Publications

Aging Induces an Nlrp3 Inflammasome-Dependent Expansion of Adipose B Cells That Impairs Metabolic Homeostasis.
Camell CD, Günther P, Lee A, Goldberg EL, Spadaro O, Youm YH, Bartke A, Hubbard GB, Ikeno Y, Ruddle NH, Schultze J, Dixit VD
Cell Metab. 2019 Dec 3;30(6):1024-1039.e6. doi: 10.1016/j.cmet.2019.10.006. Epub 2019 Nov 14.

Abstract:

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.


Body image in older women: a mediator of BMI and wellness behaviors.
Kilpela LS, Verzijl CL, Becker CB
J Women Aging. 2019 Nov 21:1-14. doi: 10.1080/08952841.2019.1692629. [Epub ahead of print]

Abstract:

Negative body image is prevalent among mid- and late-life women. In younger women, negative body image is associated with reduced quality of life (QOL) when controlling for body mass index (BMI), and mediates the relationship between obesity and emotional wellbeing. Yet, much remains unknown about body image in older populations. In our sample of women aged 50-86 (N = 181), negative body image mediated the relationship between BMI and sleep, all four domains of QOL, negative affect, nutritious food consumption, and psychosocial impairment, but not enjoyment of physical activity. Findings suggest negative body image impacts the wellbeing of older women.


Deficiency in the DNA repair protein ERCC1 triggers a link between senescence and apoptosis in human fibroblasts and mouse skin.
Kim DE, Dollé MET, Vermeij WP, Gyenis A, Vogel K, Hoeijmakers JHJ, Wiley CD, Davalos AR, Hasty P, Desprez PY, Campisi J
Aging Cell. 2019 Nov 18:e13072. doi: 10.1111/acel.13072. [Epub ahead of print]

Abstract:

ERCC1 (excision repair cross complementing-group 1) is a mammalian endonuclease that incises the damaged strand of DNA during nucleotide excision repair and interstrand cross-link repair. Ercc1-/Δ mice, carrying one null and one hypomorphic Ercc1 allele, have been widely used to study aging due to accelerated aging phenotypes in numerous organs and their shortened lifespan. Ercc1-/Δ mice display combined features of human progeroid and cancer-prone syndromes. Although several studies report cellular senescence and apoptosis associated with the premature aging of Ercc1-/Δ mice, the link between these two processes and their physiological relevance in the phenotypes of Ercc1-/Δ mice are incompletely understood. Here, we show that ERCC1 depletion, both in cultured human fibroblasts and the skin of Ercc1-/Δ mice, initially induces cellular senescence and, importantly, increased expression of several SASP (senescence-associated secretory phenotype) factors. Cellular senescence induced by ERCC1 deficiency was dependent on activity of the p53 tumor-suppressor protein. In turn, TNFα secreted by senescent cells induced apoptosis, not only in neighboring ERCC1-deficient nonsenescent cells, but also cell autonomously in the senescent cells themselves. In addition, expression of the stem cell markers p63 and Lgr6 was significantly decreased in Ercc1-/Δ mouse skin, where the apoptotic cells are localized, compared to age-matched wild-type skin, possibly due to the apoptosis of stem cells. These data suggest that ERCC1-depleted cells become susceptible to apoptosis via TNFα secreted from neighboring senescent cells. We speculate that parts of the premature aging phenotypes and shortened health- or lifespan may be due to stem cell depletion through apoptosis promoted by senescent cells.


Exercise preserves muscle mass and force in a prostate cancer mouse model.
Patel DI, Abuchowski K, Sheikh B, Rivas P, Musi N, Kumar AP.
Eur J Transl Myol. 2019 Nov 12;29(4):8520. doi: 10.4081/ejtm.2019.8520. eCollection 2019 Oct 29.

Abstract:

The purpose of this study was to examine the effects of exercise in modulating biomarkers of sarcopenia in a treatment naïve transgenic adenocardinoma of the mouse prostate (TRAMP) model. Thirty TRAMP mice were randomized to either exercise (voluntary wheel running) or no-treatment control group for a period of 20 weeks. During necropsy, gastrocnemius muscles and prostate tumors were harvested and weighed. Gastrocnemius concentrations of myostatin, insulin-like growth factor (IGF)-1 and tumor necrosis factor (TNF)-α were quantified. Exercise mice had greater muscle mass than controls (p=0.04). Myostatin was significantly lower in the exercise group compared to controls (p=0.01). Exercise mice maintained forelimb grip force while control mice had a significaint decrease (p=0.01). No significant difference was observed in pre-post all limb grip strength. Further, forelimb and all limb grip strength was negatively associated with tumor mass (p<0.01).


Analytical challenges of shotgun lipidomics at different resolution of measurements.
Wang J, Han X
TrAC Trends in Analytical Chemistry. 2019 Oct 17. doi: 10.1016/j.trac.2019.115697. [In press]

Abstract:

The essence of shotgun lipidomics is to maintain consistency of the chemical environment of lipid samples during mass spectrometry acquisition. This strategy is suitable for large-scale quantitative analysis. This strategy also allows sufficient time to collect data to improve the signal-to-noise ratio. The initial approach of shotgun lipidomics was the electrospray ionization (ESI)-based direct infusion mass spectrometry strategy. With development of mass spectrometry for small molecules, shotgun lipidomics methods have been extended to matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) and ambient mass spectrometry, including MS imaging methods. Furthermore, the object of analysis has extended from organ and body fluid levels to tissue and cell levels with technological developments. In this article, we summarize the status and technical challenges of shotgun lipidomics at different resolution of measurements from the mass spectrometry perspective.


Can Oral Health and Oral-derived Biospecimens Predict Progression of Dementia?
Orr ME, Reveles KR, Yeh CK, Young EH, Han X
Oral Diseases. 2019 Sep 21. doi: 10.1111/odi.13201. [Epub ahead of print]

Abstract:

Growing evidence indicates that oral health and brain health are interconnected. Declining cognition and dementia coincide with lack of self-preservation, including oral hygiene. The oral microbiota plays an important role in maintaining oral health. Emerging evidence suggests a link between oral dysbiosis and cognitive decline in patients with Alzheimer’s disease. This review showcases the recent advances connecting oral health and cognitive function during aging and the potential utility of oral-derived biospecimens to inform on brain health. Collectively, experimental findings indicate that the connection between oral health and cognition cannot be underestimated; moreover, oral biospecimens are abundant and readily obtainable without invasive procedures, which may help inform on cognitive health.


Neuronal microtubules impact lifespan.
Apple E, Chen L
Aging (Albany NY). 2019 Sep 6;11(17):6616-6617. doi: 10.18632/aging.102224. Epub 2019 Sep 6.


Loss of mitochondrial energetics is associated with poor recovery of muscle function but not mass following disuse atrophy.
Trevino MB, Zhang X, Standley RA, Wang M, Han X, Reis FCG, Periasamy M, Yu G, Kelly DP, Goodpaster BH, Vega RB, Coen PM
American Journal of Physiology. Endocrinology and Metabolism. 2019 Sep 3. doi: 10.1152/ajpendo.00161.2019. [Epub ahead of print]

Abstract:

Skeletal muscle atrophy is a clinically important outcome of disuse due to injury, immobilization and bed rest. Disuse atrophy is accompanied by mitochondrial dysfunction which likely contributes to activation of the muscle atrophy program. However, the linkage of muscle mass and mitochondrial energetics, during disuse atrophy and its recovery is incompletely understood. Transcriptomic analysis of muscle biopsies from healthy older adults subject to complete bed rest revealed marked inhibition of mitochondrial energy metabolic pathways. To determine the temporal sequence of muscle atrophy, and changes in intramyocellular lipid and mitochondrial energetics, we conducted a time course of hind limb unloading induced atrophy in adult mice. Mitochondrial respiration and calcium retention capacity were diminished while H2O2emission was increased in as soon as 3 days of unloading, prior to significant muscle atrophy. These changes were associated with a decrease in total cardiolipin and profound changes in remodeled cardiolipin species. Hindlimb unloading performed in muscle-specific PGC-1a/bknockout mice, a model of mitochondrial dysfunction, did not affect muscle atrophy but impacted muscle function. These data suggest early mitochondrial remodeling affects muscle function but not mass during disuse atrophy. Early alterations in mitochondrial energetics and lipid remodeling may represent novel targets to prevent muscle functional impairment caused by disuse and to enhance recovery from periods of muscle atrophy.


A Non-canonical Role of YAP/TEAD Is Required for Activation of Estrogen-Regulated Enhancers in Breast Cancer.
Zhu C, Li L, Zhang Z1 Bi M, Wang H, Su W, Hernandez K, Liu P, Chen J, Chen M, Huang TH, Chen L*, Liu Z*
Molecular Cell. 2019 Aug 22;75(4):791-806.e8. doi: 10.1016/j.molcel.2019.06.010. Epub 2019 Jul 11. *co-corresponding authors

Abstract:

YAP/TEAD are nuclear effectors of the Hippo pathway, regulating organ size and tumorigenesis largely through promoter-associated function. However, their function as enhancer regulators remains poorly understood. Through an in vivo proximity-dependent labeling (BioID) technique, we identified YAP1 and TEAD4 protein as co-regulators of ERα on enhancers. The binding of YAP1/TEAD4 to ERα-bound enhancers is augmented upon E2 stimulation and is required for the induction of E2/ERα target genes and E2-induced oncogenic cell growth. Furthermore, their enhancer binding is a prerequisite for enhancer activation marked by eRNA transcription and for the recruitment of the enhancer activation machinery component MED1. The binding of TEAD4 on active ERE-containing enhancers is independent of its DNA-binding behavior, and instead, occurs through protein-tethering trans-binding. Our data reveal a non-canonical function of YAP1 and TEAD4 as ERα cofactors in regulating cancer growth, highlighting the potential of YAP/TEAD as possible actionable drug targets for ERα+ breast cancer.


Tutorial on lipidomics.
Wang J, Wang C, Han X
Analytica Chimica Acta. 2019 Jul 11;1061:28-41. doi: 10.1016/j.aca.2019.01.043. Epub 2019 Feb 1.

Abstract:

The mainstream of lipidomics involves mass spectrometry-based, systematic, and large-scale studies of the structure, composition, and quantity of lipids in biological systems such as organs, cells, and body fluids. As increasingly more researchers in broad fields are beginning to pay attention to and actively learn about the lipidomic technology, some introduction on the topic is needed to help the newcomers to better understand the field. This tutorial seeks to introduce the basic knowledge about lipidomics and to provide readers with some core ideas and the most important approaches for studying the field.


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