D. E. Harrison

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Inhibition of the TOR signalling pathway by genetic or pharmacological intervention extends lifespan in invertebrates, including yeast, nematodes and fruitflies; however, whether inhibition of mTOR signalling can extend lifespan in a mammalian species was unknown. Here we report that rapamycin, an inhibitor of the mTOR pathway, extends median and maximal(More)
Single-gene mutations that extend lifespan provide valuable tools for the exploration of the molecular basis for age-related changes in cell and tissue function and for the pathophysiology of age-dependent diseases. We show here that mice homozygous for loss-of-function mutations at the Pit1 (Snell dwarf) locus show a >40% increase in mean and maximal(More)
Rapamycin was administered in food to genetically heterogeneous mice from the age of 9 months and produced significant increases in life span, including maximum life span, at each of three test sites. Median survival was extended by an average of 10% in males and 18% in females. Rapamycin attenuated age-associated decline in spontaneous activity in males(More)
Rapamycin increases lifespan in mice, but whether this represents merely inhibition of lethal neoplastic diseases, or an overall slowing in multiple aspects of aging is currently unclear. We report here that many forms of age-dependent change, including alterations in heart, liver, adrenal glands, endometrium, and tendon, as well as age-dependent decline in(More)
To better characterize aging in mice, the Jackson Aging Center carried out a lifespan study of 31 genetically-diverse inbred mouse strains housed in a specific pathogen-free facility. Clinical assessments were carried out every 6 months, measuring multiple age-related phenotypes including neuromuscular, kidney and heart function, body composition, bone(More)
Rapamycin, an inhibitor of mTOR kinase, increased median lifespan of genetically heterogeneous mice by 23% (males) to 26% (females) when tested at a dose threefold higher than that used in our previous studies; maximal longevity was also increased in both sexes. Rapamycin increased lifespan more in females than in males at each dose evaluated, perhaps(More)
We used stochastic modeling and computer simulation to study the replication, apoptosis, and differentiation of murine hemopoietic stem cells (HSCs) in vivo. This approach allows description of the behavior of an unobserved population (ie, HSCs) on the basis of the behavior of observed progeny cells (ie, granulocytes and lymphocytes). The results of(More)
The National Institute on Aging's Interventions Testing Program was established to evaluate agents that are purported to increase lifespan and delay the appearance of age-related disease in genetically heterogeneous mice. Up to five compounds are added to the study each year and each compound is tested at three test sites (The Jackson Laboratory, University(More)
OBJECTIVE To define effects of strain on PHSC (primitive hematopoietic stem cells) senescence (decline in function with age) in vivo, and to map a locus that regulates PHSC senescence. MATERIALS AND METHODS Long-term function and self-renewal were compared in bone marrow cells (BMC) from old and young mice of three strains: BALB/cBy (BALB), DBA/2 (D2) and(More)
Using 5-color fluorescence-activated cell sorting, we isolated a subset of murine pluripotent hematopoietic stem cells (PHSC) with the phenotype Lin(-) Sca(+) kit(+) CD38(+) CD34(-) that appears to fulfill the criteria for most primitive PHSC. In the presence of whole bone marrow (BM) competitor cells, these cells produced reconstitution in lethally(More)