Age-associated changes in cardiac matrix and integrins

Burgess, Maria Lonnett; McCrea, Jennifer; Hedrick, Heather L.

doi:10.1016/s0047-6374(01)00296-2

Cited by 109 publications

(88 citation statements)

References 54 publications

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“…Some collagen family members were also up-regulated, including Type XV collagen alpha 1, Type VI collagen alpha 3, Type IV collagen alpha 1, and Type VI collagen alpha 2. These observations are consistent with previous findings that the aging heart undergoes ECM protein deposition (30), fibrosis (31), and cardiomyocyte hypertrophy (11).…”

Section: Aging Results In Expression Of Genes Encoding Structural Prosupporting

confidence: 93%

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Lee

Allison

Brand

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

289

218

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To provide a global analysis of gene expression in the aging heart, we monitored the expression of 9,977 genes simultaneously in 5-and 30-month-old male B6C3F1 mice by using high-density oligonucleotide microarrays and several statistical techniques. Aging was associated with transcriptional alterations consistent with a metabolic shift from fatty acid to carbohydrate metabolism, increased expression of extracellular matrix genes, and reduced protein synthesis. Caloric restriction (CR) started at 14 months of age resulted in a 19% global inhibition of age-related changes in gene expression. Interestingly, CR also resulted in alterations in gene expression consistent with preserved fatty acid metabolism, reduced endogenous DNA damage, decreased innate immune activity, apoptosis modulation, and a marked cytoskeletal reorganization. These observations provide evidence that aging of the heart is associated with specific transcriptional alterations, and that CR initiated in middle age may retard heart aging by inducing a profound transcriptional reprogramming.W hen started either early in life or at middle age, caloric restriction (CR) increases average and maximum lifespan, and reduces the incidence and delays the onset of spontaneous cancers and several other age-related diseases (1). Additionally, CR reduces the age-associated increase in reactive oxygen species (ROS)-induced molecular damage (2-5). Previously, we have used high-density oligonucleotide arrays to define aging and CR-related transcriptional alterations in mouse skeletal muscle (6) and brain (7). These reports provided evidence for an age-associated stress response characterized by the induction of heat-shock factors and other oxidative stress-induced transcripts. CR prevented these age-related alterations completely or partially. Both studies provided further support for the concept that oxidative stress may be an important, and perhaps underlying cause of the aging process of postmitotic tissues.The cardiac myocyte is the most energy demanding cell in the body, contracting constantly, 3 billion times or more in the average human lifespan (8), requiring large supplies of high-energy phosphates (9). Age-related changes in human and rodent hearts include a reduction in the number of myocytes (10, 11), myocyte hypertrophy (11, 12), cardiac fibrosis (13), lipofuscin pigment accumulation (14), a reduction in calcium transport across sarcoplasmic reticulum membrane (15), and alterations in the response to ␤-adrenergic stimulation (16). Collectively, these alterations likely contribute to age-related heart diseases being the leading cause of mortality in the U.S. (17). CR reduces the severity of spontaneous cardiomyopathy in male Sprague-Dawley rats (18) and prevents age-associated alterations in late diastolic function in B6D2F 1 mice (19). At the molecular level, CR reduces the concentration of both 8-hydroxydeoxyguanosine in DNA (20) and dityrosine cross-linking of proteins (21) in the heart of aging mice, and prevents somatic mitochondrial genomic rear...

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Section: Aging Results In Expression Of Genes Encoding Structural Prosupporting

confidence: 93%

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Lee

Allison

Brand

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

289

218

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“…We and others have previously reported that from middle-age and old-age (but not senescent), mice showed increases in wall thickness and LV mass, with no difference in ejection fraction (Burgess et al 2001;Slama et al 2004;Lindsey et al 2005;Rosa et al 2005). Age-related cardiac hypertrophy has also been demonstrated in middle-aged and old rats (Yin et al 1980;Besse et al 1993).…”

Section: Discussionmentioning

confidence: 69%

Age-related cardiac muscle sarcopenia: Combining experimental and mathematical modeling to identify mechanisms

Lin

Lopez

Jin³

et al. 2008

Experimental Gerontology

101

109

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Age-related skeletal muscle sarcopenia has been extensively studied and smooth muscle sarcopenia has been recently described, but age-related cardiac sarcopenia has not been previously examined. Therefore, we evaluated adult (7.5±0.5 months; n=27) and senescent (31.8±0.4 months; n=26) C57BL/6J mice for cardiac sarcopenia using physiological, histological, and biochemical assessments. Mice do not develop hypertension, even into senescence, which allowed us to decouple vascular effects and monitor cardiac-dependent variables. We then developed a mathematical model to describe the relationship between age-related changes in cardiac muscle structure and function. Our results showed that, compared to adult mice, senescent mice demonstrated increased left ventricular (LV) end diastolic dimension, decreased wall thickness, and decreased ejection fraction, indicating dilation and reduced contractile performance. Myocyte numbers decreased, and interstitial fibrosis was punctate but doubled in the senescent mice, indicating reparative fibrosis. Electrocardiogram analysis showed that PR interval and QRS interval increased and R amplitude decreased in the senescent mice, indicating prolonged conduction times consistent with increased fibrosis. Intracellular lipid accumulation was accompanied by a decrease in glycogen stores in the senescent mice. Mathematical simulation indicated that changes in LV dimension, collagen deposition, wall stress, and wall stiffness precede LV dysfunction. We conclude that age-related cardiac sarcopenia occurs in mice and that LV remodeling due to increased end diastolic pressure could be an underlying mechanism for age-related LV dysfunction.

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“…22,24 Connective tissue content and collagen cross-linking also decreased with endurance training. 25,26 Furthermore, exercise appears to have an antiapoptotic effect on myocytes that likely enhances chamber distensibility because myocytes are less stiff than collagen. 26,27 Thus, it is possible that lifelong endurance training may maintain myocyte volume and cell size and limit the development of fibrosis, thus preserving cardiac compliance.…”

Section: Physiologic Differences Between Ventricular Compliance and Rmentioning

confidence: 99%

The Effects of Aging and Physical Activity on Doppler Measures of Diastolic Function

Prasad

Popović

Arbab‐Zadeh

et al. 2007

The American Journal of Cardiology

152

157

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Healthy aging results in changes in Doppler measures of diastolic function. It is unclear whether these alterations are a specific manifestation of the aging process or reflect a cardiac adaptation to a more sedentary lifestyle. It was hypothesized that healthy, but sedentary, aging would result in slowing of diastolic filling and myocardial relaxation, whereas lifelong endurance training would prevent such changes. Doppler data were measured in young subjects and sedentary and fit seniors across a broad range of loading conditions. Thirteen sedentary healthy (70 ± 4 years) and 12 fit Masters athlete (68 ± 3 years) seniors were recruited. Twelve young healthy (32 ± 9 years) subjects were used for comparison. Pulmonary capillary wedge pressure and Doppler variables were measured at the 6 loading conditions of baseline (twice), -15 and -30 mm Hg lower body negative pressure, and 2 levels of saline solution infusion. Doppler variables consisted of early and late mitral inflow velocity (E/A) ratio, isovolumetric relaxation time (IVRT), tissue Doppler velocities (TDI E mean ), and propagation velocity of mitral inflow. Aging resulted in a decrease in E/A ratio (p <0.001), TDI E mean (p <0.001), and propagation velocity of mitral inflow (p <0.001) and an increase in IVRT (p = 0.001). Lifelong endurance training did not completely prevent the changes in E/A ratio (p = 0.212), IVRT (p = 0.546), or propagation velocity of mitral inflow (p = 1.00). Fit seniors were able to achieve E/A ratios of 1.0 during baseline and saline solution infusion. TDI E mean was higher in fit versus sedentary seniors at baseline (p = 0.012) and during maximal lower body negative pressure (p = 0.036), but not during saline solution infusion (p = 0.493). In conclusion, age-associated abnormalities in Doppler measures of myocardial filling and relaxation are only partially minimized by lifelong endurance training and therefore may be more specific to the aging process than secondary to years of deconditioning.Normal aging, even in the absence of co-morbidities, results in marked changes in Doppler measures of ventricular filling and relaxation, including reversal of the early and late mitral inflow velocities (decreased E/A ratio) and prolongation of isovolumetric relaxation time (IVRT). 1 These variables, although reproducible, have several limitations in their ability to accurately reflect diastolic function, including significant preload dependence and lack of specificity for dynamic relaxation processes. 2 In addition, it is unclear whether alterations in these Doppler variables with senescence are a specific manifestation of the aging process or reflect a secondary cardiac adaptation to a more sedentary lifestyle. Recently, our laboratory showed that static left ventricular stiffness markedly increased during healthy sedentary aging, whereas lifelong endurance training preserved static left ventricular compliance. 4 These data showed that ≥1 component of diastole, namely static chamber compliance, was significantly influenced by fit...

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Age-associated changes in cardiac matrix and integrins

Cited by 109 publications

References 54 publications

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Transcriptional profiles associated with aging and middle age-onset caloric restriction in mouse hearts

Age-related cardiac muscle sarcopenia: Combining experimental and mathematical modeling to identify mechanisms

The Effects of Aging and Physical Activity on Doppler Measures of Diastolic Function

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