SCIENCE LIBRARY

Peer-reviewed articles by leading researchers in the field of Telomere Biology, as presented in key scientific journals. Click on any of the topics below in the Index to read articles in each subject, or scroll down the pages to see all articles.

Subject Index:

1. Shortening Telomeres Cause Problems
2. Telomeres and Aging
3. Telomere Length and Lifespan
4. Telomerase Activation
5. Telomeres and the Immune System
6. Telomeres and Cardiovascular Health
7. Telomeres and Cancer
8. Telomere Lengths Measurements
9. Telomeres and Telomerase in the News, and General Articles

I. Shortening Telomeres Cause Problems:

Cell aging in relation to stress arousal and cardiovascular disease risk factors. (2006)
Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Psychoneuroendocrinology. 2006 Apr;31(3):277-87.

We previously reported that psychological stress is linked to and possibly accelerates cellular aging, as reflected by lower PBMC telomerase and shortened telomeres. Psychological stress is a major risk factor for cardiovascular disease (CVD), with multiple behavioral and physiological mediators. Telomere shortness has been associated with CVD, but the relationship between low telomerase activity, a potential precursor to telomere shortening, and CVD risk factors has not been examined in humans. Here we examine whether telomere length and telomerase in leukocytes are associated with physiological signs of stress arousal and CVD risk factors in 62 healthy women. Low telomerase activity in leukocytes was associated with exaggerated autonomic reactivity to acute mental stress and elevated nocturnal epinephrine. Further, low telomerase activity was associated with the major risk factors for CVD -smoking, poor lipid profile, high systolic blood pressure, high fasting glucose, greater abdominal adiposity-as well as to a composite Metabolic Syndrome variable. Telomere length was related only to elevated stress hormones (catecholamines and cortisol). Thus, we propose that low leukocyte telomerase constitutes an early marker of CVD risk, possibly preceding shortened telomeres, that results in part from chronic stress arousal. Possible cellular mechanisms by which low telomerase may link stress and traditional risk factors to CVD are discussed. These findings may implicate telomerase as a novel and important mediator of the effects of psychological stress on physical health and disease.
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Accelerated telomere shortening in response to life stress (2004)
Elissa S. Epel, Elizabeth H. Blackburn, Jue Lin, Firdaus S. Dhabhar, Nancy E. Adler, Jason D. Morrow, and Richard M. Cawthon

Numerous studies demonstrate links between chronic stress and indices of poor health, including risk factors for cardiovascular disease and poorer immune function. Nevertheless, the exact mechanisms of how stress gets "under the skin" remain elusive. We investigated the hypothesis that stress impacts health by modulating the rate of cellular aging. Here we provide evidence that psychological stress - both perceived stress and chronicity of stress - is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, which are known determinants of cell senescence and longevity, in peripheral blood mononuclear cells from healthy pre-menopausal women. Women with the highest levels of perceived stress have telomeres shorter on average by the equivalent of at least one decade of additional aging compared to low stress women. These findings have implications for understanding how, at the cellular level, stress may promote earlier onset of age-related diseases.
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Telomere length, stem cells and aging (2007)
Maria A Blasco, Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain. Published online 17 September 2007/ Nature Chemical Biology 2007.38

Telomere shortening occurs concomitant with organismal aging, and it is accelerated in the context of human diseases associated with mutations in telomerase, such as some cases of dyskeratosis congenita, idiopathic pulmonary fibrosis and aplastic anemia. People with these diseases, as well as Terc-deficient mice, show decreased lifespan coincidental with a premature loss of tissue renewal, which suggests that telomerase is rate-limiting for tissue homeostasis and organismal survival. These findings have gained special relevance as they suggest that telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. If this is true, stem cell dysfunction provoked by telomere shortening may be one of the mechanisms responsible for organismal aging in both humans and mice. Here, we will review the current evidence linking telomere shortening to aging and stem cell dysfunction.
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Telomere shortening and aging (2007)
H. Jiang, Z. Ju, K.L. Rudolph; Z Gerontol Geriat 40:314-324; 2007

Telomeres form the ends of human chromosomes. Telomeres shorten with each round of cell division and this mechanism limits proliferation of human cells to a finite number of cell divisions by inducing replicative senescence, differentiation, or apoptosis. Telomere shortening can act as a tumor suppressor. However, as a downside, there is growing evidence indicating that telomere shortening also limits stem cell function, regeneration, and organ maintenance during ageing. Moreover, telomere shortening during aging and disease is associated with increasing cancer risk. In this review we summarize our current knowledge on the role of telomere shortening in human ageing, chronic diseases, and cancer.
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Leukocyte Telomere Length and Cardiovascular Disease in the Cardiovascular Health Study (2007)
Annette L. Fitzpatrick, Richard A. Kronmal, Jeffrey P. Gardner, Bruce M. Psaty, Nancy S. Jenny, Russell P. Tracy, Jeremy Walston, Masyuki Kimura, and Abraham Aviv. American Journal of Epidemiology 2007; 165:14-21.

The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age ¼ 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio ¼ 3.08, 95% confidence interval: 1.22, 7.73) and stroke (hazard ratio ¼ 3.22, 95% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.
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Accelerated Telomere Erosion Is Associated with a Declining Immune Function of Caregivers of Alzheimer's Disease Patients (2007)
Amanda K. Damjanovic, Yinhua Yang, Ronald Glaser, Janice K. Kiecolt-Glaser, Huy Nguyen, Bryon Laskowski, Yixiao Zou, David Q. Beversdorf,_and Nan-ping Weng. The Journal of Immunology, 2007, 179: 4249-4254.

Caregivers of Alzheimer's disease patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, PBMC composition, in vitro activation- induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p < 0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF-_ and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 kb, respectively, p < 0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p < 0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T cell function and accelerated immune cell aging as suggested by excessive telomere loss.
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Evidence that Aging and Amyloid Promote Microglial Cell Senescence (2007)
Barry E. Flanary, Nicole W. Sammons, Cuong Nguyen, Douglas Walker, and Wolfgang J. Streit. REJUVENATION RESEARCH, Volume 10, Number 1, 2007

Advanced age and presence of intracerebral amyloid deposits are known to be major risk factors for development of neurodegeneration in Alzheimer's disease (AD), and both have been associated with microglial activation. However, the specific role of activated microglia in AD pathogenesis remains unresolved. Here we report that microglial cells exhibit significant telomere shortening and reduction of telomerase activity with normal aging in rats, and that in humans there is a tendency toward telomere shortening with presence of dementia. Human brains containing high amyloid loads demonstrate a significantly higher degree of microglial dystrophy than nondemented, amyloid-free control subjects. Collectively, these findings show that microglial cell senescence associated with telomere shortening and normal aging is exacerbated by the presence of amyloid. They suggest that degeneration of microglia is a factor in the pathogenesis of AD.
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OA May Be A Sign of Faster Biological Aging (2006)
Denise Mann Kleinman, CIAO Med

LONDON, UK- Patients with osteoarthritis (OA) were biologically about 11 years older than control subjects who were the same chronological age but did not have OA, according to new research on aging and arthritis.1 Guangju Zhai, MD, of St. Thomas' Hospital in London, UK and colleagues report that OA may actually be a marker for accelerated biological aging and that the telomere "molecular clock" in OA patients showed this effect even after the researchers controlled for obesity, age, sex, and smoking.
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Telomere length in human natural killer cell subsets. (2007)
Ouyang Q, Baerlocher G, Vulto I, Lansdorp PM. Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada, V5Z 1L3. Ann N Y Acad Sci. 2007 Jun;1106:240-52.

Natural killer (NK) cells are cytotoxic cells that play a critical role in the innate immune response against infections and tumors. In the elderly, the cytotoxic function of NK cells is often compromised. Telomeres progressively shorten with each cell division and with age in most somatic cells eventually leading to chromosomal instability and cellular senescence. We studied the telomere length in NK cell subsets isolated from peripheral blood using "flow FISH," a method in which the hybridization of telomere probe in cells of interest is measured relative to internal controls in the same tube. We found that the average telomere length in human NK cells decreased with age as was previously found for human T lymphocytes. Separation of adult NK cells based on CD56 and CD16 expression revealed that the telomere length was significantly shorter in CD56(dim)CD16(+) (mature) NK cells compared to CD56(bright)CD16(-) (immature) NK cells from the same donor. Furthermore, sorting of NK cells based on expression of activation markers, such as NKG2D and LFA-1, revealed that NK cells expressing these markers have significantly shorter telomeres. Telomere fluorescence was very heterogeneous in NK cells expressing CD94, killer inhibitory receptor (KIR), NKG2A, or CD161. Our observations indicate that telomeric DNA in NK cells is lost with cell division and with age similar to what has been observed for most other hematopoietic cells. Telomere attrition in NK cells is a plausible cause for diminished NK cell function in the elderly.
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The Association Between Physical Activity in Leisure Time and Leukocyte Telomere Length(2008)
Lynn F. Cherkas, PhD; Janice L. Hunkin, BSc; Bernet S. Kato, PhD; J. Brent Richards, MD; Jeffrey P. Gardner, PhD; Gabriela L. Surdulescu, MSc; Masayuki Kimura, MD, PhD; Xiaobin Lu, MD; Tim D. Spector, MD, FRCP; Abraham Aviv, MD; Arch Intern Med. 2008;168(2):154-158

Background: Physical inactivity is an important risk factor for many aging-related diseases. Leukocyte telomere dynamics (telomere length and age-dependent attrition rate) are ostensibly a biological indicator of human aging. We therefore tested the hypothesis that physical activity level in leisure time (over the past 12 months) is associated with leukocyte telomere length (LTL) in normal healthy volunteers.

Results: Leukocyte telomere length was positively associated with increasing physical activity level in leisure time (P_.001); this association remained significant after adjustment for age, sex, body mass index, smoking, socioeconomic status, and physical activity at work. The LTLs of the most active subjects were 200 nucleotides longer than those of the least active subjects (7.1 and 6.9 kilobases, respectively; P=.006). This finding was confirmed in a small group of twin pairs discordant for physical activity level (on average, the LTL of more active twins was 88 nucleotides longer than that of less active twins; P=.03).

Conclusions: A sedentary lifestyle (in addition to smoking, high body mass index, and low socioeconomic status) has an effect on LTL and may accelerate the aging process. This provides a powerful message that could be used by clinicians to promote the potentially antiaging effect of regular exercise.
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II. Telomeres and Aging:

Telomerase-based approaches to enhance immunity to viruses during ageing (2007)
Rita Effros Presentation Summary for SENS (Aubrey de Grey) Conference 6 Sept 2007
R.B. Effros David Geffen School of Medicine at UCLA, Department of Pathology and Laboratory Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA

The immune system plays a role not only in controlling infections, but also in certain age-related pathologies, such as atherosclerosis, osteoporosis, cancer and Alzheimer's disease. In humans, ageing is associated with the accumulation of high proportions of CD8 (cytotoxic) T lymphocytes with markers of replicative senescence, including inability to proliferate, altered cytokine profiles, absence of the critical co-stimulatory receptor, CD28, reduced anti-viral function, shortened telomeres and loss of telomerase inducibility. Most of these senescent CD8 T lymphocytes are specific for latent viruses acquired early in life, and thus, reflect the constant "work" required over many decades to keep these infections from re-emerging. Since high proportions of senescent CD8 T lymphocytes are correlated with such deleterious outcomes as early mortality in the very old, reduced responses to vaccines, immune suppression, and, in persons infected with HIV, accelerated progression to AIDS, our research has focused on strategies to prevent or retard the process of replicative senescence. In earlier work, we documented that gene transduction with the human telomerase catalytic component (hTERT) leads to enhanced proliferation, telomere length stabilization, and increased anti-viral immunity. Current experiments are testing small molecule telomerase activators, which would be more suitable for clinical use, for their effects on CD8 T lymphocyte biology. Our data demonstrate that exposure to TAT2, one of these activators, significantly enhances telomerase activity, increases the ability of T lymphocytes to control viral production, enhances proliferation, increases production of anti-viral cytokines/chemokines, and retards telomere loss. The enhanced telomerase activity is associated with increased hTERT gene transcription. These studies support the notion that therapeutic manipulation of telomerase in human T lymphocytes may provide novel clinical avenues to enhancing viral immunity and retarding the immune exhaustion associated with ageing. (These studies were supported by the National Institutes of Health, TA Therapeutics, Ltd, and Geron Corporation).

Telomerase induction in T cells: A cure for aging and disease? (2007)
Rita B. Effros, Experimental Gerontology, Volume 42, Issue 5, May 2007, 416-420.

Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8(+)CD28(-) T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation."

Telomere length, stem cells and aging (2007)
Maria A Blasco, Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain. Published online 17 September 2007/ Nature Chemical Biology 2007.38

Telomere shortening occurs concomitant with organismal aging, and it is accelerated in the context of human diseases associated with mutations in telomerase, such as some cases of dyskeratosis congenita, idiopathic pulmonary fibrosis and aplastic anemia. People with these diseases, as well as Terc-deficient mice, show decreased lifespan coincidental with a premature loss of tissue renewal, which suggests that telomerase is rate-limiting for tissue homeostasis and organismal survival. These findings have gained special relevance as they suggest that telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. If this is true, stem cell dysfunction provoked by telomere shortening may be one of the mechanisms responsible for organismal aging in both humans and mice. Here, we will review the current evidence linking telomere shortening to aging and stem cell dysfunction.
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Telomere shortening and aging (2007)
H. Jiang, Z. Ju, K.L. Rudolph; Z Gerontol Geriat 40:314-324; 2007

Telomeres form the ends of human chromosomes. Telomeres shorten with each round of cell division and this mechanism limits proliferation of human cells to a finite number of cell divisions by inducing replicative senescence, differentiation, or apoptosis. Telomere shortening can act as a tumor suppressor. However, as a downside, there is growing evidence indicating that telomere shortening also limits stem cell function, regeneration, and organ maintenance during ageing. Moreover, telomere shortening during aging and disease is associated with increasing cancer risk. In this review we summarize our current knowledge on the role of telomere shortening in human ageing, chronic diseases, and cancer.
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Shared environmental factors associated with telomere length maintenance in elderly male twins (2007)
Nazmul Huda, Hiromi Tanaka, Brittney-Shea Herbert, Terry Reed and David Gilley
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Aging Cell, 2007.

During aging, chromosome ends, or telomeres, gradually erode or shorten with each somatic cell division. Loss of telomere length homeostasis has been linked to age-related disease. Remarkably, specific environmental assaults, both physical and psychological, have been shown to correlate with shortened telomeres. However, the extent that genetic and/or environmental factors may influence telomere length during later stages of lifespan is not known. Telomere length was measured in 686 male US World War II and Korean War veteran monozygotic (MZ) and dizygotic (DZ) twins (including 181 MZ and 125 DZ complete pairs) with a mean age of 77.5 years (range 73-85 years). During the entire process of telomere length measurement, participant age and twin status were completely blinded. White blood cell mean telomere length shortened in this elderly population by 71 base pairs per year ( P <0.0001). We observed no evidence of heritable effects in this elderly population on telomere length maintenance, but rather find that telomere length was largely associated with shared environmental factors (P <0.0001). Additionally, we found that individuals with hypertension and cardiovascular disease had significantly shorter telomeres (P =0.0025 and 0.002, respectively). Our results emphasize that shared environmental factors can have a primary impact on telomere length maintenance in elderly humans. Key words: aging; environment; genetics; telomeres.
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Telomere Length in Different Tissues of Elderly Patients (2000)
Friedrich U, Griese E, Schwab M, Fritz P, Thon K, Klotz U Mech Ageing Dev. 2000;15:89-99

Telomeres are supposed to play a role in cellular aging and might contribute to the genetic background of human aging and longevity. During the past few years telomere length has been measured in various human tissues. However, very little is known about the individual telomere loss in different tissues from the same donor. Therefore we have measured telomere restriction fragment (TRF) length in three unrelated tissues (leukocytes, skin and synovial tissue) of nine elderly patients (age range 73-95 years old).

Dependent on the tissue specific proliferation rate we have found significantly shorter telomeres (6546±519 bp, mean±S.D.) in leukocytes compared to skin (7792±596 bp, P<0.01) and synovial tissue (7910±420 bp, P<0.001). In general, we have observed an inverse relationship between donor age and TRF length which becomes significant in leukocytes (P=0.04, R(2)=0.49) and skin specimens (P=0.006, R(2)=0.81). Interestingly, linear correlations (P values between 0.017 and 0.038, R(2) values between 0.54 and 0.79) were also obtained on comparison of telomere length in each pair of two different tissues from the same donor without taking donor age into account. This suggests that genetic determination of the regulation of telomere length is tissue-independent. Furthermore, our results indicate that TRF measurement in easily accessible tissues such as blood could serve as a surrogate parameter for the relative telomere length in other tissues.

Telomeres: Cancer to Human Aging (2006)
Sheila A. Stewart1 and ­ Robert A. Weinberg2,*
1 Departments of Cell Biology and Physiology and of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
2 Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142. Annu Rev Cell Dev Biol. 2006;22:531-57

The cell phenotypes of senescence and crisis operate to circumscribe the proliferative potential of mammalian cells, suggesting that both are capable of operating in vivo to suppress the formation of tumors. The key regulators of these phenotypes are the telomeres, which are located at the ends of chromosomes and operate to protect the chromosomes from end-to-end fusions. Telomere erosion below a certain length can trigger crisis. The relationship between senescence and telomere function is more complex, however: Cell-physiological stresses as well as dysfunction of the complex molecular structures at the ends of telomeric DNA can trigger senescence. Cells can escape senescence by inactivating the Rb and p53 tumor suppressor proteins and can surmount crisis by activating a telomere maintenance mechanism. The resulting cell immortalization is an essential component of the tumorigenic phenotype of human cancer cells. Here we discuss how telomeres are monitored and maintained and how loss of a functional telomere influences biological functions as diverse as aging and carcinogenesis.

Cellular senescence: when bad things happen to good cells
Judith Campis and Fabrizio d'Adda di Fagagna; Nature Reviews | Molecular Cell Biology Volume 8 | September 2007 | 729

Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.
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III. Telomere Length and Lifespan:

Telomere Length and Mortality: A Study of Leukocytes in Elderly Danish Twins(2008)
Masayuki Kimura, Jacob v. B. Hjelmborg, Jeffrey P. Gardner, Lise Bathum, Michael Brimacombe, Xiaobin Lu, Lene Christiansen, James W. Vaupel, Abraham Aviv, and Kaare Christensen; American Journal of Epidemiology Advance Access published February 12, 2008

Leukocyte telomere length, representing the mean length of all telomeres in leukocytes, is ostensibly a bioindicator of human aging. The authors hypothesized that shorter telomeres might forecast imminent mortality in elderly people better than leukocyte telomere length. They performed mortality analysis in 548 same-sex Danish twins (274 pairs) aged 73-94 years, of whom 204 pairs experienced the death of one or both co-twins during 9-10 years of follow-up (1997-2007). From the terminal restriction fragment length (TRFL) distribution, the authors obtained the mean TRFL (mTRFL) and the mean values of the shorter 50% (mTRFL50) and shortest 25% (mTRFL25) of TRFLs in the distribution and computed the mode of TRFL (MTRFL). They analyzed the proportions of twin pairs in which the co-twin with the shorter telomeres died first. The proportions derived from the intrapair comparisons indicated that the shorter telomeres predicted the death of the first co-twin better than the mTRFL did (mTRFL: 0.56, 95% confidence interval (CI): 0.49, 0.63; mTRFL50: 0.59, 95% CI: 0.52, 0.66; mTRFL25: 0.59, 95% CI: 0.52, 0.66; MTRFL: 0.60, 95% CI: 0.53, 0.67). The telomere-mortality association was stronger in years 3-4 than in the rest of the follow-up period, and it grew stronger with increasing intrapair difference in all telomere parameters.
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Telomere length predicts survival independent of genetic influences (2007)
Stephanie L. Bakaysa, Lorelei A. Mucci, P. Eline Slagboom, Dorret I. Boomsma, Gerald E. McClearn, Boo Johansson and Nancy L. Pedersen. Aging Cell, 2007.

Telomeres prevent the loss of coding genetic material during chromosomal replication. Previous research suggests that shorter telomere length may be associated with lower survival. Because genetic factors are important for individual differences in both telomere length and mortality, this association could reflect genetic or environmental pleiotropy rather than a direct biological effect of telomeres. We demonstrate through within-pair analyses of Swedish twins that telomere length at advanced age is a biomarker that predicts survival beyond the impact of early familial environment and genetic factors in common with telomere length and mortality. Twins with the shortest telomeres had a three times greater risk of death during the follow-up period than their co-twins with the longest telomere measurements [hazard ratio (RR) = 2.8, 95% confidence interval 1.1-7.3, P = 0.03].
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Telomere length is paternally inherited and is associated with parental lifespan. (2007)
Njajou OT, Cawthon RM, Damcott CM, Wu SH, Ott S, Garant MJ, Blackburn EH, Mitchell BD, Shuldiner AR, Hsueh WC. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):12135-9.

Telomere length (TL) is emerging as a biomarker for aging and survival. To evaluate factors influencing this trait, we measured TL in a large homogeneous population, estimated the heritability (h(2)), and tested for parental effects on TL variation. Our sample included 356 men and 551 women, aged 18-92 years, from large Amish families. Mean TL in leukocytes was measured by quantitative PCR (mean: 6,198 +/- 1,696 bp). The h(2) of TL was 0.44 +/- 0.06 (P < 0.001), after adjusting for age, sex, and TL assay batch. As expected, TL was negatively correlated with age (r = -0.40; P < 0.001). There was no significant difference in TL between men and women, consistent with our previous findings that Amish men lived as long as Amish women. There was a stronger and positive correlation and association between TL in the offspring and paternal TL (r = 0.46, P < 0.001; beta = 0.22, P = 0.006) than offspring and maternal TL (r = 0.18, P = 0.04; beta = -0.02, P = 0.4). Furthermore, we observed a positive correlation and association between daughter's TL and paternal lifespan (r = 0.20, P < 0.001; beta = 0.21, P = 0.04), but not between daughter's TL and maternal lifespan (r = -0.01, beta = 0.04; both P = not significant). Our data, which are based on one of the largest family studies of human TL, support a link between TL and aging and lifespan and suggest a strong genetic influence, possibly via an imprinting mechanism, on TL regulation.
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Change in the telomere length distribution with age in the Japanese population. (2007)
Guan JZ, Maeda T, Sugano M, Oyama J, Higuchi Y, Makino N. Mol Cell Biochem. 2007 Oct;304(1-2):353-60. Epub 2007 Jun 27.

Telomeres play a role in cellular aging and they may also contribute to the genetic basis of human aging and longevity. A gradual loss of the telomeric repeat sequences has been reported in adult tissue specimens. This study determined the percentage of telomere restriction fragment in various molecular-sized regions in addition to measuring the average telomere length. Mean telomere restriction fragment (TRF) length was determined by Southern blot analysis using a longer telomeric repeat probe with higher sensitivity. A significant decrease in longer telomere fragments and a quick increase in the shortest fragments were observed, especially in male subjects. There was a tendency that the age-adjusted telomere length was longer in females than that observed in males, while males lose the telomeric sequence faster than females. These data indicated that the percentage of longer telomeres fragments decreased, while the shortest fragments increased quickly with age. In addition, the longest telomere fragments decreased and the short fragments increased with a relatively stable frequency with age. There was also a significant difference in the longest telomere fragment percentage between males and female in their 40s and 50s, whereas no difference was observed in the mean TRF length. Interestingly, the changing rate of the longest and the shortest range group of TRF percentage associated with aging seemed quite different between before and after 50-year old with a gender-related contrast. This contrast implies a drastic change around the age of 50 of unknown factors that affect telomere attrition.
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Leukocytes of Exceptionally Old Persons Display Ultra-short Telomeres (2007)
Kimura M1, Barbieri M2, Gardner JP1, Skurnick J1, Cao X 1, van Riel N3, Rizzo MR2, Paoliso G3, Aviv A. Am J Physiol Regul Integr Comp Physiol (September 26, 2007).

With a view to understanding the association between leukocyte telomere length and the human lifespan, we performed genome-wide telomere length analyses by the terminal restriction fragment length (TRFL) and single molecule telomere length analysis (STELA) of the X and Y chromosomes in leukocytes of exceptionally old (aged 90-104 years) and younger (aged 23-74 years) individuals. We found that the mean TRFL of 82 exceptionally old individuals was within a range projected by age-dependent TRFL attrition of 99 younger individuals. However, compared with the younger individuals, exceptionally old persons exhibited peaking of the TRFL distribution with overrepresentation of ultra-short telomeres. These findings were confirmed by the STELA. Women had longer mean TRFL than men (6.10 kb vs. 5.86 kb) and exceptionally old women exhibited fewer ultra-short telomeres than exceptionally old men. Our results have implications for gerontological studies of the limitation of lifespan in humans.
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Telomeric DNA length in cerebral gray and white matter is associated with longevity in individuals aged 70 years or older (2007)
Ken-Ichi Nakamura, Kaiyo Takubo, Naotaka Izumiyama-Shimomura, Motoji Sawabe, Tomio Arai, Hiroshi Kishimoto, Mutsunori Fujiwara, Motonobu Kato, Mitsuo Oshimura, Akio Ishii, Naoshi Ishikawa. Experimental Gerontology, 2007.

Many studies have demonstrated the association between telomere length in mitotic cells and carcinogenesis and mortality, but little attention has been focused on post-mitotic cells and human life expectancy. We assessed the relationship between telomere length in cerebral gray and white matter and longevity in 72 autopsied Japanese patients aged 0-100 years using Southern blot hybridization. The mean telomere lengths in the gray and white matter were 12.3 ± 2.5 kilobase pairs and 11.4 ± 2.1 kilobase pairs, respectively. The mean telomere lengths in 60-69 year decadal group were less than those of neonates, and declined further in the 70-79-year age group, but those in groups of further advanced age were longer than in the 70-79 year group (70-79 < 80-89 < 90-100 years of age). Thus, the 90-100-year age group possessed significantly longer telomeres than the 70s (p = 0.029). Autopsy protocols showed a decrease in the rate of cancer death in individuals in their 80s (p = 0.041) and 90s (p = 0.017) versus those in their 60s, and in their 80s the mean telomere length in the gray matter from cancer death patients was significantly shorter than that of patients who died of other diseases (p = 0.04). These data suggest that innate telomere lengths are maintained very well in the cerebrum, and are associated with longevity. Our study lends indispensable support to the hypothesis that longer telomeres protect the genome from instability (a major cause of carcinogenesis) and are beneficial for longevity. © 2007 Elsevier Inc. All rights reserved. Keywords: Telomere length; Aging; Cerebral gray matter; Cerebral white matter; Southern blotting; Longevity; Life expectancy; Cancer death; Carcinogenesis
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Human telomerase reverse transcriptase (hTERT) extends the lifespan of canine chondrocytes in vitro without inducing neoplastic transformation (2007)
Iain P. Nicholson, Elizabeth A. Gault, Christopher G. Foote, Lubna Nasir, David Bennett. The Veterinary Journal, 2007.

To determine if the exogenous expression of the human telomerase reverse transcriptase (hTERT) protein can extend the in vitro lifespan of chondrocytes from normal and osteoarthritic canine donors, articular chondrocytes were harvested and expanded initially in monolayer culture. Cells were transfected with pCIneo or pCIneo-hTERT and selected using G418. Transfectants were cultured either in monolayer or alginate beads and telomerase activity, replicative lifespan and the tumourogenic potential of the transfected cells were assessed. hTERT expression in canine chondrocytes prolonged the replicative lifespan of these cells but did not permit growth in low serum conditions or promote the formation of foci in anchorage independence assays. In addition, hTERT expression resulted in the down-regulation of MMP-1. This suggests that hTERT may represent a tool for the generation of tissue engineered chondrocytes suitable for autologous re-implantation into the affected areas of osteoarthritic joints. © 2007 Elsevier Ltd. All rights reserved. Keywords: Osteoarthritis; Chondrocyte; Senescence; Telomere; Telomerase
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Association between telomere length in blood and mortality in people aged 60 years or older (2003)
Richard M Cawthon, Ken R Smith, Elizabeth O'Brien, Anna Sivatchenko, Richard A Kerber. The Lancet, February 1, 2003.

During normal ageing, the gradual loss of telomeric DNA in dividing somatic cells can contribute to replicative senescence, apoptosis, or neoplastic transformation. In the genetic disorder skeratosis congenita, telomere shortening is accelerated, and patients have premature onset of many age-related diseases and early death. We aimed to assess an association between telomere length and mortality in 143 normal unrelated individuals over the age of 60 years. Those with shorter telomeres in blood DNA had poorer survival, attributable in part to a 3·18-fold higher mortality rate from heart disease (95% CI1.36-7·45, p=0·0079), and an 8·54-fold higher mortality rate from infectious disease (1·52-47·9, p=0·015). These results lend support to the hypothesis that telomere shortening in human beings contributes to mortality in many age-related diseases.
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Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres. (2007)
Siegl-Cachedenier I, Flores I, Klatt P, Blasco MA. J Cell Biol. 2007 Oct 22;179(2):277-90.

Organ homeostasis and organismal survival are related to the ability of stem cells to sustain tissue regeneration. As a consequence of accelerated telomere shortening, telomerase-deficient mice show defective tissue regeneration and premature death. This suggests a direct impact of telomere length and telomerase activity on stem cell biology. We recently found that short telomeres impair the ability of epidermal stem cells to mobilize out of the hair follicle (HF) niche, resulting in impaired skin and hair growth and in the suppression of epidermal stem cell proliferative capacity in vitro. Here, we demonstrate that telomerase reintroduction in mice with critically short telomeres is sufficient to correct epidermal HF stem cell defects. Additionally, telomerase reintroduction into these mice results in a normal life span by preventing degenerative pathologies in the absence of increased tumorigenesis.
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IV. Telomerase Activation:

Telomerase-based approaches to enhance immunity to viruses during aging (2007)
Rita Effros Presentation Summary for SENS (Aubrey de Grey) Conference 6 Sept 2007
R.B. Effros David Geffen School of Medicine at UCLA, Department of Pathology and Laboratory Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA

The immune system plays a role not only in controlling infections, but also in certain age-related pathologies, such as atherosclerosis, osteoporosis, cancer and Alzheimer's disease. In humans, ageing is associated with the accumulation of high proportions of CD8 (cytotoxic) T lymphocytes with markers of replicative senescence, including inability to proliferate, altered cytokine profiles, absence of the critical co-stimulatory receptor, CD28, reduced anti-viral function, shortened telomeres and loss of telomerase inducibility. Most of these senescent CD8 T lymphocytes are specific for latent viruses acquired early in life, and thus, reflect the constant "work" required over many decades to keep these infections from re-emerging. Since high proportions of senescent CD8 T lymphocytes are correlated with such deleterious outcomes as early mortality in the very old, reduced responses to vaccines, immune suppression, and, in persons infected with HIV, accelerated progression to AIDS, our research has focused on strategies to prevent or retard the process of replicative senescence. In earlier work, we documented that gene transduction with the human telomerase catalytic component (hTERT) leads to enhanced proliferation, telomere length stabilization, and increased anti-viral immunity. Current experiments are testing small molecule telomerase activators, which would be more suitable for clinical use, for their effects on CD8 T lymphocyte biology. Our data demonstrate that exposure to TAT2, one of these activators, significantly enhances telomerase activity, increases the ability of T lymphocytes to control viral production, enhances proliferation, increases production of anti-viral cytokines/chemokines, and retards telomere loss. The enhanced telomerase activity is associated with increased hTERT gene transcription. These studies support the notion that therapeutic manipulation of telomerase in human T lymphocytes may provide novel clinical avenues to enhancing viral immunity and retarding the immune exhaustion associated with ageing. (These studies were supported by the National Institutes of Health, TA Therapeutics, Ltd, and Geron Corporation).

Telomerase induction in T cells: A cure for aging and disease? (2007)
Rita B. Effros, Experimental Gerontology, Volume 42, Issue 5, May 2007, 416-420.

Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8(+)CD28(-) T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation."

Cell aging in relation to stress arousal and cardiovascular disease risk factors. (2006)
Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Psychoneuroendocrinology. 2006 Apr;31(3):277-87.

We previously reported that psychological stress is linked to and possibly accelerates cellular aging, as reflected by lower PBMC telomerase and shortened telomeres. Psychological stress is a major risk factor for cardiovascular disease (CVD), with multiple behavioral and physiological mediators. Telomere shortness has been associated with CVD, but the relationship between low telomerase activity, a potential precursor to telomere shortening, and CVD risk factors has not been examined in humans. Here we examine whether telomere length and telomerase in leukocytes are associated with physiological signs of stress arousal and CVD risk factors in 62 healthy women. Low telomerase activity in leukocytes was associated with exaggerated autonomic reactivity to acute mental stress and elevated nocturnal epinephrine. Further, low telomerase activity was associated with the major risk factors for CVD -smoking, poor lipid profile, high systolic blood pressure, high fasting glucose, greater abdominal adiposity-as well as to a composite Metabolic Syndrome variable. Telomere length was related only to elevated stress hormones (catecholamines and cortisol). Thus, we propose that low leukocyte telomerase constitutes an early marker of CVD risk, possibly preceding shortened telomeres, that results in part from chronic stress arousal. Possible cellular mechanisms by which low telomerase may link stress and traditional risk factors to CVD are discussed. These findings may implicate telomerase as a novel and important mediator of the effects of psychological stress on physical health and disease.
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Telomerase Therapeutics for Degenerative Diseases (2005)
Calvin B. Harley, PhD., Geron Corporation, 230 Constitution Drive, Menlo Park, CA, USA, 94025. Current Molecular Medicine, 2005.

Telomerase is active in early embryonic and fetal development but is down-regulated in all human somatic tissues before birth. Since telomerase is virtually absent or only transiently active in normal somatic cells throughout postnatal life, telomere length gradually decreases as a function of age in most human tissues. Although telomerase repression likely evolved as a tumor suppressor mechanism, a growing body of evidence from epidemiology and genetic studies point to a role of telomerase repression and short telomeres in a broad spectrum of diseases: (a) Humans with shorter than average telomere length are at increased risk of dying from heart disease, stroke, or infection; (b) Patients with Dyskeratosis congenita are born with shortened telomeres due to mutations in telomerase components, suffer from a variety of proliferative tissue disorders, and typically die early of bone marrow failure; and (c) Individuals with long-term chronic stress or infections have accelerated telomere shortening compared to age-matched counterparts. Telomerase activation may prove useful in the treatment of diseases associated with telomere loss. While human cells dividing in culture lose telomeric DNA and undergo changes that mirror certain age- or disease-associated changes in vivo, telomerase transduced cells have extended replicative capacities, increased resistance to stress, improved functional activities in vitro and in vivo, and no loss of differentiation capacity or growth control. In addition, telomerase transduction in vivo can prevent telomere dysfunction and cirrhotic changes in liver of telomerase knockout mice. Thus, pharmacological activation of telomerase has significant potential for the treatment of a broad spectrum of chronic or degenerative diseases.
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Telomere length, stem cells and aging (2007)
Maria A Blasco, Telomeres and Telomerase Group, Molecular Oncology Program, Spanish National Cancer Centre, Madrid, Spain. Published online 17 September 2007/ Nature Chemical Biology 2007.38

Telomere shortening occurs concomitant with organismal aging, and it is accelerated in the context of human diseases associated with mutations in telomerase, such as some cases of dyskeratosis congenita, idiopathic pulmonary fibrosis and aplastic anemia. People with these diseases, as well as Terc-deficient mice, show decreased lifespan coincidental with a premature loss of tissue renewal, which suggests that telomerase is rate-limiting for tissue homeostasis and organismal survival. These findings have gained special relevance as they suggest that telomerase activity and telomere length can directly affect the ability of stem cells to regenerate tissues. If this is true, stem cell dysfunction provoked by telomere shortening may be one of the mechanisms responsible for organismal aging in both humans and mice. Here, we will review the current evidence linking telomere shortening to aging and stem cell dysfunction.
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Telomerase reverses epidermal hair follicle stem cell defects and loss of long-term survival associated with critically short telomeres. (2007)
Siegl-Cachedenier I, Flores I, Klatt P, Blasco MA. J Cell Biol. 2007 Oct 22;179(2):277-90.

Organ homeostasis and organismal survival are related to the ability of stem cells to sustain tissue regeneration. As a consequence of accelerated telomere shortening, telomerase-deficient mice show defective tissue regeneration and premature death. This suggests a direct impact of telomere length and telomerase activity on stem cell biology. We recently found that short telomeres impair the ability of epidermal stem cells to mobilize out of the hair follicle (HF) niche, resulting in impaired skin and hair growth and in the suppression of epidermal stem cell proliferative capacity in vitro. Here, we demonstrate that telomerase reintroduction in mice with critically short telomeres is sufficient to correct epidermal HF stem cell defects. Additionally, telomerase reintroduction into these mice results in a normal life span by preventing degenerative pathologies in the absence of increased tumorigenesis.
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Telomere and telomerase in stem cells
E Hiyama and K Hiyama, British Journal of Cancer (2007) 96, 1020-1024.

Telomeres, guanine-rich tandem DNA repeats of the chromosomal end, provide chromosomal stability, and cellular replication causes their loss. In somatic cells, the activity of telomerase, a reverse transcriptase that can elongate telomeric repeats, is usually diminished after birth so that the telomere length is gradually shortened with cell divisions, and triggers cellular senescence. In embryonic stem cells, telomerase is activated and maintains telomere length and cellular immortality; however, the level of telomerase activity is low or absent in the majority of stem cells regardless of their proliferative capacity. Thus, even in stem cells, except for embryonal stem cells and cancer stem cells, telomere shortening occurs during replicative ageing, possibly at a slower rate than that in normal somatic cells. Recently, the importance of telomere maintenance in human stem cells has been highlighted by studies on dyskeratosis congenital, which is a genetic disorder in the human telomerase component. The regulation of telomere length and telomerase activity is a complex and dynamic process that is tightly linked to cell cycle regulation in human stem cells. Here we review the role of telomeres and telomerase in the function and capacity of the human stem cells.
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V. Telomeres and the Immune System:

Telomerase-based approaches to enhance immunity to viruses during ageing (2007)
Rita Effros Presentation Summary for SENS (Aubrey de Grey) Conference 6 Sept 2007
R.B. Effros David Geffen School of Medicine at UCLA, Department of Pathology and Laboratory Medicine, 10833 Le Conte Avenue, Los Angeles, CA 90095-1732, USA

The immune system plays a role not only in controlling infections, but also in certain age-related pathologies, such as atherosclerosis, osteoporosis, cancer and Alzheimer's disease. In humans, ageing is associated with the accumulation of high proportions of CD8 (cytotoxic) T lymphocytes with markers of replicative senescence, including inability to proliferate, altered cytokine profiles, absence of the critical co-stimulatory receptor, CD28, reduced anti-viral function, shortened telomeres and loss of telomerase inducibility. Most of these senescent CD8 T lymphocytes are specific for latent viruses acquired early in life, and thus, reflect the constant "work" required over many decades to keep these infections from re-emerging. Since high proportions of senescent CD8 T lymphocytes are correlated with such deleterious outcomes as early mortality in the very old, reduced responses to vaccines, immune suppression, and, in persons infected with HIV, accelerated progression to AIDS, our research has focused on strategies to prevent or retard the process of replicative senescence. In earlier work, we documented that gene transduction with the human telomerase catalytic component (hTERT) leads to enhanced proliferation, telomere length stabilization, and increased anti-viral immunity. Current experiments are testing small molecule telomerase activators, which would be more suitable for clinical use, for their effects on CD8 T lymphocyte biology. Our data demonstrate that exposure to TAT2, one of these activators, significantly enhances telomerase activity, increases the ability of T lymphocytes to control viral production, enhances proliferation, increases production of anti-viral cytokines/chemokines, and retards telomere loss. The enhanced telomerase activity is associated with increased hTERT gene transcription. These studies support the notion that therapeutic manipulation of telomerase in human T lymphocytes may provide novel clinical avenues to enhancing viral immunity and retarding the immune exhaustion associated with ageing. (These studies were supported by the National Institutes of Health, TA Therapeutics, Ltd, and Geron Corporation).

Telomerase induction in T cells: A cure for aging and disease? (2007)
Rita B. Effros, Experimental Gerontology, Volume 42, Issue 5, May 2007, 416-420.

Clinical studies have shown that high proportions of CD8 T cells with the senescent phenotype correlate with several deleterious physiologic outcomes, including poor vaccine responses, bone loss, and increased proinflammatory cytokines. CD8(+)CD28(-) T cells have also been shown to exert suppressive activity on other immune cells. Based on the central role of telomere shortening in the replicative senescence program, we are developing several telomerase-based approaches as potential immunoenhancing treatments for aging and HIV disease. Gene therapy of HIV-specific CD8 T cells with the telomerase catalytic component (hTERT) results in enhanced proliferative capacity, increased anti-viral functions, and a delay in the loss of CD28 expression, with no changes in karyotype or growth kinetics. These proof-of-principle studies have led to screening for pharmacological approaches that might mimic the gene therapy effects, in a more clinically suitable formulation."

Accelerated Telomere Erosion Is Associated with a Declining Immune Function of Caregivers of Alzheimer's Disease Patients (2007)
Amanda K. Damjanovic, Yinhua Yang, Ronald Glaser, Janice K. Kiecolt-Glaser, Huy Nguyen, Bryon Laskowski, Yixiao Zou, David Q. Beversdorf,_and Nan-ping Weng. The Journal of Immunology, 2007, 179: 4249-4254.

Caregivers of Alzheimer's disease patients endure chronic stress associated with a decline of immune function. To assess the psychological and immunological changes of caregivers, we compared depressive symptoms, PBMC composition, in vitro activation- induced proliferation and cytokine production, and telomere length and telomerase activity of 82 individuals (41 caregivers and 41 age- and gender-matched controls). We found depressive symptoms were significantly higher in caregivers than in controls (p < 0.001). Correspondingly, caregivers had significantly lower T cell proliferation but higher production of immune-regulatory cytokines (TNF-_ and IL-10) than controls in response to stimulation in vitro. We examined the impact of these changes on cellular replicative lifespan and found that caregivers had significantly shorter telomere lengths in PBMC than controls (6.2 and 6.4 kb, respectively, p < 0.05) with similar shortening in isolated T cells and monocytes and that this telomere attrition in caregivers was not due to an increase of shorter telomere possessing T cell subsets in PBMC. Finally, we showed that basal telomerase activity in PBMC and T cells was significantly higher in caregivers than in controls (p < 0.0001), pointing to an unsuccessful attempt of cells to compensate the excessive loss of telomeres in caregivers. These findings demonstrate that chronic stress is associated with altered T cell function and accelerated immune cell aging as suggested by excessive telomere loss.
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Telomere length in human natural killer cell subsets. (2007)
Ouyang Q, Baerlocher G, Vulto I, Lansdorp PM. Terry Fox Laboratory, BC Cancer Research Centre, 675 West 10th Avenue, Vancouver, BC, Canada, V5Z 1L3. Ann N Y Acad Sci. 2007 Jun;1106:240-52.

Natural killer (NK) cells are cytotoxic cells that play a critical role in the innate immune response against infections and tumors. In the elderly, the cytotoxic function of NK cells is often compromised. Telomeres progressively shorten with each cell division and with age in most somatic cells eventually leading to chromosomal instability and cellular senescence. We studied the telomere length in NK cell subsets isolated from peripheral blood using "flow FISH," a method in which the hybridization of telomere probe in cells of interest is measured relative to internal controls in the same tube. We found that the average telomere length in human NK cells decreased with age as was previously found for human T lymphocytes. Separation of adult NK cells based on CD56 and CD16 expression revealed that the telomere length was significantly shorter in CD56(dim)CD16(+) (mature) NK cells compared to CD56(bright)CD16(-) (immature) NK cells from the same donor. Furthermore, sorting of NK cells based on expression of activation markers, such as NKG2D and LFA-1, revealed that NK cells expressing these markers have significantly shorter telomeres. Telomere fluorescence was very heterogeneous in NK cells expressing CD94, killer inhibitory receptor (KIR), NKG2A, or CD161. Our observations indicate that telomeric DNA in NK cells is lost with cell division and with age similar to what has been observed for most other hematopoietic cells. Telomere attrition in NK cells is a plausible cause for diminished NK cell function in the elderly.
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Telomere and adaptive immunity (2008)
Nan-ping Weng
Laboratory of Immunology, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Drive, Baltimore, MD 21224, United States; Mechanisms of Aging and Development 2008

The adaptive immune response relies on the ability of lymphocytes to undergo periodic massive expansion. It is an enigma how lymphocytes are able to undergo this seemingly unlimited number of cell divisions. Telomeres and telomerase play a critical role in regulation of the replicative lifespan of cells, providing a potential mechanism which lymphocytes may employ. Here I will review the recent progress of the role of telomeres and telomerase in lymphocyte differentiation, function, and aging.
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VI. Telomeres and Cardiovascular Health

Cell aging in relation to stress arousal and cardiovascular disease risk factors. (2006)
Epel ES, Lin J, Wilhelm FH, Wolkowitz OM, Cawthon R, Adler NE, Dolbier C, Mendes WB, Blackburn EH. Psychoneuroendocrinology. 2006 Apr;31(3):277-87.

We previously reported that psychological stress is linked to and possibly accelerates cellular aging, as reflected by lower PBMC telomerase and shortened telomeres. Psychological stress is a major risk factor for cardiovascular disease (CVD), with multiple behavioral and physiological mediators. Telomere shortness has been associated with CVD, but the relationship between low telomerase activity, a potential precursor to telomere shortening, and CVD risk factors has not been examined in humans. Here we examine whether telomere length and telomerase in leukocytes are associated with physiological signs of stress arousal and CVD risk factors in 62 healthy women. Low telomerase activity in leukocytes was associated with exaggerated autonomic reactivity to acute mental stress and elevated nocturnal epinephrine. Further, low telomerase activity was associated with the major risk factors for CVD -smoking, poor lipid profile, high systolic blood pressure, high fasting glucose, greater abdominal adiposity-as well as to a composite Metabolic Syndrome variable. Telomere length was related only to elevated stress hormones (catecholamines and cortisol). Thus, we propose that low leukocyte telomerase constitutes an early marker of CVD risk, possibly preceding shortened telomeres, that results in part from chronic stress arousal. Possible cellular mechanisms by which low telomerase may link stress and traditional risk factors to CVD are discussed. These findings may implicate telomerase as a novel and important mediator of the effects of psychological stress on physical health and disease.
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Leukocyte Telomere Length and Cardiovascular Disease in the Cardiovascular Health Study (2007)
Annette L. Fitzpatrick, Richard A. Kronmal, Jeffrey P. Gardner, Bruce M. Psaty, Nancy S. Jenny, Russell P. Tracy, Jeremy Walston, Masyuki Kimura, and Abraham Aviv. American Journal of Epidemiology 2007; 165:14-21.

The telomere length of replicating somatic cells is inversely correlated with age and has been reported to be associated cross-sectionally with cardiovascular disease (CVD). Leukocyte telomere length, as expressed by mean terminal restriction fragment (TRF) length, was measured in 419 randomly selected participants from the Cardiovascular Health Study, comprising a community-dwelling cohort recruited in four US communities. The authors investigated associations between TRF length and selected measures of subclinical CVD/risk factors for CVD (data were collected at the 1992/1993 clinic visit) and incident CVD (ascertained through June 2002). In these participants (average age ¼ 74.2 years (standard deviation, 5.2)), mean TRF length was 6.3 kilobase pairs (standard deviation, 0.62). Significant or borderline inverse associations were found between TRF length and diabetes, glucose, insulin, diastolic blood pressure, carotid intima-media thickness, and interleukin-6. Associations with body size and C-reactive protein were modified by gender and age, occurring only in men and in participants aged 73 years or younger. In younger (but not older) participants, each shortened kilobase pair of TRF corresponded with a threefold increased risk of myocardial infarction (hazard ratio ¼ 3.08, 95% confidence interval: 1.22, 7.73) and stroke (hazard ratio ¼ 3.22, 95% confidence interval: 1.29, 8.02). These results support the hypotheses that telomere attrition may be related to diseases of aging through mechanisms involving oxidative stress, inflammation, and progression to CVD.
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Telomere dysfunction in hypertension (2007)
Jose J. Fuster, Javier Diez and Vicente Andres. Journal of Hypertension, 25:2185-2192, 2007.

Aging is a major risk factor for hypertension and associated cardiovascular disease. In most proliferative tissues, aging is characterized by shortening of the DNA component of telomeres, the specialized genetic segments that cap the end of eukaryotic chromosomes and protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, telomere shortening is thought to contribute to organismal aging and to the development of age-related diseases. Here, we review animal and human studies that have investigated the possible links between telomere ablation and the pathogenesis of hypertension and related target organ damage. Although evidence is mounting that alterations in telomerase activity and telomere shortening may play a role in the pathogenesis of hypertension, additional studies are required to understand the molecular mechanisms by which telomere dysfunction and hypertension are functionally connected. As our knowledge on this emerging field grows, the challenge will be to ascertain whether all this information might translate into clinical applications.
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Paper Recasts Alzheimer's As Cardiovascular Disorder (2007)
 

A paper in the Jan. 16, 2007, issue of the Proceedings of the National Academy of Sciences casts Alzheimer's disease against type - as a cardiovascular disorder at its root. Reduced blood flow is a well-known symptom of Alzheimer's disease, but that is viewed as an effect of the disorder.
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The telomere-telomerase axis and the heart (2007)
Kajstura J, Rota M, Urbanek K, Hosoda T, Bearzi C, Anversa P, Bolli R, Leri A.
Cardiovascular Research Institute, Department of Medicine, New York Medical College, Valhalla, New York 10595, USA.

The preservation of myocyte number and cardiac mass throughout life is dependent on the balance between cell death and cell division. Rapidly emerging evidence indicates that new myocytes can be formed through the activation and differentiation of resident cardiac progenitor cells. The critical issue is the identification of mechanisms that define the aging of cardiac progenitor cells and, ultimately, their inability to replace dying myocytes. The most reliable marker of cellular senescence is the modification of the telomere-telomerase axis, together with the expression of the cell cycle inhibitors p16INK4a and p53. Cellular senescence is characterized by biochemical events that occur within the cell. In this regard, one of the most relevant processes is represented by repeated oxidative stress that may evolve into the activation of the cell death program or result in the development of a senescent phenotype. Thus, the modulation of telomerase activity and the control of telomeric length, together with the attenuation of the formation of reactive oxygen species, may represent important therapeutic tools in regenerative medicine and in prevention of aging and diabetic cardiomyopathies.
PMID: 17034355 [PubMed - in process]

Role of telomeres in vascular senescence.
Minamino T, Komuro I.:Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, 1-8-1 Inohana, Chuo-ku, Chiba, Japan. Front. Biosci. 2008 Jan 1;13:2971-9.

Telomeres are DNA regions composed of TTAGGG repeats that are located at the ends of chromosomes. Specific proteins associate with the telomeres and form non-nucleosomal DNA-protein complexes that serve as protective caps for the chromosome ends. There is accumulating evidence that progressive telomere shortening is closely related to cardiovascular disease. For example, vascular cell senescence has been reported to occur in human atherosclerotic lesions and this change is associated with telomere shortening. Impairment of telomere integrity causes vascular dysfunction, which is prevented by the activation of telomerase. Mice with short telomeres develop hypertension and exhibit impaired neovascularization. Short telomeres have also been reported in the leukocytes of patients with cardiovascular disease or various cardiovascular risk factors. Although it remains unclear whether short telomeres directly cause cardiovascular disease, manipulation of telomere function is potentially an attractive strategy for the treatment of vascular senescence.

Telomere length and replicative aging in human vascular tissues
EDWIN CHANG AND CALVIN B. HARLEY: Proc. Natl. Acad. Sci. USA Vol. 92, pp. 11190-11194, November 1995 Cell Biology

ABSTRACT Because repeated injury of the endothelium and subsequent turnover of intimal and medial cells have been implicated in atherosclerosis, we examined telomere length, a marker of somatic cell turnover, in cells from these tissues. Telomere lengths were assessed by Southern analysis of terminal restriction fragments (TRFs) generated by Hinfl/Rsa I digestion of human genomic DNA. Mean TRF length decreased as a function of population doublings in human endothelial cell cultures from umbilical veins, iliac arteries, and iliac veins. When endothelial cells were examined for mean TRF length as a function of donor age, there was a significantly greater rate of decrease for cells from iliac arteries than from iliac veins (102 bp/yr vs. 47 bp/yr, respectively, P < 0.05), consistent with higher hemodynamic stress and increased cell turnover in arteries. Moreover, the rate of telomere loss as a function of donor age was greater in the intimal DNA of iliac arteries compared to that of the internal thoracic arteries (147 bp/yr vs. 87 bp/yr, respectively, P < 0.05), a region of the arterial tree subject to less hemodynamic stress. This indicates that the effect is not tissue specific. DNA from the medial tissue of the iliac and internal thoracic arteries showed no significant difference in the rates of decrease, suggesting that chronic stress leading to cellular senescence is more pronounced in the intima than in the media. These observations extend the use of telomere size as a marker for the replicative history of cells and are consistent with a role for focal replicative senescence in cardiovascular diseases.
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VII. Telomeres and Cancer

Tumor-Induced Senescent T Cells with Suppressor Function: A Potential Form of Tumor Immune Evasion
Carolina L. Montes, Andrei I. Chapoval, Jonas Nelson, Vbenosa Orhue, Xiaoyu Zhang, Dan H. Schulze, Scott E. Strome, and Brian R. Gastman

Senescent and suppressor T cells are reported to be increased in select patients with cancer and are poor prognostic indicators. Based on the association of these T cells and poor outcomes, we hypothesized that tumors induce senescence in T cells, which negatively effects antitumor immunity. In this report, we show that human T cells from healthy donors incubated with tumor for only 6 h at a low tumor to T-cell ratio undergo a senescence-like phenotype, characterized by the loss of CD27 and CD28 expression and telomere shortening. Tumor-induced senescence of T cells is induced by soluble factors and triggers increases in expression of senescence-associated molecules such as p53, p21, and p16. Importantly, these T cells are not only phenotypically altered, but also functionally altered as they can suppress the proliferation of responder T cells. This suppression requires cell-to-cell contact and is mediated by senescent CD4+ and CD8+ subpopulations, which are distinct from classically described natural T regulatory cells. Our observations support the novel concept that tumor can induce senescent T cells with suppressor function and may effect both the diagnosis and treatment of cancer. [Cancer Res 2008;68(3):870-9]
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Telomerase is Not an Oncogene (2002)
Calvin B. Harley, Geron Corporation, Menlo Park, CA 94025, USA. Oncogene, 2002.

In the decade since the telomere hypothesis of cellular aging was proposed, the two essential genes for human telomerase were cloned and characterized, allowing experimental proof of the causal relationships between telomere loss and replicative senescence, and telomerase activation and immortalization. These relationships were established using a variety of cultured human cell types from both normal and tumor tissues, and were largely confirmed in the telomerase knockout mouse. Taken together, the data provide strong support for the potential utility of telomerase detection and inhibition for cancer, and telomerase activation for degenerative diseases.
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Telomere shortening and aging (2007)
H. Jiang, Z. Ju, K.L. Rudolph; Z Gerontol Geriat 40:314-324; 2007

Telomeres form the ends of human chromosomes. Telomeres shorten with each round of cell division and this mechanism limits proliferation of human cells to a finite number of cell divisions by inducing replicative senescence, differentiation, or apoptosis. Telomere shortening can act as a tumor suppressor. However, as a downside, there is growing evidence indicating that telomere shortening also limits stem cell function, regeneration, and organ maintenance during ageing. Moreover, telomere shortening during aging and disease is associated with increasing cancer risk. In this review we summarize our current knowledge on the role of telomere shortening in human ageing, chronic diseases, and cancer.
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Telomere Dysfunction: A Potential Cancer Predisposition Factor (2003)
J National Cancer Inst. 2003 Aug 20;95(16)1211-18. Wu X, Amos CI, et. al.

Conclusion: "Short telomeres appear to be associated with increased risks for human bladder, head and neck, lung, and renal cell cancers."

FISH-ing for links between cancer and aging (2007)
Jan Karlseder, Ph.D., assistant professor in Salk's Regulatory Biology Laboratory, assisted by graduate student Colleen Naeger in the Karlseder lab and Anna Jauch, Ph.D., and Heidi Holgreve-Grez, Ph.D., in Heidelberg

Wielding a palette of chromosome paints, scientists at the Salk Institute for Biological Studies have taken a step closer to understanding the relationship between aging and cancer by visualizing chromosomes of cells from patients with a heritable premature aging disease known as Werner Syndrome.
In a study to be published in this week's online edition of the Proceedings of the National Academy of Sciences researchers led by Jan Karlseder, Ph.D., assistant professor in Salk's Regulatory Biology Laboratory, showed that rebuilding structures called telomeres, which are found at the tips of each chromosome, significantly blocks the type of genetic damage seen in cells of patients with Werner Syndrome.
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Telomeres: Cancer to Human Aging (2006)
Sheila A. Stewart1 and ­ Robert A. Weinberg2,*
1 Departments of Cell Biology and Physiology and of Medicine, Washington University School of Medicine, St. Louis, Missouri 63110
2 Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142. Annu Rev Cell Dev Biol. 2006;22:531-57

The cell phenotypes of senescence and crisis operate to circumscribe the proliferative potential of mammalian cells, suggesting that both are capable of operating in vivo to suppress the formation of tumors. The key regulators of these phenotypes are the telomeres, which are located at the ends of chromosomes and operate to protect the chromosomes from end-to-end fusions. Telomere erosion below a certain length can trigger crisis. The relationship between senescence and telomere function is more complex, however: Cell-physiological stresses as well as dysfunction of the complex molecular structures at the ends of telomeric DNA can trigger senescence. Cells can escape senescence by inactivating the Rb and p53 tumor suppressor proteins and can surmount crisis by activating a telomere maintenance mechanism. The resulting cell immortalization is an essential component of the tumorigenic phenotype of human cancer cells. Here we discuss how telomeres are monitored and maintained and how loss of a functional telomere influences biological functions as diverse as aging and carcinogenesis.

Cellular senescence: when bad things happen to good cells
Judith Campis and Fabrizio d'Adda di Fagagna; Nature Reviews | Molecular Cell Biology Volume 8 | September 2007 | 729

Cells continually experience stress and damage from exogenous and endogenous sources, and their responses range from complete recovery to cell death. Proliferating cells can initiate an additional response by adopting a state of permanent cell-cycle arrest that is termed cellular senescence. Understanding the causes and consequences of cellular senescence has provided novel insights into how cells react to stress, especially genotoxic stress, and how this cellular response can affect complex organismal processes such as the development of cancer and ageing.
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VIII. Telomere Lengths Measurements

Flow cytometry and FISH to measure the average length of telomeres (flow FISH). (2006)
Baerlocher GM, Vulto I, de Jong G, Lansdorp PM Terry Fox Laboratory, British Columbia Cancer Agency, 675 West 10th Avenue, Vancouver, British Columbia, V5Z 1L3, Canada. . Nat Protoc. 2006;1(5):2365-76.

Telomeres have emerged as crucial cellular elements in aging and various diseases including cancer. To measure the average length of telomere repeats in cells, we describe our protocols that use fluorescent in situ hybridization (FISH) with labeled peptide nucleic acid (PNA) probes specific for telomere repeats in combination with fluorescence measurements by flow cytometry (flow FISH). Flow FISH analysis can be performed using commercially available flow cytometers, and has the unique advantage over other methods for measuring telomere length of providing multi-parameter information on the length of telomere repeats in thousands of individual cells. The accuracy and reproducibility of the measurements is augmented by the automation of most pipetting (aspiration and dispensing) steps, and by including an internal standard (control cells) with a known telomere length in every tube. The basic protocol for the analysis of nucleated blood cells from 22 different individuals takes about 12 h spread over 2-3 days.
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Telomere Length Measurements in Leukocyte Subsets by Automated Multicolor Flow-FISH (2003)
Gabriela M. Baerlocher1 and Peter M. Lansdorp. . Cytometry Part A 55A:1-6, 2003.

Telomeres are essential protein-DNA structures at the end of chromosomes which are implicated in genome stability and cell replication. The average length of telomere repeats can be measured by in situ hybridization and flow cytometry [flow-FISH]. Such telomere length values reflect telomere shortening (resulting from cell divisions, oxidative damage and other causes) and telomere elongation (mainly resulting from telomerase activity) of the chromosome-specific telomere length inherited in the gametes. Here we report improvements in flow-FISH methodology that enable measurements of telomere length in subsets of human nucleated blood cells. Methods and Results: In order to measure the telomere length in granulocytes, naive T cells, memory T cells, B cells and natural killer (NK)/NKT cells within a blood sample, we combined flow-FISH with antibody-staining (Multicolor flow-FISH). Most steps in the staining protocol were automated using a 96-well microdispenser device. The minimum detectable difference in telomere length and the reproducibility of the method are in the range of 0.2- 0.5 kb and measurements can be made with as few as a thousand cells.
Conclusions: Automated multicolor flow-FISH will greatly facilitate studies of telomere length regulation in subsets of nucleated blood cells, especially when only few cells are available and when differences in telomere length are small.
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Telomere measurement by quantitative PCR (2002)
Richard M. Cawthon, Department of Human Genetics, University of Utah, 15 N 2030 E, Room 2100, Salt Lake City, UT 84112, USA. Nucleic Acids Research, 2002, Vol. 30, No. 10 e47

It has long been presumed impossible to measure telomeres in vertebrate DNA by PCR amplification with oligonucleotide primers designed to hybridize to the TTAGGG and CCCTAA repeats, because only primer dimer-derived products are expected. Here we present a primer pair that eliminates this problem, allowing simple and rapidmeasurement of telomeres in a closed tube, fluorescence-based assay. This assay will facilitate investigations of the biology of telomeres and the roles they play in the molecular pathophysiology of diseases and aging.
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IX. Telomeres and Telomerase in the News, and General Articles

Lasker Laurels for telomerase (2006)
de Lange T.
Laboratory for Cell Biology and Genetics, The Rockefeller University, New York, NY 10021, USA.

This year the Lasker Foundation pays tribute to telomerase, a medically important enzyme required for chromosome stability and long-term cell proliferation.
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For More Reports of Telomere Biology in the News, click here.