1. Longevity and Lineages: Toward the Integrative Biology of Degenerative Diseases in Heart, Muscle, and Bone 
Kenneth R. Chien, Gerard Karsenty 
Cell 
Volume 120, Issue 4, Pages (February 2005)
DOI: /j.cell
Copyright © 2005 Elsevier Inc. Terms and Conditions

2. Figure 1
A Model for the Diversification of Atrial, Ventricular, and Conduction System Myocyte Lineages from Native Cardiac Progenitor Cells
During the earliest stages of in vivo cardiogenesis, islet-1, a LIM homeodomain transcription factor, marks the secondary heart field and identifies a group of cardiac progenitors that ultimately form the right side of the heart and the outflow tract. Cre recombinase-mediated lineage tracing in the mouse documents that these progenitors can ultimately give rise to both ventricular (MLC2-V+) and atrial cell lineages (sarcolipin+) (Cai et al., 2003). A rare subset of these islet-1 progenitors persists in the right side of the postnatalhearts of mouse, rat, and humans (Laugwitz et al., 2005). In the mouse, the islet-1 progenitor pool can be expanded on cardiac mesenchymal cell feeder layers that release a progenitor renewal factor (Laugwitz et al., 2005). The purified progenitors can spontaneously downregulate islet-1 expression and subsequently enter a fully differentiated ventricular cardiomyocyte phenotype. In addition, a subset of the progenitor-derived cardiomyocytes display spontaneous pacemaking activity, suggesting the possibility oftheir entry into a conduction system-like lineage (Laugwitz et al., 2005). This latter point remains to be formally proven by in vivo lineage tracing and direct measurement of pacemaker channel function (HCN+). Figure adapted from Laugwitz et al. (2005).
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3. Figure 2
The Aging Heart Phenotype: Selective Defects in Specific Cardiac Lineages
During the course of human aging, cardiac defects arise that reflect the influence of the aging process on distinct cell lineages. In the aging atrium, there is a marked increase in the onset of atrial fibrillation, an arrhythmia that is associated with the complete loss of organized atrial contraction. This loss of atrial contraction leads to pooling of blood in the atrium and the formation of blood clots that can give rise to embolic stroke, which is a major cause of cardiac morbidity in the elderly. In the ventricular chamber, there is an increased stiffness and tension, largely due to impairment of the activity of the cardiac calcium pump that triggers cardiac relaxation. This decrease in relaxation can promote the onset of heart failure, which is triggered by defects in calcium cycling (see text for details and references). In the cardiac conduction system, there can be a loss of regular pacemaker firing in the sinoatrial node that normally sets the heart beat, which can ultimately lead to a life-threatening slow heart rate (sick sinus syndrome) requiring electrical pacemaker implantation. In the aging atrioventricular node, there can be the onset of conduction system myocyte dropout and fibrosis that can lead to complete heart block, which also requires artificial pacemaker therapy.
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4. Figure 3
Mitochondrial Mutator Mice Validate the mtDNA Mutation Theory for Mammalian Aging
The generation of mice which harbor a mutation in the mitochondrial DNA polymerase PolgA displays a progressive increase in mitochondrial DNA mutations. These mutations ultimately lead to defects in mitochondrial respiratory function, even at relatively low mitochondrial mutational load. A number of premature aging phenotypes are found in these mice, including a form of cardiomyopathy that is found in the aging heart. (Figure adapted with the assistance of N. Larsson.)
Cell  , DOI: ( /j.cell )
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5. Figure 4
IGF-1 Signaling Pathways that Regulate Growth in the Normal and Aging Skeletal Muscle
(Figure adapted with the assistance and input of D. Glass). For details, see text.
Cell  , DOI: ( /j.cell )
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6. Figure 5
Schematic Representation of the Control of the Differentiation of Osteoclast Cell Lineages by Local Factors in Osteoblasts
Osteoblast cell lineages secrete three critical regulators. M-CSF acts as a survival factor for osteoclast progenitor following its binding to its receptor C.fms. RANK-Ligand (RANK-L) is an osteoclast differentiation factor that binds to its receptor RANK. In addition, osteoprotegerin (OPG), which is a soluble TNFα receptor, is a decoy receptor for RANK-L and therefore acts as a negative regulator of osteoclast differentiation.
Cell  , DOI: ( /j.cell )
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7. Figure 6 Known Systemic Regulators of Bone Formation
Parathyroid hormone (PTH) binds to its receptor (PPR) and induces bone formation through unknown mechanisms. The same is true for LRP5, a cellular coreceptor whose ligand may be Wnt protein. Two negative regulators of bone formation exist: thyroid stimulating hormone (TSH) and Norepinephrine (NE), a mediator of the sympathetic nervous system that binds to the β2 adrenergic receptor. Their mode of action on bone formation is currently unknown.
Cell  , DOI: ( /j.cell )
Copyright © 2005 Elsevier Inc. Terms and Conditions