Presentation on theme: "Resetting the Genetic Clock: Telomeres and Telomerase Promoters Dr. Al Sears."— Presentation transcript:
Resetting the Genetic Clock: Telomeres and Telomerase Promoters Dr. Al Sears
“The discovery of the function of telomeres and telomerase is the single MOST important discovery in the field of anti-aging medicine”
The relationship between telomeres and aging. The effect of shortened telomeres on age-related health conditions. Implications for anti-aging clinicians, including: Avoidance of factors that accelerate the loss of telomeres Currently available therapies that have been shown to slow the loss of the telomere. Telomerase activators as anti-aging therapy.
What Causes Aging? Leonard Hayflick: Cell division is a finite biological function and is inexorably tied to the aging process “Hayflick Number” describes the number of times a cell can divide Hayflick was the first to suggest the relationship between cell division and mortality, but the mechanism was not initially understood
End Replication Problem DNA polymerase can only synthesize DNA in the 5′ to 3′ direction, resulting in discontinuous replication of the lagging strand. Consequently, DNA synthesis does not extend to the very end of the lagging strand. In the absence of a protective mechanism, the end replication problem means vital genetic material (from the end of the lagging strand) would be lost during each cell division. Telomeres solve the end replication problem by protecting the cell from the loss of critical, coding base pairs.
What are Telomeres? First described in 1975 by Elizabeth Blackburn, who recently earned a Nobel Prize for her discovery. Telomeres are found at the end of all eukaryotic chromosomes The telomeres protect the chromosome from the replication-related loss of vital genetic information
Telomere Length as Marker for Aging There is an age-dependent attrition of telomere length, with losses ranging from between 30 and 150 nucleotide pairs per replication, depending on cell type. Cell division/telomere shortening continues until a critical telomere length is reached, at which point the cell is forced into senescence and can no longer replicate. Cellular senescence prevents replication of incomplete or damaged DNA. Harley CB, Futcher AB, Greider CW (1990) Telomeres shorten during ageing of human fibroblasts. Nature 345:458–460 Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R, Cohen D, Harley CB (1993) Loss of telomeric DNA during aging of normal and trisomy 21 human lymphocytes. Am J Hum Genet 52:661–667
Telomeres Tell Cells How Old They Are Telomeric mediation of gene expression may explain the relationship between telomere length and aging
DNA has Four Structural Levels Primary: the sequence of nucleotide bases Secondary: the interaction between base pairs as it forms the double-helix Tertiary: the structure of DNA in 3-dimensional space, as it wraps around histones. This structural level is partially mediated by steric effects Quaternary: the higher-level organization of DNA in chromatin
Telomeres May Affect All Four Structural Levels Primary and Secondary Structure Telomeres protect the integrity of the base pairs and preserve basic genetic information Tertiary and Quaternary Structure As telomeres shorten they may exert different steric/electronic effects, resulting in changes in the shape of DNA. These changes may, in turn, affect the genes exposed and available for transcription
Numerous studies have reported significant relationships between short telomeres and a variety of age-related health conditions.
Telomere Length & All-Cause Mortality Telomere length was assessed in 143 normal, unrelated men and women >60 years of age Individuals with the shortest telomeres had significantly decreased survival rates: 3.18-fold higher mortality rate from heart disease 8.54-fold higher mortality rate from infectious disease Cawthon RM, Smith KR, O'Brien E, Sivatchenko A, Kerber RA. Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 2003 Feb 1;361(9355):393-5.
Relationship Between Telomere Length and Age-Related Conditions T/S ratio * * = p<.05 Atzmon G, Cho M, Cawthon RM, Budagov T, et al. Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1710-7.
Telomere Length & Dementia – Nurses’ Health Study ▫62 women, > 70 years of age ▫Controlled for: age, education, smoking history, cardiovascular disease, hypertension, cholesterol levels, and diabetes ▫telomere length below the median: 12-times greater risk of being diagnosed with dementia 9.6-times greater risk of being diagnosed with mild cognitive impairment. Grodstein F, van Oijen M, Irizarry MC, Rosas HD, Hyman BT, Growdon JH, De Vivo I. Shorter telomeres may mark early risk of dementia: preliminary analysis of 62 participants from the nurses' health study. PLoS One. 2008 Feb 13;3(2):e1590. Relative telomere/single gene ratio
Telomere Length & Cardiovascular Disease 674 Caucasian males Measured mean telomere repeat copy number to single gene copy number (T/S ratio) Found that decreased T/S ratio was significantly associated with risk of MI log e -transformed T/S ratios Zee RY, Michaud SE, Germer S, Ridker PM. Association of shorter mean telomere length with risk of incident myocardial infarction: a prospective, nested case-control approach. Clin Chim Acta. 2009 May;403(1-2):139-41.
Telomere Length - a Crucial Health Indicator Telomere length is both: A marker for both cellular and organismic aging A predictor of age-related disease
Maintenance and Manipulation of Telomere Length Factors that accelerate telomere shortening Factors that slow telomere shortening Telomerase activators
Accelerating Telomere Shortening -- Homocysteine Multiple studies have shown that elevated homocysteine levels are associated with short telomeres. In one study, elevated homocysteine tripled the rate of shortening. Bull CF, O'Callaghan NJ, Mayrhofer G, Fenech MF. Telomere length in lymphocytes of older South Australian men may be inversely associated with plasma homocysteine. Rejuvenation Res. 2009 Oct;12(5):341-9. Richards JB, Valdes AM, Gardner JP, Kato BS, et al. Homocysteine levels and leukocyte telomere length. Atherosclerosis. 2008 Oct;200(2):271-7.
Accelerating Telomere Shortening - Stress Chronic stress has been shown to accelerate telomere shortening. After adjusting for age and various health/behavioral factors, women with the highest stress levels had the shortest telomeres. The degree of telomere shortening correlated to a minimum of a full decade of again Average T/S Ratio High Stress Low Stress Epel ES, Blackburn EH, Lin J, Dhabhar FS, Adler NE, Morrow JD, Cawthon RM. Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 2004 Dec 7;101(49):17312-5.
Slowing Telomere Shortening – Vitamin C Vitamin levels were assessed in 586 women aged 35-74 Analysis controlled for age, overall health, BMI, smoking, stress level, cardiovascular disease, and diabetes. Women in the 4th quartile of vitamin C intake had significantly longer telomeres relative to women in the 1 st quartile. 1 st Quartile4th Quartile Mean Telomere Length (BP) Xu Q, Parks CG, DeRoo LA, Cawthon RM, Sandler DP, Chen H. Multivitamin use and telomere length in women. Am J Clin Nutr. 2009 Jun;89(6):1857-63.
Slowing Telomere Shortening – Omega-3 P<.001 for linear trend across quartiles Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH, Whooley MA. Association of marine omega-3 fatty acid levels with telomeric aging in patients with coronary heart disease. JAMA. 2010 Jan 20;303(3):250-7.
Telomerase Telomerase is the enzyme responsible for re- building telomeres by adding nucleotide repeats (TTAGGG). Telomerase activity is observed in fetal tissue, adult germ cells, and tumor cells. Activity is nearly undetectable in somatic cells.
Activation of telomerase has been shown to reverse aging in cells, tissues and whole organisms
Telomerase Can “Immortalize” Cells Study published in the journal Science: ▫Human retinal pigment epithelial cells and foreskin fibroblasts, were transfected with vectors encoding the human telomerase catalytic subunit (hTERT). ▫Control cells showed telomere shortening, as well as normal levels of β- galactosidase, a marker of cellular senescence. ▫Telomerase+ transfected cells exhibited longer telomeres, and reduced levels of β-galactosidase. ▫By the time the study was published, the telomerase+ cells had exceeded their expected lifespan by 20+ replications. Bodnar AG, Ouellette M, Frolkis M, Holt SE, et al. Extension of life-span by introduction of telomerase into normal human cells. Science. 1998 Jan 16;279(5349):349-52.
Telomerase Can Restore Youthful Phenotypes in Live Tissue Normal human dermal fibroblasts were transfected with hTERT and then grafted onto mouse skin. Mice grafted with telomerase-negative control cells exhibited phenotypic signs of senescence (increased fragility, reduced levels of collagen I and III, and subepidermal blistering). Mice grafted with telomerase+ cells exhibited a youthful phenotype, despite the same number of replications. Funk WD, Wang CK, Shelton DN, Harley CB, Pagon GD, Hoeffler WK. Telomerase expression restores dermal integrity to in vitro-aged fibroblasts in a reconstituted skin model. Exp Cell Res. 2000 Aug 1;258(2):270-8.
Telomerase Can Restore Youthful Phenotypes in a Whole Organism A 2010 study in the journal Nature showed that telomerase activation in mice dramatically reversed the effects of aging. A restoration of youthful phenotypes was seen in in: Testes Spleen Liver Intestines. Additional effects of telomerase activation included: Restoration of fertility Reversal of cerebral atrophy Reactivation of neural progenitor cells Jaskelioff M, Muller FL, Paik JH, Thomas E, et al. Telomerase reactivation reverses tissue degeneration in aged telomerase-deficient mice. Nature. 2010 Nov 28
Telomerase Activity Predicts Longevity Multi-generational study of Ashkenazi Jews with exceptional longevity ▫Parent group (n = 86; average age of 97 years) ▫Offspring group (n = 175) ▫Control group (n = 93) Found that the population exhibited abnormally high telomerase activity, mediated by a mutation of hTERT – a catalytic subunit of telomerase. Results link longevity with telomerase activity Atzmon G, Cho M, Cawthon RM, Budagov T, et al. Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1710-7.
Telomerase Activation TA-65 ® A naturally-occurring, highly-purified single molecule derived from the Chinese herb Astragalus Activates the hTERT gene In-vitro: Moderately activated telomerase in human keratinocytes, fibroblasts, and immune cells In vivo: Administered as part of the PattonProtocol-1, with participants given 10-50 mg of TA-65 per day for 12-months Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, Raffaele JM. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 2011 Feb;14(1):45-56.
PattonProtocol-1:Results Following 1-year on protocol, researchers observed a significant decrease in the percent of critically-short telomeres.
PattonProtocol-1:Results Percent Change from Baseline Following 1-Year on PattonProtocol-1 Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs LA, Raffaele JM. A natural product telomerase activator as part of a health maintenance program. Rejuvenation Res. 2011 Feb;14(1):45-56. P=0.017
Additional Telomerase Activators are in Development Sierra Sciences Screened 254, 593 compounds Identified 858 telomerase inducers Most potent compound is at 15.89% of goal http://www.sierrasci.com/
Exercise Increases Telomerase Activity Murine model Voluntary running for 3 weeks Exercise induced: ▫A 2.9-fold increase in aortic telomerase activity and a ▫A 3.3-fold increase in telomerase activity in circulating mononuclear cells in the spleen Human model Compared to controls, professional athletes exhibited a: ▫2.5-fold increase in telomerase activity in young athletes ▫1.8-fold increase in telomerase activity in middle-aged athletes Werner C, Fürster T, Widmann T, Pöss J, et al. Physical exercise prevents cellular senescence in circulating leukocytes and in the vessel wall. Circulation. 2009 Dec 15;120(24):2438-47.
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