Overview
The Harrison research group investigates 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. We have shown that 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 define additional aging phenotypes and to test effects of these mutations on molecular pathways critical to aging processes. This research could lead to clinical treatments that delay endocrine-driven aging.
Another line of research involves hematopoietic (blood system) stem cells. Our focus is on 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. This research may suggest clinical treatments to retard the aging of stem cells and thus delay aging of tissue functions.
The long-term goal of all research in the Harrison lab is to promote healthful aging in humans, either by delaying normal aging processes or by minimizing or eliminating diseases of aging.
Research details
QTLs That Regulate Fibroblast Proliferation, and Hematopoietic Function With No Growth Hormone
Research in the biology of aging
In modern societies, by far the largest cause of ill health is aging. Our research program addresses various aspects of aging and the influence of genetics and environment on longevity and susceptibility to age-related disease. Additional information and updates can also be found on our lab site.
It is of great interest that Pou1f1 and Prop1 mutant mice, which are phenotypic dwarfs, outlive normal controls and that these dwarfs exhibit many forestalled phenotypes of aging (Flurkey et al., 2001, Proc Natl Acad Sci 98:6736-6741; Bartke et al. 2001. Exp Gerontol 36:21-28). However, these dwarf mice are born with pituitary defects, so that life span extension may depend on developmental abnormalities, especially at the expense of reproduction. Surgical removal of the pituitary dramatically reduces circulating growth hormone (GH), insulin-like growth factor-1 (IGF-1), and thyroid hormones, similar to the effects of dwarf mutations, and this can be done at older ages.
We surgically removed pituitaries from B6CBA/F1 male mice at ages ranging from before sexual maturity (0.75 months) to late middle age (15 months). Surgery at 0.75 months after birth failed to increase life span, but mice undergoing surgery at 1 month of age had a 15% increase in mean life span (P< 0.002), and those hypophysectomized at 9 months had a 21% increase (P< 0.002), relative to controls. Importantly, maximum life spans (oldest 20% of population) were also significantly extended, suggesting that mechanisms of aging affecting multiple causes of death were delayed (Table 1).
Table 1.
| Group | Mean LS | Maximum LS | P value v. Control (Complete LS) |
P value v. Control (Maximum LS) |
N |
| HX 0.75 month | 865±40 | 1047±32 | NS | NS | 15 |
| HX 1 month | 971±21 | 1162±32 | 0.002 | 0.001 | 39 |
| HX 9 months | 1030±33 | 1175±4 | 0.002 | 0.005 | 13 |
| HX 11 months | 924±16 | 1004±18 | NS | NS | 15 |
| HX 12 months | 886±14 | 941±14 | NS | NS | 12 |
| HX 15 mohts | 812±22 | 954±32 | NS | NS | 23 |
| Controls | 848±18 | 1026± | - | - | 70 |
Surgical pituitary removal well into mature adulthood (long past any chance of maturational abnormalities as seen in dwarf mice) can dramatically extend life span, and thus may affect mechanisms timing aging processes. Similar to dwarf mice, hypophysectomized mice eat less than controls (our unpublished data), so that at least part of the life span extension may be due to a mechanism related to caloric restriction.
Table 1 suggests drawbacks as well as benefits from the surgery. Hypophysectomy at 0.75 months of age produces an impairment, probably developmental, that prevents the extension of life span. When surgery is performed after 9 months, the maximal life span benefit for pituitary withdrawal has passed, and life span is limited by early-life pituitary function. Thus the life span-extending mechanism is unlikely to be due simply to endocrine withdrawal during senescence, as might be seen if the effect resulted from removing support for endocrine-dependent tumors. Apparently, by 11 months of age, a critical period has ended during which pituitary hormone(s) must be withdrawn to increase life span.
These results are the first example of life span extension by surgical pituitary removal in mice, and extend life span significantly even if conducted surprisingly late in life. These results parallel RNA interference (RNAi) studies of the insulin-like peptide receptor daf-2 in C. elegans, which demonstrated a maximal life span benefit when daf-2 expression was diminished in the young adult, with the benefit tapering when RNAi was initiated later in life (Dillin et al., 2002, Science 298:830-834). Perhaps endocrine function operates during mature adulthood to set life span potential in a wide range of species. Our study contributes to a growing body of research that suggests that evolutionarily conserved nutrient-responsive signaling pathways may be a promising target for interventions that delay human aging.
Research in hematopoietic stem cells (HSCs)
Hematopoietic stem cells (HSCs) maintain the lineages of the peripheral blood throughout life. Understanding the mechanisms regulating HSCs may suggest clinical applications for conditions ranging from anemia to leukemia. Mutations in the vital, evolutionarily conserved Kit (c-Kit, W) receptor disrupt HSC function. Because they have very different effects, they define the portions of the Kit receptor molecule that regulate specific stages of HSC differentiation. The mutants in Table 2 have essentially normal blood parameters. Table 2. Relative repopulating ability for myeloid and lymphoid lineages in W mutants
| Relative repopulating ability for erythrocytes |
Relative repopulating ability for lymphocytes | |||||
| Donor type | 2 months | 6 months | 10 months | 2 months | 6 months | 10 months |
| B6+/+ | 100 | 100 | 100 | 100 | 100 | 100 |
| W-v/+ | 8.0 | 5.4 | 4.1 | 21 | 9.1 | 5.2 |
| W-41J/+ | 12 | 6.0 | 3.2 | 25 | 8.0 | 4.6 |
| W-41J/W-41J | /td> | 0.22 | 6.0 | 0.55 | 0.22 | |
| W-42J/+ | 0.70 | 0.18 | 6.1 | 1.6 | 0.44 | |
Relative repopulating abilities were calculated as the RU values of the mutants divided by those of the normal control, and are presented as percentage of repopulating ability in Table 2. At all time points, the relative repopulating abilities for W-42J/+ BMCs were less than 1 percent of normal in erythrocytes, and less than 7 percent in lymphocytes; W-41J/W-41J BMCs were similar. BMCs from W-41J/+ and W-v/+ functioned at least 10-fold better, but still showed severe defects compared to B6. Kit mutants consistently produced lymphocytes better than erythrocytes.
We tested the degree that the repopulation defects could be explained by relative repopulating abilities in the bone marrow HSC, identified in Figure 1. Interestingly, the specific stages were affected differently by the different mutants. While these Kit mutations affect short term (ST)-HSC a small amount, and long term (LT)-HSC more severely, W-v/+ had the most severe LT-HSC defects, although the overall defect was much less than in W-41J/W-41J or W-42J/+. This also illustrates the need to invoke additional differentiation stages, such as the CFU-S, to explain the loss of repopulation in Kit donors, shown in Table 1.
Lab staff
Principal Investigator: David E. Harrison, Ph.D.
Co-Principal Investigators: Kevin Flurkey, Ph.D., Rong Yuan, Ph.D.
Senior Staff Scientist, Emeritus: Thomas Roderick, Ph.D.
Affiliated Scientist: John Macauley, Ph.D.
Research Laboratory Manager: C. Michael Astle, B.A., S.P.A.
Postdoctoral Fellow: Rob Ertl, Ph.D.
Research Assistant III: Jonathan Archer, B.S.
Research Assistant II: Joanne Currer, A.A.S.
Research Assistant I: Milly So, B.S.; M.S.
Laboratory Technician III: Patricia Harrison, B.S., David Shultz, Bernice Stork, Pam Krason
Visiting Investigators: R. Wilson Powers III, University of Washington, Simon Klebanov, Ph.D., Columbia University, John Papaconstantinou, Ph.D., University of Texas, Galveston
Research Administrative Assistant: Ashley Stanton
Publication listings
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.
Ertl RP, Chen J, Astle CM, Duffy TM, Harrison DE. 2007. Effects of dietary restriction on hematopoietic stem cell aging are genetically regulated. BLOOD Oct 19 (Epub ahead of print).
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.
Sharma Y, Astle CM, Harrison DE. 200-, Hematopoietic stem cell function increases with the W-57 allele of the Kit oncogene. Exp Hematol (in review).
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:
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.
