Survival Characteristics and Age-Adjusted Disease Incidences in C57BL/6 Mice Fed a Commonly Used Cereal-Based Diet Modulated by Dietary Restriction

Turturro, Angelo; Duffy, Peter H.; Hass, Bruce S.; Kodell, Ralph L.; Hart, Ronald W.

doi:10.1093/gerona/57.11.b379

Cited by 90 publications

(72 citation statements)

References 46 publications

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“…Thus, the increased lifespan of Mclk1 +/2 could be the result of greater resistance to infectious microorganisms. Interestingly, in the survival experiment with Mclk1 +/2 mutants conducted previously in the background used in this study (C57BL/6J), we observed a surprisingly short lifespan for the control Mclk1 +/+ mice (20) compared with previously reported results for animals in this background (40,41). This suggests that environmental conditions, such as exposure to microorganisms, were limiting the survival of the wild-type animals in this particular experiment, yet Mclk1 +/2 mutants had significantly better survival than their Mclk1 +/+ siblings, possibly because of their hair-trigger immune response.…”

Section: Level Of Mitochondrial Changes Observed In Mclk1supporting

confidence: 70%

Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1+/− Mouse Mutants

Wang¹,

Malo

Hekimi³

2009

The Journal of Immunology

115

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Mitochondrial reactive oxygen species (ROS) are believed to stabilize hypoxia-inducible factor (HIF)-1α, a transcriptional regulator of the immune response. Mclk1 encodes a mitochondrial protein that is necessary for ubiquinone biosynthesis. Heterozygote Mclk1+/− mutant mice are long-lived despite increased mitochondrial ROS and decreased energy metabolism. In this study, Mclk1+/− mutant mice in the C57BL/6J background displayed increased basal and induced expression of HIF-1α in liver and macrophages in association with elevated expression of inflammatory cytokines, in particular TNF-α. Mutant macrophages showed increased classical and decreased alternative activation, and mutant mice were hypersensitive to LPS. Consistent with these observations in vivo, knock-down of Mclk1 in murine RAW264.7 macrophage-like cells induced increased mitochondrial ROS as well as elevated expression of HIF-1α and secretion of TNF-α. We used an antioxidant peptide targeted to mitochondria to show that altered ROS metabolism is necessary for the enhanced expression of HIF-1α, which, in turn, is necessary for increased TNF-α secretion. These findings provide in vivo evidence for the action of mitochondrial ROS on HIF-1α activity and demonstrate that changes in mitochondrial function within physiologically tolerable limits modulate the immune response. Our results further suggest that altered immune function through a limited increase in HIF-1α expression can positively impact animal longevity.

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Section: Level Of Mitochondrial Changes Observed In Mclk1supporting

confidence: 70%

Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1+/− Mouse Mutants

Wang¹,

Malo

Hekimi³

2009

The Journal of Immunology

115

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“…We hypothesized that EpiSCs might differ from other somatic stem cells in their ability to resist aging because they must maintain complete integrity of the epidermal barrier for the lifetime of the mouse. Our results suggest that there is little, if any, loss in physiological capacity of murine EpiSCs over the lifetime of a mouse (Turturro et al, 2002).…”

Section: Discussionmentioning

confidence: 64%

Epidermal stem cells are resistant to cellular aging

Stern¹,

Bickenbach

2007

Aging Cell

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SummaryThe epidermis of the skin, acting as the primary physical barrier between self and environment, is a dynamic tissue whose maintenance is critical to the survival of an organism. Like most other tissues and organs, the epidermis is maintained and repaired by a population of resident somatic stem cells. The epidermal stem cells reside in the proliferative basal cell layer and are believed to persist for the lifetime of an individual. Acting through intermediaries known as transit amplifying cells, epidermal stem cells ensure that the enormous numbers of keratinocytes required for epidermal homeostasis to be maintained are generated. This continual demand for new cell production must be met over the entire lifetime of an individual. Breakdown of the epidermal barrier would have catastrophic consequences. This leads us to question whether or not epidermal stem cells represent a unique population of cells which, by necessity, might be resistant to cellular aging. We hypothesized that the full physiologic functional capacity of epidermal stem cells is maintained over an entire lifetime. Using murine skin epidermis as our model system, we compared several properties of young and old adult epidermal stem cells. We found that, over an average mouse's lifetime, there was no measurable loss in the physiologic functional capacity of epidermal stem cells, leading us to conclude that murine epidermal stem cells resist cellular aging.

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“…B6 mice exhibit a completely different pattern of marrow and HSC aging than BALB mice; overall functional ability of marrow increases with age, and DR does not alter this effect (Figure 3). Although DR increases lifespan and decreases cancer in B6 mice, [19][20][21][22][23]25,26 DR probably fails to increase HSC functional ability in aged B6 donors because levels are already higher than that found in young controls (Figure 3). In the F1, functional ability of marrow also increases with age and is not altered by DR (Figure 4), suggesting that this B6 phenotype is genetically dominant.…”

Section: Discussionmentioning

confidence: 99%

“…[14][15][16][17][18] Dietary restriction (DR) appears to break this paradigm. It is well known that DR decreases incidences of murine cancer with age, [19][20][21] counteracts most aging processes, and extends maximal lifespan in rodents. [22][23][24][25][26] Initial work in BALB mice showed that DR prevents both the loss of HSC clonal stability and the loss of BMC functional abilities with age.…”

Section: Introductionmentioning

confidence: 99%

Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated

Ertl

Chen

Astle

et al. 2008

Blood

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Diminished stem-cell functions with age may be a major cause of anemias and other defects. Unfortunately, treatments that increase stem-cell function can also increase the incidence of cancers. Lifelong dietary restriction (DR) is known to decrease spontaneous cancers and lengthen lifespan. This study examines the effect of DR on the ability of bone marrow cells to repopulate irradiated recipients and produce erythrocytes and lymphocytes. In BALB/cByJ (BALB) mice, repopulating abilities decline with age; DR ameliorates this trend. In C57BL/6J (B6) and (BALB ؋ B6) F1 hybrid (F1) mice, repopulating abilities increase with age; DR maintains this increase. Hematopoietic stem cell (HSC) numbers are highly variable in aged BALB mice; however, the observed loss of marrow function results from a major loss in repopulating ability per HSC. DR greatly ameliorates this loss of function with age. In contrast, function per HSC in B6 mice is affected neither by age nor by DR. Thus, DR increases or maintains increased marrow repopulating ability with age in the 3 different genotypes tested, but effects on function per HSC depend on genotype. That DR increases or maintains stem-cell function with age, while decreasing cancer, has far-reaching health implications. IntroductionDecline in repopulating and differentiating abilities of hematopoietic stem cells (HSCs) is characteristic of human diseases such as aplastic anemia and bone marrow (BM) failure. The common unexplained anemias 1 in elderly people can be caused by declining HSC functions with age. These anemias are serious diseases with high financial and personal costs. 2,3 The functional defects found in HSCs may be an example of a more generalized intrinsic loss of proliferative capacity that occurs in all aged adult stem cells. 4,5 Thus, interventions that maintain HSC function with age will help alleviate these serious diseases and benefit health.Laboratory mice provide well-recognized models in which to study hematopoietic defects. Genetic regulation of the age-related decline in BM repopulating and differentiating abilities has been demonstrated by the in vivo comparison of these abilities among mouse strains. [6][7][8][9][10] The ability of bone marrow cells (BMCs) to repopulate and produce erythrocytes and lymphocytes is reduced in old DBA/2J (D2) and old BALB/cByJ (BALB) compared with young controls. However, BM from old C57BL/6J (B6) mice actually has a greater repopulating ability than BM from young controls, 6-10 although its ability to repopulate after serial transplantation diminishes. 6,11,12 These strain-related differences are apparently the result of the underlying genetic differences in stem-cell exhaustion. 11 Because the patterns of aging differ among mouse strains, it is important to examine HSC aging in more than a single strain of mice.The maximal potential lifespan of an organism may in part be determined by the increased risk of cancer concomitant with mechanisms that can maintain stem-cell function in aging subjects. 12,13 Thus, the loss of funct...

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Survival Characteristics and Age-Adjusted Disease Incidences in C57BL/6 Mice Fed a Commonly Used Cereal-Based Diet Modulated by Dietary Restriction

Cited by 90 publications

References 46 publications

Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1+/− Mouse Mutants

Elevated Mitochondrial Reactive Oxygen Species Generation Affects the Immune Response via Hypoxia-Inducible Factor-1α in Long-Lived Mclk1+/− Mouse Mutants

Epidermal stem cells are resistant to cellular aging

Effects of dietary restriction on hematopoietic stem-cell aging are genetically regulated

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