The Harrison research group has two focus areas. Under "Gerontology: Mechanisms of Aging" we investigate aging in mouse models, focusing on processes that have the potential to retard aging and prolong health. For example, one line of research investigates mutations that reduce IGF-1 and insulin function. Such mutations can increase life span and delay certain aspects of aging, especially development of cancer. Now we are developing models that combine multiple mutations. We will use these models to test effects of these mutations on physiological and molecular pathways critical to aging processes.

Under "Hematology: Stem Cells" our focus is on hematopoietic stem cells (HSCs) and other adult stem cells, which constantly proliferate and differentiate to maintain tissue functions throughout life. If aging exhausts the function of adult stem cells, the balance between damage and repair is disrupted and tissue functions become defective. Our group has found that genetic mechanisms protect hematopoietic stem cells from exhaustion in some mouse strains. Now our focus is to define the specific mechanisms. Our long-term goal is to promote healthful aging in humans, either by delaying normal aging processes or by minimizing or eliminating diseases of aging. This material is detailed on our lab site.

Scientific report

Gerontology: Mechanisms of Aging

Our research in gerontology focuses on the development and testing of hypotheses about the causes of aging in mice. As we age, we become progressively more susceptible to disease, so if we don't die from one disease, we die from the next most competitive disease--or the next. To maintain health and extend our lives, we must delay or prevent all the diseases of old age. For this reason, we search for mouse models of delayed senescence and study the mechanisms by which senescence is delayed in those models.

Natural genetic variation and senescence
In our search to discover genes that regulate maximum life spans, we studied a total of five 4-way cross populations. In two cases, the 4-way cross included 1 wild-derived strain and 3 standard inbred strains. In each case, one locus extended maximum life spans (the longest lived 16-40%, giving maximum power (Klebanov & Harrison, 2002) by at least 10-15% (Klebanov et al., 2001). Congenics were produced and their F1 hybrids followed for lifespans, data that are only now becoming available. This will confirm whether these loci alone increase lifespans, and may retard aging. If this is the case, congenics will be vital in defining anti-aging mechanisms. We also inbred a stock of mice trapped on an island, where evolutionary theory predicts retarded aging. While their lifespans are normal, fibroblast proliferation is unusually high (Yuan et al, 2005) and female reproductive life span is greatly increased (Flurkey et al. 2007). We are testing the degree to which effects on female reproduction are cell intrinsic.

Endocrine regulation and senescence
Snell dwarf and little mutant mice live longer than normal controls. We know that their endocrine environment has similarities to that of diet restricted control, increased insulin sensitivity and decreased levels of growth hormone (GH) and insulin-like growth factor 1 (IGF-1). Our studies have shown that dw and lit mutations diminish spontaneous tumors. Studies of invertebrates indicate an evolutionarily conserved function of the insulin/IGF-1 signal transduction pathway that regulates life span. Our preliminary studies in mutant mice with diminished IGF-1 signaling (Flurkey et al., 2001; 2002) are consistent with this finding. We plan to continue studies with little mice to test when normal levels of IGF-1 are needed and when health is improved with low IGF-1 levels.

Anti-aging interventions
Diet restriction (DR) is well known to increase lifespan and retard aging, but it is surprising that DR is fully effective in fat hyperinsulinemic mice. Using the C57BL/6J Lepob/Lepob (ob/ob) mouse, under DR the fat was about half of the total body weight, about 4 times the fat composition of ad lib-fed normal controls. Nonetheless, DR ob/ob mice lived as long as diet restricted genetic controls (Harrison et al., 1984; 1991). We recently found that insulin levels were 5-10 fold higher and resistance to insulin far greater in DR ob/ob than in ad lib-fed normal controls. This sets a boundary on mechanisms of DR--neither reduction of fat nor insulin resistance are required. We are investigating mechanisms underlying these effects in insulin, IFG-1 and TOR pathways.

Hematology: Stem Cells

Our research in hematology focuses on cellular and molecular mechanisms that regulate differentiation, self-renewal and aging in stem cells. Hematopoietic stem cells (HSCs) are a useful model for adult stem cells in general for 2 reasons. First, they are a well-defined example of self-renewing and differentiating cells that illustrate methods applicable to other stem cell systems. Second, they produce a wide variety of cells, not only all myeloid and lymphoid cells but natural killer cells and mast cells as well, and they produce the macrophages found in liver, lung, bone, brain and other tissues. Because HSCs turn over continually, constant proliferation is necessary.

Evaluation of stem cells
Because in vitro tests often fail to predict HSC functions, we assay function directly in vivo relative to a genetically marked marrow pool; portions are co-injected with the cells being assayed. In the recipients, percentages of differentiated cells relative to the competitor directly assay function relative to the standard competitor. Beyond being simply mean values for function, variance values are informative about numbers of stem cells that function. For example, an unambiguous measure of stem cell exhaustion is clonal instability. Recipients are repopulated with marrow mixtures from 2 distinguishable congenics, using low cell numbers and 20 or more recipients so that variances are high and correlations are accurate. From young C57BL/6J (B6) and BALB/cByJ (BALB) mice donors, the same HSCs continue to produce descendants proportionally within each recipient, and the proportion of donor-type blood cells remains stable after 3-4 months. Correlation coefficients between times are very high (0.7-0.9). This stability is lost in old BALB but not old B6, but is restored by DR (Chen et al., 2003).

Genetic regulation of stem cell function
We define strain differences in differentiation, self-renewal and aging in marrow stem cells. HSC functionality declines much more with age in BALB and DBA/2J (D2) mice than in B6 mice, following repopulating ability of HSCs, in vivo, in serially transplanted carriers. (Chen et al., 2000b). Hematopoietic stem cell (HSC) numbers are highly variable in aged BALB mice, but the observed loss of marrow function is due to a major loss in repopulating ability per HSC. DR greatly ameliorates this loss of function with age. The fact that DR, well known to reduce cancer, increases or maintains stem cell function with age has far-reaching health implications. In contrast, function per HSC in B6 mice is neither affected by age nor by DR (Ertl et al, 2008). Short-term DR early or late in life had little effect, so DR alters HSC aging, not a physiological set point, in the marrow stem cell compartment of BALB mice. Because DR reduces levels of insulin-like growth factor (IGF), we tested effects of reduced IGF in little mutant mice; effects were not significant (Sharma et al., 2005).

Genetic regulation of HSC exhaustion during development
When HSCs expand in a serially transplanted carrier, the expansion ability of HSCs from fetal vs. adult BALB mice declines about 4-fold. In sharp contrast, the expansion of HSCs from both fetal and adult B6 mice is equally functional despite a large advantage of the fetal HSCs in competitive repopulation (Yuan et al., 2005). We are now testing whether mechanisms present in young B6 and BALB mice protect HSCs in the former from exhaustion, and make the latter vulnerable.

The Kit (W) receptor
This is an essential regulatory element of HSC and erythroid progenitor cells. Several mutant Kit or W alleles have been identified with varying phenotypes in hematopoiesis, gametogenesis and melanogenesis. The degrees of defects in production of red blood cells (RBCs), melanocytes and gametes are not necessarily correlated, and there is no obvious link between these phenotypes and the molecular lesions observed with the Kit receptor. We studied 3 mutations, each due to a single base-pair change in the intracellular region of c-Kit. The W-42 mutation has a far more severe effect on long-term HSC repopulation than the W-41 and W-v mutations. Therefore, W-42 identifies a location on the tyrosine kinase region of the c-Kit receptor that is vital for HSC differentiation, perhaps interacting with vital HSC growth factors. The W-57 mutation, an 80-kb upstream deletion, increases some HSC functions, possibly removing repressive nuclear binding sites.

Evaluating function of adult stem cells (ASCs)
Competitive repopulation should be useful for measuring function in vivo,as long as ASCs produce descendant cells unambiguously identified by genetic markers and function normally in vivo in the transplantation system (currently using ectopic fetal tissues as substrates). We are currently testing whether bone marrow cells can repopulate heart tissue and produce cardiomyocytes and will test repopulation of brain and lung, in each case comparing relative repopulating abilities of mixtures of ASC subsets. A major problem has been the very limited degree of repopulation. This demonstrates the importance of cleansing the original ASCs both for assays and for clinical improvements. We will test if using W-anemic recipients facilitates repopulation of heart, brain and lung by ASCs.

Lab staff

Principal Investigator: David E. Harrison, Ph.D.
Co-Principal Investigators: Robin Ertl, Ph.D.,Kevin Flurkey, Ph.D., Rong Yuan, Ph.D.
Research Laboratory Manager: C. Michael Astle, B.A., S.P.A.
Research Assistant III: Jonathan Archer, B.S.
Research Assistant II: Joanne Currer, A.A.S.
Laboratory Technician III: Patricia Harrison, B.S., Bernice Stork, Elizabeth Adler
Laboratory Technician IV: Pam Krason
Shared Service Animal Care Technician: Vicki Hutchinson
Visiting Investigators: Terry Combs, Ph.D., University of North Carolina, Chapel Hill; Simon Klebanov, Ph.D., Columbia University, Richard A. Miller, M.D., Ph.D., University of Michigan; John Papaconstantinou, Ph.D., University of Texas, Galveston, Randy Strong
Research Administrative Assistant: Glenn Smallidge

Publication listings

Chu HP, Liao Y, Novak JS, Hu Z, Merkin JJ, Shymkiv Y, Braeckman BP, Dorovkov MV, Nguyen A, Clifford PM, Nagele RG, Harrison DE, Ellis RE, Ryazanov AG. 2014. Germline quality control: eEF2K stands guard to eliminate defective oocytes. Dev Cell. Mar 10;28(5):561-72.

Miller RA, Harrison DE, Astle CM, Fernandez E, Flurkey K, Han M, Javors MA, Li X, Nadon NL, Nelson JF, Pletcher S, Salmon AB, Sharp ZD, Roekel S, Winkleman L, Strong R. 2014. Rapamycin-mediated lifespan increase in mice is dose and sex-dependent and metabolically distinct from dietary restriction. Aging Cell. 13(3):468-77. PMCID: PMC4032600

Yuan R, Gatti EM, Krier R, Malay E, Schultz D, Peters LL, Churchill GA, Harrison DE, Paigen B. 2014. Genetic regulation of female sexual maturation and longevity through circulating IGF1. J Gerontol A Biol Sci Med Sci. doi: 10.1093/gerona/glu114.

Zhou Y, Harrison DE, Love-Myers K, Chen Y, Grider A, Wickwire K, Burgess JR, Stochelski MA, Pazdro R. 2014. Genetic analysis of tissue glutathione concentrations and redox balance. Free Radic Biol Med. 71:157-64. PMCID: PMC4043295

Harrison DE, Strong R, Allison DB, Ames BN, Astle CM, Atamna H, Fernandez E, Flurkey F, Javors MA, Nadon NL, Nelson JF, Simpkins JW, Smith D, Wilkinson JE, Miller RA. 2013. Acarbose, 17--estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males. Aging Cell. 13(2):273-82. PMCID: PMC3954939

Lamming DW, Ye L, Astle CM, Baur JA, Sabatini DM, Harrison DE. 2013. Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive. Aging Cell. 12(4):712-18. PMCID: PMC3727050

Pazdro R, Harrison DE. 2013. Murine adipose tissue-derived stromal cell apoptosis and susceptibility to oxidative stress in vitro are regulated by genetic background. PLoS One. Apr 4;8(4):e61235. PMCID: PMC3617166

Strong R, Miller RA, Astle CM, Baur JA, de Cabo R, Fernandez E, Guo W, Javors M, Kirkland JL, Nelson JF, Sinclair DA, Teter B, Williams D, Zaveri N, Nadon NL, Harrison DE. 2013. Evaluation of resveratrol, green tea extract, curcumin, oxaloacetic acid, and medium chain triglyceride oil on lifespan of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 68(1):6-16. PMCID: PMC3598361

Ye L, Widlund AL, Sims CA, Lamming DW, Guan Y, Davis JG, Sabatini DM, Harrison DE, Vang O, Baur JA. 2013. Rapamycin doses sufficient to extend lifespan do not compromise muscle mitochondrial content or endurance. Aging. 5(7):539-50. PMCID: PMC3765582

Wilkinson JE, Burmeister L, Brooks SV, Chen CC, Friedline S, Harrison DE, Hejtmancik JF, Nadon N, Strong R, Wood LK, Woodward MA, Miller RA. 2012. Rapamycin slows aging in mice. Aging Cell. 11:675-82. PMCID: PMC3434687

Ye L, Zhang EY, Xiong Q, Astle CM, Zhang P, Li Q, From AH, Harrison DE, Zhang JJ. 2012. Aging Kit mutant mice develop cardiomyopathy. PLoS One. 7(3): e33407. PMCID: PMC3302804

Yuan R, Flurkey K, Meng Q, Astle CM, Harrison DE. 2012. Genetic regulation of lifespan, metabolism and body weight in Pohn, a new wild-derived mouse strain. J Gerontol A Biol Sci Med Sci. 68(1):27-35. PMCID: PMC3598364

Yuan R, Meng Q, Nautiyal J, Flurkey K, Tsaih SW, Krier R, Parker MG, Harrison DE, Paigen B. 2012. Genetic co-regulation of age of female sexual maturation and lifespan through circulating IGF1 among inbred mouse strains. Proc Natl Acad Sci. USA. 109(21):8224-9. PMCID: PMC3361401

Zhang EY, Xiong Q, Ye L, Suntharalingam P, Wang X, Astle CM, Zhang J, Harrison DE. 2012. Fetal myocardium in the kidney capsule: an in vivo model of repopulation of myocytes by bone marrow cells. PLoS One. 7(2):e31099. PMCID:PMC3285614

Nguyen HP, Li L, Nethrapalli IS, Guo N, Toran-Allerand CD, Harrison DE, Astle CM, Schug KA. 2011. Evaluation of matrix effects in estrogen bioanalysis by liquid chromatography – tandem mass spectrometry. J Sep Sci. Jul 1. doi: 10.1002/jssc.201100219. [Epub ahead of print ]

Berndt A, Cario CL, Silva KA, Kennedy VE, Harrison DE, Paigen B, Sundberg JP. 2011. Identification of fat4 and tsc22d1 as candidate genes for spontaneous pulmonary adenomas. Cancer Res. 71(17):5779-91. PMCID: PMC3165088

Sundberg JP, Berndt A, Sundberg BA, Silva KA, Kennedy V, Bronson R, Yuan R, Paigen B, Harrison D, Schofield PN. 2011. The mouse as a model for understanding chronic diseases of aging: the histopathologic basis of aging in inbred mice. Pathobiology of Aging & Age-related Diseases 2011, 1: 7179 - DOI: 10.3402/pba.v1i0.7179

Lorenzo LP, Chen H, Shatynski KE, Clark S, Yuan R, Harrison DE, Yarowsky PJ, Williams MS. 2011. Defective hematopoietic stem cell and lymphoid progenitor development in the Ts65Dn mouse model of Down syndrome: potential role of oxidative stress. Antioxid. Redox Signaling. 15(8):2083-94. PMCID: PMC3166202

Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, Orihuela CJ, Pletcher S, Sharp ZD, Sinclair D, Starnes JW, Wilkinson JE, Nadon NL, Strong R. 2011. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci. 66(2):191-201. PMCID: PMC3021372

Flurkey K, Astle CM, Harrison DE. 2010. Life Extension by Diet Restriction and N-Acetyl-L-Cysteine in Genetically Heterogeneous HET3 Mice. J Gerontol A Biol Sci Med Sci. 65(12):1275-84.

Flurkey K, Harrison DE. 2010. Reproductive ageing: Of worms and women. Nature Nov18(468):386-7.

Novoselov SV, Kim HY, Hua D, Lee BC, Astle CM, Harrison DE, Friguet B, Moustafa ME, Carlson BA, Hatfield DL, Gladyshev VN. 2010. Regulation of selenoproteins and methionine sulfoxide reductases A and B1 by age, calorie restriction, and dietary selenium in mice. Antioxid Redox Signal; 12(7):829-38.

Alderman JM, Flurkey K, Brooks N, Naik SB, Gutierrez JM, Srinivas U, Ziara KB, Jing L, Boysen G, Bronson R, Klebanov S, Chen X, Swenberg JA, Stridsberg M, Parker CE, Harrison DE, Combs TP. 2009. Neuroendocrine inhibition of glucose production and resistance to cancer in dwarf mice. Exp Gerontol. 44:26-33.

Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors M, Fernandez E, Miller RA. 2009. Rapamycin fed from 20 months of age extends lifespan in genetically heterogeneous mice. Nature. 460:392-395.

Yuan R, Tsaih SW, Petkova S, Evsikova CM, Xing S, Marion M, Bogue M, Mills K, Peters LL, Bult C, Rosen CJ, Sundberg JP, Harrison DE, Churchill GA, Paigen BJ. 2009. Aging in 31 inbred strains of mice: study design and interim report on median lifespans. Aging Cell. 8:277-287.

Ertl RP, Chen J, Astle CM, Duffy TM, Harrison DE. 2008. Effects of dietary restriction on hematopoietic stem cell aging are genetically regulated. Blood. Oct 19 111(3):1709-1716.

Nadon NL, Strong R, Miller RA, Nelson J, Javors M, Sharp ZD, Peralba JM, Harrison DE. 2008. Design of Aging Intervention Studies: the NIA Interventions Testing Program. AGE online. April 18, 2008.

Strong R, Miller RA, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Harrison DE. 2008. Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice. Aging Cell. 7:641-650.

Brooks NL, Trent CM, Raetzsch CF, Flurkey K, Boysen G, Perfetti MT, Jeong Y-C, Klebanov S, Patel KB, Khodush VR, Kupper LL, Carling D, Swenberg JA, Harrison DE, Combs TP. 2007. Low utilization of circulating glucose after food withdrawal in Snell dwarf mice. J Biol Chem. 282(48):35069-35077.

Sharma Y, Astle CM, Harrison DE. 2007. Heterozygous Kit mutants with little or no apparent anemia exhibit large defects in overall hematopoietic stem cell function. Exp Hematol 35:214-220.

Miller RA, Harrison DE, Astle CM, Floyd RA, Flurkey K, Hensley KL, Javors MA, Leeuwenburgh C, Nelson JF, Ongini E, Nadon NL, Warner HR, Strong R. 2007. An aging interventions testing program: study design and interim report. Aging Cell 6:565-575.

Flurkey K, Brandvain Y, Klebanov S, Austad SN, Miller RA, Yuan R, Harrison DE. 2007. PohnB6F1: a cross of wild and domestic mice that is a new model of extended female reproductive life span. J Gerontol A Biol Sci Med Sci 62:1187-1198.

Powers RW III, Harrison DE, Flurkey K. 2006. Pituitary removal in adult mice increases life span. Mech Ageing Dev 127:658-659.

Yuan R, Flurkey K, Van Aelst-Bouma R, Zhang W, King B, Austad S, Miller RA, Harrison DE. 2006. Altered growth characteristics of skin fibroblasts from wild-derived mice, and genetic loci regulating fibroblast clone size. Aging Cell 5:203-212.

Klebanov S, Astle CM, DeSimone O, Ablamunits V, Harrison DE. 2005. Adipose tissue transplantation protects ob/ob mice from obesity, normalizes insulin sensitivity and restores fertility. J Endocrinol 186:203-211.

Papaconstantinou J, Deford JH, Gerstner A, Hsieh CC, Boylston WH, Guigeaux MM, Flurkey K, Harrison DE. 2005. Hepatic gene and protein expression of primary components of the IGF-1 axis in long lived Snell dwarf mice. Mech Ageing Dev 126(6-7):692-704.

Sharma Y, Flurkey K, Astle CM, Harrison DE. 2005. Mice severely deficient in growth hormone have normal hematopoiesis. Exp Hematol 33:776-783.

Yuan R, Astle CM, Chen J, Harrison DE. 2005. Genetic regulation of hematopoietic stem cell exhaustion during development and growth. Exp Hematol 33:243-250.

Boylston WH, Gerstner A, DeFord JH, Madsen M, Flurkey K, Harrison DE, Papaconstantinou J. 2004. Altered cholesterologenic and lipogenic transcriptional profile in livers of aging Snell dwarf (Pit1dw/dwJ) mice. Aging Cell 3(5):283-296.

Madsen MA, Hsieh CC, Boylston WH, Flurkey K, Harrison DE, Papaconstantinou J. 2004. Altered oxidative stress response of the long-lived Snell dwarf mouse. Biochem Biophys Res Comm 318:998-1005.

Chen J, Astle CM, Harrison DE. 2003. Hematopoietic senescence is postponed and hematopoietic stem cell function is enhanced by dietary restriction. Exp Hematol 31(11):1097-1103.

Chen J, Astle CM, Harrison DE. 2003. Hematopoietic stem cell functional failure in interleukin-2 deficient mice. J Hematother Stem Cell Res 11(6):905-912.

TeKippe M, Harrison DE, Chen J. 2003. Expansion of hematopoietic stem cell phenotype and activity in Trp53-null mice. Exp Hematol 31(6):521-527.

Chen J, Astle CM, Harrison DE. 2002. Hematopoietic stem cell functional failure in interleukin-2-deficient mice. J Hematother Stem Cell Res 11(6):905-912.

Chen J, Flurkey K, Harrison DE. 2002. A reduced peripheral blood CD4+ lymphocyte proportion is a consistent aging phenotype. Mech Ageing and Dev 123:145-153.

Chen J, Harrison DE. 2002. Quantitative trait loci regulating relative lymphocyte proportions in mouse peripheral blood. Blood 99(2):561-566.

Flurkey K, Papaconstantinou J, Harrison DE. 2002. The Snell dwarf mutation Pit 1(dw) can increase life span in mice. Mech Ageing Dev 123:121-130.

Hsieh CC, DeFord JH, Flurkey K, Harrison DE, Papaconstantinou J. 2002. Implications for the insulin signaling pathway in Snell dwarf mouse longevity: a similarity with the C. elegans longevity paradigm. Mech Ageing Dev 123:1229-1244.

Hsieh CC, DeFord JH, Flurkey K, Harrison DE, Papaconstantinou J. 2002. Effects of the Pit 1 mutation on the insulin signaling pathway: implications on the longevity of the long-lived Snell dwarf mouse. Mech Ageing Dev 123:1245-1255.

Klebanov SE, Harrison DE. 2002. Optimizing detection of QTLs retarding aging: choice of statistical model and animal requirements. Mech Ageing Dev 123:131-144.

Taylor PA, McElmurry RT, Lees CJ, Harrison DE, Blazar BR. 2002. Allogenic fetal liver cells have a distinct competitive engraftment advantage over adult bone marrow cells when infused into fetal as compared with adult severe combined immunodeficient (scid) recipients. Blood 99(5):1870-1872.

Allison DB, Miller RA, Austad SN, Bouchard C, Leibel R, Klebanov S, Johnson T, Harrison DE. 2001. Genetic variability in responses to caloric restriction in animals and in regulation of metabolism and obesity in humans. J Gerontol: Series A 56A (Spec Iss 1):55-65.

Flurkey K, Papaconstantinou J, Miller RA, Harrison, DE. 2001. Lifespan extension and delayed immune and collagen aging in mutant mice with defects in growth hormone production. Proc Natl Acad Sci USA 98:6736-6741.

Klebanov SE, Astle CM, Roderick TH, Flurkey K, Archer JR, Chen J, Harrison DE. 2001. Maximum life spans in mice are extended by wild strain alleles. Exp Biol Med 226(9):854-859.

Klebanov SE, Flurkey K, Roderick TH, Archer JR, Astle CM, Chen J, Harrison DE. 2001. Heritability of life span in mice and its implication for direct and indirect selection for longevity. Genetica 110:209-218.

Abkowitz JL, Golinelli D, Harrison DE, Guttorp P. 2000. In vivo kinetics of murine hemopoietic stem cells. Blood 96(10):3399-3405.

Chen J, Astle CM, Harrison DE. 2000. Genetic regulation of primitive hematopoietic stem cell senescence. Exp Hematol 28:442-450.

Chen J, Astle CM, Muller-Sieburg CE, Harrison DE. 2000. Primitive hemopoietic stem cell function in vivo is uniquely high in the CXB-12 mouse strain. Blood 96(13):4124-4131.

Zhao Y, Lin Y, Zhn G, Louie J, Harrison DE, Anderson WF. 2000. Murine hematopoietic stem cell characterization and its regulation in BM transplantation. Blood 96(9):3016-3022.

Chen J, Astle CM, Harrison DE. 1999. Development and aging of primitive hematopoietic stem cells in BALB/cBy mice. Exp Hematol 27:928-935.

Chen J, Astle CM, Harrison DE. 1998. Delayed immune aging in diet-restricted B6CBAT6 F1 mice is associated with preservation of naive T cells. J Gerontol 53A:B330-337.

Gardner RV, Astle CM, Harrison DE. 1997. Hematopoietic precursor cell exhaustion is a cause of proliferative defect in primitive hematopoietic stem cells (PHSC) after chemotherapy. Exp Hematol 25:495-501.

Harrison DE. 1997. Animal models showing "accelerated aging" are more likely to be useful for pathology than mechanisms of aging. Growth Dev Aging 61:167-8.

Harrison DE, Astle CM. 1997. Short- and long- term multilineage repopulating hemopoietic stem cells in late fetal and newborn mice; models for human umbilical cord blood. Blood 90:174-81.

Harrison DE, Roderick TH. 1997. Selection for maximum longevity in mice, and other mouse models for aging research. Kyoto Course on Animal Models for Aging Research. Exp Gerontol 32:65-78.

Harrison DE, Zhong RK, Jordan CT, Lemischka IR, Astle CM. 1997. Relative to adult marrow, fetal liver repopulates nearly 5 times more effectively over the long-term than short-term. Exp Hematol 25:293-7.

Archer JR, Harrison DE. 1996. L-deprenyl treatment in aged mice slightly increases lifespans, and greatly reduces fecundity by aged males. J Gerontol Biol Sci 51A:B448-53.

Zhong RK, Astle CM, Harrison DE. 1996. Distinct developmental patterns of short-term and long-term functioning lymphoid and myeloid precursors defined by limiting dilution analysis in vivo. J Immunol 157:138-45.

Zhong RK, Donnenberg AD, Edison L, Harrison DE. 1996. The appearance of Thy-1 negative donor T-cells in the peripheral circulation 3-6 weeks after bone marrow transplantation (BMT) suggests an extrathymic origin. Internat Immunol 8:171-6.

Harrison DE, Roderick TH, Paigen K. 1995. Allele capture by selection for flanking markers: a new method for analyzing multigenic traits. Growth Dev Aging 59:73-6.

Jordan CT, Astle CM, Zawadski J, Mackarenhtschian K, Lemischka IR, Harrison DE. 1995. Long term repopulating abilities of enriched fetal liver stem cells measured by competitive repopulation. Exp Hematol 23:1011-15.

Willott JF, Erway LC, Archer JR, Harrison DE. 1995. Genetics of age-related hearing loss in mice. II. Strain differences and effects of caloric restriction on cochlear pathology and evoked response thresholds. Hear Res 88:143-155.

Harrison DE. 1994. Potential misinterpretations using models of accelerated aging (guest editorial). J Gerontol 49:B245.

Biossonneault GA, Harrison DE. 1994. Obesity minimizes the immunopotentiation of food restriction in ob/ob mice. J Nutr 124:1639-46.

Harrison DE, Zsebo KM, Astle CM. 1994. Splenic primitive hematopoietic stem cell (PHSC) activity is enhanced by steel factor because of PHSC proliferation. Blood 83:3146-51.

Bronson RT, Lipman RD, Harrison DE. 1993. Age-related gliosis in the white matter of mice. Brain Res 609:124-8.

Erway LC, Willott JF, Archer JR, Harrison DE. 1993. Genetics of age-related hearing loss in mice. I: Inbred and F1 hybrid strains. Hear Res 65:125-32.

Gardner RV, Lerner C, Astle CM, Harrison DE. 1993. Assessing permanent damage to primitive hematopoietic stem cells (PHSC) after chemotherapy using the competitive repopulation assay. Canc Chemother & Pharm 32:450-4.

Harrison DE, Jordan CT, Zhong RK, Astle CM. 1993. Primitive hemopoietic stem cells: direct assay of most productive populations by competitive repopulation with simple binomial, correlation and covariance calculations. Exp Hematol 21:206-19.

Lipman RD, Gaillard ET, Harrison DE, Bronson RT. 1993. Husbandry factors and the prevalence of age-related amyloidosis in mice. Lab Anim Sci 43:439-44.

Flurkey K, Miller RA, Harrison DE. 1992. Cellular determinants of age-related decrements in the T-cell mitogen response of B6CBAF1 mice. J Gerontol 47:B115-20.

Harrison DE, Zhong RK. 1992. The same exhaustible multilineage precursor produces both myeloid and lymphoid cells as early as 3-4 weeks after marrow transplantation. Proc Nat Acad Sci USA 89:10134-8.

Lerner SP, Anderson CP, Harrison DE, Walford RL, Finch CE. 1992. Polygenic influences on the length of oestrous cycles in inbred mice involve MHC alleles. Euro J Immunogenet 19:361-71.

 Harrison, D. 1991. Last-resort medicine: could it have saved my father? Longevity (April) 78-9.

Harrison DE, Astle CM. 1991. Lymphoid and erythroid repopulation in B6W-anemic mice: a new unirradiated recipient. Exp Hematol 19:374-7.

Harrison DE, Lerner C. 1991. Most primitive hematopoietic stem cells are stimulated to cycle rapidly after treatment with 5-fluorouracil. Blood 78:1237-40.

Harrison DE, Stone M, Astle CM. 1990. Effects of transplantation on the primitive immunohematopoietic stem cell (PSC). J Exp Med 172:431-437.

Hurbain-Kosmath I, Berault A, Noel N, Polkowska J, Bohin A, Jutisz M, Leiter EH, Beamer WG, Bedigian HG, Davisson MT, Harrison DE. 1990. Gonadotropes in a novel rat pituitary tumor cell line, RC-4B/C. Establishment and partial characterization of the cell line. In Vitro Cell Dev Biol 26:431-440.

Lerner CP, Harrison DE. 1990. 5-Fluorouracil spares hemopoietic stem cells responsible for long-term repopulation. Exp Hematol 18:114-118.

Sprecher E, Becker Y, Kraal G, Hall E, Harrison D, Shultz LD. 1990. Effect of aging on epidermal dendritic cell populations in C57BL/6J mice. J Invest Dermatol 94:247-53.

Stone M, Harrison DE. 1990. A stratified binomial marker model for bone-marrow repopulation experiments. J Theoret Biol 144:267-273.

Harrison DE, Archer JR. 1989. Natural selection for extended longevity from food restriction (editorial). Growth Dev Aging 53:3-6.

Harrison DE, Astle CM, Stone M. 1989. Numbers and functions of transplantable primitive immunohematopoietic stem cells. Effects of age. J Immunol 142:3833-40.

Gardner RV, Astle CM, Harrison DE. 1988. The decrease in long-term marrow repopulating capacity seen after transplantation is not the result of irradiation-induced stromal injury. Exp Hematol 16:49-54.

Harrison DE, Archer JR. 1988. Biomarkers of aging: Tissue markers. Future research needs, strategies, directions and priorities. Exp Gerontol 23:309-25.

Harrison DE, Astle CM, DeLaittre J. 1988. Effects of transplantation and age on immunohemopoietic cell growth in the splenic microenvironment. Exp Hematol 16:213-216.

Harrison DE, Astle CM, Lerner C. 1988. Number and continuous proliferative pattern of transplanted primitive immunohematopoietic stem cells. Proc Natl Acad Sci USA 85:822-826.

Leiter EH, Premdas F, Harrison DE, Lipson LG. 1988. Aging and glucose homeostasis in C57BL/6J male mice. FASEB 2:2907-2911.

Harrison DE. 1987. A semiquantitative measure of immune responses against erythropoietic stem cell antigens. Immunogenetics 26:123-9.

Anklesaria P, Klassen V, Sakakeeny MA, FitzGerald TJ, Harrison D, Rybau ME, Greenberger JS. 1987. Biological characterization of cloned permanent stromal cell lines from anemic Sl/Sld mice and +/+ littermates. Exp Hematol 15:636-44.

Harrison DE, Archer JR. 1987. Genetic differences in effects of food restriction on aging in mice. J Nutr 117:376-382.

Harrison DE, Lerner C, Hoppe P, Carlson GA, Alling D. 1987. Large numbers of primitive stem cells are active simultaneously in aggregated embryo chimeric mice. Blood 69:773-777.

Harrison DE, Lerner CP, Spooncer E. 1987. Erythropoietic repopulating ability of stem cells from long-term marrow culture. Blood 69:1021-1025.

Danis M, Harrison DE, Thurman RG. 1985. Effect of aging on oxidative metabolism and conjugation in perfused livers of an inbred strain of mice: A pilot study. Age 8:3-8.

Miller RA, Harrison DE. 1985. Delayed reduction in T cell precursor frequencies accompanies diet-induced lifespan extension. J Immunol 134:1426-9.

Harrison DE. 1984. Do hemopoietic stem cells age? Monogr Dev Biol 17:21-41.

Astle CM, Harrison DE. 1984. Effects of marrow donor and recipient age on immune responses. J Immunol 132:673-7.

Harrison DE, Archer JR, Astle CM. 1984. Effects of food restriction on aging: separation of food intake and adiposity. Proc Natl Acad Sci USA 81:1835-8.

Harrison DE, Astle CM, Lerner C. 1984. Ultimate erythropoietic repopulating abilities of fetal, young adult, and old adult cells compared using repeated irradiation. J Exp Med 160:759-71.

Harrison DE, Mobraaten LE. 1984. Skin graft rejection in mice repopulated with marrow of the skin donor type: a Skn gene in a congenic line. Immunogenetics 19:503-9.

Landreth KS, Kincade PW, Lee G, Harrison DE. 1984. B lymphocyte precursors in embryonic and adult W anemic mice. J Immunol 132:2724-9.

Harrison DE. 1983. Long-term erythropoietic repopulating ability of old, young, and fetal stem cells. J Exp Med 157:1496-504.

Harrison DE, Archer JR. 1983. Physiological assays for biological age in mice: relationship of collagen, renal function, and longevity. Exp Aging Res 9:245-51.

Harrison DE, Carlson GA. 1983. Effects of the beige mutation and irradiation on natural resistance to marrow grafts. J Immunol 130:484-9.

Legraverend C, Harrison DE, Ruscetti FW, Nebert DW. 1983. Bone marrow toxicity induced by oral benzo(a)pyrene: protection resides at the level of the intestine and liver. Toxicol Appl Pharmacol 70:390-401.

Wilson MC, Harrison DE. 1983. Decline in male mouse pheromone with age. Biol Reprod 29:81-6.

Harrison DE. 1982. Must we grow old? Biology Digest 8:11-25.

Hackbarth H, Harrison DE. 1982. Changes with age in renal function and morphology in C57BL/6, CBA/HT6, and B6CBAF1 mice. J Gerontol 37:540-7.

Harrison DE, Archer JR, Astle CM. 1982. The effect of hypophysectomy on thymic aging in mice. J Immunol 129:2673-7.

Harrison DE, Astle CM. 1982. Loss of stem cell repopulating ability upon transplantation. Effects of donor age, cell number, and transplantation procedure. J Exp Med 156:1767-79.

Ingram DK, Archer JR, Harrison DE, Reynolds MA. 1982. Physiological and behavioral correlates of lifespan in aged C57BL/6J mice. Exp Gerontol 17:295-303.

Harrison DE. 1981. F1 hybrid resistance: long-term systemic effects sensitive to irradiation and age. Immunogenetics 13:177-87.

Harrison DE. 1980. Competitive repopulation: a new assay for long-term stem cell functional capacity. Blood 55:77-81.

Harrison DE. 1980. Lifespans of immunohemopoietic stem cell lines. Adv Pathobiol 7:187-99.

Harrison DE. 1979. Proliferative capacity of erythropoietic stem cell lines and aging: an overview. Mech Ageing Dev 9:409-26.

Harrison DE. 1979. Mouse erythropoietic stem cell lines function normally 100 months: loss related to number of transplantations. Mech Ageing Dev 9:427-33.

Harrison DE, Astle CM, DeLaittre JA. 1979. Processing by the thymus is not required for cells that cure and populate W/WV recipients. Blood 54:1152-7.

Harrison DE. 1978. Genetically defined animals valuable in testing aging of erythroid and lymphoid stem cells and microenvironments. Birth Defects 14:187-96.

Harrison DE, Archer JR. 1978. Measurement of changes in mouse tail collagen with age: temperature dependence and procedural details. Exp Gerontol 13:75-82.

Harrison DE, Archer JR, Sacher GA, Boyce FM. 1978. Tail collagen aging in mice of thirteen different genotypes and two species: relationship to biological age. Exp Gerontol 13:63-73.

Harrison DE, Astle CM, Delaittre JA. 1978. Loss of proliferative capacity in immunohemopoietic stem cells caused by serial transplantation rather than aging. J Exp Med 147:1526-31.

Harrison DE, Astle CM, Doubleday JW. 1977. Cell lines from old immunodeficient donors give normal responses in young recipients. J Immunol 118:1223-7.

Harrison DE. 1976. Avoidance of graft versus host reactions in cured W-anemic mice. Transplantation 22:47-51.

Astle CM, Harrison DE. 1976. Mitogen synergism in low-responding CBA/CaJ mice. Cell Immunol 21:192-197.

Harrison DE, Astle CM. 1976. Population of lymphoid tissues in cured W-anemic mice by donor cells. Transplantation 22:42-6.

Harrison DE, Doubleday JW. 1976. Marrow allograft success with W/Wv anemic mice: relation to skin graft survival times. Immunogenetics 3:289-97.

Harrison DE. 1975. Normal function of transplanted marrow cell lines from aged mice. J Gerontol 30:279-85.

Harrison DE. 1975. Defective erythropoietic responses of aged mice not improved by young marrow. J Gerontol 30:286-8.

Harrison DE, Cherry M. 1975. Survival of marrow allografts in W/Wv anemic mice: effect of disparity at the Ea-2 locus. Immunogenetics 2:219-29.

Harrison DE, Doubleday JW. 1975. Normal function of immunologic stem cells from aged mice. J Immunol 114:1314-7.

Harrison DE, Malathi VG, Silber R. 1975. Elevated erythrocyte nucleoside deaminase levels in genetically anemic W/Wv and Sl/Sld mice. Blood Cells 1:605-14.

Harrison DE. 1973. Normal production of erythrocytes by mouse marrow continuous for 73 months. Proc Natl Acad Sci USA 70:3184-8.

Murphy ED, Harrison DE, Roths JB. 1973. Giant granules of beige mice. A quantitative marker for granulocytes in bone marrow transplantation. Transplantation 15:526-30.

Harrison DE. 1972. Lifesparing ability (in lethally irradiated mice) of W/Wv mouse marrow with no macroscopic colonies. Radiat Res 52:553-63.

Harrison DE. 1972. Marrow transplantation and iron therapy in mouse hereditary microcytic anemia. Blood 40:893-901.

Harrison DE. 1972. Normal function of transplanted mouse erythrocyte precursors for 21 months beyond donor life spans. Nature (New Biol) 237:220-2.

Harrison DE, Russell ES. 1972. Fetal liver erythropoiesis and yolk sac cells. Science 177:187.

Harrison DE, Russell ES. 1972. The response of W/Wv and Sl/Sld anaemic mice to haemopoietic stimuli. Br J Haematol 22:155-68.

Harrison DE, Weissberger E, Taube H. 1968. Binuclear ion containing nitrogen as a bridging group. Science 159:320-2.

Harrison DE, Taube H. 1967. The formation of Ru(NH3)5 N2+ in aqueous solution by direct action of molecular nitrogen. J Am Chem Soc 89:5706.

Books, Book Chapters and Reviews:

Harrison, DE. 2011. How to Test Problems and Potential of Rapamycin and the m-TOR pathway to Increase Human Healthspan. Annals of Medicine. Invited review, in press.

Ertl RP, Harrison DE. 2009. Hematopoietic stem cell aging. In: Regenerative Medicine. Scott EW, Fisher RC (eds). Chapter 38 (in press). Jones and Bartlett, Boston MA.

Ertl RP, Harrison DE. 2008. Dietary restriction: a model system probing the cell fate decision between cancer and senescence. In: Mouse Models of Human Blood Cancers: Basic Research and Pre-Clinical Applications. Li S, (ed). Chapter 6, pp. 133-156. Springer.

Flurkey K, Currer JM, Harrison DE. 2007. The Mouse in Aging Research. In: The Mouse in Biomedical Research, 2nd Edition, Vol III, Normative Biology, Husbandry, and Models. Fox JG et al, (eds). American College of Laboratory Animal Medicine (Elsevier), Burlington, MA. pp. 637-672.

Harrison DE, Chen J, Astle CM. 2001. Repopulating patterns of primitive hematopoietic stem cells. In: Stem Cell Biology. Marshak D, et al editors. Chapter 6, pp. 111-127, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY.

Harrison DE. 1995. Book review of The SAM Model of Senescence, Takeda T (ed). Exp Gerontol 30:545-8.

Harrison DE. 1993. Competitive repopulation in unirradiated normal recipients. Blood 81:2473-2474.

Harrison DE. 1992. Difficulties with studying accelerated aging. Growth Dev Aging 56:67 (editorial).

Harrison DE. 1992. Evaluating functional abilities of primitive hemopoietic stem cells. In: Stem Cells in Hematopoiesis: Animal Models and Human Transplantation, Muller-Sieburg C et al (eds), Springer-Verlag, Curr Top Microbiol Immunol 177:13-30.

Harrison DE, Archer JR, Kent B. 1991. Genes regulate effects of dietary restriction. In: Biological Effects of Dietary Restriction, Fishbein L (ed), Springer-Verlag, pp. 264-86.

Flurkey K, Harrison DE. 1990. Use of genetic models to investigate the hypophyseal regulation of senescence. In: Genetic Effects on Aging II, Harrison DE (ed), Caldwell, NJ, Telford Press, pp. 437-56.

Harrison DE, Archer JR. 1990. Genotype modulates the effects of caloric restriction on aging processes in rodents. In: The Potential for Nutritional Modulation of the Aging Processes, Ingram et al (eds), Trumbell, CT, Food and Nutrition Press, Inc., pp. 137-56.

Miller RA, Harrison DE. 1987. A clonal analysis of age-associated changes in T-cell reactivity. In: Aging and the Immune Response, Chapter 1, Goidl EA (ed.), New York, Marcel Dekker, Inc., pp. 1-26.

Harrison DE. 1985. Cell and tissue transplantation: a means of studying the aging process. In: Handbook of the Biology of Aging, Chapter 13, Finch CE, Schneider E (eds), New York, Van Nostrand & Reinhold Co., pp. 322-56.

Harrison DE, Archer JR, Astle CM. 1983. Use of the mouse in bioassays for aging. In: Intervention in the Aging Process, Part B, Basic Research and Preclinical Screening, Regelson W, Sinex FM (eds), New York, A.R. Liss, Inc., pp. 359-75.

Harrison DE. 1982. Experience with developing assays of physiological age. In: Biological Markers of Aging, Reff ME, Schneider EL (eds), NIH Publ. No. 82-2221, pp. 2-12.

Harrison DE. 1982. The nature of aging. In: Psychopharmacology Of Old Age, Wheatley D (ed), England, Oxford Univ. Press, pp. 3-14.

Harrison DE. 1981. Immunohemopoietic stem cell lines. In: Biological Mechanisms in Aging Conference, June 23-25, 1980, Schimke RT (ed), NIH Publ. No. 81-2194, pp. 505-16.

Harrison DE. 1981. Immunopoietic stem cell lines: effects of aging and transplantation. In: Immunological Aspects of Aging, Serge D, Smith L (eds), Marcel Dekker, Inc, New York, pp. 43-56.

Harrison DE. 1981. Measuring the functional abilities of stem cell lines. In: Immunological Techniques Applied to Aging Research, Adler WH, Nordin AA (eds), UniScience, Florida, CRC Press, pp. 37-50.

Harrison DE. 1979. Use of genetic anemias in mice as tools for hematological research, In: Cellular Dynamics of Hemaopoiesis, Vol. 8, No. 2. Clinics in Haematology, Lajtha LG (ed), W R Saunders, London, pp. 239-62.

Harrison DE, Mobraaten LE. 1979. Marrow allograft survival in W/Wv anemic mice: effects on skin graft survival and effects of preimmunization. In: Experimental Hematology Today, Baum SJ, Ledney GD (eds), New York, Springer-Verlag, pp. 233-38.

Harrison DE. 1978. Is limited cell proliferation the clock that times aging? In: The Biology of Aging, Behnke JA, Finch CE, Moment GB (eds), New York, Plenum Publishing Corp., pp. 33-55.

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