Publications by authors named "Derek M Huffman"

47 Publications

Heterochronic blood exchange attenuates age-related neuroinflammation and confers cognitive benefits: do microvascular protective effects play a role?

Geroscience 2021 Jan 28. Epub 2021 Jan 28.

Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.

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http://dx.doi.org/10.1007/s11357-021-00324-2DOI Listing
January 2021

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α.

Elife 2020 12 8;9. Epub 2020 Dec 8.

Department of Nutritional Sciences, University of Oklahoma Health Sciences Center, Oklahoma City, United States.

Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.
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http://dx.doi.org/10.7554/eLife.59616DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744101PMC
December 2020

Influences of circulatory factors on intervertebral disc aging phenotype.

Aging (Albany NY) 2020 06 11;12(12):12285-12304. Epub 2020 Jun 11.

Ferguson Laboratory for Orthopaedic Research, Department of Orthopaedic Surgery, University of Pittsburgh, E1641 Biomedical Science Tower, Pittsburgh, PA 15213, USA.

Whether disc aging is influenced by factors beyond its local environment is an important unresolved question. Here we performed heterochronic parabiosis in mice to study the effects of circulating factors in young and old blood on age-associated intervertebral disc degeneration. Compared to young isochronic pairs (Y-Y), young mice paired with old mice (Y-O) showed significant increases in levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic tissue degeneration, but negligible changes in cellular senescence markers (p16, p21). Compared to old isochronic pairs (O-O), old mice paired with young mice (O-Y) exhibited a significant decrease in expression of cellular senescence markers (p16, p21, p53), but only marginal decreases in the levels of disc MMP-13 and ADAMTS4, aggrecan fragmentation, and histologic degeneration. Thus, exposing old mice to young blood circulation greatly suppressed disc cellular senescence, but only slightly decreased disc matrix imbalance and degeneration. Conversely, exposing young mice to old blood accelerated their disc matrix imbalance and tissue degeneration, with little effects on disc cellular senescence. Thus, non-cell autonomous effects of circulating factors on disc cellular senescence and matrix homeostasis are complex and suggest that disc matrix homeostasis is modulated by systemic factors and not solely through local disc cellular senescence.
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http://dx.doi.org/10.18632/aging.103421DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343497PMC
June 2020

Heterochronic parabiosis regulates the extent of cellular senescence in multiple tissues.

Geroscience 2020 06 13;42(3):951-961. Epub 2020 Apr 13.

Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, 55455, USA.

An increase in the burden of senescent cells in tissues with age contributes to driving aging and the onset of age-related diseases. Genetic and pharmacologic elimination of senescent cells extends both health span and life span in mouse models. Heterochronic parabiosis in mice has been used to identify bloodborne, circulating pro- and anti-geronic factors able to drive or slow aging, respectively. However, whether factors in the circulation also regulate senescence is unknown. Here, we measured the expression of senescence and senescence-associated secretory phenotype (SASP) markers in multiple tissues from 4- to 18-month-old male mice that were either isochronically or heterochronically paired for 2 months. In heterochronic parabionts, the age-dependent increase in senescence and SASP marker expression was reduced in old mice exposed to a young environment, while senescence markers were concurrently increased in young heterochronic parabionts. These findings were supported by geropathology analysis using the Geropathology Grading Platform that showed a trend toward reduced hepatic lesions in old heterochronic parabionts. In summary, these results demonstrate that senescence is regulated in part by circulating geronic factors and suggest that one of the possible mediators of the rejuvenating effects with heterochronic parabiosis is through the reduction of the senescent cell burden.
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http://dx.doi.org/10.1007/s11357-020-00185-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286998PMC
June 2020

Central K Channels Modulate Glucose Effectiveness in Humans and Rodents.

Diabetes 2020 06 26;69(6):1140-1148. Epub 2020 Mar 26.

Albert Einstein College of Medicine, Bronx, NY

Hyperglycemia is a potent regulator of endogenous glucose production (EGP). Loss of this "glucose effectiveness" is a major contributor to elevated plasma glucose concentrations in type 2 diabetes (T2D). K channels in the central nervous system have been shown to regulate EGP in humans and rodents. We examined the contribution of central K channels to glucose effectiveness. Under fixed hormonal conditions (studies using a pancreatic clamp), hyperglycemia suppressed EGP by ∼50% in both humans without diabetes and normal Sprague-Dawley rats. By contrast, antagonism of K channels with glyburide significantly reduced the EGP-lowering effect of hyperglycemia in both humans and rats. Furthermore, the effects of glyburide on EGP and gluconeogenic enzymes were abolished in rats by intracerebroventricular administration of the K channel agonist diazoxide. These findings indicate that about half of the suppression of EGP by hyperglycemia is mediated by central K channels. These central mechanisms may offer a novel therapeutic target for improving glycemic control in subjects with T2D.
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http://dx.doi.org/10.2337/db19-1256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7243288PMC
June 2020

Circulating anti-geronic factors from heterochonic parabionts promote vascular rejuvenation in aged mice: transcriptional footprint of mitochondrial protection, attenuation of oxidative stress, and rescue of endothelial function by young blood.

Geroscience 2020 04 15;42(2):727-748. Epub 2020 Mar 15.

Vascular Cognitive Impairment and Neurodegeneration Program, Reynolds Oklahoma Center on Aging/Center for Geroscience and Healthy Brain Aging, Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 975 NE 10th Street, BRC 1311, Oklahoma City, OK, 73104, USA.

Aging-induced functional and phenotypic alterations of the vasculature (e.g., endothelial dysfunction, oxidative stress) have a central role in morbidity and mortality of older adults. It has become apparent in recent years that cell autonomous mechanisms alone are inadequate to explain all aspects of vascular aging. The present study was designed to test the hypothesis that age-related changes in circulating anti-geronic factors contribute to the regulation of vascular aging processes in a non-cell autonomous manner. To test this hypothesis, through heterochronic parabiosis we determined the extent, if any, to which endothelial function, vascular production of ROS, and shifts in the vascular transcriptome (RNA-seq) are modulated by the systemic environment. We found that in aortas isolated from isochronic parabiont aged (20-month-old) C57BL/6 mice [A-(A); parabiosis for 8 weeks] acetylcholine-induced endothelium-dependent relaxation was impaired and ROS production (dihydroethidium fluorescence) was increased as compared with those in aortas from young isochronic parabiont (6-month-old) mice [Y-(Y)]. The presence of young blood derived from young parabionts significantly improved endothelium-dependent vasorelaxation and attenuated ROS production in vessels of heterochronic parabiont aged [A-(Y)] mice. In aortas derived from heterochronic parabiont young [Y-(A)] mice, acetylcholine-induced relaxation and ROS production were comparable with those in aortas derived from Y-(Y) mice. Using RNA-seq we assessed transcriptomic changes in the aortic arch associated with aging and heterochronic parabiosis. We identified 347 differentially expressed genes in A-(A) animals compared with Y-(Y) controls. We have identified 212 discordant genes, whose expression levels differed in the aged phenotype, but have shifted back toward the young phenotype by the presence of young blood in aged A-(Y) animals. Pathway analysis shows that vascular protective effects mediated by young blood-regulated genes include mitochondrial rejuvenation. In conclusion, a relatively short-term exposure to young blood can rescue vascular aging phenotypes, including attenuation of oxidative stress, mitochondrial rejuvenation, and improved endothelial function. Our findings provide additional evidence supporting the significant plasticity of vascular aging and evidence for the existence of anti-geronic factors capable of exerting rejuvenating effects on the aging vasculature.
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http://dx.doi.org/10.1007/s11357-020-00180-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205954PMC
April 2020

Bring Back the Rat!

J Gerontol A Biol Sci Med Sci 2020 02;75(3):405-415

Department of Biology, College of Arts and Sciences, University of Alabama at Birmingham.

As 2020 is "The Year of the Rat" in the Chinese astrological calendar, it seems an appropriate time to consider whether we should bring back the laboratory rat to front-and-center in research on the basic biology of mammalian aging. Beginning in the 1970s, aging research with rats became common, peaking in 1992 but then declined dramatically by 2018 as the mouse became preeminent. The purpose of this review is to highlight some of the historical contributions as well as current advantages of the rat as a mammalian model of human aging, because we suspect at least a generation of researchers is no longer aware of this history or these advantages. Herein, we compare and contrast the mouse and rat in the context of several biological domains relevant to their use as appropriate models of aging: phylogeny/domestication, longevity interventions, pathology/physiology, and behavior/cognition. It is not the goal of this review to give a complete characterization of the differences between mice and rats, but to provide important examples of why using rats as well as mice is important to advance our understanding of the biology of aging.
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http://dx.doi.org/10.1093/gerona/glz298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021637PMC
February 2020

Author Correction: Intestinal crypts recover rapidly from focal damage with coordinated motion of stem cells that is impaired by aging.

Sci Rep 2019 Sep 30;9(1):13992. Epub 2019 Sep 30.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, 14853, USA.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-019-43805-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6768855PMC
September 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

Telomeres and Longevity: A Cause or an Effect?

Int J Mol Sci 2019 Jul 1;20(13). Epub 2019 Jul 1.

Department of Human Biology, University of Haifa, Haifa 3498838, Israel.

Telomere dynamics have been found to be better predictors of survival and mortality than chronological age. Telomeres, the caps that protect the end of linear chromosomes, are known to shorten with age, inducing cell senescence and aging. Furthermore, differences in age-related telomere attrition were established between short-lived and long-lived organisms. However, whether telomere length is a "biological thermometer" that reflects the biological state at a certain point in life or a biomarker that can influence biological conditions, delay senescence and promote longevity is still an ongoing debate. We cross-sectionally tested telomere length in different tissues of two long-lived (naked mole-rat and ) and two short-lived (rat and mice) species to tease out this enigma. While blood telomere length of the naked mole-rat (NMR) did not shorten with age but rather showed a mild elongation, telomere length in three tissues tested in the Spalax declined with age, just like in short-lived rodents. These findings in the NMR, suggest an age buffering mechanism, while in tissues the shortening of the telomeres are in spite of its extreme longevity traits. Therefore, using long-lived species as models for understanding the role of telomeres in longevity is of great importance since they may encompass mechanisms that postpone aging.
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http://dx.doi.org/10.3390/ijms20133233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651551PMC
July 2019

Parabiosis Incompletely Reverses Aging-Induced Metabolic Changes and Oxidant Stress in Mouse Red Blood Cells.

Nutrients 2019 Jun 14;11(6). Epub 2019 Jun 14.

Department of Biochemistry and Molecular Genetics, University of Colorado Denver - Anschutz Medical Campus, 12801 East 17th Ave RC1 South, Aurora, CO 80045, USA.

Mature red blood cells (RBCs) not only account for ~83% of the total host cells in the human body, but they are also exposed to all body tissues during their circulation in the bloodstream. In addition, RBCs are devoid of de novo protein synthesis capacity and, as such, they represent a perfect model to investigate system-wide alterations of cellular metabolism in the context of aging and age-related oxidant stress without the confounding factor of gene expression. In the present study, we employed ultra-high-pressure liquid chromatography coupled with mass spectrometry (UHPLC-MS)-based metabolomics and proteomics to investigate RBC metabolism across age in male mice (6, 15, and 25 months old). We report that RBCs from aging mice face a progressive decline in the capacity to cope with oxidant stress through the glutathione/NADPH-dependent antioxidant systems. Oxidant stress to tryptophan and purines was accompanied by declines in late glycolysis and methyl-group donors, a potential compensatory mechanism to repair oxidatively damaged proteins. Moreover, heterochronic parabiosis experiments demonstrated that the young environment only partially rescued the alterations in one-carbon metabolism in old mice, although it had minimal to no impact on glutathione homeostasis, the pentose phosphate pathway, and oxidation of purines and tryptophan, which were instead aggravated in old heterochronic parabionts.
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http://dx.doi.org/10.3390/nu11061337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627295PMC
June 2019

Central IGF-1 protects against features of cognitive and sensorimotor decline with aging in male mice.

Geroscience 2019 04 10;41(2):185-208. Epub 2019 May 10.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Forchheimer Bldg, Rm 236, 1300 Morris Park Avenue, Bronx, NY, 10461, USA.

Disruptions in growth hormone/insulin-like growth factor-1 (GH/IGF-1) signaling have been linked to improved longevity in mice and humans. Nevertheless, while IGF-1 levels are associated with increased cancer risk, they have been paradoxically implicated with protection from other age-related conditions, particularly in the brain, suggesting that strategies aimed at selectively increasing central IGF-1 action may have favorable effects on aging. To test this hypothesis, we generated inducible, brain-specific (TRE-IGF-1 × Camk2a-tTA) IGF-1 (bIGF-1) overexpression mice and studied effects on healthspan. Doxycycline was removed from the diet at 12 weeks old to permit post-development brain IGF-1 overexpression, and animals were monitored up to 24 months. Brain IGF-1 levels were increased approximately twofold in bIGF-1 mice, along with greater brain weights, volume, and myelin density (P < 0.05). Age-related changes in rotarod performance, exercise capacity, depressive-like behavior, and hippocampal gliosis were all attenuated specifically in bIGF-1 male mice (P < 0.05). However, chronic brain IGF-1 failed to prevent declines in cognitive function or neurovascular coupling. Therefore, we performed a short-term intranasal (IN) treatment of either IGF-1 or saline in 24-month-old male C57BL/6 mice and found that IN IGF-1 treatment tended to reduce depressive (P = 0.09) and anxiety-like behavior (P = 0.08) and improve motor coordination (P = 0.07) and unlike transgenic mice improved motor learning (P < 0.05) and visuospatial and working memory (P < 0.05). These data highlight important sex differences in how brain IGF-1 action impacts healthspan and suggest that translational approaches that target IGF-1 centrally can restore cognitive function, a possibility that should be explored as a strategy to combat age-related cognitive decline.
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http://dx.doi.org/10.1007/s11357-019-00065-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6544744PMC
April 2019

Unexpected systemic phenotypes result from focal combined deficiencies of forebrain insulin receptor/IGF-1 receptor signaling.

Proc Natl Acad Sci U S A 2019 03 11;116(13):5852-5854. Epub 2019 Mar 11.

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

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http://dx.doi.org/10.1073/pnas.1901970116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442574PMC
March 2019

Sarcosine Is Uniquely Modulated by Aging and Dietary Restriction in Rodents and Humans.

Cell Rep 2018 10;25(3):663-676.e6

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, USA; Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA; Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY, USA. Electronic address:

A hallmark of aging is a decline in metabolic homeostasis, which is attenuated by dietary restriction (DR). However, the interaction of aging and DR with the metabolome is not well understood. We report that DR is a stronger modulator of the rat metabolome than age in plasma and tissues. A comparative metabolomic screen in rodents and humans identified circulating sarcosine as being similarly reduced with aging and increased by DR, while sarcosine is also elevated in long-lived Ames dwarf mice. Pathway analysis in aged sarcosine-replete rats identify this biogenic amine as an integral node in the metabolome network. Finally, we show that sarcosine can activate autophagy in cultured cells and enhances autophagic flux in vivo, suggesting a potential role in autophagy induction by DR. Thus, these data identify circulating sarcosine as a biomarker of aging and DR in mammalians and may contribute to age-related alterations in the metabolome and in proteostasis.
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http://dx.doi.org/10.1016/j.celrep.2018.09.065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6280974PMC
October 2018

Intestinal crypts recover rapidly from focal damage with coordinated motion of stem cells that is impaired by aging.

Sci Rep 2018 Jul 20;8(1):10989. Epub 2018 Jul 20.

Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, 14853, USA.

Despite the continuous renewal and turnover of the small intestinal epithelium, the intestinal crypt maintains a 'soccer ball-like', alternating pattern of stem and Paneth cells at the base of the crypt. To study the robustness of the alternating pattern, we used intravital two-photon microscopy in mice with fluorescently-labeled Lgr5+ intestinal stem cells and precisely perturbed the mosaic pattern with femtosecond laser ablation. Ablation of one to three cells initiated rapid motion of crypt cells that restored the alternation in the pattern within about two hours with only the rearrangement of pre-existing cells, without any cell division. Crypt cells then performed a coordinated dilation of the crypt lumen, which resulted in peristalsis-like motion that forced damaged cells out of the crypt. Crypt cell motion was reduced with inhibition of the ROCK pathway and attenuated with old age, and both resulted in incomplete pattern recovery. This suggests that in addition to proliferation and self-renewal, motility of stem cells is critical for maintaining homeostasis. Reduction of this newly-identified behavior of stem cells could contribute to disease and age-related changes.
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http://dx.doi.org/10.1038/s41598-018-29230-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054609PMC
July 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

Dietary Walnuts Protect Against Obesity-Driven Intestinal Stem Cell Decline and Tumorigenesis.

Front Nutr 2018 31;5:37. Epub 2018 May 31.

Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY, United States.

Obesity can negatively impact intestinal homeostasis, and increase colon cancer risk and related mortality. Thus, given the alarmingly high rates of obesity in the US and globally, it is critical to identify practical strategies that can break the obesity-cancer link. Walnuts have been increasingly recognized to mitigate cancer risk, and contain many bioactive constituents with antioxidant and anti-inflammatory properties that could potentially counteract pathways thought to be initiators of obesity-related cancer. Therefore, the purpose of this study was to determine if walnuts could preserve intestinal homeostasis, and attenuate tumorigenesis and growth in the context of obesity and a high calorie diet. To this end, we studied effects of walnuts on these parameters under different dietary conditions in wildtype mice, two independent models ( and ), and in MC38 colon cancer cells , respectively. Walnuts did not alter the metabolic phenotype or intestinal morphology in normal mice fed either a low-fat diet (LFD), LFD with 6% walnuts (LFD+W), high-fat diet (HFD), or HFD with 7.6% walnuts (HFD+W). However, walnuts did lead to a significant reduction in circulating CCL5 and preserved intestinal stem cell (ISC) function under HFD-fed conditions. Furthermore, walnuts reduced tumor multiplicity in male HFD+W animals, as compared to HFD controls (3.7 ± 0.5 vs. 2.5 ± 0.3; = 0.015), tended to reduce the number of adenocarcinomas (0.67 ± 0.16 vs. 0.29 ± 0.12; = 0.07), and preferentially limited tumor growth in male mice ( = 0.019) fed a high-calorie western-style diet. In summary, these data demonstrate that walnuts confer significant protection against intestinal tumorigenesis and growth and preserve ISC function in the context of a high-calorie diet and obesity. Thus, these data add to the accumulating evidence connecting walnuts as a potentially effective dietary strategy to break the obesity-colon cancer link.
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http://dx.doi.org/10.3389/fnut.2018.00037DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5990619PMC
May 2018

40 YEARS of IGF1: IGF1: the Jekyll and Hyde of the aging brain.

J Mol Endocrinol 2018 07 8;61(1):T171-T185. Epub 2018 May 8.

Institute for Aging ResearchAlbert Einstein College of Medicine, Bronx, New York, USA

The insulin-like growth factor 1 (IGF1) signaling pathway has emerged as a major regulator of the aging process, from rodents to humans. However, given the pleiotropic actions of IGF1, its role in the aging brain remains complex and controversial. While IGF1 is clearly essential for normal development of the central nervous system, conflicting evidence has emerged from preclinical and human studies regarding its relationship to cognitive function, as well as cerebrovascular and neurodegenerative disorders. This review delves into the current state of the evidence examining the role of IGF1 in the aging brain, encompassing preclinical and clinical studies. A broad examination of the data indicates that IGF1 may indeed play opposing roles in the aging brain, depending on the underlying pathology and context. Some evidence suggests that in the setting of neurodegenerative diseases that manifest with abnormal protein deposition in the brain, such as Alzheimer's disease, reducing IGF1 signaling may serve a protective role by slowing disease progression and augmenting clearance of pathologic proteins to maintain cellular homeostasis. In contrast, inducing IGF1 deficiency has also been implicated in dysregulated function of cognition and the neurovascular system, suggesting that some IGF1 signaling may be necessary for normal brain function. Furthermore, states of acute neuronal injury, which necessitate growth, repair and survival signals to persevere, typically demonstrate salutary effects of IGF1 in that context. Appreciating the dual, at times opposing 'Dr Jekyll' and 'Mr Hyde' characteristics of IGF1 in the aging brain, will bring us closer to understanding its impact and devising more targeted IGF1-related interventions.
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http://dx.doi.org/10.1530/JME-18-0093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5988994PMC
July 2018

Mesenteric visceral lipectomy using tissue liquefaction technology reverses insulin resistance and causes weight loss in baboons.

Surg Obes Relat Dis 2018 06 9;14(6):833-841. Epub 2018 Mar 9.

Department of Genetics and Southwest National Primate Research Center (SNPRC), Texas Biomedical Research Institute, San Antonio, Texas. Electronic address:

Background: Visceral obesity is associated with diabetogenic and atherogenic abnormalities, including insulin resistance and increased risk for cardiometabolic diseases and mortality. Rodent lipectomy studies have demonstrated a causal link between visceral fat and insulin resistance, yet human omentectomy studies have failed to replicate this metabolic benefit, perhaps owing to the inability to target the mesentery.

Objectives: We aimed to demonstrate that safe and effective removal of mesenteric fat could be achieved in obese insulin-resistant baboons using tissue liquefaction technology.

Setting: Southwest National Primate Research Center, San Antonio, Texas.

Methods: Tissue liquefaction technology has been developed to enable mesenteric visceral lipectomy (MVL) to be safely performed without disturbing the integrity of surrounding nerves and vessels in the mesentary. After an initial MVL optimization study (n = 3), we then performed MVL (n = 4) or sham surgery (n = 2) in a cohort of insulin-resistant baboons, and the metabolic phenotype was assessed via hyperinsulinemic-euglycemic clamps at baseline and 6 weeks later.

Results: MVL led to a 75% improvement in glucose disposal at 6-weeks follow-up (P = .01). Moreover, despite removing only an average of 430 g of mesenteric fat (~1% of total body mass), MVL led to a 14.4% reduction in total weight (P = .001). Thus, these data demonstrate that mesenteric fat can be safely targeted for removal by tissue liquefaction technology in a nonhuman primate, leading to substantial metabolic improvements, including reversal of insulin resistance and weight loss.

Conclusions: These data provide the first demonstration of successful adipose tissue removal from the mesentery in a mammal. Importantly, we have demonstrated that when MVL is performed in obese, insulin-resistant baboons, insulin resistance is reversed, and significant weight loss occurs. Therefore, trials performing MVL in humans with abdominal obesity and related metabolic sequelae should be explored as a potential clinical tool to ameliorate insulin resistance and treat type 2 diabetes.
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http://dx.doi.org/10.1016/j.soard.2018.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391994PMC
June 2018

A simplified characterization of -adenosyl-l-methionine-consuming enzymes with 1-Step EZ-MTase: a universal and straightforward coupled-assay for and setting.

Chem Sci 2017 Sep 27;8(9):6601-6612. Epub 2017 Jul 27.

Department of Biochemistry , Albert Einstein College of Medicine , 1300 Morris Park Avenue , Bronx , New York 10461 , USA . Email: ; Email: ; ; Tel: +1-718-430-4120 ; Tel: +1-718-430-4128.

Methyltransferases use -adenosyl-l-methionine (SAM) to deposit methyl marks. Many of these epigenetic 'writers' are associated with gene regulation. As cancer etiology is highly correlated with misregulated methylation patterns, methyltransferases are emerging therapeutic targets. Successful assignment of methyltransferases' roles within intricate biological networks relies on (1) the access to enzyme mechanistic insights and (2) the efficient screening of chemical probes against these targets. To characterize methyltransferases and , we report a highly-sensitive one-step deaminase-linked continuous assay where the -adenosyl-l-homocysteine (SAH) enzyme-product is rapidly and quantitatively catabolized to -inosyl-l-homocysteine (SIH). To highlight the broad capabilities of this assay, we established enzymatic characteristics of two protein arginine methyltransferases (PRMT5 and PRMT7), a histone-lysine -methyltransferase (DIM-5) and a sarcosine/dimethylglycine -methyltransferase (SDMT). Since the coupling deaminase TM0936 displays robust activity over a broad pH-range we determined the pH dependence of SDMT reaction rates. TM0936 reactions are monitored at 263 nm, so a drawback may arise when methyl acceptor substrates absorb within this UV-range. To overcome this limitation, we used an isosteric fluorescent SAM-analog: -8-aza-adenosyl-l-methionine. Most enzymes tolerated this probe and sustained methyltransfers were efficiently monitored through loss of fluorescence at 360 nm. Unlike discontinuous radioactive- and antibody-based assays, our assay provides a simple, versatile and affordable approach towards the characterization of methyltransferases. Supported by three logs of linear dynamic range, the 1-Step EZ-MTase can detect methylation rates as low as 2 μM h, thus making it possible to quantify low nanomolar concentrations of glycine -methyltransferase within crude biological samples. With '-factors above 0.75, this assay is well suited to high-throughput screening and may promote the identification of novel therapeutics.
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http://dx.doi.org/10.1039/c7sc02830jDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5676521PMC
September 2017

inactivation, but not obesity, synergizes with deficiency to drive intestinal stem cell-derived tumorigenesis.

Endocr Relat Cancer 2017 06 28;24(6):253-265. Epub 2017 Mar 28.

Department of Molecular PharmacologyAlbert Einstein College of Medicine, Bronx, New York, USA

Obesity is a major risk factor for colorectal cancer and can accelerate Lgr5+ intestinal stem cell (ISC)-derived tumorigenesis after the inactivation of However, whether non-canonical pathways involving PI3K-Akt signaling in ISCs can lead to tumor formation, and if this can be further exacerbated by obesity is unknown. Despite the synergy between and inactivation in epithelial cells on intestinal tumor formation, their combined role in Lgr5+-ISCs, which are the most rapidly dividing ISC population in the intestine, is unknown. Lgr5+-GFP mice were provided low-fat diet (LFD) or high-fat diet (HFD) for 8 months, and the transcriptome was evaluated in Lgr5+-ISCs. For tumor studies, Lgr5+-GFP and Lgr5+-GFP- mice were tamoxifen treated to inactivate in ISCs and provided LFD or HFD until 14-15 months of age. Finally, various combinations of Lgr5+-ISC-specific, and -deleted mice were generated and evaluated for histopathology and survival. HFD did not overtly alter Akt signaling in ISCs, but did increase other metabolic pathways. deficiency, but not HFD, increased BrdU-positive cells in the small intestine ( < 0.05). However, combining and deficiency synergistically increased proliferative markers, tumor pathology and mortality, in a dose-dependent fashion ( < 0.05). In summary, we show that HFD alone fails to drive Akt signaling in ISCs and that deficiency is dispensable as a tumor suppressor in Lgr5+-ISCs. However, combining and deficiency in ISCs synergistically increases proliferation, tumor formation and mortality. Thus, aberrant Wnt/β-catenin, rather than PI3K-Akt signaling, is requisite for obesity to drive Lgr5+ ISC-derived tumorigenesis.
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http://dx.doi.org/10.1530/ERC-16-0536DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5505256PMC
June 2017

Evaluating Health Span in Preclinical Models of Aging and Disease: Guidelines, Challenges, and Opportunities for Geroscience.

J Gerontol A Biol Sci Med Sci 2016 11 16;71(11):1395-1406. Epub 2016 Aug 16.

Department of Biology, University of Alabama at Birmingham.

Life extension is no longer considered sufficient evidence of delayed aging in research animals. It must also be demonstrated that a broad swathe of health indicators have been extended. During a retreat of the Geroscience Network, a consortium of basic and clinical aging researchers, potential measures of mouse health were considered for their potential as easily standardized, highly informative metrics. Major health domains considered were neuromuscular, cognitive, cardiovascular, metabolic, and inflammatory functions as well as body composition and energetics and a multitude of assays interrogating these domains. A particularly sensitive metric of health is the ability to respond to, and recover, from stress. Therefore, the Network also considered stresses of human relevance that could be implemented in mouse models to assess frailty and resilience. Mouse models already exist for responses to forced immobility, cancer chemotherapy, infectious diseases, dietary challenges, and surgical stress, and it was felt that these could be employed to determine whether putative senescence-retarding interventions increased and extended organismal robustness. The Network discussed challenges in modeling age-related human chronic diseases and concluded that more attention needs to be paid to developing disease models with later age of onset, models of co- and multimorbidity, diversifying the strains and sexes commonly used in aging research, and considering additional species.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5055649PMC
http://dx.doi.org/10.1093/gerona/glw106DOI Listing
November 2016

The Somatotropic Axis in Human Aging: Framework for the Current State of Knowledge and Future Research.

Cell Metab 2016 06;23(6):980-989

Department of Medicine, Division of Endocrinology, Institute for Aging Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Medicine, Division of Geriatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA; Department of Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Mutations resulting in reduced signaling of the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis are associated with increased life- and healthspan across model organisms. Similar findings have been noted in human cohorts with functional mutations in the somatotropic axis, suggesting that this pathway may also be relevant to human aging and protection from age-related diseases. While epidemiological data indicate that low circulating IGF-1 level may protect aging populations from cancer, results remain inconclusive regarding most other diseases. We propose that studies in humans and animals need to consider differences in sex, pathway function, organs, and time-specific effects of GH/IGF-1 signaling in order to better define the role of the somatotropic axis in aging. Agents that modulate signaling of the GH/IGF-1 pathway are available for human use, but before they can be implemented in clinical studies that target aging and age-related diseases, researchers need to address the challenges discussed in this Review.
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http://dx.doi.org/10.1016/j.cmet.2016.05.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4919980PMC
June 2016

Energetic interventions for healthspan and resiliency with aging.

Exp Gerontol 2016 12 31;86:73-83. Epub 2016 May 31.

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

Several behavioral and pharmacological strategies improve longevity, which is indicative of delayed organismal aging, with the most effective interventions extending both life- and healthspan. In free living creatures, maintaining health and function into old age requires resilience against a multitude of stressors. Conversely, in experimental settings, conventional housing of rodents limits exposure to such challenges, thereby obscuring an accurate assessment of resilience. Caloric restriction (CR) and exercise, as well as pharmacologic strategies (resveratrol, rapamycin, metformin, senolytics), are well established to improve indices of health and aging, but some paradoxical effects have been observed on resilience. For instance, CR potently retards the onset of age-related diseases, and improves lifespan to a greater extent than exercise in a variety of models. However, exercise has proven more consistently beneficial to organismal resilience against a broad array of stressors, including infections, surgery, wound healing and frailty. CR can improve cellular stress defenses and protect from frailty, but also impairs the response to infections, bed rest and healing. How an intervention will impact not only longevity, health and function, but also resiliency, is critical to better understanding translational implications. Thus, organismal robustness represents a critical, albeit understudied aspect of aging, which needs more careful attention in order to better inform on how putative age-delaying strategies will impact preservation of health and function in response to stressors with aging in humans.
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http://dx.doi.org/10.1016/j.exger.2016.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133182PMC
December 2016

Relationships between Rodent White Adipose Fat Pads and Human White Adipose Fat Depots.

Front Nutr 2016 19;3:10. Epub 2016 Apr 19.

Department of Nutrition Science, University of Alabama at Birmingham , Birmingham, AL , USA.

The objective of this review was to compare and contrast the physiological and metabolic profiles of rodent white adipose fat pads with white adipose fat depots in humans. Human fat distribution and its metabolic consequences have received extensive attention, but much of what has been tested in translational research has relied heavily on rodents. Unfortunately, the validity of using rodent fat pads as a model of human adiposity has received less attention. There is a surprisingly lack of studies demonstrating an analogous relationship between rodent and human adiposity on obesity-related comorbidities. Therefore, we aimed to compare known similarities and disparities in terms of white adipose tissue (WAT) development and distribution, sexual dimorphism, weight loss, adipokine secretion, and aging. While the literature supports the notion that many similarities exist between rodents and humans, notable differences emerge related to fat deposition and function of WAT. Thus, further research is warranted to more carefully define the strengths and limitations of rodent WAT as a model for humans, with a particular emphasis on comparable fat depots, such as mesenteric fat.
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http://dx.doi.org/10.3389/fnut.2016.00010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835715PMC
May 2016

Naturally occurring mitochondrial-derived peptides are age-dependent regulators of apoptosis, insulin sensitivity, and inflammatory markers.

Aging (Albany NY) 2016 04;8(4):796-809

Leonard Davis School of Gerontology, University of Southern California, Los Angeles, CA 90089, USA.

Mitochondria are key players in aging and in the pathogenesis of age-related diseases. Recent mitochondrial transcriptome analyses revealed the existence of multiple small mRNAs transcribed from mitochondrial DNA (mtDNA). Humanin (HN), a peptide encoded in the mtDNA 16S ribosomal RNA region, is a neuroprotective factor. An in silico search revealed six additional peptides in the same region of mtDNA as humanin; we named these peptides small humanin-like peptides (SHLPs). We identified the functional roles for these peptides and the potential mechanisms of action. The SHLPs differed in their ability to regulate cell viability in vitro. We focused on SHLP2 and SHLP3 because they shared similar protective effects with HN. Specifically, they significantly reduced apoptosis and the generation of reactive oxygen species, and improved mitochondrial metabolism in vitro. SHLP2 and SHLP3 also enhanced 3T3-L1 pre-adipocyte differentiation. Systemic hyperinsulinemic-euglycemic clamp studies showed that intracerebrally infused SHLP2 increased glucose uptake and suppressed hepatic glucose production, suggesting that it functions as an insulin sensitizer both peripherally and centrally. Similar to HN, the levels of circulating SHLP2 were found to decrease with age. These results suggest that mitochondria play critical roles in metabolism and survival through the synthesis of mitochondrial peptides, and provide new insights into mitochondrial biology with relevance to aging and human biology.
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http://dx.doi.org/10.18632/aging.100943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4925829PMC
April 2016

Central insulin-like growth factor-1 (IGF-1) restores whole-body insulin action in a model of age-related insulin resistance and IGF-1 decline.

Aging Cell 2016 Feb 4;15(1):181-6. Epub 2015 Nov 4.

Division of Endocrinology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA.

Low insulin-like growth factor-1 (IGF-1) signaling is associated with improved longevity, but is paradoxically linked with several age-related diseases in humans. Insulin-like growth factor-1 has proven to be particularly beneficial to the brain, where it confers protection against features of neuronal and cognitive decline. While aging is characterized by central insulin resistance in the face of hyperinsulinemia, the somatotropic axis markedly declines in older humans. Thus, we hypothesized that increasing IGF-1 in the brain may prove to be a novel therapeutic alternative to overcome central insulin resistance and restore whole-body insulin action in aging. Utilizing hyperinsulinemic-euglycemic clamps, we show that old insulin-resistant rats with age-related declines in IGF-1 level demonstrate markedly improved whole-body insulin action, when treated with central IGF-1, as compared to central vehicle or insulin (P < 0.05). Furthermore, central IGF-1, but not insulin, suppressed hepatic glucose production and increased glucose disposal rates in aging rats (P < 0.05). Taken together, IGF-1 action in the brain and periphery provides a 'balance' between its beneficial and detrimental actions. Therefore, we propose that strategies aimed at 'tipping the balance' of IGF-1 action centrally are the optimal approach to achieve healthy aging and longevity in humans.
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http://dx.doi.org/10.1111/acel.12415DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4717281PMC
February 2016

Low insulin-like growth factor-1 level predicts survival in humans with exceptional longevity.

Aging Cell 2014 Aug 12;13(4):769-71. Epub 2014 Mar 12.

Department of Medicine, Division of Endocrinology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, USA; Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY, USA.

Attenuated growth hormone and insulin-like growth factor-1 (GH/IGF-1) signaling is associated with extended lifespan in several animal models. However, the effect of diminished GH/IGF-1 activity on survival in humans has not been confirmed. We tested the hypothesis that IGF-1 levels in nonagenarians (n = 184), measured at study enrollment, predict the duration of their incremental survival. In the Kaplan-Meier analysis, females with IGF-1 levels below the median (≤ 96 ng mL(-1) ) had significantly longer survival compared with females with levels above the median, P < 0.01. However, this survival advantage was not observed in males (P = 0.83). On the other hand, in both males and females with a history of cancer, lower IGF-1 levels predicted longer survival (P < 0.01). IGF-1 level remained a significant predictor of survival duration in linear regression models after multivariable adjustment in females (P = 0.01) and individuals with a history of cancer (P < 0.01). We show for the first time that low IGF-1 levels predict life expectancy in exceptionally long-lived individuals.
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http://dx.doi.org/10.1111/acel.12213DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4116456PMC
August 2014

Abdominal obesity, independent from caloric intake, accounts for the development of intestinal tumors in Apc(1638N/+) female mice.

Cancer Prev Res (Phila) 2013 Mar;6(3):177-87

Department of Medicine, Division of Endocrinology, Institute for Aging Research, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Golding Building Room 502, Bronx, NY 10461, USA.

To determine whether visceral fat (VF), independent of other confounders, is causally linked to intestinal tumorigenesis, we surgically removed visceral fat in Apc(1638/N+) mice. At 15 weeks of age, male and female Apc(1638/N+) mice were randomized to one of three groups: ad libitum, visceral fat removal (VF-) and ad libitum fed, or caloric restriction, and were studied for effects on tumorigenesis and survival. As compared with ad libitum, VF- and caloric restriction reduced macroadenomas to a similar extent (P < 0.05), but only caloric restriction significantly improved survival (P < 0.05). Given that a significant group × gender interaction was observed, we next examined males and females separately. In females, macroadenomas were markedly attenuated by VF- (1.33 ± 0.23 mean ± SE; P < 0.05), but not by caloric restriction (2.35 ± 0.25; P = 0.71), as compared with ad libitum (2.50 ± 0.34). In males, however, caloric restriction (1.71 ± 0.26; P < 0.01), but not VF- (2.94 ± 0.42; P = 0.29), reduced macroadenomas, as compared with ad libitum males (3.47 ± 0.30). In females, both VF- (P = 0.05) and caloric restriction (P < 0.01) improved survival, but not in male mice (P = 0.15). The benefits observed with caloric restriction were consistent with favorable metabolic adaptations, but protection conferred in VF- females was despite lower adiponectin levels (P < 0.05), and failure to reduce body mass, total adiposity, glucose, insulin, leptin, and chemokine (C-X-C motif) ligand 1 (CXCL-1) levels. In conclusion, these data provide the first causal evidence linking visceral fat to intestinal cancer risk, and suggest that factors, other than known metabolic mediators, may impact tumor development. Furthermore, these data emphasize that strategies designed to deplete visceral fat stores in humans should be considered in the prevention of intestinal cancer. Cancer Prev Res; 6(3); 177-87. ©2012 AACR.
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http://dx.doi.org/10.1158/1940-6207.CAPR-12-0414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595118PMC
March 2013

The critical role of metabolic pathways in aging.

Diabetes 2012 Jun;61(6):1315-22

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

Aging is characterized by a deterioration in the maintenance of homeostatic processes over time, leading to functional decline and increased risk for disease and death. The aging process is characterized metabolically by insulin resistance, changes in body composition, and physiological declines in growth hormone (GH), insulin-like growth factor-1 (IGF-1), and sex steroids. Some interventions designed to address features of aging, such as caloric restriction or visceral fat depletion, have succeeded in improving insulin action and life span in rodents. Meanwhile, pharmacologic interventions and hormonal perturbations have increased the life span of several mammalian species without necessarily addressing features of age-related metabolic decline. These interventions include inhibition of the mammalian target of rapamycin and lifetime deficiency in GH/IGF-1 signaling. However, strategies to treat aging in humans, such as hormone replacement, have mostly failed to achieve their desired response. We will briefly discuss recent advances in our understanding of the complex role of metabolic pathways in the aging process and highlight important paradoxes that have emerged from these discoveries. Although life span has been the major outcome of interest in the laboratory, a special focus is made in this study on healthspan, as improved quality of life is the goal when translated to humans.
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http://dx.doi.org/10.2337/db11-1300DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357299PMC
June 2012