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Aging Effects on Cardiac Progenitor Cell Physiology

Marcello Rota, Polina Goichberg, Piero Anversa, Annarosa Leri

10.1002/cphy.c140082

Source: Volume 5, Issue 4, October 2015

Published online: September 2015

Full Article on Wiley Online Library



ABSTRACT

Cardiac aging has been confounded by the concept that the heart is a postmitotic organ characterized by a predetermined number of myocytes, which is established at birth and largely preserved throughout life until death of the organ and organism. Based on this premise, the age of cardiac cells should coincide with that of the organism; at any given time, the heart would be composed of a homogeneous population of myocytes of identical age. The discovery that stem cells reside in the heart and generate cardiac cell lineages has imposed a reconsideration of the mechanisms implicated in the manifestations of the aging myopathy. The progressive alterations of terminally differentiated myocytes, and vascular smooth muscle cells and endothelial cells may represent an epiphenomenon dictated by aging effects on cardiac progenitor cells (CPCs). Changes in the properties of CPCs with time may involve loss of self‐renewing capacity, increased symmetric division with formation of daughter committed cells, partial depletion of the primitive pool, biased differentiation to the fibroblast fate, impaired ability to migrate, and forced entry into an irreversible quiescent state. Telomere shortening is a major variable of cellular senescence and organ aging, and support the notion that CPCs with critically shortened or dysfunctional telomeres contribute to myocardial aging and chronic heart failure. These defects constitute the critical variables that define the aging myopathy in humans. Importantly, a compartment of functionally competent human CPCs persists in the decompensated heart pointing to stem cell therapy as a novel form of treatment for the aging myopathy. © 2015 American Physiological Society. Compr Physiol 5:1775‐1814, 2015.

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Figure 1. Figure 1. Schematic representation of the major determinants of cellular and tissue aging. (A) Cellular senescence is mediated by several factors, including accumulation of cytoplasmic proteins, and alterations at the epigenetic and genomic DNA levels. These aspects, which are discussed in the text, are employed for the characterization of cellular age. SA‐β‐GAL, senescence‐associated β‐galactosidase; SAHF, senescence‐associated heterochromatin foci; SASP, senescence‐associated secretory phenotype; PML‐NBs, promyelocytic leukemia protein nuclear bodies; DDR, DNA damage response. (B) Effective removal of senescent cells induces the formation of new functionally competent cells with restoration of the steady state of the organ. However, this process is largely inefficient in old and pathologic tissues, leading to the accumulation of senescent cells, conditions the age of the organ and its performance.
Figure 2. Figure 2. Schematic representation of the telomerase‐telomere system. (A, B) The formation of D‐loops and T‐loops prevents the recognition of telomeres as DNA lesions. Telomere dysfunction may depend on the loss of the shelterin protein complex (A) and DNA erosion, which occurs as a consequence of cell division and oxidative stress (B).
Figure 3. Figure 3. Old hCPCs and replicative senescence. (A, B) Primary cultures of actively growing human CPCs (young) were subjected to serial passages (replicative senescence: old), or to doxorubicin exposure (stress‐induced senescence: old). Young and old human CPCs express c‐kit (green). Nuclei are stained with DAPI (blue). The expression of Ki67 (A: red) decreases and p16INK4a (B: red) increases in old human CPCs. Data are mean ± SD. Replicative senescence: * P = 0.009, † P = 0.04; stress‐induced senescence: * P < 0.0001, † P = 0.04 (adapted, with permission, from 118).
Figure 4. Figure 4. Old human CPCs and DNA damage. (A) DNA‐damage response (DDR) foci are identified in young (left) and old (right) hCPCs by coimmunolabeling for γH2A.X (green) and 53BP1 (red). Rectangles define areas illustrated at higher magnification in the insets. Phalloidin (gray) identifies the body of the cells. (B) Only hCPCs with ≥ 2 γH2A.X foci were included in the quantitative analysis. The percentage of hCPCs positive for γH2A.X foci increases in old hCPCs. Data are mean ± SD. Replicative senescence: § P = 0.02; Stress‐induced senescence: § P = 0.03 [from 118].
Figure 5. Figure 5. Schematic representation of CPC niches in the myocardium. The compartment of cardiac niches is functionally heterogeneous. In quiescent niches, the rarely dividing and highly undifferentiated state of CPCs is preserved. In active niches, CPCs undergo frequent asymmetric replication with formation of a daughter stem cell (self‐renewal) and a daughter cell committed to the myocyte fate.
Figure 6. Figure 6. In vivo inhibition of Notch 1 function induces a dilated myopathy. (A, B) B‐mode and M‐mode echocardiography of vehicle (left) and γ‐secretase inhibitor‐injected (right) mice. (C, D) γ‐Secretase inhibition leads to ventricular dilation, depressed fractional shortening and ejection fraction (C), and increased mortality (D). (E) With respect to a control heart (left panel), ventricular dilation and wall thinning are apparent in mice in which the Notch pathway was inhibited by administration of a γ‐secretase inhibitor (central and right panels). (F) Effects of γ‐secretase inhibition on cardiac anatomy. Results are mean ± SD * P < 0.05 (adapted, with permission, from 329).
Figure 7. Figure 7. Aging and wall stress. Changes in transmural circumferential wall stress during cardiac cycle as a function of age in 4‐, 12‐, 20‐, and 29‐month‐old male Fischer 344 rats. The total duration of stress for 4‐, 12‐, 20‐, and 29‐month‐old hearts was 1.1 × 106, 1.8 × 106, 2.6 × 106, and 3.9 × 106 cubic units, respectively. ENDO, endocardium; EPI, epicardium (adapted, with permission, from 57).
Figure 8. Figure 8. Aging and myocyte number in the human heart. (A, B) Effects of aging on the relative proportion of mononucleated (A) and binucleated (B) ventricular myocytes in women and men (adapted, with permission, from 247).
Figure 9. Figure 9. Aging and myocyte number. The bar graphs show aggregate number of myocyte nuclei in the left and right ventricles. Results are mean ± SD. * P < 0.05 versus the corresponding value in 4‐month‐old rats. *** P < 0.05 versus the corresponding value in 12‐month‐old rats. **** P < 0.05 versus the corresponding value in 20‐month‐old rats (adapted, with permission, from 14).
Figure 10. Figure 10. Acute and chronic myocardial infarcts. (A, B) Myocardial infarcts incompatible with survival. The large transverse myocardial sections illustrate the left ventricle (LV), interventricular septum (IS), and right ventricle (RV). Tissue necrosis is present in a large portion of the IS and in some areas of the anterior aspect of LV (arrowheads). Foci of myocardial scarring are also detected (*) (adapted, with permission, from 251). (C, D) Explanted heart in a patient undergoing cardiac transplantation. The large transverse myocardial sections illustrate a healed myocardial infarct with thinning of the wall (C, arrowheads) and multiple sites of replacement fibrosis in the noninfarcted viable tissue (D, arrowheads) (adapted, with permission, from 35).
Figure 11. Figure 11. Depressed Ca2+ transients in myocytes from the ischemic failing heart. Ca2+ transient properties in myocytes obtained from the heart of sham operated Sprague‐Dawley rats and rats subjected to coronary artery narrowing (CAN). Results are mean ± SD. * P < 0.05 (adapted, with permission, from 56).
Figure 12. Figure 12. Schematic representation of the components of cardiac niches. The niche resembles a randomly oriented ellipsoid structure located in an ill‐defined region of the interstitium. Within the niches, lineage‐negative CSCs are typically located in the center of the niches and are clustered together with early committed cells, progenitors, and precursors. Myocyte progenitors continue to express the c‐kit receptor but show nuclear localization of myocyte transcription factors, GATA‐4, Nkx2.5, and MEF2C, in the absence of specific cytoplasmic proteins. Myocyte precursors continue to express the c‐kit receptor but show nuclear localization of myocyte transcription factors together with cytoplasmic distribution of contractile proteins. Cells within the niches are connected by gap junctions. The extracellular matrix surrounding the niche is composed of several proteins, mostly fibronectin and α2 chain of laminin (adapted, with permission, from 194).
Figure 13. Figure 13. Connexin 43 in the human myocardium. Connexin 43 (white) defines the boundaries of cardiomyocytes (α‐SA, red). Nuclei are stained by DAPI, blue.
Figure 14. Figure 14. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).
Figure 15. Figure 15. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).
Figure 16. Figure 16. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).
Figure 17. Figure 17. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).
Figure 18. Figure 18. Properties of hypoxic and normoxic CPCs, and cardiomyocytes in the young and old mouse heart. (A) Hypoxic CPCs were recognized by positivity for the hypoxic probe pimonidazole. The distribution of telomere length is shown in hypoxic Pimonidazole‐positive (Pimopos) and normoxic Pimonidazole‐negative (Pimoneg) CPCs, and myocytes from young and old mice (adapted, with permission, from 282). (B) The preservation of CPC number within the niches may depend on the classic modality of self‐renewal or on a process of population replacement. In the first case (left), each niche constitutes an independent unit controlled by asymmetric division of CPCs with formation of a daughter stem cell that is retained within the niche and a daughter committed cell that leaves the niche area. In the second case (right), population replacement involves a mutual feedback between hypoxic and normoxic niches with exchange of primitive cells, replenishing depleted or dysfunctional niches.
Figure 19. Figure 19. SCF activates preferentially growth and differentiation of hypoxic CPCs in the old heart. (A) Distribution and average values of telomere length measured by Q‐FISH in BrdU‐positive (BrdU‐pos) and BrdU‐negative (BrdU‐neg) myocytes from mice injected with saline solution (PBS) or stem cell factor (SCF). Results are mean ± SD. * P < 0.05 versus BrdU‐neg myocytes, ** P < 0.05 versus BrdU‐pos myocytes treated with PBS. (B) Echocardiographic parameters in control (PBS, green bars) and SCF‐treated (yellow bars) mice. * P < 0.05 versus PBS. dLVD, diastolic left ventricular (LV) diameter; LVEDV, LV end‐diastolic volume; dAW, diastolic anterior wall thickness; dPW, diastolic posterior wall thickness; sLVD, systolic LF diameter; LVESV, LV end‐systolic volume; sAW, systolic anterior wall thickness; sPW, systolic posterior wall thickness; EF, ejection fraction; HR, heart rate. (C) Hemodynamic measurements in PBS‐injected (green bars) and SCF‐treated (yellow bars) mice. * P < 0.05 versus PBS. HR, heart rate; LVSP, LV left ventricular systolic pressure; LVEDP, LV end‐diastolic pressure; LVDevP, LV developed pressure. (D) Diastolic anterior (P < 0.008) and posterior (P < 0.008) wall stress decreased by 56% in SCF‐treated old mice. Systolic anterior and posterior wall stress decreased 45% (P < 0.004) and 43% (P < 0.006), respectively. LV mass‐to‐chamber volume ratio increased 84% in diastole (P < 0.003) and 2.2‐fold in systole (P < 0.04) (adapted, with permission, from 282).
Figure 20. Figure 20. SCF activates preferentially growth and differentiation of hypoxic CPCs in the old heart. (A) Distribution and average values of telomere length measured by Q‐FISH in BrdU‐positive (BrdU‐pos) and BrdU‐negative (BrdU‐neg) myocytes from mice injected with saline solution (PBS) or stem cell factor (SCF). Results are mean ± SD. * P < 0.05 versus BrdU‐neg myocytes, ** P < 0.05 versus BrdU‐pos myocytes treated with PBS. (B) Echocardiographic parameters in control (PBS, green bars) and SCF‐treated (yellow bars) mice. * P < 0.05 versus PBS. dLVD, diastolic left ventricular (LV) diameter; LVEDV, LV end‐diastolic volume; dAW, diastolic anterior wall thickness; dPW, diastolic posterior wall thickness; sLVD, systolic LF diameter; LVESV, LV end‐systolic volume; sAW, systolic anterior wall thickness; sPW, systolic posterior wall thickness; EF, ejection fraction; HR, heart rate. (C) Hemodynamic measurements in PBS‐injected (green bars) and SCF‐treated (yellow bars) mice. * P < 0.05 versus PBS. HR, heart rate; LVSP, LV left ventricular systolic pressure; LVEDP, LV end‐diastolic pressure; LVDevP, LV developed pressure. (D) Diastolic anterior (P < 0.008) and posterior (P < 0.008) wall stress decreased by 56% in SCF‐treated old mice. Systolic anterior and posterior wall stress decreased 45% (P < 0.004) and 43% (P < 0.006), respectively. LV mass‐to‐chamber volume ratio increased 84% in diastole (P < 0.003) and 2.2‐fold in systole (P < 0.04) (adapted, with permission, from 282).
Figure 21. Figure 21. IGF‐1 overexpression ameliorates the functional properties of aging myocytes. (A) Representative tracings illustrating peak shortening and velocity of shortening and relengthening, Ca2+ transients, and L‐type Ca2+ current in myocytes from wild type (WT) and IGF‐1 overexpressing (TG) mice. (B) Quantitative data are shown as mean ± SD. *,† P < 0.05 versus animals at 10 to 12 months and WT mice, respectively (adapted, with permission, from 325).
Figure 22. Figure 22. IGF‐1 overexpression ameliorates the functional properties of aging myocytes. (A) Representative tracings illustrating peak shortening and velocity of shortening and relengthening, Ca2+ transients, and L‐type Ca2+ current in myocytes from wild type (WT) and IGF‐1 overexpressing (TG) mice. (B) Quantitative data are shown as mean ± SD. *,† P < 0.05 versus animals at 10 to 12 months and WT mice, respectively (adapted, with permission, from 325).
Figure 23. Figure 23. Schematic representation of the IGF‐1‐Akt‐telomerase axis. Mouse model in which the expression of insulin‐like growth factor 1 (IGF‐1) is driven by the myocyte restricted α‐myosin heavy chain (α‐MHC) promoter. Binding of IGF‐1 to the IGF‐1 receptor (IGF‐1R) results in phosphorylation of PI‐3 kinase (PI3K), which, in turn, phosphorylates and activates Akt kinase. Phosphorylated Akt binds to a consensus site in the telomerase protein enhancing its catalytic activity and promoting telomere elongation.
Figure 24. Figure 24. Nuclear targeted Akt and myocyte mechanics. (A) Traces of unloaded myocyte shortening at 1‐Hz pacing rate. (B) Average parameters of myocyte contraction for wild‐type mice (WT) and mice overexpressing α‐MHC‐nuclear Akt (TG) are shown as mean ± SEM. (C) Ca2+ transients in myocytes paced at 1 Hz and superimposed traces. (D) Ca2+ transient properties for WT and TG are shown as mean ± SEM (adapted, with permission, from 273).
Figure 25. Figure 25. Schematic representation of the effects of stromal‐derived factor 1 (SDF‐1) on CPCs. Myocardial ischemia is characterized by an increased expression of SDF‐1, which binds to CXCR4 in CPCs promoting their migration from the niches and homing in the border zone. Activation of the SDF‐1‐CXCR4 system in CPCs results in engraftment and proliferation of CPCs in proximity of the infarct, ultimately promoting vascular regeneration.


Figure 1. Schematic representation of the major determinants of cellular and tissue aging. (A) Cellular senescence is mediated by several factors, including accumulation of cytoplasmic proteins, and alterations at the epigenetic and genomic DNA levels. These aspects, which are discussed in the text, are employed for the characterization of cellular age. SA‐β‐GAL, senescence‐associated β‐galactosidase; SAHF, senescence‐associated heterochromatin foci; SASP, senescence‐associated secretory phenotype; PML‐NBs, promyelocytic leukemia protein nuclear bodies; DDR, DNA damage response. (B) Effective removal of senescent cells induces the formation of new functionally competent cells with restoration of the steady state of the organ. However, this process is largely inefficient in old and pathologic tissues, leading to the accumulation of senescent cells, conditions the age of the organ and its performance.


Figure 2. Schematic representation of the telomerase‐telomere system. (A, B) The formation of D‐loops and T‐loops prevents the recognition of telomeres as DNA lesions. Telomere dysfunction may depend on the loss of the shelterin protein complex (A) and DNA erosion, which occurs as a consequence of cell division and oxidative stress (B).


Figure 3. Old hCPCs and replicative senescence. (A, B) Primary cultures of actively growing human CPCs (young) were subjected to serial passages (replicative senescence: old), or to doxorubicin exposure (stress‐induced senescence: old). Young and old human CPCs express c‐kit (green). Nuclei are stained with DAPI (blue). The expression of Ki67 (A: red) decreases and p16INK4a (B: red) increases in old human CPCs. Data are mean ± SD. Replicative senescence: * P = 0.009, † P = 0.04; stress‐induced senescence: * P < 0.0001, † P = 0.04 (adapted, with permission, from 118).


Figure 4. Old human CPCs and DNA damage. (A) DNA‐damage response (DDR) foci are identified in young (left) and old (right) hCPCs by coimmunolabeling for γH2A.X (green) and 53BP1 (red). Rectangles define areas illustrated at higher magnification in the insets. Phalloidin (gray) identifies the body of the cells. (B) Only hCPCs with ≥ 2 γH2A.X foci were included in the quantitative analysis. The percentage of hCPCs positive for γH2A.X foci increases in old hCPCs. Data are mean ± SD. Replicative senescence: § P = 0.02; Stress‐induced senescence: § P = 0.03 [from 118].


Figure 5. Schematic representation of CPC niches in the myocardium. The compartment of cardiac niches is functionally heterogeneous. In quiescent niches, the rarely dividing and highly undifferentiated state of CPCs is preserved. In active niches, CPCs undergo frequent asymmetric replication with formation of a daughter stem cell (self‐renewal) and a daughter cell committed to the myocyte fate.


Figure 6. In vivo inhibition of Notch 1 function induces a dilated myopathy. (A, B) B‐mode and M‐mode echocardiography of vehicle (left) and γ‐secretase inhibitor‐injected (right) mice. (C, D) γ‐Secretase inhibition leads to ventricular dilation, depressed fractional shortening and ejection fraction (C), and increased mortality (D). (E) With respect to a control heart (left panel), ventricular dilation and wall thinning are apparent in mice in which the Notch pathway was inhibited by administration of a γ‐secretase inhibitor (central and right panels). (F) Effects of γ‐secretase inhibition on cardiac anatomy. Results are mean ± SD * P < 0.05 (adapted, with permission, from 329).


Figure 7. Aging and wall stress. Changes in transmural circumferential wall stress during cardiac cycle as a function of age in 4‐, 12‐, 20‐, and 29‐month‐old male Fischer 344 rats. The total duration of stress for 4‐, 12‐, 20‐, and 29‐month‐old hearts was 1.1 × 106, 1.8 × 106, 2.6 × 106, and 3.9 × 106 cubic units, respectively. ENDO, endocardium; EPI, epicardium (adapted, with permission, from 57).


Figure 8. Aging and myocyte number in the human heart. (A, B) Effects of aging on the relative proportion of mononucleated (A) and binucleated (B) ventricular myocytes in women and men (adapted, with permission, from 247).


Figure 9. Aging and myocyte number. The bar graphs show aggregate number of myocyte nuclei in the left and right ventricles. Results are mean ± SD. * P < 0.05 versus the corresponding value in 4‐month‐old rats. *** P < 0.05 versus the corresponding value in 12‐month‐old rats. **** P < 0.05 versus the corresponding value in 20‐month‐old rats (adapted, with permission, from 14).


Figure 10. Acute and chronic myocardial infarcts. (A, B) Myocardial infarcts incompatible with survival. The large transverse myocardial sections illustrate the left ventricle (LV), interventricular septum (IS), and right ventricle (RV). Tissue necrosis is present in a large portion of the IS and in some areas of the anterior aspect of LV (arrowheads). Foci of myocardial scarring are also detected (*) (adapted, with permission, from 251). (C, D) Explanted heart in a patient undergoing cardiac transplantation. The large transverse myocardial sections illustrate a healed myocardial infarct with thinning of the wall (C, arrowheads) and multiple sites of replacement fibrosis in the noninfarcted viable tissue (D, arrowheads) (adapted, with permission, from 35).


Figure 11. Depressed Ca2+ transients in myocytes from the ischemic failing heart. Ca2+ transient properties in myocytes obtained from the heart of sham operated Sprague‐Dawley rats and rats subjected to coronary artery narrowing (CAN). Results are mean ± SD. * P < 0.05 (adapted, with permission, from 56).


Figure 12. Schematic representation of the components of cardiac niches. The niche resembles a randomly oriented ellipsoid structure located in an ill‐defined region of the interstitium. Within the niches, lineage‐negative CSCs are typically located in the center of the niches and are clustered together with early committed cells, progenitors, and precursors. Myocyte progenitors continue to express the c‐kit receptor but show nuclear localization of myocyte transcription factors, GATA‐4, Nkx2.5, and MEF2C, in the absence of specific cytoplasmic proteins. Myocyte precursors continue to express the c‐kit receptor but show nuclear localization of myocyte transcription factors together with cytoplasmic distribution of contractile proteins. Cells within the niches are connected by gap junctions. The extracellular matrix surrounding the niche is composed of several proteins, mostly fibronectin and α2 chain of laminin (adapted, with permission, from 194).


Figure 13. Connexin 43 in the human myocardium. Connexin 43 (white) defines the boundaries of cardiomyocytes (α‐SA, red). Nuclei are stained by DAPI, blue.


Figure 14. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).


Figure 15. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).


Figure 16. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).


Figure 17. Human cardiac stem cells and biomarkers of senescence. (A‐D) Biomarkers of senescence in hCPCs from explanted and donor hearts were analyzed by linear regression. TIFs, telomere dysfunction‐induced foci (adapted, with permission, from 62).


Figure 18. Properties of hypoxic and normoxic CPCs, and cardiomyocytes in the young and old mouse heart. (A) Hypoxic CPCs were recognized by positivity for the hypoxic probe pimonidazole. The distribution of telomere length is shown in hypoxic Pimonidazole‐positive (Pimopos) and normoxic Pimonidazole‐negative (Pimoneg) CPCs, and myocytes from young and old mice (adapted, with permission, from 282). (B) The preservation of CPC number within the niches may depend on the classic modality of self‐renewal or on a process of population replacement. In the first case (left), each niche constitutes an independent unit controlled by asymmetric division of CPCs with formation of a daughter stem cell that is retained within the niche and a daughter committed cell that leaves the niche area. In the second case (right), population replacement involves a mutual feedback between hypoxic and normoxic niches with exchange of primitive cells, replenishing depleted or dysfunctional niches.


Figure 19. SCF activates preferentially growth and differentiation of hypoxic CPCs in the old heart. (A) Distribution and average values of telomere length measured by Q‐FISH in BrdU‐positive (BrdU‐pos) and BrdU‐negative (BrdU‐neg) myocytes from mice injected with saline solution (PBS) or stem cell factor (SCF). Results are mean ± SD. * P < 0.05 versus BrdU‐neg myocytes, ** P < 0.05 versus BrdU‐pos myocytes treated with PBS. (B) Echocardiographic parameters in control (PBS, green bars) and SCF‐treated (yellow bars) mice. * P < 0.05 versus PBS. dLVD, diastolic left ventricular (LV) diameter; LVEDV, LV end‐diastolic volume; dAW, diastolic anterior wall thickness; dPW, diastolic posterior wall thickness; sLVD, systolic LF diameter; LVESV, LV end‐systolic volume; sAW, systolic anterior wall thickness; sPW, systolic posterior wall thickness; EF, ejection fraction; HR, heart rate. (C) Hemodynamic measurements in PBS‐injected (green bars) and SCF‐treated (yellow bars) mice. * P < 0.05 versus PBS. HR, heart rate; LVSP, LV left ventricular systolic pressure; LVEDP, LV end‐diastolic pressure; LVDevP, LV developed pressure. (D) Diastolic anterior (P < 0.008) and posterior (P < 0.008) wall stress decreased by 56% in SCF‐treated old mice. Systolic anterior and posterior wall stress decreased 45% (P < 0.004) and 43% (P < 0.006), respectively. LV mass‐to‐chamber volume ratio increased 84% in diastole (P < 0.003) and 2.2‐fold in systole (P < 0.04) (adapted, with permission, from 282).


Figure 20. SCF activates preferentially growth and differentiation of hypoxic CPCs in the old heart. (A) Distribution and average values of telomere length measured by Q‐FISH in BrdU‐positive (BrdU‐pos) and BrdU‐negative (BrdU‐neg) myocytes from mice injected with saline solution (PBS) or stem cell factor (SCF). Results are mean ± SD. * P < 0.05 versus BrdU‐neg myocytes, ** P < 0.05 versus BrdU‐pos myocytes treated with PBS. (B) Echocardiographic parameters in control (PBS, green bars) and SCF‐treated (yellow bars) mice. * P < 0.05 versus PBS. dLVD, diastolic left ventricular (LV) diameter; LVEDV, LV end‐diastolic volume; dAW, diastolic anterior wall thickness; dPW, diastolic posterior wall thickness; sLVD, systolic LF diameter; LVESV, LV end‐systolic volume; sAW, systolic anterior wall thickness; sPW, systolic posterior wall thickness; EF, ejection fraction; HR, heart rate. (C) Hemodynamic measurements in PBS‐injected (green bars) and SCF‐treated (yellow bars) mice. * P < 0.05 versus PBS. HR, heart rate; LVSP, LV left ventricular systolic pressure; LVEDP, LV end‐diastolic pressure; LVDevP, LV developed pressure. (D) Diastolic anterior (P < 0.008) and posterior (P < 0.008) wall stress decreased by 56% in SCF‐treated old mice. Systolic anterior and posterior wall stress decreased 45% (P < 0.004) and 43% (P < 0.006), respectively. LV mass‐to‐chamber volume ratio increased 84% in diastole (P < 0.003) and 2.2‐fold in systole (P < 0.04) (adapted, with permission, from 282).


Figure 21. IGF‐1 overexpression ameliorates the functional properties of aging myocytes. (A) Representative tracings illustrating peak shortening and velocity of shortening and relengthening, Ca2+ transients, and L‐type Ca2+ current in myocytes from wild type (WT) and IGF‐1 overexpressing (TG) mice. (B) Quantitative data are shown as mean ± SD. *,† P < 0.05 versus animals at 10 to 12 months and WT mice, respectively (adapted, with permission, from 325).


Figure 22. IGF‐1 overexpression ameliorates the functional properties of aging myocytes. (A) Representative tracings illustrating peak shortening and velocity of shortening and relengthening, Ca2+ transients, and L‐type Ca2+ current in myocytes from wild type (WT) and IGF‐1 overexpressing (TG) mice. (B) Quantitative data are shown as mean ± SD. *,† P < 0.05 versus animals at 10 to 12 months and WT mice, respectively (adapted, with permission, from 325).


Figure 23. Schematic representation of the IGF‐1‐Akt‐telomerase axis. Mouse model in which the expression of insulin‐like growth factor 1 (IGF‐1) is driven by the myocyte restricted α‐myosin heavy chain (α‐MHC) promoter. Binding of IGF‐1 to the IGF‐1 receptor (IGF‐1R) results in phosphorylation of PI‐3 kinase (PI3K), which, in turn, phosphorylates and activates Akt kinase. Phosphorylated Akt binds to a consensus site in the telomerase protein enhancing its catalytic activity and promoting telomere elongation.


Figure 24. Nuclear targeted Akt and myocyte mechanics. (A) Traces of unloaded myocyte shortening at 1‐Hz pacing rate. (B) Average parameters of myocyte contraction for wild‐type mice (WT) and mice overexpressing α‐MHC‐nuclear Akt (TG) are shown as mean ± SEM. (C) Ca2+ transients in myocytes paced at 1 Hz and superimposed traces. (D) Ca2+ transient properties for WT and TG are shown as mean ± SEM (adapted, with permission, from 273).


Figure 25. Schematic representation of the effects of stromal‐derived factor 1 (SDF‐1) on CPCs. Myocardial ischemia is characterized by an increased expression of SDF‐1, which binds to CXCR4 in CPCs promoting their migration from the niches and homing in the border zone. Activation of the SDF‐1‐CXCR4 system in CPCs results in engraftment and proliferation of CPCs in proximity of the infarct, ultimately promoting vascular regeneration.
References
 1. Abbott JD , Huang Y , Liu D , Hickey R , Krause DS , Giordano FJ . Stromal cell‐derived factor‐1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation 110: 3300‐5, 2004.
 2. Abhayaratna WP , Srikusalanukul W , Budge MM . Aortic stiffness for the detection of preclinical left ventricular diastolic dysfunction: Pulse wave velocity versus pulse pressure. J Hypertens 26: 758‐764, 2008.
 3. Abkowitz JL , Robinson AE , Kale S , Long MW , Chen J . Mobilization of hematopoietic stem cells during homeostasis and after cytokine exposure. Blood 102: 1249‐53, 2003.
 4. Aicher A , Zeiher AM , Dimmeler S . Mobilizing endothelial progenitor cells. Hypertension 45: 321‐5, 2005.
 5. Alvarez P , Carrillo E , Velez C , Hita‐Contreras F , Martinez‐Amat A , Rodriguez‐Serrano F , Boulaiz H , Ortiz R , Melguizo C , Prados J , Aranega A . Regulatory systems in bone marrow for hematopoietic stem/progenitor cells mobilization and homing. Biomed Res Int 2013: 312656, 2013.
 6. An N , Kraft AS , Kang Y . Abnormal hematopoietic phenotypes in Pim kinase triple knockout mice. J Hematol Oncol 6: 12, 2013.
 7. Anthony BA , Link DC . Regulation of hematopoietic stem cells by bone marrow stromal cells. Trends Immunol 35: 32‐7, 2014.
 8. Anton B , Vitetta L , Cortizo F , Sali A . Can we delay aging? The biology and science of aging. Ann N Y Acad Sci 1057: 525‐535, 2005.
 9. Anversa P . Aging and longevity: The IGF‐1 enigma. Circ Res 97: 411‐414, 2005.
 10. Anversa P , Kajstura J . Ventricular myocytes are not terminally differentiated in the adult mammalian heart. Circ Res 83: 1‐14, 1998.
 11. Anversa P , Kajstura J , Leri A , Bolli R . Life and death of cardiac stem cells: A paradigm shift in cardiac biology. Circulation 113: 1451‐1463, 2006.
 12. Anversa P , Olivetti G . Cellular basis of myocardial growth. In: Page E , Fozzard HA , Solaro RJ , editors. Handbook of Physiology. Oxford: Oxford University Press; 2002, pp. 75‐144.
 13. Anversa P , Palackal T , Sonnenblick EH , Olivetti G , Capasso JM . Hypertensive cardiomyopathy. Myocyte nuclei hyperplasia in the mammalian rat heart. J Clin Invest 85: 994‐997, 1990.
 14. Anversa P , Palackal T , Sonnenblick EH , Olivetti G , Meggs LG , Capasso JM . Myocyte cell loss and myocyte cellular hyperplasia in the hypertrophied aging rat heart. Circ Res 67: 871‐885, 1990.
 15. Anversa P , Rota M , Urbanek K , Hosoda T , Sonnenblick EH , Leri A , Kajstura J , Bolli R . Myocardial aging–a stem cell problem. Basic Res Cardiol 100: 482‐493, 2005.
 16. Anversa P , Sonnenblick EH . Ischemic cardiomyopathy: Pathophysiologic mechanisms. Prog Cardiovasc Dis 33: 49‐70, 1990.
 17. Ara T , Tokoyoda K , Okamoto R , Koni PA , Nagasawa T . The role of CXCL12 in the organ‐specific process of artery formation. Blood 105: 3155‐61, 2005.
 18. Arai F , Hosokawa K , Toyama H , Matsumoto Y , Suda T . Role of N‐cadherin in the regulation of hematopoietic stem cells in the bone marrow niche. Ann NY Acad Sci 1266: 72‐77, 2012.
 19. Armanios M , Alder JK , Parry EM , Karim B , Strong MA , Greider CW . Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet 85: 823‐832, 2009.
 20. Arvanitis D , Davy A . Eph/ephrin signaling: Networks. Genes Dev 22: 416‐29, 2008.
 21. Arwert EN , Hoste E , Watt FM . Epithelial stem cells, wound healing and cancer. Nat Rev Cancer 12: 170‐80, 2012.
 22. Askari AT , Unzek S , Popovic ZB , Goldman CK , Forudi F , Kiedrowski M , Rovner A , Ellis SG , Thomas JD , DiCorleto PE , Topol EJ , Penn MS . Effect of stromal‐cell‐derived factor 1 on stem‐cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 362: 697‐703, 2003.
 23. Aurigemma GP . Diastolic heart failure–a common and lethal condition by any name. N Engl J Med 355: 308‐310, 2006.
 24. Avolio AP , Deng FQ , Li WQ , Luo YF , Huang ZD , Xing LF , O'Rourke MF . Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: Comparison between urban and rural communities in China. Circulation 71: 202‐210, 1985.
 25. Bailey B , Fransioli J , Gude NA , Alvarez R Jr , Zhang X , Gustafsson ÅB , Sussman MA . Sca‐1 knockout impairs myocardial and cardiac progenitor cell function. Circ Res 111: 750‐760, 2012.
 26. Baker DJ , Wijshake T , Tchkonia T , LeBrasseur NK , Childs BG , van de Sluis B , Kirkland JL , van Deursen JM . Clearance of p16Ink4a‐positive senescent cells delays ageing‐associated disorders. Nature 479: 232‐236, 2011.
 27. Ballard VL . Stem cells for heart failure in the aging heart. Heart Fail Rev 15: 447‐56, 2010.
 28. Barker N . Adult intestinal stem cells: Critical drivers of epithelial homeostasis and regeneration. Nat Rev Mol Cell Biol 15: 19‐33, 2014.
 29. Barton PJ , Felkin LE , Birks EJ , Cullen ME , Banner NR , Grindle S , Hall JL , Miller LW , Yacoub MH . Myocardial insulin‐like growth factor‐I gene expression during recovery from heart failure after combined left ventricular assist device and clenbuterol therapy. Circulation 112: I46‐I50, 2005.
 30. Batlle E , Henderson JT , Beghtel H , van den Born MM , Sancho E , Huls G , Meeldijk J , Robertson J , van de Wetering M , Pawson T , Clevers H . Beta‐catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 111: 251‐63, 2002.
 31. Bearzi C , Leri A , Lo Monaco F , Rota M , Gonzalez A , Hosoda T , Pepe M , Qanud K , Ojaimi C , Bardelli S , D'Amario D , D'Alessandro DA , Michler RE , Dimmeler S , Zeiher AM , Urbanek K , Hintze TH , Kajstura J , Anversa P . Identification of a coronary vascular progenitor cell in the human heart. Proc Natl Acad Sci U S A 106: 15885‐15890, 2009.
 32. Bearzi C , Rota M , Hosoda T , Tillmanns J , Nascimbene A , De Angelis A , Yasuzawa‐Amano S , Trofimova I , Siggins RW , Lecapitaine N , Cascapera S , Beltrami AP , D'Alessandro DA , Zias E , Quaini F , Urbanek K , Michler RE , Bolli R , Kajstura J , Leri A , Anversa P . Human cardiac stem cells. Proc Natl Acad Sci U S A 104: 14068‐14073, 2007.
 33. Beauséjour CM , Krtolica A , Galimi F , Narita M , Lowe SW , Yaswen P , Campisi J . Reversal of human cellular senescence: Roles of the p53 and p16 pathways. EMBO J 22: 4212‐4222, 2003.
 34. Beltrami AP , Barlucchi L , Torella D , Baker M , Limana F , Chimenti S , Kasahara H , Rota M , Musso E , Urbanek K , Leri A , Kajstura J , Nadal‐Ginard B , Anversa P . Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114: 763‐776, 2003.
 35. Beltrami CA , Finato N , Rocco M , Feruglio GA , Puricelli C , Cigola E , Quaini F , Sonnenblick EH , Olivetti G , Anversa P . Structural basis of end‐stage failure in ischemic cardiomyopathy in humans. Circulation 89: 151‐163, 1994.
 36. Benjamin EJ , Levy D , Anderson KM , Wolf PA , Plehn JF , Evans JC , Comai K , Fuller DL , Sutton MS . Determinants of Doppler indexes of left ventricular diastolic function in normal subjects (the Framingham Heart Study). Am J Cardiol 70: 508‐515, 1992.
 37. Bernardes de Jesus B , Blasco MA . Aging by telomere loss can be reversed. Cell Stem Cell 8: 3‐4, 2011.
 38. Bernardes de Jesus B , Blasco MA . Telomerase at the intersection of cancer and aging. Trends Genet 29: 513‐520, 2013.
 39. Bernardes de Jesus B , Vera E , Schneeberger K , Tejera AM , Ayuso E , Bosch F , Blasco MA . Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med 4: 691‐704, 2012.
 40. Blasco MA . Telomeres and human disease: Ageing, cancer and beyond. Nat Rev Genet 6: 611‐622, 2005.
 41. Boengler K , Konietzka I , Buechert A , Heinen Y , Garcia‐Dorado D , Heusch G , Schulz R . Loss of ischemic preconditioning's cardioprotection in aged mouse hearts is associated with reduced gap junctional and mitochondrial levels of connexin 43. Am J Physiol Heart Circ Physiol 292: H1764‐H1769, 2007.
 42. Bojovic B , Booth RE , Jin Y , Zhou X , Crowe DL . Alternative lengthening of telomeres in cancer stem cells in vivo. Oncogene 34: 611‐620, 2015.
 43. Bokov AF , Garg N , Ikeno Y , Thakur S , Musi N , DeFronzo RA , Zhang N , Erickson RC , Gelfond J , Hubbard GB , Adamo ML , Richardson A . Does reduced IGF‐1R signaling in Igf1r+/‐ mice alter aging? PLoS One 6: e26891, 2011.
 44. Boni A , Urbanek K , Nascimbene A , Hosoda T , Zheng H , Delucchi F , Amano K , Gonzalez A , Vitale S , Ojaimi C , Rizzi R , Bolli R , Yutzey KE , Rota M , Kajstura J , Anversa P , Leri A . Notch1 regulates the fate of cardiac progenitor cells. Proc Natl Acad Sci U S A 105: 15529‐15534, 2008.
 45. Bonig H , Papayannopoulou T . Mobilization of hematopoietic stem/progenitor cells: General principles and molecular mechanisms. Methods Mol Biol 904: 1‐14, 2012.
 46. Bonig H , Papayannopoulou T . Hematopoietic stem cell mobilization: Updated conceptual renditions. Leukemia 27: 24‐31, 2013.
 47. Borillo GA , Mason M , Quijada P , Völkers M , Cottage C , McGregor M , Din S , Fischer K , Gude N , Avitabile D , Barlow S , Alvarez R , Truffa S , Whittaker R , Glassy MS , Gustafsson AB , Miyamoto S , Glembotski CC , Gottlieb RA , Brown JH , Sussman MA . Pim‐1 kinase protects mitochondrial integrity in cardiomyocytes. Circ Res 106: 1265‐1274, 2010.
 48. Borlaug BA , Melenovsky V , Redfield MM , Kessler K , Chang HJ , Abraham TP , Kass DA . Impact of arterial load and loading sequence on left ventricular tissue velocities in humans. J Am Coll Cardiol 50: 1570‐1577, 2007.
 49. Boyd AW , Bartlett PF , Lackmann M . Therapeutic targeting of EPH receptors and their ligands. Nat Rev Drug Discov 13: 39‐62, 2014.
 50. Boyle AJ , Shih H , Hwang J , Ye J , Lee B , Zhang Y , Kwon D , Jun K , Zheng D , Sievers R , Angeli F , Yeghiazarians Y , Lee R . Cardiomyopathy of aging in the mammalian heart is characterized by myocardial hypertrophy, fibrosis and a predisposition towards cardiomyocyte apoptosis and autophagy. Exp Gerontol 46: 549‐59, 2011.
 51. Braun KM , Niemann C , Jensen UB , Sundberg JP , Silva‐Vargas V , Watt FM . Manipulation of stem cell proliferation and lineage commitment: Visualisation of label‐retaining cells in wholemounts of mouse epidermis. Development 130: 5241‐5255, 2003.
 52. Bromage DI , Davidson SM , Yellon DM . Stromal derived factor 1alpha: A chemokine that delivers a two‐pronged defence of the myocardium. Pharmacol Ther 143: 305‐315, 2014.
 53. Brown WT . Progeria: A human‐disease model of accelerated aging. Am J Clin Nutr 55: 1222S‐1224S, 1992.
 54. Bush JO , Soriano P . Eph/ephrin signaling: Genetic, phosphoproteomic, and transcriptomic approaches. Semin Cell Dev Biol 23: 26‐34, 2012.
 55. Bustos ML , Huleihel L , Kapetanaki MG , Lino‐Cardenas CL , Mroz L , Ellis BM , McVerry BJ , Richards TJ , Kaminski N , Cerdenes N , Mora AL , Rojas M . Aging mesenchymal stem cells fail to protect because of impaired migration and antiinflammatory response. Am J Respir Crit Care Med 189: 787‐98, 2014.
 56. Capasso JM , Li P , Anversa P . Cytosolic calcium transients in myocytes isolated from rats with ischemic heart failure. Am J Physiol 265: H1953‐H1964, 1993.
 57. Capasso JM , Palackal T , Olivetti G , Anversa P . Severe myocardial dysfunction induced by ventricular remodeling in aging rat hearts. Am J Physiol 259: H1086‐H1096, 1990.
 58. Carroll B , Hewitt G , Korolchuk VI . Autophagy and ageing: Implications for age‐related neurodegenerative diseases. Essays Biochem 55: 119‐131, 2013.
 59. Castaldo C , Di Meglio F , Nurzynska D , Romano G , Maiello C , Bancone C , Müller P , Böhm M , Cotrufo M , Montagnani S . CD117‐positive cells in adult human heart are localized in the subepicardium, and their activation is associated with laminin‐1 and alpha6 integrin expression. Stem Cells 26: 1723‐1731, 2008.
 60. Ceradini DJ , Kulkarni AR , Callaghan MJ , Tepper OM , Bastidas N , Kleinman ME , Capla JM , Galiano RD , Levine JP , Gurtner GC . Progenitor cell trafficking is regulated by hypoxic gradients through HIF‐1 induction of SDF‐1. Nat Med 10: 858‐64, 2004.
 61. Cerone MA , Londono‐Vallejo JA , Bacchetti S . Telomere maintenance by telomerase and by recombination can coexist in human cells. Hum Mol Genet 10: 1945‐1952, 2001.
 62. Cesselli D , Beltrami AP , D'Aurizio F , Marcon P , Bergamin N , Toffoletto B , Pandolfi M , Puppato E , Marino L , Signore S , Livi U , Verardo R , Piazza S , Marchionni L , Fiorini C , Schneider C , Hosoda T , Rota M , Kajstura J , Anversa P , Beltrami CA , Leri A . Effects of age and heart failure on human cardiac stem cell function. Am J Pathol 179: 349‐366, 2011.
 63. Chang FT , McGhie JD , Chan FL , Tang MC , Anderson MA , Mann JR , Andy Choo KH , Wong LH . PML bodies provide an important platform for the maintenance of telomeric chromatin integrity in embryonic stem cells. Nucleic Acids Res 41: 4447‐4458, 2013.
 64. Chaves VE , Júnior FM , Bertolini GL . The metabolic effects of growth hormone in adipose tissue. Endocrine 44: 293‐302, 2013.
 65. Chen MA . Heart failure with preserved ejection fraction in older adults. Am J Med 122: 713‐723, 2009.
 66. Chen Z , Pan X , Yao Y , Yan F , Chen L , Huang R , Ma G . Epigenetic regulation of cardiac progenitor cells marker c‐kit by stromal cell derived factor‐1alpha. PLoS One 8: e69134, 2013.
 67. Chen Z , Pan X , Yao Y , Yan F , Chen L , Huang R , Ma G . Regulation of c‐kit+ progenitor cells by stromal cell derived factor‐1alpha in adult murine heart. Heart Lung Circ 23: 75‐81, 2014.
 68. Cheng M , Zhou J , Wu M , Boriboun C , Thorne T , Liu T , Xiang Z , Zeng Q , Tanaka T , Tang YL , Kishore R , Tomasson MH , Miller RJ , Losordo DW , Qin G . CXCR4‐mediated bone marrow progenitor cell maintenance and mobilization are modulated by c‐kit activity. Circ Res 107: 1083‐93, 2010.
 69. Chimenti C , Kajstura J , Torella D , Urbanek K , Heleniak H , Colussi C , Di Meglio F , Nadal‐Ginard B , Frustaci A , Leri A , Maseri A , Anversa P . Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res 93: 604‐613, 2003.
 70. Chiong M , Wang ZV , Pedrozo Z , Cao DJ , Troncoso R , Ibacache M , Criollo A , Nemchenko A , Hill JA , Lavandero S . Cardiomyocyte death: Mechanisms and translational implications. Cell Death Dis 2: e244, 2011.
 71. Chung I , Osterwald S , Deeg KI , Rippe K . PML body meets telomere: The beginning of an ALTernate ending? Nucleus 3: 263‐275, 2012.
 72. Chumley MJ , Catchpole T , Silvany RE , Kernie SG , Henkemeyer M . EphB receptors regulate stem/progenitor cell proliferation, migration, and polarity during hippocampal neurogenesis. J Neurosci 27: 13481‐90, 2007.
 73. Clevers H . The intestinal crypt, a prototype stem cell compartment. Cell 154: 274‐84, 2013.
 74. Collins‐Hooper H , Woolley TE , Dyson L , Patel A , Potter P , Baker RE , Gaffney EA , Maini PK , Dash PR , Patel K . Age‐related changes in speed and mechanism of adult skeletal muscle stem cell migration. Stem Cells 30: 1182‐95, 2012.
 75. Conover CA , Bale LK , Mader JR , Mason MA , Keenan KP , Marler RJ . Longevity and age‐related pathology of mice deficient in pregnancy‐associated plasma protein‐A. J Gerontol A Biol Sci Med Sci 65: 590‐599, 2010.
 76. Conover JC , Doetsch F , Garcia‐Verdugo JM , Gale NW , Yancopoulos GD , Alvarez‐Buylla A . Disruption of Eph/ephrin signaling affects migration and proliferation in the adult subventricular zone. Nat Neurosci 3: 1091‐7, 2000.
 77. Cottage CT , Bailey B , Fischer KM , Avitable D , Collins B , Tuck S , Quijada P , Gude N , Alvarez R , Muraski J , Sussman MA . Cardiac progenitor cell cycling stimulated by pim‐1 kinase. Circ Res 106: 891‐901, 2010.
 78. Cottage CT , Neidig L , Sundararaman B , Din S , Joyo AY , Bailey B , Gude N , Hariharan N , Sussman MA . Increased mitotic rate coincident with transient telomere lengthening resulting from pim‐1 overexpression in cardiac progenitor cells. Stem Cells 30: 2512‐2522, 2012.
 79. Cottler‐Fox MH , Lapidot T , Petit I , Kollet O , DiPersio JF , Link D , Devine S . Stem cell mobilization. Hematology Am Soc Hematol Educ Program 419‐437, 2003.
 80. Coulthard MG , Morgan M , Woodruff TM , Arumugam TV , Taylor SM , Carpenter TC , Lackmann M , Boyd AW . Eph/Ephrin signaling in injury and inflammation. Am J Pathol 181: 1493‐503, 2012.
 81. Cristofalo VJ , Allen RG , Pignolo RJ , Martin BG , Beck JC . Relationship between donor age and the replicative lifespan of human cells in culture: A reevaluation. Proc Natl Acad Sci U S A 95: 10614‐10619, 1998.
 82. Cristofalo VJ , Beck J , Allen RG . Cell senescence: An evaluation of replicative senescence in culture as a model for cell aging in situ. J Gerontol A Biol Sci Med Sci 58: B776‐B781, 2003.
 83. Dai DF , Chen T , Johnson SC , Szeto H , Rabinovitch PS . Cardiac aging: From molecular mechanisms to significance in human health and disease. Antioxid Redox Signal 16: 1492‐526, 2012.
 84. Dai S , Yuan F , Mu J , Li C , Chen N , Guo S , Kingery J , Prabhu SD , Bolli R , Rokosh G . Chronic AMD3100 antagonism of SDF‐1alpha‐CXCR4 exacerbates cardiac dysfunction and remodeling after myocardial infarction. J Mol Cell Cardiol 49: 587‐97, 2010.
 85. Dar A , Goichberg P , Shinder V , Kalinkovich A , Kollet O , Netzer N , Margalit R , Zsak M , Nagler A , Hardan I , Resnick I , Rot A , Lapidot T . Chemokine receptor CXCR4‐dependent internalization and resecretion of functional chemokine SDF‐1 by bone marrow endothelial and stromal cells. Nat Immunol 6: 1038‐46, 2005.
 86. Dar A , Kollet O , Lapidot T . Mutual, reciprocal SDF‐1/CXCR4 interactions between hematopoietic and bone marrow stromal cells regulate human stem cell migration and development in NOD/SCID chimeric mice. Exp Hematol 34: 967‐75, 2006.
 87. de Haan G , Van Zant G . Intrinsic and extrinsic control of hemopoietic stem cell numbers: Mapping of a stem cell gene. J Exp Med 186: 529‐536, 1997.
 88. De Keulenaer GW , Brutsaert DL . Systolic and diastolic heart failure are overlapping phenotypes within the heart failure spectrum. Circulation 123: 1996‐2005, 2011.
 89. De Saint‐Hubert M , Prinsen K , Mortelmans L , Verbruggen A , Mottaghy FM . Molecular imaging of cell death. Methods 48(2):178‐187, 2009.
 90. Debacq‐Chainiaux F , Erusalimsky JD , Campisi J , Toussaint O . Protocols to detect senescence‐associated beta‐galactosidase (SA‐betagal) activity, a biomarker of senescent cells in culture and in vivo. Nat Protoc 4: 1798‐1806, 2009.
 91. Deelen J , Beekman M , Codd V , Trompet S , Broer L , Hägg S , Fischer K , Thijssen PE , Suchiman HE , Postmus I , Uitterlinden AG , Hofman A , de Craen AJ , Metspalu A , Pedersen NL , van Duijn CM , Jukema JW , Houwing‐Duistermaat JJ , Samani NJ , Slagboom PE . Leukocyte telomere length associates with prospective mortality independent of immune‐related parameters and known genetic markers. Int J Epidemiol 43: 878‐886, 2014.
 92. Dhein S , Hammerath SB . Aspects of the intercellular communication in aged hearts: Effects of the gap junction uncoupler palmitoleic acid. Naunyn Schmiedebergs Arch Pharmacol 364: 397‐408, 2001.
 93. Di Meglio F , Castaldo C , Nurzynska D , Miraglia R , Romano V , Russolillo V , Giuseppina L , Vosa C , Montagnani S . Localization and origin of cardiac CD117‐positive cells: Identification of a population of epicardially‐derived cells in adult human heart. Ital J Anat Embryol 115: 71‐78, 2010.
 94. Di Meglio F , Castaldo C , Nurzynska D , Romano V , Miraglia R , Bancone C , Langella G , Vosa C , Montagnani S . Epithelial‐mesenchymal transition of epicardial mesothelium is a source of cardiac CD117‐positive stem cells in adult human heart. J Mol Cell Cardiol 49: 719‐727, 2010.
 95. Dimmeler S , Ding S , Rando TA , Trounson A . Translational strategies and challenges in regenerative medicine. Nat Med 20: 814‐21, 2014.
 96. Dimmeler S , Leri A . Aging and disease as modifiers of efficacy of cell therapy. Circ Res 102: 1319‐30, 2008.
 97. Dimri GP , Lee X , Basile G , Acosta M , Scott G , Roskelley C , Medrano EE , Linskens M , Rubelj I , Pereira‐Smith O , et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc Natl Acad Sci U S A 92: 9363‐9367, 1995.
 98. Doring Y , Pawig L , Weber C , Noels H . The CXCL12/CXCR4 chemokine ligand/receptor axis in cardiovascular disease. Front Physiol 5: 212, 2014.
 99. Dries JL , Kent SD , Virag JA . Intramyocardial administration of chimeric ephrinA1‐Fc promotes tissue salvage following myocardial infarction in mice. J Physiol 589: 1725‐40, 2011.
 100. Dundr M . Nuclear bodies: Multifunctional companions of the genome. Curr Opin Cell Biol 24: 415‐422, 2012.
 101. Ellison GM , Torella D , Dellegrottaglie S , Perez‐Martinez C , Perez de Prado A , Vicinanza C , Purushothaman S , Galuppo V , Iaconetti C , Waring CD , Smith A , Torella M , Cuellas Ramon C , Gonzalo‐Orden JM , Agosti V , Indolfi C , Galinanes M , Fernandez‐Vazquez F , Nadal‐Ginard B . Endogenous cardiac stem cell activation by insulin‐like growth factor‐1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol 58: 977‐86, 2011.
 102. Fadini GP , Albiero M , Seeger F , Poncina N , Menegazzo L , Angelini A , Castellani C , Thiene G , Agostini C , Cappellari R , Boscaro E , Zeiher A , Dimmeler S , Avogaro A . Stem cell compartmentalization in diabetes and high cardiovascular risk reveals the role of DPP‐4 in diabetic stem cell mobilopathy. Basic Res Cardiol 108: 313, 2013.
 103. Fazio S , Sabatini D , Capaldo B , Vigorito C , Giordano A , Guida R , Pardo F , Biondi B , Saccà L . A preliminary study of growth hormone in the treatment of dilated cardiomyopathy. N Engl J Med 334: 809‐814, 1996.
 104. Fischer KM , Cottage CT , Wu W , Din S , Gude NA , Avitabile D , Quijada P , Collins BL , Fransioli J , Sussman MA . Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim‐1 kinase. Circulation 120: 2077‐2087, 2009.
 105. Flores I , Blasco MA . The role of telomeres and telomerase in stem cell aging. FEBS Lett 584: 3826‐3830, 2010.
 106. Flores I , Cayuela ML , Blasco MA . Effects of telomerase and telomere length on epidermal stem cell behavior. Science 309: 1253‐6, 2005.
 107. Funayama R , Saito M , Tanobe H , Ishikawa F . Loss of linker histone H1 in cellular senescence. J Cell Biol 175: 869‐880, 2006.
 108. Fyhrquist F , Saijonmaa O , Strandberg T . The roles of senescence and telomere shortening in cardiovascular disease. Nat Rev Cardiol 10: 274‐283, 2013.
 109. Garg AD , Martin S , Golab J , Agostinis P . Danger signalling during cancer cell death: Origins, plasticity and regulation. Cell Death Differ 21: 26‐38, 2014.
 110. Geiger H , True JM , de Haan G , Van Zant G . Age‐ and stage‐specific regulation patterns in the hematopoietic stem cell hierarchy. Blood 98: 2966‐2972, 2001.
 111. Geissler S , Textor M , Kuhnisch J , Konnig D , Klein O , Ode A , Pfitzner T , Adjaye J , Kasper G , Duda GN . Functional comparison of chronological and in vitro aging: Differential role of the cytoskeleton and mitochondria in mesenchymal stromal cells. PLoS One 7: e52700, 2012.
 112. Genander M . Eph and ephrins in epithelial stem cell niches and cancer. Cell Adh Migr 6: 126‐130, 2012.
 113. Genander M , Holmberg J , Frisen J . Ephrins negatively regulate cell proliferation in the epidermis and hair follicle. Stem Cells 28: 1196‐1205, 2010.
 114. Gerstenblith G , Frederiksen J , Yin FC , Fortuin NJ , Lakatta EG , and Weisfeldt ML . Echocardiographic assessment of a normal adult aging population. Circulation 56: 273‐278, 1977.
 115. Ghadge SK , Muhlstedt S , Ozcelik C , Bader M . SDF‐1alpha as a therapeutic stem cell homing factor in myocardial infarction. Pharmacol Ther 129: 97‐108, 2011.
 116. Go AS , Mozaffarian D , Roger VL , Benjamin EJ , Berry JD , Blaha MJ , Dai S , Ford ES , Fox CS , Franco S , Fullerton HJ , Gillespie C , Hailpern SM , Heit JA , Howard VJ , Huffman MD , Judd SE , Kissela BM , Kittner SJ , Lackland DT , Lichtman JH , Lisabeth LD , Mackey RH , Magid DJ , Marcus GM , Marelli A , Matchar DB , McGuire DK , Mohler ER 3rd , Moy CS , Mussolino ME , Neumar RW , Nichol G , Pandey DK , Paynter NP , Reeves MJ , Sorlie PD , Stein J , Towfighi A , Turan TN , Virani SS , Wong ND , Woo D , Turner MB ; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics–2014 update: A report from the American Heart Association. Circulation 129:e28‐e292, 2014.
 117. Goichberg P , Bai Y , D'Amario D , Ferreira‐Martins J , Fiorini C , Zheng H , Signore S , del Monte F , Ottolenghi S , D'Alessandro DA , Michler RE , Hosoda T , Anversa P , Kajstura J , Rota M , Leri A . The ephrin A1‐EphA2 system promotes cardiac stem cell migration after infarction. Circ Res 108: 1071‐83, 2011.
 118. Goichberg P , Kannappan R , Cimini M , Bai Y , Sanada F , Sorrentino A , Signore S , Kajstura J , Rota M , Anversa P , Leri A . Age‐associated defects in EphA2 signaling impair the migration of human cardiac progenitor cells. Circulation 128: 2211‐2223, 2013.
 119. Golan K , Vagima Y , Goichberg P , Gur‐Cohen S , Lapidot T . MT1‐MMP and RECK: Opposite and essential roles in hematopoietic stem and progenitor cell retention and migration. J Mol Med (Berl) 89: 1167‐1174, 2011.
 120. Gonzalez A , Rota M , Nurzynska D , Misao Y , Tillmanns J , Ojaimi C , Padin‐Iruegas ME , Muller P , Esposito G , Bearzi C , Vitale S , Dawn B , Sanganalmath SK , Baker M , Hintze TH , Bolli R , Urbanek K , Hosoda T , Anversa P , Kajstura J , Leri A . Activation of cardiac progenitor cells reverses the failing heart senescent phenotype and prolongs lifespan. Circ Res 102: 597‐606, 2008.
 121. Gratwohl A , Baldomero H . Trends of hematopoietic stem cell transplantation in the third millennium. Curr Opin Hematol 16: 420‐426, 2009.
 122. Gray DA , Woulfe J . Lipofuscin and aging: A matter of toxic waste. Sci Aging Knowledge Environ 2005: re1, 2005.
 123. Gude N , Muraski J , Rubio M , Kajstura J , Schaefer E , Anversa P , Sussman MA . Akt promotes increased cardiomyocyte cycling and expansion of the cardiac progenitor cell population. Circ Res 99: 381‐388, 2006.
 124. Gude N , Sussman M . Notch signaling and cardiac repair. J Mol Cell Cardiol 52: 1226‐1232, 2012.
 125. Guerra S , Leri A , Wang X , Finato N , Di Loreto C , Beltrami CA , Kajstura J , Anversa P . Myocyte death in the failing human heart is gender dependent. Circ Res 85: 856‐866, 1999.
 126. Guo J , Jie W , Shen Z , Li M , Lan Y , Kong Y , Guo S , Li T , Zheng S . SCF increases cardiac stem cell migration through PI3K/AKT and MMP2/9 signaling. Int J Mol Med 34: 112‐118, 2014.
 127. Hadley EC , Lakatta EG , Morrison‐Bogorad M , Warner HR , Hodes RJ . The future of aging therapies. Cell 120: 557‐567, 2005.
 128. Hajjar RJ , Hulot JS . Myocardial delivery of stromal cell‐derived factor 1 in patients with ischemic heart disease: Safe and promising. Circ Res 112: 746‐747, 2013.
 129. Hara Y , Nomura T , Yoshizaki K , Frisen J , Osumi N . Impaired hippocampal neurogenesis and vascular formation in ephrin‐A5‐deficient mice. Stem Cells 28: 974‐983, 2010.
 130. Harley CB , Futcher AB , Greider CW . Telomeres shorten during ageing of human fibroblasts. Nature 345: 458‐460, 1990.
 131. Hayflick L . The limited in vitro lifetime of human diploid cell strains. Exp Cell Res 37: 614‐636, 1965.
 132. Heazlewood SY , Oteiza A , Cao H , Nilsson SK . Analyzing hematopoietic stem cell homing, lodgment, and engraftment to better understand the bone marrow niche. Ann N Y Acad Sci 1310: 119‐128, 2014.
 133. Herbig U , Ferreira M , Condel L , Carey D , Sedivy JM . Cellular senescence in aging primates. Science 311: 1257, 2006.
 134. Hewitt G , Jurk D , Marques FD , Correia‐Melo C , Hardy T , Gackowska A , Anderson R , Taschuk M , Mann J , Passos JF . Telomeres are favoured targets of a persistent DNA damage response in ageing and stress‐induced senescence. Nat Commun 3: 708, 2012.
 135. Hills SA , Diffley JF . DNA replication and oncogene‐induced replicative stress. Curr Biol 24: R435‐R444, 2014.
 136. Hoggatt J , Speth JM , Pelus LM . Concise review: Sowing the seeds of a fruitful harvest: Hematopoietic stem cell mobilization. Stem Cells 31: 2599‐2606, 2013.
 137. Holland DJ , Kumbhani DJ , Ahmed SH , Marwick TH . Effects of treatment on exercise tolerance, cardiac function, and mortality in heart failure with preserved ejection fraction. A meta‐analysis. J Am Coll Cardiol 57: 1676‐1686, 2011.
 138. Holmberg J , Armulik A , Senti KA , Edoff K , Spalding K , Momma S , Cassidy R , Flanagan JG , Frisen J . Ephrin‐A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis. Genes Dev 19: 462‐471, 2005.
 139. Holmberg J , Genander M , Halford MM , Anneren C , Sondell M , Chumley MJ , Silvany RE , Henkemeyer M , Frisen J . EphB receptors coordinate migration and proliferation in the intestinal stem cell niche. Cell 125: 1151‐1163, 2006.
 140. Holzenberger M , Dupont J , Ducos B , Leneuve P , Géloën A , Even PC , Cervera P , Le Bouc Y . IGF‐1 receptor regulates lifespan and resistance to oxidative stress in mice. Nature 421: 182‐187, 2003.
 141. Hosoda T , D'Amario D , Cabral‐Da‐Silva MC , Zheng H , Padin‐Iruegas ME , Ogorek B , Ferreira‐Martins J , Yasuzawa‐Amano S , Amano K , Ide‐Iwata N , Cheng W , Rota M , Urbanek K , Kajstura J , Anversa P , Leri A . Clonality of mouse and human cardiomyogenesis in vivo. Proc Natl Acad Sci U S A 106: 17169‐17174, 2009.
 142. Hsu YC , Li L , Fuchs E . Emerging interactions between skin stem cells and their niches. Nat Med 20: 847‐856, 2014.
 143. Hsu YC , Li L , Fuchs E . Transit‐amplifying cells orchestrate stem cell activity and tissue regeneration. Cell 157: 935‐949, 2014.
 144. Hu MC , Shiizaki K , Kuro‐o M , Moe OW . Fibroblast growth factor 23 and Klotho: Physiology and pathophysiology of an endocrine network of mineral metabolism. Annu Rev Physiol 75: 503‐533, 2013.
 145. Hu X , Dai S , Wu WJ , Tan W , Zhu X , Mu J , Guo Y , Bolli R , Rokosh G . Stromal cell derived factor‐1 alpha confers protection against myocardial ischemia/reperfusion injury: Role of the cardiac stromal cell derived factor‐1 alpha CXCR4 axis. Circulation 116: 654‐663, 2007.
 146. Huang Y , Liang P , Liu D , Huang J , Songyang Z . Telomere regulation in pluripotent stem cells. Protein Cell 5: 194‐202, 2014.
 147. Irie N , Takada Y , Watanabe Y , Matsuzaki Y , Naruse C , Asano M , Iwakura Y , Suda T , Matsuo K . Bidirectional signaling through ephrinA2‐EphA2 enhances osteoclastogenesis and suppresses osteoblastogenesis. J Biol Chem 284: 14637‐14644, 2009.
 148. Iso Y , Yamaya S , Sato T , Poole CN , Isoyama K , Mimura M , Koba S , Kobayashi Y , Takeyama Y , Spees JL , Suzuki H . Distinct mobilization of circulating CD271 +mesenchymal progenitors from hematopoietic progenitors during aging and after myocardial infarction. Stem Cells Transl Med 1: 462‐468, 2012.
 149. Itkin T , Kaufmann KB , Gur‐Cohen S , Ludin A , Lapidot T . Fibroblast growth factor signaling promotes physiological bone remodeling and stem cell self‐renewal. Curr Opin Hematol 20: 237‐244, 2013.
 150. Jantunen E . Novel strategies for blood stem cell mobilization: Special focus on plerixafor. Expert Opin Biol Ther 11: 1241‐1248, 2011.
 151. Janzen V , Forkert R , Fleming HE , Saito Y , Waring MT , Dombkowski DM , Cheng T , DePinho RA , Sharpless NE , Scadden DT . Stem‐cell ageing modified by the cyclin‐dependent kinase inhibitor p16INK4a. Nature 443: 421‐426, 2006.
 152. Jaskelioff M , Muller FL , Paik JH , Thomas E , Jiang S , Adams AC , Sahin E , Kost‐Alimova M , Protopopov A , Cadiñanos J , Horner JW , Maratos‐Flier E , Depinho RA . Telomerase reactivation reverses tissue degeneration in aged telomerase‐deficient mice. Nature 469: 102‐106, 2011.
 153. Jeyapalan JC , Ferreira M , Sedivy JM , Herbig U . Accumulation of senescent cells in mitotic tissue of aging primates. Mech Ageing Dev 128: 36‐44, 2007.
 154. Junnila RK , List EO , Berryman DE , Murrey JW , Kopchick JJ . The GH/IGF‐1 axis in ageing and longevity. Nat Rev Endocrinol 9: 366‐376, 2013.
 155. Kajstura J , Gurusamy N , Ogórek B , Goichberg P , Clavo‐Rondon C , Hosoda T , D'Amario D , Bardelli S , Beltrami AP , Cesselli D , Bussani R , del Monte F , Quaini F , Rota M , Beltrami CA , Buchholz BA , Leri A , Anversa P . Myocyte turnover in the aging human heart. Circ Res 107: 1374‐1386, 2010.
 156. Kajstura J , Rota M , Hall SR , Hosoda T , D'Amario D , Sanada F , Zheng H , Ogórek B , Rondon‐Clavo C , Ferreira‐Martins J , Matsuda A , Arranto C , Goichberg P , Giordano G , Haley KJ , Bardelli S , Rayatzadeh H , Liu X , Quaini F , Liao R , Leri A , Perrella MA , Loscalzo J , Anversa P . Evidence for human lung stem cells. N Engl J Med 364: 1795‐1806, 2011.
 157. Kalmbach K , Robinson LG Jr, Wang F , Liu L , Keefe D . Telomere length reprogramming in embryos and stem cells. Biomed Res Int 2014: 925121, 2014.
 158. Katayama Y , Battista M , Kao WM , Hidalgo A , Peired AJ , Thomas SA , Frenette PS . Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124: 407‐421, 2006.
 159. Kawamoto A , Losordo DW . Endothelial progenitor cells for cardiovascular regeneration. Trends Cardiovasc Med 18: 33‐37, 2008.
 160. Kienstra KA , Hirschi KK . Vascular progenitor cell mobilization. Methods Mol Biol 904: 155‐164, 2012.
 161. Kim DH , Kundu JK , Surh YJ . Redox modulation of p53: Mechanisms and functional significance. Mol Carcinog 50: 222‐234, 2011.
 162. Kimura W , Sadek HA . The cardiac hypoxic niche: Emerging role of hypoxic microenvironment in cardiac progenitors. Cardiovasc Diagn Ther 2: 278‐289, 2012.
 163. Kishi S , Uchiyama J , Baughman AM , Goto T , Lin MC , Tsai SB . The zebrafish as a vertebrate model of functional aging and very gradual senescence. Exp Gerontol 38: 777‐786, 2003.
 164. Kitzman DW , Gardin JM , Gottdiener JS , Arnold A , Boineau R , Aurigemma G , Marino EK , Lyles M , Cushman M , Enright PL ; Cardiovascular Health Study Research Group. Importance of heart failure with preserved systolic function in patients > or = 65 years of age. CHS Research Group. Cardiovascular Health Study. Am J Cardiol 87: 413‐419, 2001.
 165. Klein R . Eph/ephrin signaling in morphogenesis, neural development and plasticity. Curr Opin Cell Biol 16: 580‐589, 2004.
 166. Kocabas F , Mahmoud AI , Sosic D , Porrello ER , Chen R , Garcia JA , DeBerardinis RJ , Sadek HA . The hypoxic epicardial and subepicardial microenvironment. J Cardiovasc Transl Res 5: 654‐665, 2012.
 167. Kohler J , Popov C , Klotz B , Alberton P , Prall WC , Haasters F , Muller‐Deubert S , Ebert R , Klein‐Hitpass L , Jakob F , Schieker M , Docheva D . Uncovering the cellular and molecular changes in tendon stem/progenitor cells attributed to tendon aging and degeneration. Aging Cell 12: 988‐999, 2013.
 168. Kollet O , Canaani J , Kalinkovich A , Lapidot T . Regulatory cross talks of bone cells, hematopoietic stem cells and the nervous system maintain hematopoiesis. Inflamm Allergy Drug Targets 11: 170‐180, 2012.
 169. Kollet O , Dar A , Lapidot T . The multiple roles of osteoclasts in host defense: Bone remodeling and hematopoietic stem cell mobilization. Annu Rev Immunol 25: 51‐69, 2007.
 170. Kollet O , Vagima Y , D'Uva G , Golan K , Canaani J , Itkin T , Gur‐Cohen S , Kalinkovich A , Caglio G , Medaglia C , Ludin A , Lapid K , Shezen E , Neufeld‐Cohen A , Varol D , Chen A , Lapidot T . Physiologic corticosterone oscillations regulate murine hematopoietic stem/progenitor cell proliferation and CXCL12 expression by bone marrow stromal progenitors. Leukemia 27: 2006‐2015, 2013.
 171. Konstandin MH , Toko H , Gastelum GM , Quijada P , De La Torre A , Quintana M , Collins B , Din S , Avitabile D , Völkers M , Gude N , Fässler R , Sussman MA . Fibronectin is essential for reparative cardiac progenitor cell response after myocardial infarction. Circ Res 113: 115‐125, 2013.
 172. Kopp HG , Avecilla ST , Hooper AT , Rafii S . The bone marrow vascular niche: Home of HSC differentiation and mobilization. Physiology (Bethesda) 20: 349‐356, 2005.
 173. Koudstaal S , Bastings MM , Feyen DA , Waring CD , van Slochteren FJ , Dankers PY , Torella D , Sluijter JP , Nadal‐Ginard B , Doevendans PA , Ellison GM , Chamuleau SA . Sustained delivery of insulin‐like growth factor‐1/hepatocyte growth factor stimulates endogenous cardiac repair in the chronic infarcted pig heart. J Cardiovasc Transl Res 7: 232‐241, 2014.
 174. Kretzschmar K , Watt FM . Markers of epidermal stem cell subpopulations in adult mammalian skin. Cold Spring Harb Perspect Med 4: pii: a013631, 2014.
 175. Krishnamurthy J , Ramsey MR , Ligon KL , Torrice C , Koh A , Bonner‐Weir S , Sharpless NE . p16INK4a induces an age‐dependent decline in islet regenerative potential. Nature 443: 453‐457, 2006.
 176. Krishnamurthy J , Torrice C , Ramsey MR , Kovalev GI , Al‐Regaiey K , Su L , Sharpless NE . Ink4a/Arf expression is a biomarker of aging. J Clin Invest 114: 1299‐1307, 2004.
 177. Kuang D , Zhao X , Xiao G , Ni J , Feng Y , Wu R , Wang G . Stem cell factor/c‐kit signaling mediated cardiac stem cell migration via activation of p38 MAPK. Basic Res Cardiol 103: 265‐273, 2008.
 178. Kuijper S , Turner CJ , Adams RH . Regulation of angiogenesis by Eph‐ephrin interactions. Trends Cardiovasc Med 17: 145‐151, 2007.
 179. Kuro‐o M , Matsumura Y , Aizawa H , Kawaguchi H , Suga T , Utsugi T , Ohyama Y , Kurabayashi M , Kaname T , Kume E , Iwasaki H , Iida A , Shiraki‐Iida T , Nishikawa S , Nagai R , Nabeshima YI . Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 390: 45‐51, 1997.
 180. Kurz DJ , Decary S , Hong Y , Erusalimsky JD . Senescence‐associated (beta)‐galactosidase reflects an increase in lysosomal mass during replicative ageing of human endothelial cells. J Cell Sci 113: 3613‐3622, 2000.
 181. Lackmann M , Boyd AW . Eph, a protein family coming of age: More confusion, insight, or complexity? Sci Signal 1: re2, 2008.
 182. Lakatta EG , Levy D . Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part I: Aging arteries: A “set up” for vascular disease. Circulation 107: 139‐146, 2003.
 183. Lakatta EG , Levy D . Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part II: the aging heart in health: Links to heart disease. Circulation 107: 346‐354, 2003.
 184. Lakatta EG . Arterial and cardiac aging: Major shareholders in cardiovascular disease enterprises: Part III: Cellular and molecular clues to heart and arterial aging. Circulation 107: 490‐497, 2003.
 185. Lalli G . Extracellular signals controlling neuroblast migration in the postnatal brain. Adv Exp Med Biol 800: 149‐180, 2014.
 186. Lam BS , Adams GB . Hematopoietic stem cell lodgment in the adult bone marrow stem cell niche. Int J Lab Hematol 32: 551‐558, 2010.
 187. Lapid K , Glait‐Santar C , Gur‐Cohen S , Canaani J , Kollet O , Lapidot T . Egress and mobilization of hematopoietic stem and progenitor cells: A dynamic multi‐facet process. StemBook. Cambridge (MA): Harvard Stem Cell Institute, 2008.
 188. Lapidot T , Dar A , Kollet O . How do stem cells find their way home? Blood 106: 1901‐10, 2005.
 189. Lapidot T , Kollet O . The essential roles of the chemokine SDF‐1 and its receptor CXCR4 in human stem cell homing and repopulation of transplanted immune‐deficient NOD/SCID and NOD/SCID/B2m(null) mice. Leukemia 16: 1992‐2003, 2002.
 190. Lapidot T , Kollet O . The brain‐bone‐blood triad: Traffic lights for stem‐cell homing and mobilization. Hematology Am Soc Hematol Educ Program 2010: 1‐6, 2010.
 191. Lapidot T , Petit I . Current understanding of stem cell mobilization: The roles of chemokines, proteolytic enzymes, adhesion molecules, cytokines, and stromal cells. Exp Hematol 30: 973‐981, 2002.
 192. Lavin MF , Kozlov S . ATM activation and DNA damage response. Cell Cycle 6: 931‐942, 2007.
 193. Lechel A , Satyanarayana A , Ju Z , Plentz RR , Schaetzlein S , Rudolph C , Wilkens L , Wiemann SU , Saretzki G , Malek NP , Manns MP , Buer J , Rudolph KL . The cellular level of telomere dysfunction determines induction of senescence or apoptosis in vivo. EMBO Rep 6: 275‐281, 2005.
 194. Leri A , Anversa P , Frischman WH . In: Leri A , Anversa P , Frishman WH , editors. Cardiovascular Regeneration and Stem Cell Therapy. Malden, Massachusetts, USA: Blackwell Publishing, 2007, pp. 1‐227.
 195. Leri A , Franco S , Zacheo A , Barlucchi L , Chimenti S , Limana F , Nadal‐Ginard B , Kajstura J , Anversa P , Blasco MA . Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J 22: 131‐139, 2003.
 196. Leri A , Kajstura J , Anversa P . Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 85: 1373‐1416, 2005.
 197. Leri A , Liu Y , Wang X , Kajstura J , Malhotra A , Meggs LG , Anversa P . Overexpression of insulin‐like growth factor‐1 attenuates the myocyte renin‐angiotensin system in transgenic mice. Circ Res 84: 752‐762, 1999.
 198. Leri A , Rota M , Hosoda T , Goichberg P , Anversa P . Cardiac stem cell niches. Stem Cell Res pii: S1873‐S5061, 2014.
 199. Li B , Setoguchi M , Wang X , Andreoli AM , Leri A , Malhotra A , Kajstura J , Anversa P . Insulin‐like growth factor‐1 attenuates the detrimental impact of nonocclusive coronary artery constriction on the heart. Circ Res 84: 1007‐1019, 1999.
 200. Li Q , Li B , Wang X , Leri A , Jana KP , Liu Y , Kajstura J , Baserga R , Anversa P . Overexpression of insulin‐like growth factor‐1 in mice protects from myocyte death after infarction, attenuating ventricular dilation, wall stress, and cardiac hypertrophy. J Clin Invest 100: 1991‐1999, 1997.
 201. Li Q , Ren J . Influence of cardiac‐specific overexpression of insulin‐like growth factor 1 on lifespan and aging‐associated changes in cardiac intracellular Ca2 +homeostasis, protein damage and apoptotic protein expression. Aging Cell 6: 799‐806, 2007.
 202. Li Q , Wu S , Li SY , Lopez FL , Du M , Kajstura J , Anversa P , Ren J . Cardiac‐specific overexpression of insulin‐like growth factor 1 attenuates aging‐associated cardiac diastolic contractile dysfunction and protein damage. Am J Physiol Heart Circ Physiol 292: H1398‐H1403, 2007.
 203. Liang SX , Phillips WD . Migration of resident cardiac stem cells in myocardial infarction. Anat Rec (Hoboken) 296: 184‐911, 2013.
 204. Limana F , Bertolami C , Mangoni A , Di Carlo A , Avitabile D , Mocini D , Iannelli P , De Mori R , Marchetti C , Pozzoli O , Gentili C , Zacheo A , Germani A , Capogrossi MC . Myocardial infarction induces embryonic reprogramming of epicardial c‐kit(+) cells: Role of the pericardial fluid. J Mol Cell Cardiol 48: 609‐618, 2010.
 205. Limana F , Zacheo A , Mocini D , Mangoni A , Borsellino G , Diamantini A , De Mori R , Battistini L , Vigna E , Santini M , Loiaconi V , Pompilio G , Germani A , Capogrossi MC . Identification of myocardial and vascular precursor cells in human and mouse epicardium. Circ Res 101: 1255‐1265, 2007.
 206. Linke A , Muller P , Nurzynska D , Casarsa C , Torella D , Nascimbene A , Castaldo C , Cascapera S , Bohm M , Quaini F , Urbanek K , Leri A , Hintze TH , Kajstura J , Anversa P . Stem cells in the dog heart are self‐renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci U S A 102: 8966‐8971, 2005.
 207. Lisabeth EM , Falivelli G , Pasquale EB . Eph receptor signaling and ephrins. Cold Spring Harb Perspect Biol 5: pii: a009159, 2013.
 208. Liu JP , Baker J , Perkins AS , Robertson EJ , Efstratiadis A . Mice carrying null mutations of the genes encoding insulin‐like growth factor I (Igf‐1) and type 1 IGF receptor (Igf1r). Cell 75: 59‐72, 1993.
 209. Lopez‐Lluch G , Irusta PM , Navas P , de Cabo R . Mitochondrial biogenesis and healthy aging. Exp Gerontol 43: 813‐819, 2008.
 210. Lucas D , Bruns I , Battista M , Mendez‐Ferrer S , Magnon C , Kunisaki Y , Frenette PS . Norepinephrine reuptake inhibition promotes mobilization in mice: Potential impact to rescue low stem cell yields. Blood 119: 3962‐3965, 2012.
 211. Ma Q , Jones D , Borghesani PR , Segal RA , Nagasawa T , Kishimoto T , Bronson RT , Springer TA . Impaired B‐lymphopoiesis, myelopoiesis, and derailed cerebellar neuron migration in CXCR4‐ and SDF‐1‐deficient mice. Proc Natl Acad Sci U S A 95: 9448‐9453, 1998.
 212. Macarthur JW Jr. , Cohen JE , McGarvey JR , Shudo Y , Patel JB , Trubelja A , Fairman AS , Edwards BB , Hung G , Hiesinger W , Goldstone AB , Atluri P , Wilensky RL , Pilla JJ , Gorman JH III , Gorman RC , Woo YJ . Preclinical evaluation of the engineered stem cell chemokine stromal cell‐derived factor 1alpha analog in a translational ovine myocardial infarction model. Circ Res 114: 650‐659, 2014.
 213. MacArthur JW Jr. , Purcell BP , Shudo Y , Cohen JE , Fairman A , Trubelja A , Patel J , Hsiao P , Yang E , Lloyd K , Hiesinger W , Atluri P , Burdick JA , Woo YJ . Sustained release of engineered stromal cell‐derived factor 1‐alpha from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction. Circulation 128: S79‐S86, 2013.
 214. Madonna R , Rokosh G , De Caterina R , Bolli R . Hepatocyte growth factor/Met gene transfer in cardiac stem cells–potential for cardiac repair. Basic Res Cardiol 105: 443‐452, 2010.
 215. Maki T , Liang AC , Miyamoto N , Lo EH , Arai K . Mechanisms of oligodendrocyte regeneration from ventricular‐subventricular zone‐derived progenitor cells in white matter diseases. Front Cell Neurosci 7: 275, 2013.
 216. Mallat Z , Tedgui A , Fontaliran F , Frank R , Durigon M , Fontaine G . Evidence of apoptosis in arrhythmogenic right ventricular dysplasia. N Engl J Med 335: 1190‐1196, 1996.
 217. Mani K . Programmed cell death in cardiac myocytes: Strategies to maximize post‐ischemic salvage. Heart Fail Rev 13: 193‐209, 2008.
 218. Martinez P , Blasco MA . Telomeric and extra‐telomeric roles for telomerase and the telomere‐binding proteins. Nat Rev Cancer 11: 161‐176, 2011.
 219. Marquez‐Curtis LA , Janowska‐Wieczorek A . Enhancing the migration ability of mesenchymal stromal cells by targeting the SDF‐1/CXCR4 axis. Biomed Res Int 2013: 561098, 2013.
 220. Marquez‐Curtis LA , Turner AR , Sridharan S , Ratajczak MZ , Janowska‐Wieczorek A . The ins and outs of hematopoietic stem cells: Studies to improve transplantation outcomes. Stem Cell Rev 7: 590‐607, 2011.
 221. Martínez P , Flores JM , Blasco MA . 53BP1 deficiency combined with telomere dysfunction activates ATR‐dependent DNA damage response. J Cell Biol 197: 283‐300, 2012.
 222. McCarron JK , Stringer BW , Day BW , Boyd AW . Ephrin expression and function in cancer. Future Oncol 6: 165‐176, 2010.
 223. McEniery CM , Yasmin Hall IR , Qasem A , Wilkinson IB , Cockcroft JR . Normal vascular aging: Differential effects on wave reflection and aortic pulse wave velocity: The Anglo‐Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol 46: 1753‐1760, 2005.
 224. Mendelson A , Frenette PS . Hematopoietic stem cell niche maintenance during homeostasis and regeneration. Nat Med 20: 833‐846, 2014.
 225. Mendez‐Ferrer S , Lucas D , Battista M , Frenette PS . Haematopoietic stem cell release is regulated by circadian oscillations. Nature 452: 442‐427, 2008.
 226. Mendez‐Ferrer S , Michurina TV , Ferraro F , Mazloom AR , Macarthur BD , Lira SA , Scadden DT , Ma'ayan A , Enikolopov GN , Frenette PS . Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466: 829‐834, 2010.
 227. Merino JJ , Bellver‐Landete V , Oset‐Gasque MJ , Cubelos B . CXCR4/CXCR7 molecular involvement in neuronal and neural progenitor migration: Focus in CNS repair. J Cell Physiol 230: 27‐42, 2015.
 228. Mitchell GF , Gudnason V , Launer LJ , Aspelund T , Harris TB . Hemodynamics of increased pulse pressure in older women in the community‐based Age, Gene/Environment Susceptibility‐Reykjavik Study. Hypertension 51: 1123‐1128, 2008.
 229. Mitchell GF , Wang N , Palmisano JN , Larson MG , Hamburg NM , Vita JA , Levy D , Benjamin EJ , Vasan RS . Hemodynamic correlates of blood pressure across the adult age spectrum: Noninvasive evaluation in the Framingham Heart Study. Circulation 122: 1379‐1386, 2010.
 230. Mohsin S , Khan M , Nguyen J , Alkatib M , Siddiqi S , Hariharan N , Wallach K , Monsanto M , Gude N , Dembitsky W , Sussman MA . Rejuvenation of human cardiac progenitor cells with Pim‐1 kinase. Circ Res 113: 1169‐1179, 2013.
 231. Molofsky AV , Slutsky SG , Joseph NM , He S , Pardal R , Krishnamurthy J , Sharpless NE , Morrison SJ . Increasing p16INK4a expression decreases forebrain progenitors and neurogenesis during ageing. Nature 443: 448‐452, 2006.
 232. Morrish TA , Bekbolysnov D , Velliquette D , Morgan M , Ross B , Wang Y , Chaney B , McQuigg J , Fager N , Maine IP . Multiple mechanisms contribute to telomere maintenance. J Cancer Biol Res 1: 1012, 2013.
 233. Morrison SJ , Scadden DT . The bone marrow niche for haematopoietic stem cells. Nature 505: 327‐334, 2014.
 234. Muraski JA , Rota M , Misao Y , Fransioli J , Cottage C , Gude N , Esposito G , Delucchi F , Arcarese M , Alvarez R , Siddiqi S , Emmanuel GN , Wu W , Fischer K , Martindale JJ , Glembotski CC , Leri A , Kajstura J , Magnuson N , Berns A , Beretta RM , Houser SR , Schaefer EM , Anversa P , Sussman MA . Pim‐1 regulates cardiomyocyte survival downstream of Akt. Nat Med 13: 1467‐1475, 2007.
 235. Nabetani A and Ishikawa F . Alternative lengthening of telomeres pathway: Recombination‐mediated telomere maintenance mechanism in human cells. J Biochem 149: 5‐14, 2011.
 236. Nadal‐Ginard B , Ellison GM , Torella D . Absence of evidence is not evidence of absence: Pitfalls of cre knock‐ins in the c‐Kit locus. Circ Res 115: 415‐418, 2014.
 237. Nagasawa T , Hirota S , Tachibana K , Takakura N , Nishikawa S , Kitamura Y , Yoshida N , Kikutani H , Kishimoto T . Defects of B‐cell lymphopoiesis and bone‐marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF‐1. Nature 382: 635‐8, 1996.
 238. Nakamura Y , Arai F , Iwasaki H , Hosokawa K , Kobayashi I , Gomei Y , Matsumoto Y , Yoshihara H , Suda T . Isolation and characterization of endosteal niche cell populations that regulate hematopoietic stem cells. Blood 116: 1422‐1432, 2010.
 239. Narita M , Nũnez S , Heard E , Narita M , Lin AW , Hearn SA , Spector DL , Hannon GJ , Lowe SW . Rb‐mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113: 703‐716, 2003.
 240. Narula J , Haider N , Virmani R , DiSalvo TG , Kolodgie FD , Hajjar RJ , Schmidt U , Semigran MJ , Dec GW , Khaw BA . Apoptosis in myocytes in end‐stage heart failure. N Engl J Med 335: 1182‐1189, 1996.
 241. Nass R , Johannsson G , Christiansen JS , Kopchick JJ , Thorner MO . The aging population–is there a role for endocrine interventions? Growth Horm IGF Res 19: 89‐100, 2009.
 242. Nishida K , Kyoi S , Yamaguchi O , Sadoshima J , Otsu K . The role of autophagy in the heart. Cell Death Differ 16: 31‐38, 2009.
 243. Nishimura Y , Ii M , Qin G , Hamada H , Asai J , Takenaka H , Sekiguchi H , Renault MA , Jujo K , Katoh N , Kishimoto S , Ito A , Kamide C , Kenny J , Millay M , Misener S , Thorne T , Losordo DW . CXCR4 antagonist AMD3100 accelerates impaired wound healing in diabetic mice. J Invest Dermatol 132: 711‐720, 2012.
 244. Olivetti G , Abbi R , Quaini F , Kajstura J , Cheng W , Nitahara JA , Quaini E , Di Loreto C , Beltrami CA , Krajewski S , Reed JC , Anversa P . Apoptosis in the failing human heart. N Engl J Med 336: 1131‐1141, 1997.
 245. Olivetti G , Giordano G , Corradi D , Melissari M , Lagrasta C , Gambert SR , Anversa P . Gender differences and aging: Effects on the human heart. J Am Coll Cardiol 26: 1068‐1079, 1995.
 246. Olivetti G , Melissari M , Balbi T , Quaini F , Cigola E , Sonnenblick EH , Anversa P . Myocyte cellular hypertrophy is responsible for ventricular remodelling in the hypertrophied heart of middle aged individuals in the absence of cardiac failure. Cardiovasc Res 28: 1199‐1208, 1994.
 247. Olivetti G , Melissari M , Balbi T , Quaini F , Sonnenblick EH , Anversa P . Myocyte nuclear and possible cellular hyperplasia contribute to ventricular remodeling in the hypertrophic senescent heart in humans. J Am Coll Cardiol 24: 140‐149, 1994.
 248. Olivetti G , Melissari M , Capasso JM , Anversa P . Cardiomyopathy of the aging human heart. Myocyte loss and reactive cellular hypertrophy. Circ Res 68: 1560‐1568, 1991.
 249. Olivetti G , Quaini F , Sala R , Lagrasta C , Corradi D , Bonacina E , Gambert SR , Cigola E , Anversa P . Acute myocardial infarction in humans is associated with activation of programmed myocyte cell death in the surviving portion of the heart. J Mol Cell Cardiol 28: 2005‐2016, 1996.
 250. Okubo T , Yanai N , Obinata M . Stromal cells modulate ephrinB2 expression and transmigration of hematopoietic cells. Exp Hematol 34: 330‐338, 2006.
 251. Owan TE , Hodge DO , Herges RM , Jacobsen SJ , Roger VL , Redfield MM . Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355: 251‐259, 2006.
 252. Palm W , de Lange T . How shelterin protects mammalian telomeres. Annu Rev Genet 42: 301‐334, 2008.
 253. Pasquale EB . Eph receptor signalling casts a wide net on cell behaviour. Nat Rev Mol Cell Biol 6: 462‐475, 2005.
 254. Pasquale EB . Eph‐ephrin bidirectional signaling in physiology and disease. Cell 133: 38‐52, 2008.
 255. Pasquale EB . Eph receptors and ephrins in cancer: Bidirectional signalling and beyond. Nat Rev Cancer 10: 165‐180, 2010.
 256. Penn MS , Mendelsohn FO , Schaer GL , Sherman W , Farr M , Pastore J , Rouy D , Clemens R , Aras R , Losordo DW . An open‐label dose escalation study to evaluate the safety of administration of nonviral stromal cell‐derived factor‐1 plasmid to treat symptomatic ischemic heart failure. Circ Res 112: 816‐825, 2013.
 257. Pillarisetti K , Gupta SK . Cloning and relative expression analysis of rat stromal cell derived factor‐1 (SDF‐1)1: SDF‐1 alpha mRNA is selectively induced in rat model of myocardial infarction. Inflammation 25: 293‐300, 2001.
 258. Pitulescu ME , Adams RH . Eph/ephrin molecules–a hub for signaling and endocytosis. Genes Dev 24: 2480‐2492, 2010.
 259. Plikus MV , Gay DL , Treffeisen E , Wang A , Supapannachart RJ , Cotsarelis G . Epithelial stem cells and implications for wound repair. Semin Cell Dev Biol 23: 946‐953, 2012.
 260. Poliakov A , Cotrina M , Wilkinson DG . Diverse roles of eph receptors and ephrins in the regulation of cell migration and tissue assembly. Dev Cell 7: 465‐480, 2004.
 261. Potten CS , Loeffler M . Stem cells: Attributes, cycles, spirals, pitfalls and uncertainties. Lessons for and from the crypt. Development 110: 1001‐1020, 1990.
 262. Poulos MG , Guo P , Kofler NM , Pinho S , Gutkin MC , Tikhonova A , Aifantis I , Frenette PS , Kitajewski J , Rafii S , Butler JM . Endothelial Jagged‐1 is necessary for homeostatic and regenerative hematopoiesis. Cell Rep 4: 1022‐1034, 2013.
 263. Rankin SM . Chemokines and adult bone marrow stem cells. Immunol Lett 145: 47‐54, 2012.
 264. Ratajczak MZ , Kim C , Janowska‐Wieczorek A , Ratajczak J . The expanding family of bone marrow homing factors for hematopoietic stem cells: Stromal derived factor 1 is not the only player in the game. ScientificWorldJournal 2012: 758512, 2012.
 265. Ratajczak MZ , Zuba‐Surma EK , Wojakowski W , Ratajczak J , Kucia M . Bone Marrow ‐ Home of Versatile Stem Cells. Transfus Med Hemother 35: 248‐259, 2008.
 266. Redaelli G , Malhotra A , Li B , Li P , Sonnenblick EH , Hofmann PA , Anversa P . Effects of constitutive overexpression of insulin‐like growth factor‐1 on the mechanical characteristics and molecular properties of ventricular myocytes. Circ Res 82: 594‐603, 1998.
 267. Reiss K , Cheng W , Ferber A , Kajstura J , Li P , Li B , Olivetti G , Homcy CJ , Baserga R , Anversa P . Overexpression of insulin‐like growth factor‐1 in the heart is coupled with myocyte proliferation in transgenic mice. Proc Natl Acad Sci U S A 93: 8630‐8635, 1996.
 268. Rocha V , Broxmeyer HE . New approaches for improving engraftment after cord blood transplantation. Biol Blood Marrow Transplant 16: S126‐S132, 2010.
 269. Roman MJ , Ganau A , Saba PS , Pini R , Pickering TG , Devereux, RB . Impact of arterial stiffening on left ventricular structure. Hypertension 36: 489‐494, 2000.
 270. Rossi S , Baruffi S , Bertuzzi A , Miragoli M , Corradi D , Maestri R , Alinovi R , Mutti A , Musso E , Sgoifo A , Brisinda D , Fenici R , Macchi, E . Ventricular activation is impaired in aged rat hearts. Am J Physiol Heart Circ Physiol 295: H2336‐H2347, 2008.
 271. Rota M , Boni A , Urbanek K , Padin‐Iruegas ME , Kajstura TJ , Fiore G , Kubo H , Sonnenblick EH , Musso E , Houser SR , Leri A , Sussman MA , Anversa P . Nuclear targeting of Akt enhances ventricular function and myocyte contractility. Circ Res 97: 1332‐1341, 2005.
 272. Rota M , Hosoda T , De Angelis A , Arcarese ML , Esposito G , Rizzi R , Tillmanns J , Tugal D , Musso E , Rimoldi O , Bearzi C , Urbanek K , Anversa P , Leri A , Kajstura J . The young mouse heart is composed of myocytes heterogeneous in age and function. Circ Res 101: 387‐399, 2007.
 273. Rota M , Padin‐Iruegas ME , Misao Y , De Angelis A , Maestroni S , Ferreira‐Martins J , Fiumana E , Rastaldo R , Arcarese ML , Mitchell TS , Boni A , Bolli R , Urbanek K , Hosoda T , Anversa P , Leri A , Kajstura J . Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Circ Res 103: 107‐116, 2008.
 274. Roubenoff R , Parise H , Payette HA , Abad LW , D'Agostino R , Jacques PF , Wilson PW , Dinarello CA , Harris TB . Cytokines, insulin‐like growth factor 1, sarcopenia, and mortality in very old community‐dwelling men and women: The Framingham Heart Study. Am J Med 115: 429‐435, 2003.
 275. Rowe JW , Kahn RL . Human aging: Usual and successful. Science 237: 143‐149, 1987.
 276. Rubart M , Field LJ . Cardiac regeneration: Repopulating the heart. Annu Rev Physiol 68: 29‐49, 2006.
 277. Rudolph KL , Chang S , Lee HW , Blasco M , Gottlieb GJ , Greider C , DePinho RA . Longevity, stress response, and cancer in aging telomerase‐deficient mice. Cell 96: 701‐712, 1999.
 278. Sahin E , Colla S , Liesa M , Moslehi J , Müller FL , Guo M , Cooper M , Kotton D , Fabian AJ , Walkey C , Maser RS , Tonon G , Foerster F , Xiong R , Wang YA , Shukla SA , Jaskelioff M , Martin ES , Heffernan TP , Protopopov A , Ivanova E , Mahoney JE , Kost‐Alimova M , Perry SR , Bronson R , Liao R , Mulligan R , Shirihai OS , Chin L , DePinho RA . Telomere dysfunction induces metabolic and mitochondrial compromise. Nature 470: 359‐365, 2011.
 279. Sahin E , Depinho RA . Linking functional decline of telomeres, mitochondria and stem cells during ageing. Nature 464: 520‐528, 2010.
 280. Sanada F , Kim J , Czarna A , Chan NY , Signore S , Ogórek B , Isobe K , Wybieralska E , Borghetti G , Pesapane A , Sorrentino A , Mangano E , Cappetta D , Mangiaracina C , Ricciardi M , Cimini M , Ifedigbo E , Perrella MA , Goichberg P , Choi AM , Kajstura J , Hosoda T , Rota M , Anversa P , Leri A . c‐Kit‐positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circ Res 114: 41‐55, 2014.
 281. Salama R , Sadaie M , Hoare M , Narita M . Cellular senescence and its effector programs. Genes Dev 28: 99‐114, 2014.
 282. Salomoni P , Pandolfi PP . The role of PML in tumor suppression. Cell 108: 165‐170, 2002.
 283. Savill J , Fadok V . Corpse clearance defines the meaning of cell death. Nature 407: 784‐788, 2000.
 284. Saxena A , Fish JE , White MD , Yu S , Smyth JW , Shaw RM , DiMaio JM , Srivastava D . Stromal cell‐derived factor‐1alpha is cardioprotective after myocardial infarction. Circulation 117: 2224‐2231, 2008.
 285. Scadden DT . The stem‐cell niche as an entity of action. Nature 441: 1075‐1079, 2006.
 286. Scadden DT . Nice neighborhood: Emerging concepts of the stem cell niche. Cell 157: 41‐50, 2014.
 287. Schmitt M , Publicover A , Orchard KH , Gorlach M , Wang L , Schmitt A , Mani J , Tsirigotis P , Kuriakose R , Nagler A . Biosimilar G‐CSF based mobilization of peripheral blood hematopoietic stem cells for autologous and allogeneic stem cell transplantation. Theranostics 4: 280‐289, 2014.
 288. Schuettpelz LG , Link DC . Regulation of hematopoietic stem cell activity by inflammation. Front Immunol 4: 204, 2013.
 289. Schulman SP , Lakatta EG , Fleg JL , Lakatta L , Becker LC , Gerstenblith G . Age‐related decline in left ventricular filling at rest and exercise. Am J Physiol 263: H1932‐H1938, 1992.
 290. Schulz C , von Andrian UH , Massberg S . Hematopoietic stem and progenitor cells: Their mobilization and homing to bone marrow and peripheral tissue. Immunol Res 44: 160‐168, 2009.
 291. Serrano M , Blasco MA . Putting the stress on senescence. Curr Opin Cell Biol 13: 748‐753, 2001.
 292. Serrano M , Lin AW , McCurrach ME , Beach D , Lowe SW . Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell 88: 593‐602, 1997.
 293. Severino J , Allen RG , Balin S , Balin A , Cristofalo VJ . Is beta‐galactosidase staining a marker of senescence in vitro and in vivo? Exp Cell Res 257: 162‐171, 2000.
 294. Sharpless NE , Bardeesy N , Lee KH , Carrasco D , Castrillon DH , Aguirre AJ , Wu EA , Horner JW , DePinho RA . Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature 413: 86‐91, 2001.
 295. Sharpless NE , DePinho RA . How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 8: 703‐713, 2007.
 296. Sherlock M , Toogood AA . Aging and the growth hormone/insulin like growth factor‐I axis. Pituitary 10: 189‐203, 2007.
 297. Sherr CJ , DePinho RA . Cellular senescence: Mitotic clock or culture shock? Cell 102: 407‐410, 2000.
 298. Sheydina A , Riordon DR , Boheler KR . Molecular mechanisms of cardiomyocyte aging. Clin Sci (Lond) 121: 315‐329, 2011.
 299. Shirvaikar N , Marquez‐Curtis LA , Janowska‐Wieczorek A . Hematopoietic stem cell mobilization and homing after transplantation: The role of MMP‐2, MMP‐9, and MT1‐MMP. Biochem Res Int 2012: 685267, 2012.
 300. Shiojima I , Walsh K . Regulation of cardiac growth and coronary angiogenesis by the Akt/PKB signaling pathway. Genes Dev 20: 3347‐3365, 2006.
 301. Shiraishi I , Melendez J , Ahn Y , Skavdahl M , Murphy E , Welch S , Schaefer E , Walsh K , Rosenzweig A , Torella D , Nurzynska D , Kajstura J , Leri A , Anversa P , Sussman MA . Nuclear targeting of Akt enhances kinase activity and survival of cardiomyocytes. Circ Res 94: 884‐891, 2004.
 302. Simsek T , Kocabas F , Zheng J , Deberardinis RJ , Mahmoud AI , Olson EN , Schneider JW , Zhang CC , Sadek HA . The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche. Cell Stem Cell 7: 380‐390, 2010.
 303. Sikora E , Arendt T , Bennett M , Narita M . Impact of cellular senescence signature on ageing research. Ageing Res Rev 10: 146‐152, 2011.
 304. Sjögren K , Liu JL , Blad K , Skrtic S , Vidal O , Wallenius V , LeRoith D , Törnell J , Isaksson OG , Jansson JO , Ohlsson C . Liver‐derived insulin‐like growth factor I (IGF‐I) is the principal source of IGF‐I in blood but is not required for postnatal body growth in mice. Proc Natl Acad Sci U S A 96: 7088‐7092, 1999.
 305. Smart N , Bollini S , Dubé KN , Vieira JM , Zhou B , Davidson S , Yellon D , Riegler J , Price AN , Lythgoe MF , Pu WT , Riley PR . De novo cardiomyocytes from within the activated adult heart after injury. Nature 474: 640‐644, 2011.
 306. Sohni A , Verfaillie CM . Mesenchymal stem cells migration homing and tracking. Stem Cells Int 2013: 130763, 2013.
 307. Spiegel A , Kalinkovich A , Shivtiel S , Kollet O , Lapidot T . Stem cell regulation via dynamic interactions of the nervous and immune systems with the microenvironment. Cell Stem Cell 3: 484‐492, 2008.
 308. Stange DE , Clevers H . Concise review: The yin and yang of intestinal (cancer) stem cells and their progenitors. Stem Cells 31: 2287‐2295, 2013.
 309. Stearns SC . Issues in evolutionary medicine. Am J Hum Biol 17: 131‐140, 2005.
 310. Stein M , Noorman M , van Veen TA , Herold E , Engelen MA , Boulaksil M , Antoons G , Jansen JA , van Oosterhout MF , Hauer RN , de Bakker JM , van Rijen HV . Dominant arrhythmia vulnerability of the right ventricle in senescent mice. Heart Rhythm 5: 438‐448, 2008.
 311. Suda T , Takubo K , Semenza GL . Metabolic regulation of hematopoietic stem cells in the hypoxic niche. Cell Stem Cell 9: 298‐310, 2011.
 312. Sugimura R , He XC , Venkatraman A , Arai F , Box A , Semerad C , Haug JS , Peng L , Zhong XB , Suda T , Li L . Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell 150: 351‐365, 2012.
 313. Sussman MA , Anversa P . Myocardial aging and senescence: Where have the stem cells gone? Annu Rev Physiol 66: 29‐48, 2004.
 314. Svensson J , Sjögren K , Fäldt J , Andersson N , Isaksson O , Jansson JO , Ohlsson C . Liver‐derived IGF‐I regulates mean life span in mice. PLoS One 6: e22640, 2011.
 315. Swinne CJ , Shapiro EP , Lima SD , Fleg JL . Age‐associated changes in left ventricular diastolic performance during isometric exercise in normal subjects. Am J Cardiol 69: 823‐826, 1992.
 316. Tachibana K , Hirota S , Iizasa H , Yoshida H , Kawabata K , Kataoka Y , Kitamura Y , Matsushima K , Yoshida N , Nishikawa S , Kishimoto T , Nagasawa T . The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393: 591‐594, 1998.
 317. Taira N , Yoshida K . Post‐translational modifications of p53 tumor suppressor: Determinants of its functional targets. Histol Histopathol 27: 437‐443, 2012.
 318. Takubo K , Aida J , Izumiyama‐Shimomura N , Ishikawa N , Sawabe M , Kurabayashi R , Shiraishi H , Arai T , Nakamura K . Changes of telomere length with aging. Geriatr Gerontol Int 10: S197‐S206, 2010.
 319. Tchkonia T , Zhu Y , van Deursen J , Campisi J , Kirkland JL . Cellular senescence and the senescent secretory phenotype: Therapeutic opportunities. J Clin Invest 123: 966‐972, 2013.
 320. Thorner MO . Statement by the Growth Hormone Research Society on the GH/IGF‐I axis in extending health span. J Gerontol A Biol Sci Med Sci 64: 1039‐1044, 2009.
 321. Tomás‐Loba A , Flores I , Fernández‐Marcos PJ , Cayuela ML , Maraver A , Tejera A , Borrás C , Matheu A , Klatt P , Flores JM , Viña J , Serrano M , Blasco MA . Telomerase reverse transcriptase delays aging in cancer‐resistant mice. Cell 135: 609‐622, 2008.
 322. Torella D , Ellison GM , Nadal‐Ginard B . Adult c‐kit(pos) cardiac stem cells fulfill Koch's postulates as causal agents for cardiac regeneration. Circ Res 114: e24‐e26, 2014.
 323. Torella D , Rota M , Nurzynska D , Musso E , Monsen A , Shiraishi I , Zias E , Walsh K , Rosenzweig A , Sussman MA , Urbanek K , Nadal‐Ginard B , Kajstura J , Anversa P , Leri A . Cardiac stem cell and myocyte aging, heart failure, and insulin‐like growth factor‐1 overexpression. Circ Res 94: 514‐524, 2004.
 324. Torjesen AA , Sigurethsson S , Westenberg JJ , Gotal JD , Bell V , Aspelund T , Launer LJ , de Roos A , Gudnason V , Harris TB , Mitchell GF . Pulse pressure relation to aortic and left ventricular structure in the Age, Gene/Environment Susceptibility (AGES)‐Reykjavik Study. Hypertension 64: 756‐761, 2014.
 325. Uchida S , De Gaspari P , Kostin S , Jenniches K , Kilic A , Izumiya Y , Shiojima I , Grosse Kreymborg K , Renz H , Walsh K , Braun T . Sca1‐derived cells are a source of myocardial renewal in the murine adult heart. Stem Cell Reports 1: 397‐410, 2013.
 326. Ueda H , Nakamura T , Matsumoto K , Sawa Y , Matsuda H . A potential cardioprotective role of hepatocyte growth factor in myocardial infarction in rats. Cardiovasc Res 51: 41‐50, 2001.
 327. Urbanek K , Cabral‐da‐Silva MC , Ide‐Iwata N , Maestroni S , Delucchi F , Zheng H , Ferreira‐Martins J , Ogórek B , D'Amario D , Bauer M , Zerbini G , Rota M , Hosoda T , Liao R , Anversa P , Kajstura J , Leri A . Inhibition of notch1‐dependent cardiomyogenesis leads to a dilated myopathy in the neonatal heart. Circ Res 107: 429‐441, 2010.
 328. Urbanek K , Cesselli D , Rota M , Nascimbene A , De Angelis A , Hosoda T , Bearzi C , Boni A , Bolli R , Kajstura J , Anversa P , Leri A . Stem cell niches in the adult mouse heart. Proc Natl Acad Sci U S A 103: 9226‐9231, 2006.
 329. Urbanek K , Quaini F , Tasca G , Torella D , Castaldo C , Nadal‐Ginard B , Leri A , Kajstura J , Quaini E , Anversa P . Intense myocyte formation from cardiac stem cells in human cardiac hypertrophy. Proc Natl Acad Sci U S A 100: 10440‐10445, 2003.
 330. Urbanek K , Rota M , Cascapera S , Bearzi C , Nascimbene A , De Angelis A , Hosoda T , Chimenti S , Baker M , Limana F , Nurzynska D , Torella D , Rotatori F , Rastaldo R , Musso E , Quaini F , Leri A , Kajstura J , Anversa P . Cardiac stem cells possess growth factor‐receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long‐term survival. Circ Res 97: 663‐673, 2005.
 331. Vadivel A , van Haaften T , Alphonse RS , Rey‐Parra GJ , Ionescu L , Haromy A , Eaton F , Michelakis E , Thebaud B . Critical role of the axonal guidance cue EphrinB2 in lung growth, angiogenesis, and repair. Am J Respir Crit Care Med 185: 564‐574, 2012.
 332. Vagima Y , Lapid K , Kollet O , Goichberg P , Alon R , Lapidot T . Pathways implicated in stem cell migration: The SDF‐1/CXCR4 axis. Methods Mol Biol 750: 277‐289, 2011.
 333. van Berlo JH , Kanisicak O , Maillet M , Vagnozzi RJ , Karch J , Lin SC , Middleton RC , Marbán E , Molkentin JD . c‐kit+ cells minimally contribute cardiomyocytes to the heart. Nature 509: 337‐341, 2014.
 334. van Empel VP , Bertrand AT , Hofstra L , Crijns HJ , Doevendans PA , De Windt LJ . Myocyte apoptosis in heart failure. Cardiovasc Res 67: 21‐29, 2005.
 335. Vanuytsel T , Senger S , Fasano A , Shea‐Donohue T . Major signaling pathways in intestinal stem cells. Biochim Biophys Acta 1830: 2410‐2426, 2013.
 336. Vaziri H , Benchimol S . From telomere loss to p53 induction and activation of a DNA‐damage pathway at senescence: The telomere loss/DNA damage model of cell aging. Exp Gerontol 31: 295‐301, 1996.
 337. Vihanto MM , Plock J , Erni D , Frey BM , Frey FJ , Huynh‐Do U . Hypoxia up‐regulates expression of Eph receptors and ephrins in mouse skin. Faseb J 19: 1689‐1691, 2005.
 338. von Zglinicki T , Saretzki G , Ladhoff J , d'Adda di Fagagna F , Jackson SP . Human cell senescence as a DNA damage response. Mech Ageing Dev 126: 111‐117, 2005.
 339. Vurusaner B , Poli G , Basaga H . Tumor suppressor genes and ROS: Complex networks of interactions. Free Radic Biol Med 52: 7‐18, 2012.
 340. Wang K , Zhao X , Kuang C , Qian D , Wang H , Jiang H , Deng M , Huang L . Overexpression of SDF‐1alpha enhanced migration and engraftment of cardiac stem cells and reduced infarcted size via CXCR4/PI3K pathway. PLoS One 7: e43922, 2012.
 341. Williams SE , Beronja S , Pasolli HA , Fuchs E . Asymmetric cell divisions promote Notch‐dependent epidermal differentiation. Nature 470: 353‐358, 2011.
 342. Winkler IG , Levesque JP . Mechanisms of hematopoietic stem cell mobilization: When innate immunity assails the cells that make blood and bone. Exp Hematol 34: 996‐1009, 2006.
 343. Winkler IG , Sims NA , Pettit AR , Barbier V , Nowlan B , Helwani F , Poulton IJ , van Rooijen N , Alexander KA , Raggatt LJ , Levesque JP . Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116: 4815‐4828, 2010.
 344. Wnuk M , Hlushchuk R , Janot M , Tuffin G , Martiny‐Baron G , Holzer P , Imbach‐Weese P , Djonov V , Huynh‐Do U . Podocyte EphB4 signaling helps recovery from glomerular injury. Kidney Int 81: 1212‐1225, 2012.
 345. Wong LS , van der Harst P , de Boer RA , Huzen J , van Gilst WH , van Veldhuisen DJ . Aging, telomeres and heart failure. Heart Fail Rev 15: 479‐86, 2010.
 346. Wright DE , Wagers AJ , Gulati AP , Johnson FL , Weissman IL . Physiological migration of hematopoietic stem and progenitor cells. Science 294: 1933‐1936, 2001.
 347. Wykosky J , Palma E , Gibo DM , Ringler S , Turner CP , Debinski W . Soluble monomeric EphrinA1 is released from tumor cells and is a functional ligand for the EphA2 receptor. Oncogene 27: 7260‐7273, 2008.
 348. Xiao RP , Cheng H , Zhou YY , Kuschel M , Lakatta EG . Recent advances in cardiac beta(2)‐adrenergic signal transduction. Circ Res 85: 1092‐1100, 1999.
 349. Yakar S , Liu JL , Stannard B , Butler A , Accili D , Sauer B , LeRoith D . Normal growth and development in the absence of hepatic insulin‐like growth factor I. Proc Natl Acad Sci U S A 96: 7324‐7329, 1999.
 350. Yamaguchi J , Kusano KF , Masuo O , Kawamoto A , Silver M , Murasawa S , Bosch‐Marce M , Masuda H , Losordo DW , Isner JM , Asahara T . Stromal cell‐derived factor‐1 effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization. Circulation 107: 1322‐1328, 2003.
 351. Yamani MH , Ratliff NB , Cook DJ , Tuzcu EM , Yu Y , Hobbs R , Rincon G , Bott‐Silverman C , Young JB , Smedira N , Starling RC . Peritransplant ischemic injury is associated with up‐regulation of stromal cell‐derived factor‐1. J Am Coll Cardiol 46: 1029‐1035, 2005.
 352. Yamashita K , Kajstura J , Discher DJ , Wasserlauf BJ , Bishopric NH , Anversa P , Webster KA . Reperfusion‐activated Akt kinase prevents apoptosis in transgenic mouse hearts overexpressing insulin‐like growth factor‐1. Circ Res 88: 609‐614, 2001.
 353. Yaniz‐Galende E , Chen J , Chemaly E , Liang L , Hulot JS , McCollum L , Arias T , Fuster V , Zsebo KM , Hajjar RJ . Stem cell factor gene transfer promotes cardiac repair after myocardial infarction via in situ recruitment and expansion of c‐kit+ cells. Circ Res 111: 1434‐4145, 2012.
 354. Yellon DM , Malik A , Pickard Mj J , Bromage D , Davidson MS , Sivaraman V , He Z . 224 Stromal derived factor 1 alpha is a mediator of conditioning in human and rat myocardium. Heart 100(Suppl 3): A121‐A122, 2014.
 355. Zhang R , Chen W , Adams PD . Molecular dissection of formation of senescence‐associated heterochromatin foci. Mol Cell Biol 27: 2343‐2358, 2007.
 356. Zhang S , Luo X , Wan F , Lei T . The roles of hypoxia‐inducible factors in regulating neural stem cells migration to glioma stem cells and determinating their fates. Neurochem Res 37: 2659‐2666, 2012.
 357. Zhao C , Irie N , Takada Y , Shimoda K , Miyamoto T , Nishiwaki T , Suda T , Matsuo K . Bidirectional ephrinB2‐EphB4 signaling controls bone homeostasis. Cell Metab 4: 111‐121, 2006.
 358. Zhou B , Ma Q , Rajagopal S , Wu SM , Domian I , Rivera‐Feliciano J , Jiang D , von Gise A , Ikeda S , Chien KR , Pu WT . Epicardial progenitors contribute to the cardiomyocyte lineage in the developing heart. Nature 454: 109‐113, 2008.
 359. Zhou W , Bao S . PML‐mediated signaling and its role in cancer stem cells. Oncogene 33: 1475‐1484, 2014.
 360. Zou YR , Kottmann AH , Kuroda M , Taniuchi I , Littman DR . Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393: 595‐599, 1998.

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Article Title: Aging Effects on Cardiac Progenitor Cell Physiology
 

How to Cite

Marcello Rota, Polina Goichberg, Piero Anversa, Annarosa Leri. Aging Effects on Cardiac Progenitor Cell Physiology . Compr Physiol 2015, 5: 1775-1814. doi: 10.1002/cphy.c140082