Assessing Lifespan and Aging Phenotypes Resulting From FOXO3 Induction Using Mouse Models

Abstract Environmental signals, including caloric restriction and oxidative stress, trigger FoxO3 to upregulate genes involved in stress resistance, metabolism, cell cycle arrest, and apoptosis that may help mitigate age-related diseases. Activation of FoxO3 has been shown to have a profound life-extending effect on model organisms. Protective SNPs in FOXO3 are strongly associated with exceptional longevity in humans. The objective of this study is test the relation between FoxO3 and longevity using mouse models. We generated a mouse line containing an extra copy of FoxO3 that can be induced at any age. In our model, FoxO3 remains driven by its natural promoter to avoid mis-expression in inappropriate cells and to maintain the gene’s ability to respond to signals such as stress. We are utilizing this new model to assess survival endpoints and test a panel of aging phenotypes reflecting healthspan throughout the mouse lifespan and compare these to similar human phenotypes.

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Terpenoids as Potential Geroprotectors

Antioxidants ◽

10.3390/antiox9060529 ◽

2020 ◽

Vol 9 (6) ◽

pp. 529

Author(s):

Ekaterina Proshkina ◽

Sergey Plyusnin ◽

Tatyana Babak ◽

Ekaterina Lashmanova ◽

Faniya Maganova ◽

...

Keyword(s):

Quality Of Life ◽

Stress Resistance ◽

Biological Effects ◽

Plant Secondary Metabolites ◽

Mechanisms Of Action ◽

Model Organisms ◽

Age Related ◽

Evolutionarily Conserved ◽

Low Toxicity

Terpenes and terpenoids are the largest groups of plant secondary metabolites. However, unlike polyphenols, they are rarely associated with geroprotective properties. Here we evaluated the conformity of the biological effects of terpenoids with the criteria of geroprotectors, including primary criteria (lifespan-extending effects in model organisms, improvement of aging biomarkers, low toxicity, minimal adverse effects, improvement of the quality of life) and secondary criteria (evolutionarily conserved mechanisms of action, reproducibility of the effects on different models, prevention of age-associated diseases, increasing of stress-resistance). The number of substances that demonstrate the greatest compliance with both primary and secondary criteria of geroprotectors were found among different classes of terpenoids. Thus, terpenoids are an underestimated source of potential geroprotectors that can effectively influence the mechanisms of aging and age-related diseases.

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Glucose increases the lifespan of post-reproductive C. elegans independently of FOXO

10.1101/347435 ◽

2018 ◽

Cited By ~ 1

Author(s):

Wang Lei ◽

Caroline Beaudoin-Chabot ◽

Guillaume Thibault

Keyword(s):

Er Stress ◽

Stress Resistance ◽

Metabolic Diseases ◽

Strong Association ◽

Cellular Damage ◽

Model Organisms ◽

Dependent Manner ◽

C Elegans ◽

Age Related ◽

Er Homeostasis

ABSTRACTAging is one of the most critical risk factors for the development of metabolic syndromes1. Prominent metabolic diseases, namely type 2 diabetes and insulin resistance, have a strong association with endoplasmic reticulum (ER) stress2. Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage by adapting to stress conditions and restoring ER homeostasis3,4. However, adaptive genes upregulated from the UPR tend to decrease with age5. Although stress resistance correlates with increased longevity in a variety of model organisms, the links between the UPR, ER stress resistance, and longevity remain poorly understood. Here, we show that supplementing bacteria diet with 2% glucose (high glucose diet, HGD) in post-reproductive 7-day-old (7DO) C. elegans significantly extend their lifespan in contrast to shortening the lifespan of reproductive 3-day-old (3DO) animals. The insulin-IGF receptor DAF-2 and its immediate downstream target, phosphoinositide 3-kinase (PI3K) AGE-1, were found to be critical factors in extending the lifespan of 7DO worms on HGD. The downstream transcription factor forkhead box O (FOXO) DAF-16 did not extend the lifespan of 7DO worms on HGD in contrast of its previously reported role in modulating lifespan of 3DO worms6. Furthermore, we identified that UPR activation through the highly conserved ATF-6 and PEK-1 sensors significantly extended the longevity of 7DO worms on HGD but not through the IRE-1 sensor. Our results demonstrate that HGD extends lifespan of post-reproductive worms in a UPR-dependent manner but independently of FOXO. Based on these observations, we hypothesise that HGD activates the otherwise quiescent UPR in aged worms to overcome age-related stress and to restore ER homeostasis. In contrast, young adult animals subjected to HGD leads to unresolved ER stress, conversely leading to a deleterious stress response.

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Some naturally occurring compounds that increase longevity and stress resistance in model organisms of aging

Biogerontology ◽

10.1007/s10522-019-09817-2 ◽

2019 ◽

Vol 20 (5) ◽

pp. 583-603 ◽

Cited By ~ 7

Author(s):

Darío R. Gómez-Linton ◽

Silvestre Alavez ◽

Adriana Alarcón-Aguilar ◽

Norma E. López-Diazguerrero ◽

Mina Konigsberg ◽

...

Keyword(s):

Stress Resistance ◽

Model Organisms ◽

Naturally Occurring

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Impact of Polyphenolic-Food on Longevity: An Elixir of Life. An Overview

Antioxidants ◽

10.3390/antiox10040507 ◽

2021 ◽

Vol 10 (4) ◽

pp. 507

Author(s):

Rosaria Meccariello ◽

Stefania D’Angelo

Keyword(s):

Oxidative Stress ◽

Food Sources ◽

Preventive Action ◽

Nutritional Interventions ◽

Beneficial Effects ◽

Age Related ◽

Macromolecular Damage ◽

And Oxidative Stress

Aging and, particularly, the onset of age-related diseases are associated with tissue dysfunction and macromolecular damage, some of which can be attributed to accumulation of oxidative damage. Recently, growing interest has emerged on the beneficial effects of plant-based diets for the prevention of chronic diseases including obesity, diabetes, and cardiovascular disease. Several studies collectively suggests that the intake of polyphenols and their major food sources may exert beneficial effects on improving insulin resistance and related diabetes risk factors, such as inflammation and oxidative stress. They are the most abundant antioxidants in the diet, and their intake has been associated with a reduced aging in humans. Polyphenolic intake has been shown to be effective at ameliorating several age-related phenotypes, including oxidative stress, inflammation, impaired proteostasis, and cellular senescence, both in vitro and in vivo. In this paper, effects of these phytochemicals (either pure forms or polyphenolic-food) are reviewed and summarized according to affected cellular signaling pathways. Finally, the effectiveness of the anti-aging preventive action of nutritional interventions based on diets rich in polyphenolic food, such as the diets of the Blue zones, are discussed.

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Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

Communications Biology ◽

10.1038/s42003-021-01723-z ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Anastasiya Börsch ◽

Daniel J. Ham ◽

Nitish Mittal ◽

Lionel A. Tintignac ◽

Eugenia Migliavacca ◽

...

Keyword(s):

Muscle Mass ◽

Inflammatory Responses ◽

Molecular Data ◽

Model Organisms ◽

Sequencing Data ◽

Phenotypic Analysis ◽

Age Related ◽

Analogous Data ◽

Species Specific ◽

And Function

AbstractSarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

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Apoptosis in the Extraosseous Calcification Process

Cells ◽

10.3390/cells10010131 ◽

2021 ◽

Vol 10 (1) ◽

pp. 131

Author(s):

Federica Boraldi ◽

Francesco Demetrio Lofaro ◽

Daniela Quaglino

Keyword(s):

Genetic Basis ◽

Membrane Vesicles ◽

Matrix Vesicles ◽

Apoptotic Bodies ◽

Connective Tissues ◽

Mineralization Process ◽

Mitochondrial Alterations ◽

Age Related ◽

And Oxidative Stress ◽

And Cartilage

Extraosseous calcification is a pathologic mineralization process occurring in soft connective tissues (e.g., skin, vessels, tendons, and cartilage). It can take place on a genetic basis or as a consequence of acquired chronic diseases. In this last case, the etiology is multifactorial, including both extra- and intracellular mechanisms, such as the formation of membrane vesicles (e.g., matrix vesicles and apoptotic bodies), mitochondrial alterations, and oxidative stress. This review is an overview of extraosseous calcification mechanisms focusing on the relationships between apoptosis and mineralization in cartilage and vascular tissues, as these are the two tissues mostly affected by a number of age-related diseases having a progressively increased impact in Western Countries.

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Modulation of Age-Related Biochemical Changes and Oxidative Stress by Vitamin C and Glutathione Supplementation in Old Rats

Annals of Nutrition and Metabolism ◽

10.1159/000065402 ◽

2002 ◽

Vol 46 (5) ◽

pp. 165-168 ◽

Cited By ~ 11

Author(s):

M.A. Amer

Keyword(s):

Oxidative Stress ◽

Vitamin C ◽

Biochemical Changes ◽

Age Related ◽

Old Rats ◽

And Oxidative Stress

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Abstract 426: Laminin Downregulation Facilitates Cardiomyocyte Coupling in situ to Increase Contractile Function

Circulation Research ◽

10.1161/res.119.suppl_1.426 ◽

2016 ◽

Vol 119 (suppl_1) ◽

Author(s):

Ayla Sessions ◽

Gaurav Kaushik ◽

Adam Engler

Keyword(s):

Basement Membrane ◽

Contractile Function ◽

Current Model ◽

Model Systems ◽

Model Organisms ◽

Muscle Physiology ◽

Heart Tube ◽

Age Related ◽

New Evidence

Aging is associated with extensive remodeling of the heart, including basement membrane extracellular matrix (ECM) components that surround cardiomyocytes. Remodeling is thought to contribute to impaired cardiac mechanotransduction, but the contribution of specific basement membrane ECM components to age-related cardiac remodeling is unclear, owing to current model systems being complex and slow to age. To investigate the effect of basement membrane remodeling on mechanical function in genetically tractable, rapidly aging, and simple model organisms, we employed Drosophila melanogaster, which has a simple trilayered heart tube composed of only basement membrane ECM. We observed differential regulation of collagens between laboratory Drosophila strains , i.e. yellow-white ( yw ) and white-1118 ( w 1118 ), leading to changes in muscle physiology, which were linked to severity of dysfunction with age. Therefore, we sought to understand the extent to which basement membrane ECM modulates lateral cardiomyocyte coupling and contractile function during aging. Cardiac-restricted knockdown of ECM genes Pericardin , Laminin A , and Viking in Drosophila prevented age-associated heart tube restriction and increased contractility, even under viscous load. Most notably, reduction of Laminin A expression decreased levels of other genes that co-assemble in ECM, leading to overall preservation of contractile velocity and extension of median organismal lifespan by 3 weeks or 39%. These data provide new evidence of a direct link between basement membrane ECM homeostasis, contractility, and maintenance of lifespan.

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SGLT2 inhibitors as calorie restriction-mimetics: insights on longevity pathways and age-related diseases

Endocrinology ◽

10.1210/endocr/bqab079 ◽

2021 ◽

Author(s):

Caroline W S Hoong ◽

Marvin W J Chua

Keyword(s):

Calorie Restriction ◽

Stress Resistance ◽

Target Genes ◽

Metabolic Diseases ◽

Vascular Inflammation ◽

Sglt2 Inhibitors ◽

Acid Oxidation ◽

The Metabolic Syndrome ◽

Age Related ◽

Energy Deprivation

Abstract SGLT2 inhibitors induce glycosuria, reduce insulin levels, promote fatty acid oxidation and ketogenesis. By promoting a nutrient deprivation state, SGLT2 inhibitors upregulate the energy deprivation sensors AMPK and SIRT1, inhibit the nutrient sensors mTOR and insulin/IGF-1, and modulate the closely-linked HIF-2α/HIF-1α pathways. Phosphorylation of AMPK and upregulation of adiponectin and PPAR-α favour a reversal of the metabolic syndrome which have been linked to suppression of chronic inflammation. Downregulation of insulin/IGF1 pathways and mTOR signalling from a reduction in glucose and circulating amino acids promote cellular repair mechanisms including autophagy and proteostasis which confer cellular stress resistance and attenuate cellular senescence. SIRT1, another energy sensor activated by NAD+ in nutrient-deficient states, is reciprocally activated by AMPK, and can deacetylate and activate transcription factors such as PCG-1α, TFAM and NRF2 that regulate mitochondrial biogenesis. FOXO3 transcription factor which target genes in stress resistance, is also activated by AMPK and SIRT1. Modulation of these pathways by SGLT2 inhibitors have been shown to alleviate metabolic diseases, attenuate vascular inflammation and arterial stiffness, improve mitochondrial function and reduce oxidative stress-induced tissue damage. Compared to other calorie restriction mimetics such as metformin, rapamycin, resveratrol and NAD+ precursors, SGLT2 inhibitors appear to be the most promising in the treatment of ageing-related diseases, due to its regulation of multiple longevity pathways that closely resemble that achieved by calorie restriction, and their established efficacy in reduction in cardiovascular events and all-cause mortality. Evidence is compelling for the role of SGLT2 inhibitors as a calorie restriction mimetic in anti-ageing therapeutics.

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