: Telomere reverses aging 2011 10 Wikgren M, Karlsson T, SÃ¶derlund H, Nordin A, Roos G, Nilsson LG, Adolfsson R, Norrback KF.,"Shorter telomere length is linked to brain atrophy and white matter hyperintensities," Age Ageing. November 14, 2013. Wikgren: Brain & telomeres 2013 11 Aida J. and others, "Telomere lengths in the oral epithelia with and without carcinoma," Eur J Cancer, January 2010;46(2):430-8. Aida: mouth cancers & telomeres 2010 12 Diehl Malissa C., "Elevated TRF2 in advanced breast cancers with short telomeres," Breast Cancer Res Treat, June 2011, 127(3): 623â630. Published online July 13, 2010.

Diehl: cancer elevated in short telomeres 2010 13 McGrath Monica, "Telomere Length, Cigarette Smoking, and Bladder Cancer Risk in Men and Women," Cancer Epidemiol Biomarkers Prev, April 2007. McGrath: smoking & telomeres 2007 14 Rampazzo E, and others, "Relationship between telomere shortening, genetic instability, and site of tumour origin in colorectal cancers," British Journal of Cancer, April 13, 2010. Rampazzo: colon cancer & telomeres 2010 15 Shen J, Gammon MD, Terry MB, Wang Q, Bradshaw P, Teitelbaum SL, Neugut AI, Santella RM., "Telomere length, oxidative damage, antioxidants and breast cancer risk," Int J Cancer, April 2009, 1;124(7):1637-43.

Shen: Antioxidants lengthen telomeres prevent cancer 2009 16 Carlquist John and others, "Telomere Length Predicts the Life Expectancy of Patients with Heart Disease," Intermountain Medical Center, SciTechDaily, March 11, 2013. Carlquist: telomere length heart disease 2013 17 Day Michael, "Shrinking telomeres linked to heart disease," New Scientist, January 12, 2007. Day: Telomeres linked to heart disease 2007 18 Farzaneh-Far R, et. al. âAssociation of Marine Omega-3 Fatty Acid Levels With Telomeric Aging in Patients With Coronary Heart Disease.â JAMA, 2010; 303(3): 250. Farzaneh-Far: Fatty-acids & telomeres 2010 19 Farzaneh-Far Ramin, Jue Lin, Elissa Epel, Kyle Lapham, Elizabeth Blackburn, Mary A.

Whooley," Telomere Length Trajectory and Its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study," PLoS ONE, January 08, 2010, 5(1): e8612. doi:10.1371. Farzaneh-Far: Telomere heart study 2010 "Heart disease, age, male sex, and abdominal obesity also independently predicted telomere shortening." 20 Serrano, Antonio L. Vicente AndrÃ©s, "Review Telomeres and Cardiovascular Disease, Does Size Matter?" Circulation Research, February 4, 2004. Serrano: review CVD & telomeres 2004 21 Terai M, Izumiyama-Shimomura N, et. al. "Association of Telomere Shortening in Myocardium With Heart Weight Gain and Cause of Death." Sci Rep. 2013;3:2401. Terai: telomere & death 2013 22 Willet P.

and others, "Cellular aging reflected by leukocyte telomere length predicts advanced atherosclerosis and cardiovascular disease risk," Arterioscler Thromb Basc biol, 2010;30:1649-56. Willet: cell age & telomere length 2010 23 Zee R, Michaud S, Germer S, Ridker P. ââAssociation of shorter mean telomere length with risk of incident myocardial infarction: a prospective, nested case-control approach.ââ Clin Chim Acta. 2009 May;403(1-2):139-41. Zee: Telomeres & heart attack 2009 24 Tulane Center for Cardiovascular Health, "Leukocyte telomere length is associated with HDL cholesterol levels: The Bogalusa heart study," Atherosclerosis, August 2009, 205(2):620-5.

Tulane: Cholesterol linked to tolomere 2009 25 Houben JM, Mercken EM, Ketelslegers HB, Bast A, Wouters EF, Hageman GJ, Schols AM., "Telomere shortening in chronic obstructive pulmonary disease," Respir Med, February 2009, 103(2):230-6 Houben: POD linked to telomeres 2009 26 Chunfang Wang, et al., "Insight Into Why Low Calorie Diet Can Extend Lifespan -- Even If Adopted Later in Life," British Society for Research on Ageing, July 2010. Chunfang Low Cal extend telomeres 2010 27 Farzaneh-Far R, et. al. âAssociation of Marine Omega-3 Fatty Acid Levels With Telomeric Aging in Patients With Coronary Heart Disease.â JAMA, 2010; 303(3): 250.

Farzaneh-Far: Fatty-acids & telomeres 2010 28 Cipriano C, et la., "Accumulation of cells with short telomeres is associated with impaired zinc homeostasis and inflammation in old hypertensive participantsm" J Gerontol A Biol Sci Med Sci. July 2009, 64(7):745-51. Cipriano: Zinc lengthens telomeres 2009 29 Masi S, Salpea KD, Li K, Parkar M, Nibali L, Donos N, Patel K, Taddei S, Deanfield JE, D'Aiuto F, Humphries SE., "Oxidative stress, chronic inflammation, and telomere length in patients with periodontitis. Free Radic Biol Med, March 2011, 15;50(6):730-5. Masi: inflammation, and telomere length 2011 30 Farzaneh-Far Ramin, Jue Lin, Elissa Epel, Kyle Lapham, Elizabeth Blackburn, Mary A.

Whooley," Telomere Length Trajectory and Its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study," PLoS ONE, January 08, 2010, 5(1): e8612. doi:10.1371. Farzaneh-Far: Telomere heart study 2010 31 GarcÃ­a-CalzÃ³n S and others, "Longitudinal association of telomere length and obesity indices in an intervention study with a Mediterranean diet: the PREDIMED-NAVARRA trial," International Journal of Obesity, 2014, 38, 177â182; doi:10.1038/ijo.2013.68; published online 28 May 2013.

GarcÃ­a-CalzÃ³n: obesity & telomeres 2014 32 Kim S, Parks CG, DeRoo LA, Chen H, Taylor JA, Cawthon RM, Sandler DP., "Obesity and weight gain in adulthood and telomere length," Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):816-20. doi: 10.1158/1055-9965.EPI-08-0935. Kim: Obesity & telomeres 2009 33 MartÃ­nez Paula, Gonzalo GÃ³mez-LÃ³pez, Fernando GarcÃ­a, Evi Mercken, Sarah Mitchell, Juana M. Flores, Rafael de Cabo, Maria A.

Blasco, "RAP1 Protects from Obesity through Its Extratelomeric Role Regulating Gene Expression," Cell Reports, 2013; DOI: 10.1016/j.celrep.2013.05.030 MartÃ­nez: 2013 Obesity & telomeres 34 Watfa G, Dragonas C, Brosche T, Dittrich R, Sieber CC, Alecu C, Benetos A, Nzietchueng R., "Study of telomere length and different markers of oxidative stress in patients with Parkinson's disease," J Nutr Health Aging, April 15, 2011. Watfa: Parkinson's disease & telomeres 2011 35 Farzaneh-Far Ramin, Jue Lin, Elissa Epel, Kyle Lapham, Elizabeth Blackburn, Mary A.

Whooley," Telomere Length Trajectory and Its Determinants in Persons with Coronary Artery Disease: Longitudinal Findings from the Heart and Soul Study," PLoS ONE, January 08, 2010, 5(1): e8612. doi:10.1371. Farzaneh-Far: Telomere heart study 2010 "Heart disease, age, male sex, and abdominal obesity also independently predicted telomere shortening." 36 Jaskelhoff Mariela, and others, "Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice," Nature, January 6, 2011;469(7328):102-6. Jaskelhoff: Telomere reverses aging 2011 37 McGrath Monica, "Telomere Length, Cigarette Smoking, and Bladder Cancer Risk in Men and Women," Cancer Epidemiol Biomarkers Prev, April 2007. McGrath: smoking & telomeres 2007 38 Epel, E.S., E.H.

Blackburn, J. Lin, F. Dhabar, N. Adler, J. Morrow, and R. Cawthon, "Accelerated telomere shortening in response to life stress, Proc Natl Acad Sci USA, 2004, 101: 17312-15. Epel: Stress & telomeres 2004 39 Malan S, Hemmings S, Kidd M, Martin L, Seedat S., "Investigation of telomere length and psychological stress in rape victims, Depress Anxiety, December 2011, 21;28(12):1081-5. [ Post traumatic stress ] Malan: Pysch stress & telomeres 2011 40 Dellara F. Terry, Vikki G. Nolan, Stacy L. Andersen, Thomas T. Perls and Richard Cawthon, "Association of Longer Telomeres With Better Health in Centenarians," The Journals of Gerontology: Series A May 13, 2008, Volume 63, Issue 8,Pp.

809-812. Dellara: longevity & telomeres 2008 41 Jaskelhoff Mariela, and others, "Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice," Nature, January 6, 2011;469(7328):102-6. Jaskelhoff: Telomere reverses aging 2011 42 Muzumdar Radhika and Gil Atzmon, "Telomere Length and Aging," Reviews on Selected Topics of Telomere Biology. Muzumdar: Telomere Length and Aging 43 Telomere Biosciences, "Telomere Biosciences Announces: TELO-100 with T-Activator 150, a Breakthrough in Telomere Science and Age Management," PRNewswire, November 21, 2013.

Telomere Biosciences: Nutraceutical telomerase 2013 44 Willeit Peter and others, "Longitudinal Changes in Leukocyte Telomere Length and Mortality in Humans," J Gerontol A Biol Sci Med Sci, 2014: 69A (2): 231-239, first published online October 22, 2013. Willeit: telomere length & mortality 2014 45 Ornish Dean, "Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study," The Lancet Oncology, October 2013, Volume 14, Issue 11, Pages 1112 - 1120. Ornish: Telomeres & life style 2013 46 Muzumdar Radhika and Gil Atzmon, "Telomere Length and Aging," Reviews on Selected Topics of Telomere Biology.

Muzumdar: Telomere Length and Aging 47 Ornish Dean, "Effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study," The Lancet Oncology, October 2013, Volume 14, Issue 11, Pages 1112 - 1120. Ornish: Telomeres & life style 2013 48 Telomere Biosciences, "Telomere Biosciences Announces: TELO-100 with T-Activator 150, a Breakthrough in Telomere Science and Age Management," PRNewswire, November 21, 2013. Telomere Biosciences: Nutraceutical telomerase 2013 53 Mercola, "Story at a glance," Mercola.com, May 09, 2012.

Mercola: Nutrition for long telomeres 54 Richards Byron J., "Nutrition makes anti-aging possible: secrets of your telomeres," NewsWithViews.com, December 10, 2013 Richards: telomere secrets 2013 55 Farzaneh-Far R, et. al. âAssociation of Marine Omega-3 Fatty Acid Levels With Telomeric Aging in Patients With Coronary Heart Disease.â JAMA, 2010; 303(3): 250. Farzaneh-Far: Fatty-acids & telomeres 2010 56 Fenech M., "Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity," Mutat Res., November 2011.

Fenech: Folate, vitamin B12 lenghten telomeres 2011 57 Paul L, Cattaneo M, D'Angelo A, Sampietro F, Fermo I, Razzari C, Fontana G, Eugene N, Jacques PF, Selhub J., "Telomere length in peripheral blood mononuclear cells is associated with folate status in men," J Nutr. July 2009, 139(7):1273-8. Paul: folic acid link telomeres 2009 58 Fenech M., "Folate (vitamin B9) and vitamin B12 and their function in the maintenance of nuclear and mitochondrial genome integrity," Mutat Res., November 2011.

Fenech: Folate, vitamin B12 lenghten telomeres 2011 59 Martin H, Uring-Lambert B, Adrian M, Lahlou A, Bonet A, Demougeot C, Devaux S, Laurant P, Richert L, Berthelot A., "Effects of long-term dietary intake of magnesium on oxidative stress, apoptosis and ageing in rat liver," Magnes Res, June 2008, 21(2):124-30. Martin: Mg deficience shorter telomeres 2008 60 Cipriano C, et la., "Accumulation of cells with short telomeres is associated with impaired zinc homeostasis and inflammation in old hypertensive participantsm" J Gerontol A Biol Sci Med Sci. July 2009, 64(7):745-51. Cipriano: Zinc lengthens telomeres 2009 61 Furumoto K, Inoue E, Nagao N, Hiyama E, Miwa N.

Age-dependent telomere shortening is slowed down by enrichment of intracellular vitamin C via suppression of oxidative stress. Life Sci. Decembe 1998 63(11):935-48. Furumoto: Vit C protects telomeres 1998 62 Chan Ruth, Jean Woo, Eddie Suen, Jason Leung and Nelson Tang, "Chinese tea consumption is associated with longer telomere length in elderly Chinese men," British Journal of Nutrition. January 2010, Volume 103/Issue 01, pp 107-113. Chan: tea lengthens telomeres 2010 63 Shen J, Gammon MD, Terry MB, Wang Q, Bradshaw P, Teitelbaum SL, Neugut AI, Santella RM., "Telomere length, oxidative damage, antioxidants and breast cancer risk," Int J Cancer, April 2009, 1;124(7):1637-43.

Shen: Antioxidants lengthen telomeres prevent cancer 2009 64 Fossel Michael, "Use of telomere length as a biomarker for aging and age-related disease," Current Translational Geriatrics and Experimental Gerontology Reports, June 10, 2013, Vol 1, Issue 2, pp. 121-127. Fossel: Telomere biomarkers 2012 65 Ericfein, "mortal Animals and the Human Link," WonderRecessive Health Science Technology, July 7, 2013. Ericfein immortal jellyfish, lobsters 2013 66 TA-65 doctor, "Telomerase Activation." TA-65 doctor bioclock 67 Siegal Lee J., "Are Telomeres the key to aging and cancer?" Genetic Science learning center, The University of Utah, January 2, 2006. Siegel: learning center 2006 Hydra has ability to live forever!

Although it is unknown precisely how hydra maintain their telomere length so impeccably, recent studies have revealed that a gene called FoxO, which has a direct influence on stem cells, is likely the answer. When FoxO activity is reduced in Hydra their powers wane and they suddenly show signs of aging. FoxO is also responsible for stem cell activity in humans. Greater FoxO activity is routinely found in people with abnormally long lifespans, like centenarians. It may be possible to increase FoxO activity from an early age, maintain levels of stem cells in the body, and thus increase human lifespan by 1000â²s of years; maybe even forever." 68 Cwynar Eva, Telomere testing, Cwynar: Telomere testing 69 Andrews Bill, and Jon Cornell, "Bill Andrews on Telomere Basics: CURING AGING," Sierra Sciences, 2010. Andrews: curing aging 2010 69 Cawthon, R. M., K. R. Smith, et al. .

"Association between telomere length in blood and mortality in people aged 60 years or older." Lancet, 2003, 361(9355): 393-5. Cawthon: death 7 telomeres 2003 70 Russo Juniper, "5 immortal animals," Voices Yahoo, January 6, 2011. Russo: Immortal animals 2011 71 Palmer Roxanne, "Immortal Jellyfish To Ageless Aspen Trees: Animals And Plants Who Found The Fountain Of Youth," International Business Times, January 07, 2013. Palmer: ageless trees 2013 72 Leaf & Limb Tree Service, "The Worldâs Oldest Trees," 2014. World's oldest trees 73 Wyatt Holly, "Longer Telomeres Through Healthy Living," Aegis, November 7, 2013.

Wyatt: exercise & telomeres 2013 Aging reversed in mice: Researchers gave lab mice a special compound [telomerase] that acted on a part of the DNA that activates a hidden part of the DNA to produce an enzyme called telomerase. The result was a reversal of all these signs of aging. The miceâs intelligence not only came back, but it reverted back to youthful status. The shrinkage of the brain reversed, their hair became shiny and thick again, and there eyesight returned. In addition, they became sexually active again and fertility returned. Jaskelhoff: Telomere reverses aging 2011 Base pairs: In human blood cells, the length of telomeres ranges from 8,000 base pairs at birth to 3,000 base pairs as people age and as low as 1,500 in elderly people. [ An entire chromosome has about 150 million base pairs.) ] Each time a cell divides, an average person loses 30 to 200 base pairs from the ends of that cell's telomeres.

Cells normally can divide only about 50 to 70 times, with telomeres getting progressively shorter until the cells become senescent, die or sustain genetic damage that can cause cancer. Telomeres do not shorten with age in tissues such as heart muscle in which cells do not continually divide. Bodnar, et al., "Extension of life-span by introduction of telomerase into normal human cells," Science, 1998. Calado Rodrigo and Neal Young "Telomeres in disease," The Scientist, May 1, 2012. Calado: Telomeres & disease 2012 "Telomere Timeline: In the 1930s, Hermann Muller and Barbara McClintock observed that fragmented chromosomes tended to fuse with each other, while normal chromosomes were stable, and they predicated characteristics of the ânatural endsâ to explain this difference.

Muller named these ends âtelomeres.â Almost 40 years later, Alexey Olovnikov, on theoretical grounds, and James Watson, based on phage experiments, recognized a fundamental problem regarding the mechanics of DNA replication, during which a small amount of genetic information is lost with every cell division. In the late 1970s, Elizabeth Blackburn and Joseph Gall discovered the structure of telomeresâshort, highly repetitive noncoding nucleotide sequencesâin the ciliated protozoanÂ Tetrahymena. In 1982, Blackburn and Jack Szostak elucidated how telomeres in yeast could serve as a buffer for the coding DNA during replication, and postulated the existence of an enzyme that could rebuild telomeresâan enzyme discovered by Blackburn and Carol Greider inÂ TetrahymenaÂ 3 years later. By 1988, the sequence of the human telomere was known, and researchers began actively investigating its role in aging and cancer. Subsequent work showed that the telomeres in certain proliferative cells are actively repaired.

For their work on telomeres, Blackburn, Greider, and Szostak were awarded the 2009 Nobel Prize in Physiology or Medicine. " Cassidy, Aedin et al., "Associations between diet, lifestyle factors, and telomere length in women," The American Journal of Clinical Nutrition, 2010, (1273-1280) Cassidy: lifestyle & telomeres 2010 Hayflick Limit: It was once believed that cell lines were immortal. But to reproduce, each successive generation of cells needs to unzip and copy all 46 chromosomes, giving each daughter a perfect copy. Leonard Hayflick discovered that non-stem (i.e. non-telomerase active) cells in a dish can only divide around 60 times before the telomeres become too short to survive. The limit on a cellâs maximum lifespan with respect to its descendants is known as its âHayflick Limit.â Because DNA is unzipped and copied from an original, complimentary strand, any daughter cellâs telomeres canât be longer than its motherâs and will actually be shortened each division.

This is known as â¦. Replicative Senescence. Â Highfield Roger, "How Henrietta's cells gave us new hope," The Telegraph, August 18, 2007. Highfield: cells living forever in lab 2007 "The study of cancer cells that never die has helped researchers better understand aging. Henrietta Lack's cancer cells HeLa have become standard medical lab tool for testing medications and so on." Horner J, Maratos-Flier E, Depinho R, et. al. âTelomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice.â Nature, January 6 2011;469(7328):102-6. Jaskelhoff: Telomere reverses aging 2011 How telomeres work: Telomere DNA has over 1000 bases [ building blocks ], with the sequence TTAGGG, that repeats over and over. In order to divide, a normal cell has to replicate all the DNA in its chromosomes. But normal cells have difficulty in copying the last few bases on the telomere.

As a result, the telomere shortens with each round of DNA replication and cell division. As a cell ages, the telomere keeps shortening until it reaches a finite length. At that point cells stop dividing. This halt in growth is triggered by a gene called p53 that is activated in response to DNA damage. A telomere that has become too short no longer protects the chromosome from DNA damage. When the damage takes place, p53 responds by stopping cell replication and forces it into senescence. Lamb Neil," Telomeres - the aglets of the genomic world," Hudson_Alpha Institute for biotechnology, 2009-10 Winter Lamb: Telomeres 2010 Makpol S, Durani LW, Chua KH, Mohd Yusof YA, Wan Ngah WZ., "Tocotrienol-rich fraction prevents cell cycle arrest and elongates telomere length in senescent human diploid fibroblasts," J Biomed Biotechnol, March 2011.

Makpol: Vit E ectends telomeres 2011 Noble prize in Physiology/Medicine in 2008 [ for the discovery of how chromosomes are protected by telomeres ]: Jack W. Zostak, Carol W. Greider, Elizabeth H. Blackburn O'Connor, C., "Telomeres of human chromosomes," Nature Education, 2001, 1(1):166. O'Connor: Telomere replication 2001 Papp Z, Czuriga D, Balogh L, Balogh Ã, BorbÃ©ly A., "How Cardiomyocytes Make The Heart Old." Curr Pharm Biotechnol," 2012;13(13):2515-21. Richards J Brent, "Higher serum vitamin D concentrations are associated with longer leukocyte telomere length in women," American Society for Clinical Nutrition, 2007.

Richards: Vit D lengthens telomeres 2007 Tomas, et al., "Telomerase Reverse Transcriptase Delays Aging in Cancer-Resistant Mice," Cell, November 14, 2008, 135, 609â622. Tomas: telomerase delays aging 2008 Willeit Peter, Willeit Johann, Mayr Anita, Weger Siegfried, Oberhollenzer Friedrich, BrandstÃ¤tter Anita, Kronenberg Florian, Kiechl Stefan, "Telomere length and risk of incident cancer and cancer mortality," JAMA 2010, 304 (1): 69â75. Willeit cancer & telomere lemgth2010 Wonga Liza S.M., Rudolf A. de Boera, Nilesh J. Samanib, Dirk J. van Veldhuisena and Pim van der Harsta, "Telomere biology in heart failure," European Journal of heart failure, 2008, 10 (11): 1049-1056.

Wonga: Telomeres & heart failure 2008 "There was a statistically significant inverse relationship between telomere length and both cancer incidence and mortality." Of Cells and Limits | The Scientist Magazine® Profile Of Cells and Limits Leonard Hayflick has been unafraid to speak his mind, whether it is to upend a well-entrenched dogma or to challenge the federal government. At 86, he’s nowhere near retirement. By Anna Azvolinsky | March 1, 2015 LEONARD HAYFLICK Adjunct Professor of Anatomy University of California, San Francisco© RAMIN RAHIMIANLeonard Hayflick learned to culture cells under the tutelage of a famous expert, Charles Pomerat. In 1958, after completing his fellowship in Pomerat’s lab, Hayflick became a member of the Wistar Institute in Philadelphia, providing cell cultures for its researchers. “It was a golden opportunity because it would leave me with plenty of time and resources to do what I wanted to do without worrying about getting grants or being subject to supervision.” Hayflick was interested in detecting viruses that might cause human cancer.

He would extract viruses from the culture fluid in which he grew cancer cells and attempt to transform normal cells into tumor cells. Human adult cells frequently contained unwanted viruses, so Hayflick obtained tissue from fetuses to use as a source of virus-free normal cells. He found that tissue from the lung, which is already a discrete organ by three months of embryonic development, was best for making fibroblast cell strains. “Like everyone else who did cell culture, I was persuaded to believe the 60-year-old dogma that when you culture cells, they have the capacity to divide forever. In practice, this never happened and people attributed their failure to ignorance of culturing methods, media formulation, and other things like the cleanliness of glassware.” “It is possible that the etiology of all age-associated diseases is in the molecular state that exists in old cells.” But Hayflick noticed a consistent pattern: in all 25 normal fetal cell strains he created, after about 50 population doublings, the cells were metabolically active but had stopped dividing. Together with cytogeneticist Paul Moorhead, he designed a simple but clever experiment to test whether the cells’ limited capacity to replicate in culture was caused by microbial contamination or some unknown culture condition.

It had recently been shown that female cells could be distinguished from male cells by the presence of Barr bodies formed from the inactive X chromosome in female cells. Hayflick mixed equal numbers of female cells that had divided 10 times with male cells that had doubled 40 times and found that after another 20 doublings of the mixed culture, only the female cells remained. “This showed that replication ceased not because of some extrinsic factor, but because of an intrinsic cell phenomenon—a revolutionary idea at the time.” Hayflick’s study was published in Experimental Cell Research in 1961, after first being rejected by another prominent journal—The Journal of Experimental Medicine. The rejection letter came from Francis Peyton Rous who received the Nobel Prize a few years later for his discovery of chicken tumor viruses.

“I can still quote from that letter: ‘Anyone who has worked with tissue culture knows that if the cells are provided with the proper milieu in vitro they will replicate indefinitely.’ He also called my suggestion that our observation suggests something about cellular senescence and aging ‘notably rash.’ ” The theory that all cells are generally immortal in culture was first postulated at the birth of cell culture in the early 1900s and was well publicized by Alexis Carrel of Rockefeller University in New York City who had developed a cell strain from chicken heart cells that he claimed had been growing for more than 40 years. After showing that normal cells are mortal, Hayflick also reported, for the first time, that cancer cells were uniquely immortal—a claim that could not be made without first establishing that normal cells are mortal. He also discovered that his normal human fetal cells had a memory. When fetal cells frozen at different population doublings were thawed, the cells remembered the doubling at which they had been frozen and only divided until they reached a total of 50 divisions. Hayflick’s work was criticized and he was ridiculed.

It took about 10 years for a more general acceptance that normal cells have a limited life span in vitro, a phenomenon now known as the Hayflick limit. The Nobel Prize–winning discovery of telomere shortening and the expression of telomerase explained Hayflick’s observations. Here, Hayflick talks about creating one of the most widely used cell strains, how he sued the federal government, and his discontent with the field of aging research. Hayflick Heads Out An explosive interest. Hayflick grew up in southwest Philadelphia and became interested in chemistry in elementary school, sparked by the gift of a Gilbert chemistry set. Hayflick made fireworks and rockets and experimented with heat and cold production. His mother encouraged him, even signing a permission statement that allowed Hayflick to purchase metallic sodium. With string, tin cans, water, and the sodium, he built rockets that traveled three to four stories into the air. College-bound. After completing high school in 1945, Hayflick was accepted by the University of Pennsylvania, but first enlisted and served 18 months in the US Army so he could help pay for college through the GI Bill. “That was a fortunate decision.

Had I not enlisted, I would have been drafted for the Korean War.” Building confidence. After majoring in microbiology at Penn, Hayflick worked for the Philadelphia-based pharmaceutical company Merck, Sharp and Dohme and then returned to Penn as a graduate student. While earning a master’s degree, Hayflick identified the first field isolate of a mycoplasma as the source of an ear infection in the rat colony at the adjoining Wistar Institute. A new type of culture. Hayflick studied the behavior of mycoplasmas in cell culture before it was known that these organisms are common, but often silent, contaminants of cell cultures. (See “ Out, Damned Mycoplasma! ,” The Scientist, December 2013.) “This was the first time that anyone purposefully put mycoplasmas into cell culture.” Hayflick Hits His Stride A popular cell strain. Hayflick cultured the famous WI-38 strain from fetal female lung tissue in 1962 and developed the technology to make poliovirus and other vaccines in this strain . By then, Hayflick was getting requests for his cells from all around the world.

WI-38 cells have been used to produce most of the world’s human virus vaccines, including those against adenoviruses, measles, rabies, chicken pox, mumps, rubella, polio, and hepatitis A. Hayflick gave WI-38 gratis to the world’s human virus vaccine manufacturers because, at that time, living cells could not be patented. But while Hayflick promoted the use of his cells for vaccine production, there was resistance, mainly from the National Cancer Institute and the precursor of the Food and Drug Administration’s vaccine-control authority, which made unfounded statements that using Hayflick’s cells would be dangerous because of their alleged potential to mutate and become cancerous. Mycoplasma expertise. As head of Wistar’s tissue-culture facility and an expert on mycoplasmas, colleagues would send Hayflick cell cultures to be tested for their presence. A visit from an NIH colleague got Hayflick working on “walking pneumonia,” known medically as primary atypical pneumonia, a common disease in young adults worldwide. Previously, researchers had been unsuccessful in isolating a virus as the etiological agent for this form of pneumonia.

From an egg yolk sample thought to contain the causative virus, Hayflick isolated a mycoplasm a that had not been described before and named it Mycoplasma pneumoniae. This was the first human disease shown to be caused by mycoplasmas, and it made the front page of The New York Times. Aging clock. After moving to Stanford University in 1968, Hayflick’s lab continued to investigate how human cells in culture maintain a memory of the number of divisions they have made. In 1975, he and his graduate student, Woodring Wright, showed that this counter was located in the nucleus . A lawsuit. “My development of WI-38 was done without government or private support and because of the great demand for WI-38 cells, I was awarded an NIH contract only to ‘store and distribute’ the cells.” When Hayflick moved to Stanford the contract ended, but the demand for WI-38 cultures continued. Hayflick began to charge $25—the same amount charged by the American Type Culture Collection at the time—to ship his cells, and put the funds into a holding account until a decision was made about disposition of those funds.

“This seemed to me to be reasonable, but some people at the NIH and the FDA interpreted this to be theft of government property, and that I was selling WI-38 for personal gain. They entered my lab in my absence and confiscated all of the frozen WI-38 ampoules.” Hayflick sued the federal government in 1975, claiming that the NIH had violated the Privacy Act of 1974 by releasing their findings before allowing him to reply and by illegally confiscating WI-38. “Who owns WI-38 or any other continuously dividing human cell culture is not easily settled. There are several stakeholders—the researchers who give the cells value, their institution, the individual from whom the cells are derived, and the organization that supports the research.” The suit was ultimately settled outside of court, at the request of the Justice Department, who found itself in an impossible position for a number of reasons. First, living cells were now patentable. Second, an executive order by President Reagan and the Bayh-Dole Act made it legal to use tax payer–supported research materials for commercial exploitation. Third, the emerging biotechnology industry was founded on materials developed in federally funded academic research labs.

If the government prevailed in Hayflick’s lawsuit, the biotech industry would be jeopardized, so industry lawyers prepared amicus briefs on Hayflick’s behalf should his case go to trial. Finally, the NIH itself was by now offering products made in their own laboratories for commercial use. As part of the settlement, Hayflick received some of the confiscated ampoules of WI-38 as well as the funds from mailing the WI-38 cultures. All of these funds went to pay his legal expenses. And Hayflick had supporters. After the settlement, a letter published in Science signed by 85 scientists stated that they objected to the behavior of the NIH and the FDA ( 215:240-42, 1982 ). According to Hayflick, his position that biologists, like other scientists, have intellectual property rights helped start a revolution in thinking, resulting in many biologists later becoming successful entrepreneurs. Due credit. Hayflick has been credited with starting the field of cellular biogerontology, the study of the aging of cells. His work set a new direction for aging research. “The focus had been on extracellular causes of aging such as stress or radiation.

I suggested that what I had found was teaching us something about the biology of aging, and the term senescence became widely used. My work refocused the field onto intracellular events as the etiology of aging,” he says. Hayflick Has a Say A matter of linguistics. “The term ‘research on aging’ has become muddled. Most scientists fail to understand that despite the fact that the ‘aging’ tag exists on their center, institute, or organization, most of the research is not on aging, but on age- associated diseases or longevity determinants. One problem that this linguistics issue creates is the diversion of more than 50 percent of the National Institute on Aging’s budget to Alzheimer’s disease research and less than 5 percent on the fundamental biology of aging. We should do Alzheimer’s research, but not at the expense of research on the fundamental biology of aging. For more than 50 years, aging research has meant research on age-associated diseases and this will tell us nothing about the cause of aging. It is remarkable to observe that a major medical concept that ‘the greatest risk factor for all age-associated diseases is aging’ has resulted in so little research on aging.

It is possible that the etiology of all age-associated diseases is in the molecular state that exists in old cells or cells near the end of their lineage. I’ve been vocal about this for 40 years. And as a consequence of that you don’t make too many friends. But I am more interested in the truth than making friends.” Longevity vs. aging. “Many confuse aging with longevity determination, which is indirectly driven by genes. There are no genes for aging. There are genes to maintain the biological functionality of an organism up to and including reproductive success. There is no mechanism that immediately causes death after reproductive maturation; it’s too costly. Longevity determination asks ‘Why do we live as long as we do?’ Aging research asks ‘Why does everything ultimately fail?’ and that is a huge difference.” Just the facts. Rebecca Skloot, author of The Immortal Life of Henrietta Lacks , had contacted Hayflick during her research for the book as he knew the personalities involved, including those who had originally cultured the HeLa cells. “Unfortunately, much of what I told her was hyped by her editors, as I’ll give her the benefit of the doubt. There are a lot of inaccuracies in the book.

One is the allegation that HeLa cells have saved lives and benefited the health of more people than any other cell population. That is false. WI-38 has benefited 2 billion people who have received vaccines made in these cells. Another is that HeLa cells were the first immortal cell population; that was L929 developed by Wilton Earle at the NIH nine years earlier. But this doesn’t take away from importance of the book. It raises the property rights and ownership issue of self-duplicating biological entities, which I have been addressing for 30 years.” Retirement? Hayflick continues to mentor, consult, write, lecture, organize conferences on aging, and travel to meetings. “I have not stopped doing anything except running a wet lab. I’ve never retired because I don’t know a definition of that word that applies. I have an enormous correspondence network worldwide, and I spend a lot of time keeping up with the scientific literature. I am also writing my autobiography.

My mother lived to be 106, so I am hopeful that I may have inherited some of her longevity determinants.” Greatest Hits Developed the first normal human diploid fibroblast cell strains such as WI-38 and the technology for producing vaccines against polio and other human viral diseases Discovered that normal human cells are mortal, have a memory located in the nucleus, and eventually become senescent. This finding is now called “the Hayflick limit” and is explained by telomere attrition. Discovered that cancer cells are immortal, now explained by the expression of the enzyme telomerase Discovered that “walking pneumonia” in humans is caused by a previously unknown species of mycoplasma Invented powdered cell-culture media and the first inverted microscope for viewing cell cultures Changed the thinking of biologists about their intellectual property rights Further Reading

Question: Named for a scientist who discovered it in 1961, what is the term for the number of times a normal cell population will divide before it stops?
Answer: Hayflick limit