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Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairment.

Candice E Van Skike, Jordan B Jahrling, Angela B Olson, Naomi L Sayre, Stacy A Hussong, Zoltan Ungvari, James D Lechleiter, Veronica Galvan.
American Journal of Physiology – Heart and Circulatory Physiology. 2018 Apr 1. doi: 10.1152/ajpheart.00570.2017. Epub 2017 Dec 22.

Abstract

An intact blood-brain barrier (BBB) limits entry of proinflammatory and neurotoxic blood-derived factors into the brain parenchyma. The BBB is damaged in Alzheimer’s disease (AD), which contributes significantly to the progression of AD pathologies and cognitive decline. However, the mechanisms underlying BBB breakdown in AD remain elusive, and no interventions are available for treatment or prevention. We and others recently established that inhibition of the mammalian/mechanistic target of rapamycin (mTOR) pathway with rapamycin yields significant neuroprotective effects, improving cerebrovascular and cognitive function in mouse models of AD. To test whether mTOR inhibition protects the BBB in neurological diseases of aging, we treated hAPP(J20) mice modeling AD and low-density lipoprotein receptor-null (LDLR-/-) mice modeling vascular cognitive impairment with rapamycin. We found that inhibition of mTOR abrogates BBB breakdown in hAPP(J20) and LDLR-/- mice. Experiments using an in vitro BBB model indicated that mTOR attenuation preserves BBB integrity through upregulation of specific tight junction proteins and downregulation of matrix metalloproteinase-9 activity. Together, our data establish mTOR activity as a critical mediator of BBB breakdown in AD and, potentially, vascular cognitive impairment and suggest that rapamycin and/or rapalogs could be used for the restoration of BBB integrity. NEW & NOTEWORTHY This report establishes mammalian/mechanistic target of rapamycin as a critical mediator of blood-brain barrier breakdown in models of Alzheimer’s disease and vascular cognitive impairment and suggests that drugs targeting the target of rapamycin pathway could be used for the restoration of blood-brain barrier integrity in disease states.


Hydrogen sulfide ameliorates aging-associated changes in the kidney.

Hak Joo Lee, Denis Feliers, Jeffrey L Barnes, Sae Oh, Goutam Ghosh Choudhury, Vivian Diaz, Veronica Galvan, Randy Strong, James Nelson, Adam Salmon, Christopher G Kevil, Balakuntalam S Kasinath
Geroscience. 2018 Apr;40(2):163-176. doi: 10.1007/s11357-018-0018-y. Epub 2018 May 1.

Abstract

Aging is associated with replacement of normal kidney parenchyma by fibrosis. Because hydrogen sulfide (H2S) ameliorates kidney fibrosis in disease models, we examined its status in the aging kidney. In the first study, we examined kidney cortical H2S metabolism and signaling pathways related to synthesis of proteins including matrix proteins in young and old male C57BL/6 mice. In old mice, increase in renal cortical content of matrix protein involved in fibrosis was associated with decreased H2S generation and AMPK activity, and activation of insulin receptor (IR)/IRS-2-Akt-mTORC1-mRNA translation signaling axis that can lead to increase in protein synthesis. In the second study, we randomized 18-19 month-old male C57BL/6 mice to receive 30 μmol/L sodium hydrosulfide (NaHS) in drinking water vs. water alone (control) for 5 months. Administration of NaHS increased plasma free sulfide levels. NaHS inhibited the increase in kidney cortical content of matrix proteins involved in fibrosis and ameliorated glomerulosclerosis. NaHS restored AMPK activity and inhibited activation of IR/IRS-2-Akt-mTORC1-mRNA translation axis. NaHS inhibited age-related increase in kidney cortical content of p21, IL-1β, and IL-6, components of the senescence-associated secretory phenotype. NaHS abolished increase in urinary albumin excretion seen in control mice and reduced serum cystatin C levels suggesting improved glomerular clearance function. We conclude that aging-induced changes in the kidney are associated with H2S deficiency. Administration of H2S ameliorates aging-induced kidney changes probably by inhibiting signaling pathways leading to matrix protein synthesis.


The development of a specific pathogen free (SPF) barrier colony of marmosets (Callithrix jacchus) for aging research.

Ross CN, Austad S, Brasky K, Brown CJ, Forney LJ, Gelfond JA, Lanford R, Richardson A, Tardif SD
Aging (Albany NY). 2017 Dec 7;9(12):2544-2558. doi: 10.18632/aging.101340.

Abstract:

A specific pathogen free (SPF) barrier colony of breeding marmosets (Callithrix jacchus) was established at the Barshop Institute for Longevity and Aging Studies. Rodent and other animal models maintained as SPF barrier colonies have demonstrated improved health and lengthened lifespans enhancing the quality and repeatability of aging research. The marmosets were screened for two viruses and several bacterial pathogens prior to establishing the new SPF colony. Twelve founding animals successfully established a breeding colony with increased reproductive success, improved health parameters, and increased median lifespan when compared to a conventionally housed, open colony. The improved health and longevity of marmosets from the SPF barrier colony suggests that such management can be used to produce a unique resource for future studies of aging processes in a nonhuman primate model.


Determinants of rodent longevity in the chaperone-protein degradation network.

Rodriguez KA, Valentine JM, Kramer DA, Gelfond JA, Kristan DM, Nevo E, Buffenstein R
Cell Stress Chaperones. 2016 May;21(3):453-66. doi: 10.1007/s12192-016-0672-x. Epub 2016 Feb 19.

Abstract:

Proteostasis is an integral component of healthy aging, ensuring maintenance of protein structural and functional integrity with concomitant impact upon health span and longevity. In most metazoans, increasing age is accompanied by a decline in protein quality control resulting in the accrual of damaged, self-aggregating cytotoxic proteins. A notable exception to this trend is observed in the longest-lived rodent, the naked mole-rat (NMR, Heterocephalus glaber) which maintains proteostasis and proteasome-mediated degradation and autophagy during aging. We hypothesized that high levels of the proteolytic degradation may enable better maintenance of proteostasis during aging contributing to enhanced species maximum lifespan potential (MLSP). We test this by examining proteasome activity, proteasome-related HSPs, the heat-shock factor 1 (HSF1) transcription factor, and several markers of autophagy in the liver and quadriceps muscles of eight rodent species with divergent MLSP. All subterranean-dwelling species had higher levels of proteasome activity and autophagy, possibly linked to having to dig in soils rich in heavy metals and where underground atmospheres have reduced oxygen availability. Even after correcting for phylogenetic relatedness, a significant (p < 0.02) positive correlation between MLSP, HSP25, HSF1, proteasome activity, and autophagy-related protein 12 (ATG12) was observed, suggesting that the proteolytic degradation machinery and maintenance of protein quality play a pivotal role in species longevity among rodents.


Graded Proteasome Dysfunction in Caenorhabditis elegans Activates an Adaptive Response Involving the Conserved SKN-1 and ELT-2 Transcription Factors and the Autophagy-Lysosome Pathway.

Keith SA, Maddux SK, Zhong Y, Chinchankar MN, Ferguson AA, Ghazi A, Fisher AL.
PLoS Genet. 2016 Feb 1;12(2):e1005823. doi: 10.1371/journal.pgen.1005823. eCollection 2016 Feb.

Abstract

The maintenance of cellular proteins in a biologically active and structurally stable state is a vital endeavor involving multiple cellular pathways. One such pathway is the ubiquitin-proteasome system that represents a major route for protein degradation, and reductions in this pathway usually have adverse effects on the health of cells and tissues. Here, we demonstrate that loss-of-function mutants of the Caenorhabditis elegans proteasome subunit, RPN-10, exhibit moderate proteasome dysfunction and unexpectedly develop both increased longevity and enhanced resistance to multiple threats to the proteome, including heat, oxidative stress, and the presence of aggregation prone proteins. The rpn-10 mutant animals survive through the activation of compensatory mechanisms regulated by the conserved SKN-1/Nrf2 and ELT-2/GATA transcription factors that mediate the increased expression of genes encoding proteasome subunits as well as those mediating oxidative- and heat-stress responses. Additionally, we find that the rpn-10 mutant also shows enhanced activity of the autophagy-lysosome pathway as evidenced by increased expression of the multiple autophagy genes including atg-16.2, lgg-1, and bec-1, and also by an increase in GFP::LGG-1 puncta. Consistent with a critical role for this pathway, the enhanced resistance of the rpn-10 mutant to aggregation prone proteins depends on autophagy genes atg-13, atg-16.2, and prmt-1. Furthermore, the rpn-10 mutant is particularly sensitive to the inhibition of lysosome activity via either RNAi or chemical means. We also find that the rpn-10 mutant shows a reduction in the numbers of intestinal lysosomes, and that the elt-2 gene also plays a novel and vital role in controlling the production of functional lysosomes by the intestine. Overall, these experiments suggest that moderate proteasome dysfunction could be leveraged to improve protein homeostasis and organismal health and longevity, and that the rpn-10 mutant provides a unique platform to explore these possibilities.


Dynamic differences in oxidative stress and the regulation of metabolism with age in visceral versus subcutaneous adipose.

Liu R, Pulliam DA, Liu Y, Salmon AB.
Redox Biol. 2015 Dec;6:401-408. doi: 10.1016/j.redox.2015.07.014. Epub 2015 Sep 3.

Abstract

Once thought only as storage for excess nutrients, adipose tissue has been shown to be a dynamic organ implicated in the regulation of many physiological processes. There is emerging evidence supporting differential roles for visceral and subcutaneous white adipose tissue in maintaining health, although how these roles are modulated by the aging process is not clear. However, the proposed beneficial effects of subcutaneous fat suggest that targeting maintenance of this tissue could lead to healthier aging. In this study, we tested whether alterations in adipose function with age might be associated with changes in oxidative stress. Using visceral and subcutaneous adipose from C57BL/6 mice, we discovered effects of both age and depot location on markers of lipolysis and adipogenesis. Conversely, accumulation of oxidative damage and changes in enzymatic antioxidant expression with age were largely similar between these two depots. The activation of each of the stress signaling pathways JNK and MAPK/ERK was relatively suppressed in subcutaneous adipose tissue suggesting reduced sensitivity to oxidative stress. Similarly, pre-adipocytes from subcutaneous adipose were significantly more resistant than visceral-derived cells to cell death caused by oxidative stress. Cellular respiration in visceral-derived cells was dramatically higher than in cells derived from subcutaneous adipose despite little evidence for differences in mitochondrial density. Together, our data identify molecular mechanisms by which visceral and subcutaneous adipose differ with age and suggest potential targetable means to preserve healthy adipose aging.


Metabolic consequences of long-term rapamycin exposure on common marmoset monkeys (Callithrix jacchus).

Ross C, Salmon A, Strong R, Fernandez E, Javors M, Richardson A, Tardif S.
Aging (Albany NY). 2015 Nov;7(11):964-73. doi: 10.18632/aging.100843.

Abstract:

Rapamycin has been shown to extend lifespan in rodent models, but the effects on metabolic health and function have been widely debated in both clinical and translational trials. Prior to rapamycin being used as a treatment to extend both lifespan and healthspan in the human population, it is vital to assess the side effects of the treatment on metabolic pathways in animal model systems, including a closely related non-human primate model. In this study, we found that long-term treatment of marmoset monkeys with orally-administered encapsulated rapamycin resulted in no overall effects on body weight and only a small decrease in fat mass over the first few months of treatment. Rapamycin treated subjects showed no overall changes in daily activity counts, blood lipids, or significant changes in glucose metabolism including oral glucose tolerance. Adipose tissue displayed no differences in gene expression of metabolic markers following treatment, while liver tissue exhibited suppressed G6Pase activity with increased PCK and GPI activity. Overall, the marmosets revealed only minor metabolic consequences of chronic treatment with rapamycin and this adds to the growing body of literature that suggests that chronic and/or intermittent rapamycin treatment results in improved health span and metabolic functioning. The marmosets offer an interesting alternative animal model for future intervention testing and translational modeling.

Keywords: animal models; antiaging; healthspan; longevity; nonhuman primate; sirolimus.


p53 and rapamycin are additive.

Christy B, Demaria M, Campisi J, Huang J, Jones D, Dodds SG, Williams C, Hubbard G, Livi CB, Gao X, Weintraub S, Curiel T, Sharp ZD, Hasty P.
Oncotarget. 2015 Jun 30;6(18):15802-13. doi: 10.18632/oncotarget.4602.

Abstract:

Mechanistic target of rapamycin (mTOR) is a kinase found in a complex (mTORC1) that enables macromolecular synthesis and cell growth and is implicated in cancer etiology. The rapamycin-FK506 binding protein 12 (FKBP12) complex allosterically inhibits mTORC1. In response to stress, p53 inhibits mTORC1 through a separate pathway involving cell signaling and amino acid sensing. Thus, these different mechanisms could be additive. Here we show that p53 improved the ability of rapamycin to: 1) extend mouse life span, 2) suppress ionizing radiation (IR)-induced senescence-associated secretory phenotype (SASP) and 3) increase the levels of amino acids and citric acid in mouse embryonic stem (ES) cells. This additive effect could have implications for cancer treatment since rapamycin and p53 are anti-oncogenic.

Keywords: SASP; longevity; mTOR; p53; rapamycin.


Obesity-induced oxidative stress, accelerated functional decline with age and increased mortality in mice

Zhang Y, Fischer KE, Soto V, Liu Y, Sosnowska D, Richardson A, Salmon AB.
Arch Biochem Biophys. 2015 Jun 15;576:39-48. doi: 10.1016/j.abb.2014.12.018. Epub 2015 Jan 3.

Abstract

Obesity is a serious chronic disease that increases the risk of numerous co-morbidities including metabolic syndrome, cardiovascular disease and cancer as well as increases risk of mortality, leading some to suggest this condition represents accelerated aging. Obesity is associated with significant increases in oxidative stress in vivo and, despite the well-explored relationship between oxidative stress and aging, the role this plays in the increased mortality of obese subjects remains an unanswered question. Here, we addressed this by undertaking a comprehensive, longitudinal study of a group of high fat-fed obese mice and assessed both their changes in oxidative stress and in their performance in physiological assays known to decline with aging. In female C57BL/6J mice fed a high-fat diet starting in adulthood, mortality was significantly increased as was oxidative damage in vivo. High fat-feeding significantly accelerated the decline in performance in several assays, including activity, gait, and rotarod. However, we also found that obesity had little effect on other markers of function and actually improved performance in grip strength, a marker of muscular function. Together, this first comprehensive assessment of longitudinal, functional changes in high fat-fed mice suggests that obesity may induce segmental acceleration of some of the aging process.

Keywords: Gait; Grip strength; Longevity; Obesity; Oxidation; Respirometry; Rotarod.


The paradoxical role of thioredoxin on oxidative stress and aging.

Cunningham GM, Roman MG, Flores LC, Hubbard GB, Salmon AB, Zhang Y, Gelfond J, Ikeno Y.
Arch Biochem Biophys. 2015 Jun 15;576:32-8. doi: 10.1016/j.abb.2015.02.025. Epub 2015 Feb 26.

Abstract:

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.

Keywords: Aging; Cancer; Knockout mouse; Oxidative stress; Thioredoxin; Transgenic mouse.