SINGLE-CELL TRANSCRIPTOMICS OF AGING MOUSE ISLET REVEALS AGE-RELATED RECRUITMENT OF ISLET-RESIDENT MACROPHAGE

Abstract Type 2 diabetes (T2D) prevalence increases with age. The notion of inevitable progression of T2D has been challenged by reports of remission in some human T2D cases; however, this remission is dependent on islet function reserve. To elucidate the molecular mechanisms driving islet cell dysfunction, it is necessary to understand islet cell composition, diversity, and function throughout the lifespan. We generated a single-cell transcriptomic atlas of healthy islets isolated from young (5 weeks old), middle-aged (12 months old), and older-aged (25 months old) mice. Cell clustering identified 13 initial cell clusters that were further sub-clustered. This single-cell RNAseq profile showed that each cell type/group has different markers and functional characteristics and that age causes a remarkable shift in islet cell composition, diversity, and number. By comparing macrophages from young and old mice, we also found that aged islets contain a higher number of islet-resident macrophages. Overall, this single-cell islet atlas covers nearly all cells in the normal islet and allows a comprehensive exploration of all transcriptional states throughout the lifespan.

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From Genetic Association to Molecular Mechanisms for Islet-cell Dysfunction in Type 2 Diabetes

Journal of Molecular Biology ◽

10.1016/j.jmb.2019.12.045 ◽

2020 ◽

Vol 432 (5) ◽

pp. 1551-1578 ◽

Cited By ~ 5

Author(s):

Katia K. Mattis ◽

Anna L. Gloyn

Keyword(s):

Type 2 Diabetes ◽

Genetic Association ◽

Islet Cell ◽

Molecular Mechanisms ◽

Cell Dysfunction

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Telomere Length and Oxidative Stress and Its Relation with Metabolic Syndrome Components in the Aging

Biology ◽

10.3390/biology10040253 ◽

2021 ◽

Vol 10 (4) ◽

pp. 253

Author(s):

Graciela Gavia-García ◽

Juana Rosado-Pérez ◽

Taide Laurita Arista-Ugalde ◽

Itzen Aguiñiga-Sánchez ◽

Edelmiro Santiago-Osorio ◽

...

Keyword(s):

Oxidative Stress ◽

Metabolic Syndrome ◽

Telomere Length ◽

Scientific Evidence ◽

Telomeric Dna ◽

Biochemical Alterations ◽

The Metabolic Syndrome ◽

Age Related ◽

And Function

A great amount of scientific evidence supports that Oxidative Stress (OxS) can contribute to telomeric attrition and also plays an important role in the development of certain age-related diseases, among them the metabolic syndrome (MetS), which is characterised by clinical and biochemical alterations such as obesity, dyslipidaemia, arterial hypertension, hyperglycaemia, and insulin resistance, all of which are considered as risk factors for type 2 diabetes mellitus (T2DM) and cardiovascular diseases, which are associated in turn with an increase of OxS. In this sense, we review scientific evidence that supports the association between OxS with telomere length (TL) dynamics and the relationship with MetS components in aging. It was analysed whether each MetS component affects the telomere length separately or if they all affect it together. Likewise, this review provides a summary of the structure and function of telomeres and telomerase, the mechanisms of telomeric DNA repair, how telomere length may influence the fate of cells or be linked to inflammation and the development of age-related diseases, and finally, how the lifestyles can affect telomere length.

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Targeting Age-Related Pathways in Heart Failure

Circulation Research ◽

10.1161/circresaha.119.315889 ◽

2020 ◽

Vol 126 (4) ◽

pp. 533-551 ◽

Cited By ~ 7

Author(s):

Haobo Li ◽

Margaret H. Hastings ◽

James Rhee ◽

Lena E. Trager ◽

Jason D. Roh ◽

...

Keyword(s):

Heart Failure ◽

Elderly Population ◽

Molecular Mechanisms ◽

The Elderly ◽

Structure And Function ◽

Experimental Platform ◽

Age Related ◽

Cardiac Structure And Function ◽

And Function ◽

Increased Susceptibility

During aging, deterioration in cardiac structure and function leads to increased susceptibility to heart failure. The need for interventions to combat this age-related cardiac decline is becoming increasingly urgent as the elderly population continues to grow. Our understanding of cardiac aging, and aging in general, is limited. However, recent studies of age-related decline and its prevention through interventions like exercise have revealed novel pathological and cardioprotective pathways. In this review, we summarize recent findings concerning the molecular mechanisms of age-related heart failure and highlight exercise as a valuable experimental platform for the discovery of much-needed novel therapeutic targets in this chronic disease.

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Metabolic reprogramming of human CD8+ memory T cells through loss of SIRT1

Journal of Experimental Medicine ◽

10.1084/jem.20161066 ◽

2017 ◽

Vol 215 (1) ◽

pp. 51-62 ◽

Cited By ~ 35

Author(s):

Mark Y. Jeng ◽

Philip A. Hull ◽

Mingjian Fei ◽

Hye-Sook Kwon ◽

Chia-Lin Tsou ◽

...

Keyword(s):

T Cells ◽

Molecular Mechanisms ◽

Memory T Cells ◽

Cell Metabolism ◽

Global Gene Expression ◽

Metabolic Reprogramming ◽

Transcriptional Reprogramming ◽

Age Related ◽

Global Gene Expression Profiling ◽

And Function

The expansion of CD8+CD28– T cells, a population of terminally differentiated memory T cells, is one of the most consistent immunological changes in humans during aging. CD8+CD28– T cells are highly cytotoxic, and their frequency is linked to many age-related diseases. As they do not accumulate in mice, many of the molecular mechanisms regulating their fate and function remain unclear. In this paper, we find that human CD8+CD28– T cells, under resting conditions, have an enhanced capacity to use glycolysis, a function linked to decreased expression of the NAD+-dependent protein deacetylase SIRT1. Global gene expression profiling identified the transcription factor FoxO1 as a SIRT1 target involved in transcriptional reprogramming of CD8+CD28– T cells. FoxO1 is proteasomally degraded in SIRT1-deficient CD8+CD28– T cells, and inhibiting its activity in resting CD8+CD28+ T cells enhanced glycolytic capacity and granzyme B production as in CD8+CD28– T cells. These data identify the evolutionarily conserved SIRT1–FoxO1 axis as a regulator of resting CD8+ memory T cell metabolism and activity in humans.

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Resveratrol Attenuates Copper-Induced Senescence by Improving Cellular Proteostasis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/3793817 ◽

2017 ◽

Vol 2017 ◽

pp. 1-12 ◽

Cited By ~ 4

Author(s):

Liliana Matos ◽

Alexandra Monteiro Gouveia ◽

Henrique Almeida

Keyword(s):

Molecular Mechanisms ◽

Protein Quality ◽

Replicative Senescence ◽

Beneficial Effects ◽

Cell Dysfunction ◽

Age Related ◽

Cell Tissue ◽

Autophagy Induction ◽

Human Disorders ◽

Senescence Associated Genes

Copper sulfate-induced premature senescence (CuSO4-SIPS) consistently mimetized molecular mechanisms of replicative senescence, particularly at the endoplasmic reticulum proteostasis level. In fact, disruption of protein homeostasis has been associated to age-related cell/tissue dysfunction and human disorders susceptibility. Resveratrol is a polyphenolic compound with proved antiaging properties under particular conditions. In this setting, we aimed to evaluate resveratrol ability to attenuate cellular senescence induction and to unravel related molecular mechanisms. Using CuSO4-SIPS WI-38 fibroblasts, resveratrol is shown to attenuate typical senescence alterations on cell morphology, senescence-associated beta-galactosidase activity, and cell proliferation. The mechanisms implicated in this antisenescence effect seem to be independent of senescence-associated genes and proteins regulation but are reliant on cellular proteostasis improvement. In fact, resveratrol supplementation restores copper-induced increased protein content, attenuates BiP level, and reduces carbonylated and polyubiquitinated proteins by autophagy induction. Our data provide compelling evidence for the beneficial effects of resveratrol by mitigating CuSO4-SIPS stressful consequences by the modulation of protein quality control systems. These findings highlight the importance of a balanced cellular proteostasis and add further knowledge on molecular mechanisms mediating resveratrol antisenescence effects. Moreover, they contribute to identifying specific molecular targets whose modulation will prevent age-associated cell dysfunction and improve human healthspan.

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Protein Posttranslational Modifications: Roles in Aging and Age-Related Disease

Oxidative Medicine and Cellular Longevity ◽

10.1155/2017/5716409 ◽

2017 ◽

Vol 2017 ◽

pp. 1-19 ◽

Cited By ~ 50

Author(s):

Ana L. Santos ◽

Ariel B. Lindner

Keyword(s):

Posttranslational Modifications ◽

Molecular Mechanisms ◽

Molecular Processes ◽

Progressive Decline ◽

Age Related ◽

Evolutionarily Conserved ◽

Protein Posttranslational Modifications ◽

Aging Models ◽

The Relationship

Aging is characterized by the progressive decline of biochemical and physiological function in an individual. Consequently, aging is a major risk factor for diseases like cancer, obesity, and type 2 diabetes. The cellular and molecular mechanisms of aging are not well understood, nor is the relationship between aging and the onset of diseases. One of the hallmarks of aging is a decrease in cellular proteome homeostasis, allowing abnormal proteins to accumulate. This phenomenon is observed in both eukaryotes and prokaryotes, suggesting that the underlying molecular processes are evolutionarily conserved. Similar protein aggregation occurs in the pathogenesis of diseases like Alzheimer’s and Parkinson’s. Further, protein posttranslational modifications (PTMs), either spontaneous or physiological/pathological, are emerging as important markers of aging and aging-related diseases, though clear causality has not yet been firmly established. This review presents an overview of the interplay of PTMs in aging-associated molecular processes in eukaryotic aging models. Understanding PTM roles in aging could facilitate targeted therapies or interventions for age-related diseases. In addition, the study of PTMs in prokaryotes is highlighted, revealing the potential of simple prokaryotic models to uncover complex aging-associated molecular processes in the emerging field of microbiogerontology.

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Dysregulation of adipose ILC2 underlies thermogenic failure in aging

10.1101/2020.09.08.288431 ◽

2020 ◽

Author(s):

Emily L. Goldberg ◽

Irina Shchukina ◽

Yun-Hee Youm ◽

Christina D. Camell ◽

Tamara Dlugos ◽

...

Keyword(s):

Adipose Tissue ◽

Core Body Temperature ◽

Lymphoid Cells ◽

Adipose Tissue Inflammation ◽

Age Related ◽

Core Body ◽

Old Mice ◽

Functional Defects ◽

Age Related Changes

AbstractAging impairs the integrated immunometabolic responses which have evolved to maintain core body temperature in homeotherms to survive cold-stress, infections, and dietary restriction. Adipose tissue inflammation regulates the thermogenic stress response but how adipose tissue-resident cells instigate thermogenic failure in aged are unknown. Here, we define alterations in the adipose-resident immune system and identify that type 2 innate lymphoid cells (ILC2) are lost in aging. Restoration of ILC2 numbers in aged mice to levels seen in adults through IL-33 supplementation failed to rescue old mice from metabolic impairment and cold-induced lethality. Transcriptomic analyses revealed intrinsic defects in aged ILC2, and adoptive transfer of adult ILC2 are sufficient to protect old mice against cold. Thus, the functional defects in adipose ILC2 during aging drive thermogenic failure.One Sentence SummaryAge-related changes in adipose tissue drive reprogramming of ILC2 that leads to impaired cold tolerance

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ROLE OF INSULIN IN BRAIN: DELVE INTO THE MOLECULAR MECHANISMS

10.14293/s2199-1006.1.sor-.ppkjzat.v1 ◽

2021 ◽

Author(s):

Sofia Khanam

Keyword(s):

Molecular Mechanisms ◽

Insulin Signalling ◽

Diabetic Patients ◽

Functional Activities ◽

Mitochondrial Alterations ◽

Age Related ◽

The Brain ◽

And Oxidative Stress

We have learned over the last several decades that the brain is an important target for insulin action. In central nervous system (CNS) it mainly affects feeding behaviour and various aspects of memory and cognition. Insulin signalling in CNS has emerged as a novel field of research since decreases brain insulin levels and signalling were associated to impaired learning, memory and age-related neurodegenerative diseases. Alterations of these functional activities may contribute to the manifestation of several clinical entities, such as central insulin resistance, type 2 diabetes mellitus (T2DM) and Alzheimer’s disease (AD). A close alliance between T2DM and AD has been reported, to the extent that AD is twice more frequent in diabetic patients. There are links between T2DM and AD through mitochondrial alterations and oxidative stress, altered energy and glucose metabolism, cholesterol modifications, dysfunctional protein O-GlcNAcylation, formation of amyloid plaques, altered Aβ metabolism and tau hyperphosphorylation. Herewith, we aim to integrate the metabolic, neuromodulatory, and neuroprotective roles of insulin in two age-related pathologies: T2DM and AD, both in terms of intracellular signalling and potential therapeutic approach.

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FTIR Spectroscopy as a Tool to Study Age-Related Changes in Cardiac and Skeletal Muscle of Female C57BL/6J Mice

Molecules ◽

10.3390/molecules26216410 ◽

2021 ◽

Vol 26 (21) ◽

pp. 6410

Author(s):

Sandra Magalhães ◽

Idália Almeida ◽

Filipa Martins ◽

Fátima Camões ◽

Ana R. Soares ◽

...

Keyword(s):

Skeletal Muscle ◽

Ftir Spectroscopy ◽

Conformational Changes ◽

Molecular Mechanisms ◽

Protein Secondary Structure ◽

Multivariate Statistical ◽

Age Related ◽

Muscle Tissues ◽

Aging Studies ◽

Old Mice

Studying aging is important to further understand the molecular mechanisms underlying this physiological process and, ideally, to identify a panel of aging biomarkers. Animals, in particular mice, are often used in aging studies, since they mimic important features of human aging, age quickly, and are easy to manipulate. The present work describes the use of Fourier Transform Infrared (FTIR) spectroscopy to identify an age-related spectroscopic profile of the cardiac and skeletal muscle tissues of C57BL/6J female mice. We acquired ATR-FTIR spectra of cardiac and skeletal muscle at four different ages: 6; 12; 17 and 24 months (10 samples at each age) and analyzed the data using multivariate statistical tools (PCA and PLS) and peak intensity analyses. The results suggest deep changes in protein secondary structure in 24-month-old mice compared to both tissues in 6-month-old mice. Oligomeric structures decreased with age in both tissues, while intermolecular β-sheet structures increased with aging in cardiac muscle but not in skeletal muscle. Despite FTIR spectroscopy being unable to identify the proteins responsible for these conformational changes, this study gives insights into the potential of FTIR to monitor the aging process and identify an age-specific spectroscopic signature.

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