Publications
Tau protein aggregation is associated with cellular senescence in the brain.
Musi N, Valentine JM, Sickora KR, Baeuerle E, Thompson CS, Shen Q, Orr ME.
Aging Cell. 2018 Dec;17(6):e12840. doi: 10.1111/acel.12840. Epub 2018 Oct 11.
Abstract
Tau protein accumulation is the most common pathology among degenerative brain diseases, including Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), traumatic brain injury (TBI), and over twenty others. Tau-containing neurofibrillary tangle (NFT) accumulation is the closest correlate with cognitive decline and cell loss (Arriagada, Growdon, Hedley-Whyte, & Hyman, ), yet mechanisms mediating tau toxicity are poorly understood. NFT formation does not induce apoptosis (de Calignon, Spires-Jones, Pitstick, Carlson, & Hyman, 2009), which suggests that secondary mechanisms are driving toxicity. Transcriptomic analyses of NFT-containing neurons microdissected from postmortem AD brain revealed an expression profile consistent with cellular senescence. This complex stress response induces aberrant cell cycle activity, adaptations to maintain survival, cellular remodeling, and metabolic dysfunction. Using four AD transgenic mouse models, we found that NFTs, but not Aβ plaques, display a senescence-like phenotype. Cdkn2a transcript level, a hallmark measure of senescence, directly correlated with brain atrophy and NFT burden in mice. This relationship extended to postmortem brain tissue from humans with PSP to indicate a phenomenon common to tau toxicity. Tau transgenic mice with late-stage pathology were treated with senolytics to remove senescent cells. Despite the advanced age and disease progression, MRI brain imaging and histopathological analyses indicated a reduction in total NFT density, neuron loss, and ventricular enlargement. Collectively, these findings indicate a strong association between the presence of NFTs and cellular senescence in the brain, which contributes to neurodegeneration. Given the prevalence of tau protein deposition among neurodegenerative diseases, these findings have broad implications for understanding, and potentially treating, dozens of brain diseases.
NFκB Regulates Muscle Development and Mitochondrial Function.
Valentine JM, Li ME, Shoelson SE, Zhang N, Reddick RL, Musi N
J Gerontol A Biol Sci Med Sci. 2018 Nov 13. doi: 10.1093/gerona/gly262. [Epub ahead of print]
Abstract:
NFκB is a transcription factor that controls immune and inflammatory signaling pathways. In skeletal muscle, NFκB has been implicated in the regulation of metabolic processes and tissue mass; yet, its affects on mitochondrial function in this tissue are unclear. To investigate the role of NFκB on mitochondrial function and its relationship with muscle mass across the lifespan, we study a mouse model with muscle-specific NFκB suppression (MISR mice). In wild type mice there was a natural decline in muscle mass with aging that was accompanied by decreased mitochondrial function and mRNA expression of electron transport chain subunits. NFκB inactivation downregulated expression of PPARGC1A, while upregulating TFEB and PPARGC1B, as well as decreased gastrocnemius (but not soleus) muscle mass in early life (1-6 months old). Lower oxygen consumption rates occurred in gastrocnemius and soleus muscles from young MISR mice, whereas soleus (but not gastrocnemius) muscles from old MISR mice displayed increased oxygen consumption compared to age-matched controls. We conclude that the NFκB pathway plays an important role in muscle development and growth. The extent to which NFκB suppression alters mitochondrial function is age-dependent and muscle-specific. Lastly, mitochondrial function and muscle mass are tightly associated in both genotypes and across the lifespan.
Tau‐induced nuclear envelope invagination causes a toxic accumulation of mRNA in Drosophila
Cornelison GL, Levy SA, Jenson T, Frost B
Aging Cell. 2018 Nov 9:e12847. doi: 10.1111/acel.12847. [Epub ahead of print]
Abstract
The nucleus is a spherical dual-membrane bound organelle that encapsulates genomic DNA. In eukaryotes, messenger RNAs (mRNA) are transcribed in the nucleus and transported through nuclear pores into the cytoplasm for translation into protein. In certain cell types and pathological conditions, nuclei harbor tubular invaginations of the nuclear envelope known as the “nucleoplasmic reticulum.” Nucleoplasmic reticulum expansion has recently been established as a mediator of neurodegeneration in tauopathies, including Alzheimer’s disease. While the presence of pore-lined, cytoplasm-filled, nuclear envelope invaginations has been proposed to facilitate the rapid export of RNAs from the nucleus to the cytoplasm, the functional significance of nuclear envelope invaginations in regard to RNA export in any disorder is currently unknown. Here, we report that polyadenylated RNAs accumulate within and adjacent to tau-induced nuclear envelope invaginations in a Drosophila model of tauopathy. Genetic or pharmacologic inhibition of RNA export machinery reduces accumulation of polyadenylated RNA within and adjacent to nuclear envelope invaginations and reduces tau-induced neuronal death. These data are the first to point toward a possible role for RNA export through nuclear envelope invaginations in the pathogenesis of a neurodegenerative disorder and suggest that nucleocytoplasmic transport machinery may serve as a possible novel class of therapeutic targets for the treatment of tauopathies.
Long-term treatment with the mTOR inhibitor rapamycin has minor effect on clinical laboratory markers in middle-aged marmosets.
Sills AM, Artavia JM, DeRosa BD, Ross CN, Salmon AB
American Journal of Primatology. 2018 Oct 12:e22927. doi: 10.1002/ajp.22927. [Epub ahead of print].
Abstract:
Interventions to extend lifespan and improve health with increasing age would have significant impact on a growing aged population. There are now several pharmaceutical interventions that extend lifespan in laboratory rodent models with rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR) being the most well studied. In this study, we report on the hematological effects in a cohort of middle-aged common marmosets (Callithrix jacchus) that were enrolled in a study to test the effects of daily rapamycin treatment on aging in this species. In addition, we assessed whether sex was a significant factor in either baseline assessment or as an interaction with rapamycin treatment. Among our cohort at baseline, we found few differences in either basic morphology or hematological markers of blood cell counts, metabolism or inflammation between male and female marmosets. After dosing with rapamycin, surprisingly we found trough blood concentrations of rapamycin were significantly lower in female compared to male marmosets. Despite this pharmacological difference, both sexes had only minor changes in cellular blood counts after 9 months of rapamycin. These data then suggest that the potential clinical hematological side effects of rapamycin are not likely outcomes of long-term rapamycin in relatively healthy, middle-aged marmosets.
Inhibition of mTOR protects the blood-brain barrier in models of Alzheimer’s disease and vascular cognitive impairment.
Van Skike CE, Jahrling JB, Olson AB, Sayre NL, Hussong SA, Ungvari Z, Lechleiter JD, Galvan V.
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.
Lee HJ, Feliers D, Barnes JL, Oh S, Choudhury GG2, Diaz V, Galvan V, Strong R, Nelson J, Salmon A, Kevil CG, Kasinath BS
Geroscience. 2018 Apr;40(2):163-176. doi: 10.1007/s11357-018-0018-y. Epub 2018 May 1.
PMCID: PMC5964063
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.