X-Message-Number: 24070 Date: Sat, 8 May 2004 10:16:21 -0700 (PDT) From: Doug Skrecky <> Subject: stem cells and aging Am Heart J. 2003 Oct;146(4 Suppl):S5-12 Loss of bone marrow-derived vascular progenitor cells leads to inflammation and atherosclerosis. BACKGROUND: Aging represents the most powerful risk for the development of atherosclerosis and atherosclerotic thromboembolic complications. Yet, the mechanism by which aging affects the arterial wall and its deterioration has remained essentially uncharacterized. FINDINGS: Chronic injuries to the arterial wall contribute to the development of atherosclerosis. However, it is important to note that a complex repair system that involves both local and bone marrow-derived cells maintains arterial homeostasis and integrity. With this review, we explain how the age-dependent failure of the bone marrow to produce vascular progenitor cells responsible for such arterial repair--an inability that results from the impact of a lifetime of risk factors such as hyperlipidemia--drives atherosclerosis and its thromboembolic complications. As a consequence of such failure, the normal processes of arterial wall repair and rejuvenation are impaired. The disequilibrium that ensues between injury of the arterial wall and repair leads to atherosclerotic inflammation and consequent thromboembolic complications. CONCLUSION: The bone marrow and derived progenitor cells represent key regulators of atherosclerosis, and progress in the prevention and treatment of atherosclerosis and its thromboembolic complications will need to take into account this new dimension for the disease process. Circulation. 2003 Jul 29;108(4):457-63. Epub 2003 Jul 14 Aging, progenitor cell exhaustion, and atherosclerosis. BACKGROUND: Atherosclerosis is largely attributed to chronic vascular injury, as occurs with excess cholesterol; however, the effect of concomitant vascular aging remains unexplained. We hypothesize that the effect of time in atherosclerosis progression is related to obsolescence of endogenous progenitor cells that normally repair and rejuvenate the arteries. METHODS AND RESULTS: Here we show that chronic treatment with bone marrow-derived progenitor cells from young nonatherosclerotic ApoE-/- mice prevents atherosclerosis progression in ApoE-/- recipients despite persistent hypercholesterolemia. In contrast, treatment with bone marrow cells from older ApoE-/- mice with atherosclerosis is much less effective. Cells with vascular progenitor potential are decreased in the bone marrow of aging ApoE-/- mice, but cells injected from donor mice engraft on recipient arteries in areas at risk for atherosclerotic injury. CONCLUSIONS: Our data indicate that progressive progenitor cell deficits may contribute to the development of atherosclerosis. J Clin Invest. 2004 Jan;113(1):4-7. Do tumor-suppressive mechanisms contribute to organism aging by inducing stem cell senescence? Stem/progenitor cells ensure tissue and organism homeostasis and might represent a frequent target of transformation. Although these cells are potentially immortal, their life span is restrained by signaling pathways (p19-p53; p16-Rb) that are activated by DNA damage (telomere dysfunction, environmental stresses) and lead to senescence or apoptosis. Execution of these checkpoint programs might lead to stem cell depletion and organism aging, while their inactivation contributes to tumor formation. EMBO J. 2003 Aug 15;22(16):4212-22. Reversal of human cellular senescence: roles of the p53 and p16 pathways. Telomere erosion and subsequent dysfunction limits the proliferation of normal human cells by a process termed replicative senescence. Replicative senescence is thought to suppress tumorigenesis by establishing an essentially irreversible growth arrest that requires activities of the p53 and pRB tumor suppressor proteins. We show that, depending on expression of the pRB regulator p16, replicative senescence is not necessarily irreversible. We used lentiviruses to express specific viral and cellular proteins in senescent human fibroblasts and mammary epithelial cells. Expression of telomerase did not reverse the senescence arrest. However, cells with low levels of p16 at senescence resumed robust growth upon p53 inactivation, and limited growth upon expression of oncogenic RAS. In contrast, cells with high levels of p16 at senescence failed to proliferate upon p53 inactivation or RAS expression, although they re-entered the cell cycle without growth after pRB inactivation. Our results indicate that the senescence response to telomere dysfunction is reversible and is maintained primarily by p53. However, p16 provides a dominant second barrier to the unlimited growth of human cells. Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=24070