Publications by authors named "Yuji Ikeno"

69 Publications

Development of a Geropathology Grading Platform for nonhuman primates.

Aging Pathobiol Ther 2020 ;2(1):16-19

Department of Comparative Medicine, School of Medicine, University of Washington, Seattle, WA, USA.

A geropathology grading platform (GGP) for assessing age-related lesions has been established and validated for in inbred strain of mice. Because nonhuman primates (NHPs) share significant similarities in aging and spontaneous chronic diseases with humans, they provide excellent translational value for correlating histopathology with biological and pathological events associated with increasing age. Descriptive age-associated pathology has been described for rhesus macaques and marmosets, but a grading platform similar to the mouse GGP does not exist. The value of these NHP models is enhanced by considerable historical data from clinical, bio-behavioral, and social domains that align with health span in these animals. Successful adaptation of the mouse GGP for NHPs will include 1) expanding the range of organs examined; 2) standardizing necropsy collection, tissue trimming, and descriptive lesion terminology; 3) expanding beyond rhesus macaques and marmosets to include other commonly used NHPs in research; and 4) creating a national resource for age-related pathology to complement the extensive in-life datasets. Adaptation of the GGP to include translational models other than mice will be crucial to advance geropathology designed to enhance aging research.
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http://dx.doi.org/10.31491/apt.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7717498PMC
January 2020

Diagnostic value of circulating cell-free mtDNA in patients with suspected thyroid cancer: ND4/ND1 ratio as a new potential plasma marker.

Mitochondrion 2020 11 7;55:145-153. Epub 2020 Oct 7.

University of Texas Health San Antonio, United States. Electronic address:

Thyroid cancer is the most common endocrine malignancy, and its incidence continues to rise. For clinicians with cancer patients, choosing and interpreting diagnostic laboratory studies has become increasingly important. Previously, changes in plasma free mitochondrial DNA levels have been found in colorectal, breast, lung, and urinary cancers, and have demonstrated diagnostic value. In this study, we investigated whether the occurrence and development of thyroid cancer might be predicted using mtDNA copy number (ND1), mtDNA integrity (ND4/ND1) and levels of cell-free nDNA (GAPDH). We analyzed ND1, ND4, and GAPDH levels in plasma and blood cells from 75 patients with thyroid cancer, 40 patients with nodular goiter, and 107 normal controls using real-time PCR. Although both the thyroid nodule and thyroid cancer patients had significantly increased ND1 levels, the ND4/ND1 ratio in the thyroid cancer group was higher than the thyroid nodule group (P < 0.05), and significantly higher than the normal control group (P < 0.01). Plasma levels of nuclear DNA (GAPDH) in the thyroid cancer group were also higher compared to normal (P < 0.05). These results indicate that increased intactness of plasma free mtDNA is associated with increased levels of plasma cell-free nDNA, and that the ND4/ND1 ratio has the potential to be a new detection indicator in thyroid cancer. Furthermore, we classified thyroid cancer patients according to clinical data including age, tumor size, and metastasis. We found significantly higher levels of GAPDH in malignant tissues. Because ND4/ND1 correlated with plasma GAPDH in the plasma studies, this also suggests a potential relationship between ND4 intactness and thyroid tumor tissue size. Taken together, our findings suggest a tumor-specific process involving increased release of intact mtDNA, detectable in the plasma, which differentiates normal patients from patients with thyroid cancer.
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http://dx.doi.org/10.1016/j.mito.2020.09.007DOI Listing
November 2020

Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis.

Cell Metab 2019 12 14;30(6):1024-1039.e6. Epub 2019 Nov 14.

Department of Comparative Medicine, Yale School of Medicine, New Haven, CT 06520, USA; Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA; Yale Center for Research on Aging, Yale School of Medicine, New Haven, CT 06520, USA. Electronic address:

During aging, visceral adiposity is often associated with alterations in adipose tissue (AT) leukocytes, inflammation, and metabolic dysfunction. However, the contribution of AT B cells in immunometabolism during aging is unexplored. Here, we show that aging is associated with an expansion of a unique population of resident non-senescent aged adipose B cells (AABs) found in fat-associated lymphoid clusters (FALCs). AABs are transcriptionally distinct from splenic age-associated B cells (ABCs) and show greater expansion in female mice. Functionally, whole-body B cell depletion restores proper lipolysis and core body temperature maintenance during cold stress. Mechanistically, the age-induced FALC formation, AAB, and splenic ABC expansion is dependent on the Nlrp3 inflammasome. Furthermore, AABs express IL-1R, and inhibition of IL-1 signaling reduces their proliferation and increases lipolysis in aging. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging AT.
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http://dx.doi.org/10.1016/j.cmet.2019.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944439PMC
December 2019

The enigmatic role of growth hormone in age-related diseases, cognition, and longevity.

Geroscience 2019 12 4;41(6):759-774. Epub 2019 Sep 4.

Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, 6900 Lake Nona Blvd., Orlando, FL, 32827, USA.

Growth hormone (GH) is secreted by the anterior pituitary gland and regulates various metabolic processes throughout the body. GH and IGF-1 levels are markedly reduced in older humans, leading some to hypothesize GH supplementation could be a viable "anti-aging" therapy. However, there is still much debate over the benefits and risks of GH administration. While an early study of GH administration reported reduced adiposity and lipid levels and increased bone mineral density, subsequent studies failed to show significant benefits. Conversely, other studies found positive effects of GH deficiency including extended life span, improved cognitive function, resistance to diseases such as cancer and diabetes, and improved insulin sensitivity despite a higher fat percentage. Thus, the roles of GH in aging and cognition remain unclear, and there is currently not enough evidence to support use of GH as an anti-aging or cognitive impairment therapy. Additional robust and longer-duration studies of efficacy and safety of GH administration are needed to determine if modulating GH levels could be a successful strategy for treating aging and age-related diseases.
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http://dx.doi.org/10.1007/s11357-019-00096-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6925094PMC
December 2019

Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis.

Cell Metab 2019 05 3;29(5):1061-1077.e8. Epub 2019 Jan 3.

Institute for Cell and Molecular Biosciences, Newcastle University Institute for Ageing, Campus for Ageing and Vitality, Newcastle upon Tyne NE4 5PL, UK; Robert and Arlene Kogod Center on Aging, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA; Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:

Cellular senescence entails a stable cell-cycle arrest and a pro-inflammatory secretory phenotype, which contributes to aging and age-related diseases. Obesity is associated with increased senescent cell burden and neuropsychiatric disorders, including anxiety and depression. To investigate the role of senescence in obesity-related neuropsychiatric dysfunction, we used the INK-ATTAC mouse model, from which p16-expressing senescent cells can be eliminated, and senolytic drugs dasatinib and quercetin. We found that obesity results in the accumulation of senescent glial cells in proximity to the lateral ventricle, a region in which adult neurogenesis occurs. Furthermore, senescent glial cells exhibit excessive fat deposits, a phenotype we termed "accumulation of lipids in senescence." Clearing senescent cells from high fat-fed or leptin receptor-deficient obese mice restored neurogenesis and alleviated anxiety-related behavior. Our study provides proof-of-concept evidence that senescent cells are major contributors to obesity-induced anxiety and that senolytics are a potential new therapeutic avenue for treating neuropsychiatric disorders.
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http://dx.doi.org/10.1016/j.cmet.2018.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509403PMC
May 2019

Extension of longevity and reduction of inflammation is ovarian-dependent, but germ cell-independent in post-reproductive female mice.

Geroscience 2019 02 13;41(1):25-38. Epub 2018 Dec 13.

Department of Animal, Dairy and Veterinary Sciences, Center for Integrated BioSystems, School of Veterinary Medicine, Utah State University, 4700 Old Main Hill, Logan, UT, 84322, USA.

Cardiovascular disease, rare in premenopausal women, increases sharply at menopause and is typically accompanied by chronic inflammation. Previous work in our laboratory demonstrated that replacing senescent ovaries in post-reproductive mice with young, actively cycling ovaries restored many health benefits, including decreased cardiomyopathy and restoration of immune function. Our objective here was to determine if depletion of germ cells from young transplanted ovaries would alter the ovarian-dependent extension of life and health span. Sixty-day-old germ cell-depleted and germ cell-containing ovaries were transplanted to post-reproductive, 17-month-old mice. Mean life span for female CBA/J mice is approximately 644 days. Mice that received germ cell-containing ovaries lived 798 days (maximum = 815 days). Mice that received germ cell-depleted ovaries lived 880 days (maximum = 1046 days), 29% further past the time of surgery than mice that received germ cell-containing ovaries. The severity of inflammation was reduced in all mice that received young ovaries, whether germ cell-containing or germ cell-depleted. Aging-associated inflammatory cytokine changes were reversed in post-reproductive mice by 4 months of new-ovary exposure. In summary, germ cell depletion enhanced the longevity-extending effects of the young, transplanted ovaries and, as with germ cell-containing ovaries, decreased the severity of inflammation, but did so independent of germ cells. Based on these observations, we propose that gonadal somatic cells are programed to preserve the somatic health of the organism with the intent of facilitating future germline transmission. As reproductive potential decreases or is lost, the incentive to preserve the somatic health of the organism is lost as well.
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http://dx.doi.org/10.1007/s11357-018-0049-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6423149PMC
February 2019

Continuous overexpression of thioredoxin 1 enhances cancer development and does not extend maximum lifespan in male C57BL/6 mice.

Pathobiol Aging Age Relat Dis 2018 23;8(1):1533754. Epub 2018 Oct 23.

Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.

We examined the effects of continuous overexpression of thioredoxin (Trx) 1 on aging in Trx1 transgenic mice [Tg()]. This study was conducted to test whether increased thioredoxin expression over the lifespan in mice would alter aging and age-related pathology because our previous study demonstrated that Tg(act-) mice had no significant maximum life extension, possibly due to the use of actin as a promoter, which may have resulted in loss of Trx1 overexpression during aging. To test this hypothesis, we generated new Trx1 transgenic mice using a fragment of the human genome containing the gene with an endogenous promoter to ensure continuous overexpression of Trx1 throughout the lifespan. Universal overexpression of Trx1 was observed, and Trx1 overexpression was maintained during aging (up to 22-24 months old) in the Tg() mice. The levels of Trx1 are significantly higher (approximately 4 to 31 fold) in all of the tissues examined in the Tg() mice compared to the wild-type (WT) littermates. The overexpression of Trx1 did not cause any changes in the levels of Trx2, glutaredoxin, glutathione, or other major antioxidant enzymes. The survival study demonstrated that male Tg() mice slightly extended the earlier part of the lifespan compared to WT littermates, but no significant life extension was observed over the lifespan. The cross-sectional pathological analysis (22-25 months old) showed that Tg() mice had a significantly higher severity of lymphoma and more tumor burden than WT mice, which was associated with the suppression of the apoptosis signal-regulating kinase 1 (ASK1) pathway. Our findings suggest that the increased levels of Trx1 over the lifespan in Tg() mice showed some beneficial effects (slight extension of lifespan) in the earlier part of life but had no significant effects on median or maximum lifespans, and increased Trx1 levels enhanced tumor development in old mice.
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http://dx.doi.org/10.1080/20010001.2018.1533754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201794PMC
October 2018

Daily Fasting Improves Health and Survival in Male Mice Independent of Diet Composition and Calories.

Cell Metab 2019 01 6;29(1):221-228.e3. Epub 2018 Sep 6.

Translational Gerontology Branch, National Institute on Aging, NIH, Baltimore, MD 21224, USA. Electronic address:

The importance of dietary composition and feeding patterns in aging remains largely unexplored, but was implicated recently in two prominent nonhuman primate studies. Here, we directly compare in mice the two diets used in the primate studies focusing on three paradigms: ad libitum (AL), 30% calorie restriction (CR), and single-meal feeding (MF), which accounts for differences in energy density and caloric intake consumed by the AL mice. MF and CR regimes enhanced longevity regardless of diet composition, which alone had no significant impact within feeding regimens. Like CR animals, MF mice ate quickly, imposing periods of extended daily fasting on themselves that produced significant improvements in morbidity and mortality compared with AL. These health and survival benefits conferred by periods of extended daily fasting, independent of dietary composition, have major implications for human health and clinical applicability.
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http://dx.doi.org/10.1016/j.cmet.2018.08.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6326845PMC
January 2019

Thioredoxin overexpression in both the cytosol and mitochondria accelerates age-related disease and shortens lifespan in male C57BL/6 mice.

Geroscience 2018 12 18;40(5-6):453-468. Epub 2018 Aug 18.

Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX, 78245, USA.

To investigate the role of increased levels of thioredoxin (Trx) in both the cytosol (Trx1) and mitochondria (Trx2) on aging, we have conducted a study to examine survival and age-related diseases using male mice overexpressing Trx1 and Trx2 (TXNTg × TXN2Tg). Our study demonstrated that the upregulation of Trx in both the cytosol and mitochondria in male TXNTg × TXN2Tg C57BL/6 mice resulted in a significantly shorter lifespan compared to wild-type (WT) mice. Cross-sectional pathology data showed a slightly higher incidence of neoplastic diseases in TXNTg × TXN2Tg mice than WT mice. The incidence of lymphoma, a major neoplastic disease in C57BL/6 mice, was slightly higher in TXNTg × TXN2Tg mice than in WT mice, and more importantly, the severity of lymphoma was significantly higher in TXNTg × TXN2Tg mice compared to WT mice. Furthermore, the total number of histopathological changes in the whole body (disease burden) was significantly higher in TXNTg × TXN2Tg mice compared to WT mice. Therefore, our study suggests that overexpression of Trx in both the cytosol and mitochondria resulted in deleterious effects on aging and accelerated the development of age-related diseases, especially cancer, in male C57BL/6 mice.
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http://dx.doi.org/10.1007/s11357-018-0039-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6294725PMC
December 2018

Senolytics improve physical function and increase lifespan in old age.

Nat Med 2018 08 9;24(8):1246-1256. Epub 2018 Jul 9.

Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA.

Physical function declines in old age, portending disability, increased health expenditures, and mortality. Cellular senescence, leading to tissue dysfunction, may contribute to these consequences of aging, but whether senescence can directly drive age-related pathology and be therapeutically targeted is still unclear. Here we demonstrate that transplanting relatively small numbers of senescent cells into young mice is sufficient to cause persistent physical dysfunction, as well as to spread cellular senescence to host tissues. Transplanting even fewer senescent cells had the same effect in older recipients and was accompanied by reduced survival, indicating the potency of senescent cells in shortening health- and lifespan. The senolytic cocktail, dasatinib plus quercetin, which causes selective elimination of senescent cells, decreased the number of naturally occurring senescent cells and their secretion of frailty-related proinflammatory cytokines in explants of human adipose tissue. Moreover, intermittent oral administration of senolytics to both senescent cell-transplanted young mice and naturally aged mice alleviated physical dysfunction and increased post-treatment survival by 36% while reducing mortality hazard to 65%. Our study provides proof-of-concept evidence that senescent cells can cause physical dysfunction and decreased survival even in young mice, while senolytics can enhance remaining health- and lifespan in old mice.
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http://dx.doi.org/10.1038/s41591-018-0092-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6082705PMC
August 2018

Late-life targeting of the IGF-1 receptor improves healthspan and lifespan in female mice.

Nat Commun 2018 06 19;9(1):2394. Epub 2018 Jun 19.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, 10461, USA.

Diminished growth factor signaling improves longevity in laboratory models, while a reduction in the somatotropic axis is favorably linked to human aging and longevity. Given the conserved role of this pathway on lifespan, therapeutic strategies, such as insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibodies (mAb), represent a promising translational tool to target human aging. To this end, we performed a preclinical study in 18-mo-old male and female mice treated with vehicle or an IGF-1R mAb (L2-Cmu, Amgen Inc), and determined effects on aging outcomes. Here we show that L2-Cmu preferentially improves female healthspan and increases median lifespan by 9% (P = 0.03) in females, along with a reduction in neoplasms and inflammation (P ≤ 0.05). Thus, consistent with other models, targeting IGF-1R signaling appears to be most beneficial to females. Importantly, these effects could be achieved at advanced ages, suggesting that IGF-1R mAbs could represent a promising therapeutic candidate to delay aging.
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http://dx.doi.org/10.1038/s41467-018-04805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6008442PMC
June 2018

IGF-1 has sexually dimorphic, pleiotropic, and time-dependent effects on healthspan, pathology, and lifespan.

Geroscience 2017 04 13;39(2):129-145. Epub 2017 Apr 13.

Reynolds Oklahoma Center on Aging, Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, 975 NE 10th Street, SLY-BRC 1303, Oklahoma City, OK, 73104, USA.

Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.
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http://dx.doi.org/10.1007/s11357-017-9971-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5411370PMC
April 2017

A new role for oxidative stress in aging: The accelerated aging phenotype in Sod1 mice is correlated to increased cellular senescence.

Redox Biol 2017 04 2;11:30-37. Epub 2016 Nov 2.

Department of Geriatric Medicine and the Reynolds Oklahoma Center on Aging, Oklahoma University Health Science Center, Oklahoma City, OK, USA; Oklahoma City VA Medical Center, Oklahoma City, OK, USA. Electronic address:

In contrast to other mouse models that are deficient in antioxidant enzymes, mice null for Cu/Zn-superoxide dismutase (Sod1 mice) show a major decrease in lifespan and several accelerated aging phenotypes. The goal of this study was to determine if cell senescence might be a contributing factor in the accelerated aging phenotype observed in the Sod1 mice. We focused on kidney because it is a tissue that has been shown to a significant increase in senescent cells with age. The Sod1 mice are characterized by high levels of DNA oxidation in the kidney, which is attenuated by DR. The kidney of the Sod1 mice also have higher levels of double strand DNA breaks than wild type (WT) mice. Expression (mRNA and protein) of p16 and p21, two of the markers of cellular senescence, which increased with age, are increased significantly in the kidney of Sod1 mice as is β-gal staining cells. In addition, the senescence associated secretory phenotype was also increased significantly in the kidney of Sod1 mice compared to WT mice as measured by the expression of transcripts for IL-6 and IL-1β. Dietary restriction of the Sod1 mice attenuated the increase in DNA damage, cellular senescence, and expression of IL-6 and IL-1β. Interestingly, the Sod1 mice showed higher levels of circulating cytokines than WT mice, suggesting that the accelerated aging phenotype shown by the Sod1 mice could result from increased inflammation arising from an accelerated accumulation of senescent cells. Based on our data with Sod1 mice, we propose that various bouts of increased oxidative stress over the lifespan of an animal leads to the accumulation of senescent cells. The accumulation of senescent cells in turn leads to increased inflammation, which plays a major role in the loss of function and increased pathology that are hallmark features of aging.
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http://dx.doi.org/10.1016/j.redox.2016.10.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5109248PMC
April 2017

Effects of Sex, Strain, and Energy Intake on Hallmarks of Aging in Mice.

Cell Metab 2016 06;23(6):1093-1112

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, 251 Bayview Boulevard, Suite 100, Baltimore, MD 21224, USA. Electronic address:

Calorie restriction (CR) is the most robust non-genetic intervention to delay aging. However, there are a number of emerging experimental variables that alter CR responses. We investigated the role of sex, strain, and level of CR on health and survival in mice. CR did not always correlate with lifespan extension, although it consistently improved health across strains and sexes. Transcriptional and metabolomics changes driven by CR in liver indicated anaplerotic filling of the Krebs cycle together with fatty acid fueling of mitochondria. CR prevented age-associated decline in the liver proteostasis network while increasing mitochondrial number, preserving mitochondrial ultrastructure and function with age. Abrogation of mitochondrial function negated life-prolonging effects of CR in yeast and worms. Our data illustrate the complexity of CR in the context of aging, with a clear separation of outcomes related to health and survival, highlighting complexities of translation of CR into human interventions.
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http://dx.doi.org/10.1016/j.cmet.2016.05.027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4911707PMC
June 2016

Liver specific expression of Cu/ZnSOD extends the lifespan of Sod1 null mice.

Mech Ageing Dev 2016 Mar 1;154:1-8. Epub 2016 Feb 1.

Oklahoma City VA Medical Center, Oklahoma City, OK, USA; Oklahoma University Health Science Center, Oklahoma City, OK, USA. Electronic address:

Genetic ablation of CuZn-superoxide dismutase (Sod1) in mice (Sod1(-/-) mice) leads to shortened lifespan with a dramatic increase in hepatocellular carcinoma and accelerated aging phenotypes, including early onset sarcopenia. To study the tissue specific effects of oxidative stress in the Sod1(-/-) mice, we generated mice that only express the human SOD1 gene specifically in the liver of Sod1(-/-) mice (Sod1(-/-)/hSOD1(alb) mice). Expression of hSOD1 in the liver of Sod1(-/-) mice improved liver function, reduced oxidative damage in liver, and partially restored the expression of several genes involved in tumorigenesis, which are abnormally expressed in the livers of the Sod1(-/-) mice. However, liver specific expression of hSOD1 did not prevent the loss of body weight and muscle mass and alterations in the structure of neuromuscular junctions. The expression of hSOD1 in the liver of Sod1(-/-) mice significantly improved the lifespan of Sod1(-/-) mice; however, the lifespan of the Sod1(-/-)/hSOD1(alb) mice was still significantly shorter than wild type mice.
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http://dx.doi.org/10.1016/j.mad.2016.01.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855307PMC
March 2016

Significant life extension by ten percent dietary restriction.

Ann N Y Acad Sci 2016 Jan 22;1363:11-7. Epub 2015 Dec 22.

Department of Biobehavioral Health, Pennsylvania State University, State College, Pennsylvania.

Although it is well documented that dietary restriction (DR) increases the life span of rodents and other animals, this increase is observed at relatively high levels of DR, in which rodents are typically fed 40% less than that consumed by rodents fed ad libitum. It is generally assumed that lower levels of DR will have a lesser impact on life span; however, there are very little published data on the effect of low levels of DR on life span. In this study, we show that 10% DR increased life span to almost the same extent as 40% DR. While both 10% and 40% DR resulted in similar changes in non-neoplastic lesions, 10% DR had no significant effect on the incidence of neoplasia (except for pituitary adenoma), and 40% DR resulted in a significant reduction (40%) in neoplasia. These data clearly demonstrate that the life span of F344 rats does not increase linearly with the level of DR; rather, even a low level of DR can substantially affect life span. This rodent study has important translational implications because it suggests that a modest reduction in calories might have significant health benefits for humans.
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http://dx.doi.org/10.1111/nyas.12982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4836177PMC
January 2016

Rapamycin Increases Mortality in db/db Mice, a Mouse Model of Type 2 Diabetes.

J Gerontol A Biol Sci Med Sci 2016 07 5;71(7):850-7. Epub 2015 Oct 5.

Department of Medicine, The Barshop Institute for Longevity and Aging Studies, University of Texas Health Sciences Center, San Antonio. Research Service and.

We examined the effect of rapamycin on the life span of a mouse model of type 2 diabetes, db/db mice. At 4 months of age, male and female C57BLKSJ-lepr (db/db) mice (db/db) were placed on either a control diet, lacking rapamycin or a diet containing rapamycin and maintained on these diets over their life span. Rapamycin was found to reduce the life span of the db/db mice. The median survival of male db/db mice fed the control and rapamycin diets was 349 and 302 days, respectively, and the median survival of female db/db mice fed the control and rapamycin diets was 487 and 411 days, respectively. Adjusting for gender differences, rapamycin increased the mortality risk 1.7-fold in both male and female db/db mice. End-of-life pathological data showed that suppurative inflammation was the main cause of death in the db/db mice, which is enhanced slightly by rapamycin treatment.
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http://dx.doi.org/10.1093/gerona/glv170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906320PMC
July 2016

Measures of Healthspan as Indices of Aging in Mice-A Recommendation.

J Gerontol A Biol Sci Med Sci 2016 Apr 22;71(4):427-30. Epub 2015 Aug 22.

Department of Biology, University of Alabama at Birmingham.

Over the past decade, a large number of discoveries have shown that interventions (genetic, pharmacological, and nutritional) increase the lifespan of invertebrates and laboratory rodents. Therefore, the possibility of developing antiaging interventions for humans has gone from a dream to a reality. However, it has also become apparent that we need more information than just lifespan to evaluate the translational potential of any proposed antiaging intervention to humans. Information is needed on how an intervention alters the "healthspan" of an animal, that is, how the physiological functions that change with age are altered. In this report, we describe the utility and the limitations of assays in mice currently available for measuring a wide range of physiological functions that potentially impact quality of life. We encourage investigators and reviewers alike to expect at minimum an overall assessment of health in several domains across several ages before an intervention is labeled as "increasing healthspan." In addition, it is important that investigators indicate any tests in which the treated group did worse or did not differ statistically from controls because overall health is a complex phenotype, and no intervention discovered to date improves every aspect of health. Finally, we strongly recommend that functional measurements be performed in both males and females so that sex differences in the rate of functional decline in different domains are taken into consideration.
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http://dx.doi.org/10.1093/gerona/glv080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834833PMC
April 2016

IGF-1 Regulates Vertebral Bone Aging Through Sex-Specific and Time-Dependent Mechanisms.

J Bone Miner Res 2016 Feb 3;31(2):443-54. Epub 2015 Sep 3.

Reynolds Oklahoma Center on Aging, Donald W. Reynolds Department of Geriatric Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, whereas others report that loss of IGF-1 is beneficial because it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igf(f/f) mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan: early in postnatal development (crossing albumin-cyclic recombinase [Cre] mice with Igf(f/f) mice); and in early adulthood and in late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using micro-computed tomography (μCT) and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NF-κB-ligand (RANKL) levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2-fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data suggest the age-related loss of vertebral bone density in females can be reduced by modifying circulating IGF-1 levels early in life.
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http://dx.doi.org/10.1002/jbmr.2689DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4854536PMC
February 2016

The Geropathology Research Network: An Interdisciplinary Approach for Integrating Pathology Into Research on Aging.

J Gerontol A Biol Sci Med Sci 2016 Apr 4;71(4):431-4. Epub 2015 Aug 4.

Department of Comparative Medicine, University of Washington, Seattle.

Geropathology is the study of aging and age-related lesions and diseases in the form of whole necropsies/autopsies, surgical biopsies, histology, and molecular biomarkers. It encompasses multiple subspecialties of geriatrics, anatomic pathology, molecular pathology, clinical pathology, and gerontology. In order to increase the consistency and scope of communication in the histologic and molecular pathology assessment of tissues from preclinical and clinical aging studies, a Geropathology Research Network has been established consisting of pathologists and scientists with expertise in the comparative pathology of aging, the design of aging research studies, biostatistical methods for analysis of aging data, and bioinformatics for compiling and annotating large sets of data generated from aging studies. The network provides an environment to promote learning and exchange of scientific information and ideas for the aging research community through a series of symposia, the development of uniform ways of integrating pathology into aging studies, and the statistical analysis of pathology data. The efforts of the network are ultimately expected to lead to a refined set of sentinel biomarkers of molecular and anatomic pathology that could be incorporated into preclinical and clinical aging intervention studies to increase the relevance and productivity of these types of investigations.
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http://dx.doi.org/10.1093/gerona/glv079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5014185PMC
April 2016

Removal of growth hormone receptor (GHR) in muscle of male mice replicates some of the health benefits seen in global GHR-/- mice.

Aging (Albany NY) 2015 Jul;7(7):500-12

Global disruption of the GH receptor in mice (GHR-/-) produces a large and reproducible extension in lifespan. Since lack of GH action in muscle resulting in improved glucose homeostasis is potentially a mechanism by which GHR-/- mice are long-lived, and since no information on muscle-specific GHR disruption in females is available, we generated and characterized a line of muscle-specific GHR disrupted (MuGHRKO) mice. As expected, male MuGHRKO mice had improved fasting blood glucose, insulin, c-peptide, and glucose tolerance. In contrast, female MuGHRKO mice exhibited normal glucose, insulin, and glucose tolerance. Body weight was mildly but significantly altered in opposite directions in males (decreased) and females (increased) compared to controls. Grip strength and treadmill endurance were unchanged with advanced age in both sexes, suggesting that the direct action of GH on muscle has minimal effect on age-related musculoskeletal frailty. Longevity was unchanged in both sexes at Ohio University and significantly increased for males at University of Michigan. These data suggest that removal of GHR in muscle of male MuGHRKO mice replicates some of the health benefits seen in global GHR-/- mice including improvements to glucose homeostasis and smaller body weight in males, which may explain the trends observed in lifespan.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4543039PMC
http://dx.doi.org/10.18632/aging.100766DOI Listing
July 2015

MTOR regulates the pro-tumorigenic senescence-associated secretory phenotype by promoting IL1A translation.

Nat Cell Biol 2015 Aug 6;17(8):1049-61. Epub 2015 Jul 6.

Buck Institute for Research on Aging, Novato, California 94945, USA.

The TOR (target of rapamycin) kinase limits longevity by poorly understood mechanisms. Rapamycin suppresses the mammalian TORC1 complex, which regulates translation, and extends lifespan in diverse species, including mice. We show that rapamycin selectively blunts the pro-inflammatory phenotype of senescent cells. Cellular senescence suppresses cancer by preventing cell proliferation. However, as senescent cells accumulate with age, the senescence-associated secretory phenotype (SASP) can disrupt tissues and contribute to age-related pathologies, including cancer. MTOR inhibition suppressed the secretion of inflammatory cytokines by senescent cells. Rapamycin reduced IL6 and other cytokine mRNA levels, but selectively suppressed translation of the membrane-bound cytokine IL1A. Reduced IL1A diminished NF-κB transcriptional activity, which controls much of the SASP; exogenous IL1A restored IL6 secretion to rapamycin-treated cells. Importantly, rapamycin suppressed the ability of senescent fibroblasts to stimulate prostate tumour growth in mice. Thus, rapamycin might ameliorate age-related pathologies, including late-life cancer, by suppressing senescence-associated inflammation.
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http://dx.doi.org/10.1038/ncb3195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691706PMC
August 2015

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan.

Cell Metab 2015 Jul 18;22(1):86-99. Epub 2015 Jun 18.

Longevity Institute, School of Gerontology, and Department of Biological Sciences, University of Southern California, Los Angeles, CA 90089, USA; IFOM, FIRC Institute of Molecular Oncology, 20139 Milano, Italy. Electronic address:

Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.
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http://dx.doi.org/10.1016/j.cmet.2015.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4509734PMC
July 2015

New insights and current concepts of the oxidative stress theory of aging.

Authors:
Yuji Ikeno

Arch Biochem Biophys 2015 Jun 28;576. Epub 2015 Mar 28.

Barshop Institute for Longevity and Aging Studies, Audie L. Murphy Memorial VA Hospital, San Antonio, TX, United States.

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http://dx.doi.org/10.1016/j.abb.2015.03.019DOI Listing
June 2015

New insights and current concepts of the oxidative stress theory of aging.

Authors:
Yuji Ikeno

Arch Biochem Biophys 2015 Jun 28;576. Epub 2015 Mar 28.

Barshop Institute for Longevity and Aging Studies, Audie L. Murphy Memorial VA Hospital, San Antonio, TX, United States.

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http://dx.doi.org/10.1016/j.abb.2015.03.019DOI Listing
June 2015

The paradoxical role of thioredoxin on oxidative stress and aging.

Arch Biochem Biophys 2015 Jun 26;576:32-8. Epub 2015 Feb 26.

Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78245, United States; Department of Pathology, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, United States; Research Service, Audie L. Murphy VA Hospital South Texas Veterans Health Care System, San Antonio, TX 78229, United States; Geriatric Research and Education Clinical Center, Audie L. Murphy VA Hospital South Texas Veterans Health Care System, San Antonio, TX 78229, United States. Electronic address:

In spite of intensive study, there is still controversy about the free radical or oxidative stress theory of aging, particularly in mammals. Our laboratory has conducted the first detailed studies on the role of thioredoxin (Trx) in the cytosol (Trx1) and in mitochondria (Trx2) on oxidative stress and aging using unique mouse models either overexpressing or down-regulating Trx1 or Trx2. The results generated from our lab and others indicate that: (1) oxidative stress and subsequent changes in signaling pathways could have different pathophysiological impacts at different stages of life; (2) changes in redox-sensitive signaling controlled by levels of oxidative stress and redox state could play more important roles in pathophysiology than accumulation of oxidative damage; (3) changes in oxidative stress and redox state in different cellular compartments (cytosol, mitochondria, or nucleus) could play different roles in pathophysiology during aging, and their combined effects show more impact on aging than changes in either oxidative stress or redox state alone; and (4) the roles of oxidative stress and redox state could have different pathophysiological consequences in different organs/tissues/cells or pathophysiological conditions. To critically test the role of oxidative stress on aging and investigate changes in redox-sensitive signaling pathways, further study is required.
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http://dx.doi.org/10.1016/j.abb.2015.02.025DOI Listing
June 2015

Altered metabolism and resistance to obesity in long-lived mice producing reduced levels of IGF-I.

Am J Physiol Endocrinol Metab 2015 Apr 3;308(7):E545-53. Epub 2015 Feb 3.

Department of Pathology and Laboratory Medicine, Drexel University College of Medicine, Philadelphia, Pennsylvania;

The extension of lifespan due to reduced insulin-like growth factor 1 (IGF-I) signaling in mice has been proposed to be mediated through alterations in metabolism. Previously, we showed that mice homozygous for an insertion in the Igf1 allele have reduced levels of IGF-I, are smaller, and have an extension of maximum lifespan. Here, we tested whether this specific reduction of IGF-I alters glucose metabolism both on normal rodent chow and in response to high-fat feeding. We found that female IGF-I-deficient mice were lean on a standard rodent diet but paradoxically displayed an insulin-resistant phenotype. However, these mice gained significantly less weight than normal controls when placed on a high-fat diet. In control animals, insulin response was significantly impaired by high-fat feeding, whereas IGF-I-deficient mice showed a much smaller shift in insulin response after high-fat feeding. Gluconeogenesis was also elevated in the IGF-I-deficient mice relative to controls on both normal and high-fat diet. An analysis of metabolism and respiratory quotient over 24 h indicated that the IGF-I-deficient mice preferentially utilized fatty acids as an energy source when placed on a high-fat diet. These results indicate that reduction in the circulating and tissue IGF-I levels can produce a metabolic phenotype in female mice that increases peripheral insulin resistance but renders animals resistant to the deleterious effects of high-fat feeding.
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http://dx.doi.org/10.1152/ajpendo.00558.2014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4385875PMC
April 2015

Reduced expression of MYC increases longevity and enhances healthspan.

Cell 2015 Jan 22;160(3):477-88. Epub 2015 Jan 22.

Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, RI 02912, USA. Electronic address:

MYC is a highly pleiotropic transcription factor whose deregulation promotes cancer. In contrast, we find that Myc haploinsufficient (Myc(+/-)) mice exhibit increased lifespan. They show resistance to several age-associated pathologies, including osteoporosis, cardiac fibrosis, and immunosenescence. They also appear to be more active, with a higher metabolic rate and healthier lipid metabolism. Transcriptomic analysis reveals a gene expression signature enriched for metabolic and immune processes. The ancestral role of MYC as a regulator of ribosome biogenesis is reflected in reduced protein translation, which is inversely correlated with longevity. We also observe changes in nutrient and energy sensing pathways, including reduced serum IGF-1, increased AMPK activity, and decreased AKT, TOR, and S6K activities. In contrast to observations in other longevity models, Myc(+/-) mice do not show improvements in stress management pathways. Our findings indicate that MYC activity has a significant impact on longevity and multiple aspects of mammalian healthspan.
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http://dx.doi.org/10.1016/j.cell.2014.12.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624921PMC
January 2015

Reductions in serum IGF-1 during aging impair health span.

Aging Cell 2014 Jun 30;13(3):408-18. Epub 2013 Dec 30.

Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, 10461, USA.

In lower or simple species, such as worms and flies, disruption of the insulin-like growth factor (IGF)-1 and the insulin signaling pathways has been shown to increase lifespan. In rodents, however, growth hormone (GH) regulates IGF-1 levels in serum and tissues and can modulate lifespan via/or independent of IGF-1. Rodent models, where the GH/IGF-1 axis was ablated congenitally, show increased lifespan. However, in contrast to rodents where serum IGF-1 levels are high throughout life, in humans, serum IGF-1 peaks during puberty and declines thereafter during aging. Thus, animal models with congenital disruption of the GH/IGF-1 axis are unable to clearly distinguish between developmental and age-related effects of GH/IGF-1 on health. To overcome this caveat, we developed an inducible liver IGF-1-deficient (iLID) mouse that allows temporal control of serum IGF-1. Deletion of liver Igf-1 gene at one year of age reduced serum IGF-1 by 70% and dramatically impaired health span of the iLID mice. Reductions in serum IGF-1 were coupled with increased GH levels and increased basal STAT5B phosphorylation in livers of iLID mice. These changes were associated with increased liver weight, increased liver inflammation, increased oxidative stress in liver and muscle, and increased incidence of hepatic tumors. Lastly, despite elevations in serum GH, low levels of serum IGF-1 from 1 year of age compromised skeletal integrity and accelerated bone loss. We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology.
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http://dx.doi.org/10.1111/acel.12188DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4326899PMC
June 2014