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Journal ArticleDOI

The roles of senescence and telomere shortening in cardiovascular disease

01 May 2013-Nature Reviews Cardiology (Nat Rev Cardiol)-Vol. 10, Iss: 5, pp 274-283
TL;DR: The 'senescence-associated secretory phenotype' of senescent cells exerts a wide range of autocrine and paracrine activities aimed at tissue repair but which also fuel degenerative and proliferative alterations that contribute to cardiovascular disease.
Abstract: Cellular senescence, defined as arrest during the cell cycle (G₀), is involved in the complex process of the biological ageing of tissues, organs, and organisms. Senescence is driven by many factors including oxidative stress, the DNA damage and repair response, inflammation, mitogenic signals, and telomere shortening. Telomeres are shortened by each cell division until a critical length is reached and dysfunction ensues. DNA-repair pathways are then recruited and cells enter senescence, losing their capacity to proliferate. In addition to cell division, factors causing telomere shortening include DNA damage, inflammation, and oxidative stress. Both cardiovascular risk factors and common cardiovascular diseases, such as atherosclerosis, heart failure, and hypertension, are associated with short leucocyte telomeres, but causality remains undetermined. Telomere length does not satisfy strict criteria for being a biomarker of ageing, but adds predictive power to that of chronological age, and can be considered a marker of cardiovascular ageing. The 'senescence-associated secretory phenotype' of senescent cells exerts a wide range of autocrine and paracrine activities aimed at tissue repair, but which also fuel degenerative and proliferative alterations that contribute to cardiovascular disease. In this Review, the relationship between telomere shortening, senescence, and cardiovascular disease is discussed.
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Journal ArticleDOI
TL;DR: This review focuses on biochemical concepts of lipidPeroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting geneexpression and promoting cell death.
Abstract: Lipid peroxidation can be described generally as a process under which oxidants such as free radicals attack lipids containing carbon-carbon double bond(s), especially polyunsaturated fatty acids (PUFAs). Over the last four decades, an extensive body of literature regarding lipid peroxidation has shown its important role in cell biology and human health. Since the early 1970s, the total published research articles on the topic of lipid peroxidation was 98 (1970–1974) and has been increasing at almost 135-fold, by up to 13165 in last 4 years (2010–2013). New discoveries about the involvement in cellular physiology and pathology, as well as the control of lipid peroxidation, continue to emerge every day. Given the enormity of this field, this review focuses on biochemical concepts of lipid peroxidation, production, metabolism, and signaling mechanisms of two main omega-6 fatty acids lipid peroxidation products: malondialdehyde (MDA) and, in particular, 4-hydroxy-2-nonenal (4-HNE), summarizing not only its physiological and protective function as signaling molecule stimulating gene expression and cell survival, but also its cytotoxic role inhibiting gene expression and promoting cell death. Finally, overviews of in vivo mammalian model systems used to study the lipid peroxidation process, and common pathological processes linked to MDA and 4-HNE are shown.

3,647 citations


Cites background from "The roles of senescence and telomer..."

  • ...In addition to cell division, factors causing telomere shortening include DNA damage, inflammation, and oxidative stress [306]....

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Journal ArticleDOI
TL;DR: In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, respectively, and antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.
Abstract: Recent discoveries are redefining our view of cellular senescence as a trigger of tissue remodelling that acts during normal embryonic development and upon tissue damage. To achieve this, senescent cells arrest their own proliferation, recruit phagocytic immune cells and promote tissue renewal. This sequence of events - senescence, followed by clearance and then regeneration - may not be efficiently completed in aged tissues or in pathological contexts, thereby resulting in the accumulation of senescent cells. Increasing evidence indicates that both pro-senescent therapies and antisenescent therapies can be beneficial. In cancer and during active tissue repair, pro-senescent therapies contribute to minimize the damage by limiting proliferation and fibrosis, respectively. Conversely, antisenescent therapies may help to eliminate accumulated senescent cells and to recover tissue function.

1,830 citations

Journal ArticleDOI
TL;DR: In contrast, genetically determined short telomeres were associated with low cancer mortality but not with all-cause mortality, and long telomere-shortening alleles were not associated with cardiovascular, other, or all- cause mortality.
Abstract: Background: Short telomeres in peripheral blood leukocytes are associated with older age and age-related diseases. We tested the hypotheses that short telomeres are associated with both increased cancer mortality and all-cause mortality. Methods: Individuals (n = 64 637) were recruited from 1991 onwards from two Danish prospective cohort studies: the Copenhagen City Heart Study and the Copenhagen General Population Study. All had telomere length measured by quantitative polymerase chain reaction and the genotypes rs1317082 ( TERC), rs7726159 (TERT), and rs2487999 (OBFC1) determined. The sum of telomere-shortening alleles from these three genotypes was calculated. We conducted Cox regression analyses and instrumental variable analyses using the allele sum as an instrument. All statistical tests were twosided. Results: Among 7607 individuals who died during follow-up (0–22 years, median = 7 years), 2420 had cancer and 2633 had cardiovascular disease as causes of death. Decreasing telomere length deciles were associated with increasing allcause mortality ( P trend = 2*10–15 ). The multivariable-adjusted hazard ratio of all-cause mortality was 1.40 (95% confidence interval [CI] = 1.25 to 1.57) for individuals in the shortest vs the longest decile. Results were similar for cancer mortality and cardiovascular mortality. Telomere length decreased 69 base pairs (95% CI = 61 to 76) per allele for the allele sum, and the per-allele hazard ratio for cancer mortality was 0.95 (95% CI = 0.91 to 0.99). Allele sum was not associated with cardiovascular, other, or all-cause mortality. Conclusion: Short telomeres in peripheral blood leukocytes were associated with high mortality in association analyses. In contrast, genetically determined short telomeres were associated with low cancer mortality but not with all-cause mortality.

241 citations


Cites background from "The roles of senescence and telomer..."

  • ...Telomere length in leukocytes has been investigated as a potential biomarker for age-related diseases such as cardiovascular disease (4,5), chronic obstructive pulmonary disease (6–8), and diabetes (9,10)....

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Journal Article
TL;DR: In this article, the authors found that patients with chronic heart failure (CHF) have shorter telomeres compared with age-balanced and gender-balanced healthy individuals, and the median telomere length ratio was 0.64.
Abstract: OBJECTIVES This study sought to test the hypothesis that patients with chronic heart failure (CHF) have shorter telomeres compared with age-balanced and gender-balanced healthy individuals. BACKGROUND Telomere length is considered to be a marker of biological aging. Chronic heart failure might be viewed as a condition associated with accelerated biological aging. METHODS The telomere length ratio of leukocytes was determined prospectively by a quantitative polymerase chain reaction-based method in a case-control setting involving 803 participants: 183 healthy individuals and 620 CHF patients, ages 40 to 80 years, New York Heart Association functional class II to IV, and left ventricular ejection fraction of 0.40 or less. RESULTS The median telomere length ratio was 0.64 (interquartile range [IQR] 0.47 to 0.88) in CHF patients compared with 1.05 (IQR 0.86 to 1.29) in control patients (p < 0.001). The telomere length ratio in CHF patients related to severity of disease (median value [IQR] of patients with New York Heart Association class II, III, or IV function was 0.67 [0.48 to 0.92], 0.63 [0.46 to 0.86], and 0.55 [0.46 to 0.75], respectively; p for trend <0.05). In addition, telomeres were shorter in patients with an ischemic compared with a nonischemic etiology of CHF. Patients with none, 1 (coronary, cerebral, or peripheral vascular disease), 2 (any combination of the previous), or 3 atherosclerotic manifestations had a median (IQR) telomere length of 0.72 (0.51 to 1.01), 0.65 (0.48 to 0.87), 0.48 (0.39 to 0.72), and 0.43 (0.27 to 0.67), respectively (p for trend <0.001). CONCLUSIONS Telomere length is shorter in patients with CHF compared with age-balanced and gender-balanced control patients, and related to the severity of disease. In addition, telomere length was incrementally shorter according to the presence and extent of atherosclerotic disease manifestations.

235 citations

References
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Journal Article
Carol L. Baird1
TL;DR: A randomized controlled experiment is designed to test whether access to affordable day care (in the form of subsidies, for example) would incentivize Saudi mothers to search actively for employment and to remain employed once they are hired.
Abstract: This pilot aims to better understand the market for childcare in Saudi Arabia – both the supply and demand sides – and to design a randomized controlled experiment to test whether access to affordable day care (in the form of subsidies, for example) would incentivize Saudi mothers to search actively for employment and to remain employed once they are hired. In addition, the study seeks to understand the degree to which employment early on in one’s life impacts employment in later stages. The pilot will provide information on the groups of women the experiment should target, appropriate levels for the childcare subsidy, and the quality and current geographic locations of daycare sites. Expected Impact Determine the effects of facilitating childcare access on Saudi women’s employment. PRINCIPAL INVESTIGATORS  Boston University Patricia Cortes  Harvard University Claudia Goldin  Swarthmore College Jennifer Peck

9,609 citations

Journal ArticleDOI
03 Apr 2009-Science
TL;DR: The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.
Abstract: It has been difficult to establish whether we are limited to the heart muscle cells we are born with or if cardiomyocytes are generated also later in life. We have taken advantage of the integration of carbon-14, generated by nuclear bomb tests during the Cold War, into DNA to establish the age of cardiomyocytes in humans. We report that cardiomyocytes renew, with a gradual decrease from 1% turning over annually at the age of 25 to 0.45% at the age of 75. Fewer than 50% of cardiomyocytes are exchanged during a normal life span. The capacity to generate cardiomyocytes in the adult human heart suggests that it may be rational to work toward the development of therapeutic strategies aimed at stimulating this process in cardiac pathologies.

2,804 citations

Journal ArticleDOI
10 Nov 2011-Nature
TL;DR: Data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.
Abstract: Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

2,738 citations

Journal ArticleDOI
TL;DR: Evidence is provided that psychological stress--both perceived stress and chronicity of stress--is significantly associated with higher oxidative stress, lower telomerase activity, and shorter telomere length, in peripheral blood mononuclear cells from healthy premenopausal women.
Abstract: 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 premenopausal 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.

2,706 citations

Journal ArticleDOI
TL;DR: The current data argue that shelterin is emerging as a protein complex with DNA remodeling activity that acts together with several associated DNA repair factors to change the structure of the telomeric DNA, thereby protecting chromosome ends.
Abstract: Added by telomerase, arrays of TTAGGG repeats specify the ends of human chromosomes. A complex formed by six telomere-specific proteins associates with this sequence and protects chromosome ends. By analogy to other chromosomal protein complexes such as condensin and cohesin, I will refer to this complex as shelterin. Three shelterin subunits, TRF1, TRF2, and POT1 directly recognize TTAGGG repeats. They are interconnected by three additional shelterin proteins, TIN2, TPP1, and Rap1, forming a complex that allows cells to distinguish telomeres from sites of DNA damage. Without the protective activity of shelterin, telomeres are no longer hidden from the DNA damage surveillance and chromosome ends are inappropriately processed by DNA repair pathways. How does shelterin avert these events? The current data argue that shelterin is not a static structural component of the telomere. Instead, shelterin is emerging as a protein complex with DNA remodeling activity that acts together with several associated DNA repair factors to change the structure of the telomeric DNA, thereby protecting chromosome ends. Six shelterin subunits: TRF1, TRF2, TIN2, Rap1, TPP1, and POT1.

2,698 citations