http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

The study of extracellular vesicles (EVs) has the potential to identify unknown cellular and molecular mechanisms in intercellular communication and in organ homeostasis and disease. Exosomes, with an average diameter of ~100 nanometers, are a subset of EVs. The biogenesis of exosomes involves their origin in endosomes, and subsequent interactions with other intracellular vesicles and organelles generate the final content of the exosomes. Their diverse constituents include nucleic acids, proteins, lipids, amino acids, and metabolites, which can reflect their cell of origin. In various diseases, exosomes offer a window into altered cellular or tissue states, and their detection in biological fluids potentially offers a multicomponent diagnostic readout. The efficient exchange of cellular components through exosomes can inform their applied use in designing exosome-based therapeutics.

The biology, function, and biomedical applications of exosomes

Over the past decade, the Nomenclature Committee on Cell Death (NCCD) has formulated guidelines for the definition and interpretation of cell death from morphological, biochemical, and functional perspectives. Since the field continues to expand and novel mechanisms that orchestrate multiple cell death pathways are unveiled, we propose an updated classification of cell death subroutines focusing on mechanistic and essential (as opposed to correlative and dispensable) aspects of the process. As we provide molecularly oriented definitions of terms including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence, and mitotic catastrophe, we discuss the utility of neologisms that refer to highly specialized instances of these processes. The mission of the NCCD is to provide a widely accepted nomenclature on cell death in support of the continued development of the field.

https://biblio.ugent.be/publication/8555786/file/8555788.pdf

Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018.

https://www.mergenmetz.nl/menn/wp-content/uploads/2012/07/Insirine-of-bewegen-artikel-in-Cell.pdf

Beige Adipocytes Are a Distinct Type of Thermogenic Fat Cell in Mouse and Human

Advanced age is the main risk factor for most chronic diseases and functional deficits in humans, but the fundamental mechanisms that drive ageing remain largely unknown, impeding the development of interventions that might delay or prevent age-related disorders and maximize healthy lifespan. Cellular senescence, which halts the proliferation of damaged or dysfunctional cells, is an important mechanism to constrain the malignant progression of tumour cells. Senescent cells accumulate in various tissues and organs with ageing and have been hypothesized to disrupt tissue structure and function because of the components they secrete. However, whether senescent cells are causally implicated in age-related dysfunction and whether their removal is beneficial has remained unknown. To address these fundamental questions, we made use of a biomarker for senescence, p16(Ink4a), to design a novel transgene, INK-ATTAC, for inducible elimination of p16(Ink4a)-positive senescent cells upon administration of a drug. Here we show that in the BubR1 progeroid mouse background, INK-ATTAC removes p16(Ink4a)-positive senescent cells upon drug treatment. In tissues--such as adipose tissue, skeletal muscle and eye--in which p16(Ink4a) contributes to the acquisition of age-related pathologies, life-long removal of p16(Ink4a)-expressing cells delayed onset of these phenotypes. Furthermore, late-life clearance attenuated progression of already established age-related disorders. These data indicate that cellular senescence is causally implicated in generating age-related phenotypes and that removal of senescent cells can prevent or delay tissue dysfunction and extend healthspan.

/pdf/clearance-of-p16-ink4a-positive-senescent-cells-delays-41olwc1s7m.pdf

Clearance of p16 Ink4a -positive senescent cells delays ageing-associated disorders

Fat tissue distribution varies widely, even among patients with the same body fat content. Visceral obesity is associated with increased risk of diabetes and atherosclerosis. Recent advances in understanding of mechanisms responsible for fat distribution patterns are reviewed. Although factors extrinsic to fat depots, including hormones, innervation, and nutrient supply, affect regional distribution, it is now evident that innate characteristics of adipose cells make an important contribution. Different fat depots are essentially distinct mini-organs. Visceral cells transfer and release fatty acids more extensively, have increased glucocorticoid and reduced thiazolidinedione responses, produce more angiotensinogen, and secrete less leptin than subcutaneous cells. Together with venous drainage through the liver and elevated intra-abdominal pressure, these features contribute to the morbidity associated with increased visceral fat mass. Once more fully understood, it may be possible to exploit regional differences in intrinsic properties of adipose cells in order to develop treatments that target specific fat depots.

Different fat depots are distinct mini-organs

Objective: To evaluate a new scanning electronic microscopic (EM) method for assessing fat cell sizes and compare fat cell size distribution in human adipose tissue from different fat depots before and after weight loss.



Research Methods and Procedures: Identical human fat tissue biopsies were separated into two fractions: one used to prepare a fat cell suspension by collagenase digestion followed by photomicrography (collagenase method) and the other fixed in formalin for EM analysis. The EM method was evaluated further by determining fat cell sizes from lean and ob/ob mice. Finally, the EM method was used to assess fat cell sizes in biopsies of different human depots from before and after weight loss.



Results: Fat cell size distributions measured by the two methods were not identical, but differences were generally small. The EM method reproduced the well-documented fat cell size difference between lean and ob/ob mice. Large variation was detected in fat cell distributions among three depots in humans. Weight loss reduced fat cell sizes in subjects with large baseline fat cells but had no effect in subjects with small baseline fat cell sizes.



Discussion: Our results suggest that the EM method may be a useful alternative for fat cell size analysis of clinical samples.

New Scanning Electron Microscopic Method for Determination of Adipocyte Size in Humans and Mice

Accelerated aging in older cancer survivors.

Publisher Summary This chapter describes how aging is associated with fat tissue redistribution from subcutaneous to visceral depots. This redistribution is correlated with and may cause insulin resistance and metabolic complications, as well as functional decline and mortality in the elderly. As subcutaneous fat loses its ability to store lipids, circulating fatty acids are elevated, with fatty acids being deposited ectopically, further contributing to metabolic dysfunction. Circulating free fatty acids (FFAs) are toxic to most cell types, including aged preadipocytes, potentially exacerbating fat tissue dysfunction and establishing a vicious cycle. Thus, when the main function of fat tissue, lipid storage, which requires fat cells to be able to increase in size and preadipocytes to differentiate into new fat cells, becomes dysregulated, the other functions of adipose tissue are disrupted, including immune, hormonal/paracrine regulation, and mechanical protection. Aging and obesity exert similar effects on metabolic function and share clinical consequences. Aging and obesity are both associated with increased inflammatory cytokines in adipose tissue and systemically. These cytokines, together with reduced anti-inflammatory factor generation (e.g., adiponectin, IL-10), may have a causal role in the generation of insulin resistance, impaired glucose metabolism, and systemic inflammation and are potential targets for future therapeutic interventions. However, there are notable differences between the cellular and the molecular mechanisms of fat tissue dysfunction in aging and obesity, including differences in extent of macrophage infiltration, fat cell size, and gene expression profiles.

Aging and Adipose Tissue

MicroRNAs (miRNAs) are potent regulators of multiple biological processes. Previous studies have demonstrated that miR-146a-5p increases in normal mice during aging, while long-living Ames dwarf (df/df) mice maintain youthful levels of this miRNA. The aim of this study was to elucidate the involvement of miR-146a-5p in modulating cellular senescence and apoptosis in visceral adipose tissue of df/df mice and cultured pre-adipocytes. To test the effects of miR-146a-5p overexpression on visceral adipose tissue, wild-type, and df/df mice, were treated with miRNA-negative control-base and df/df were transfected with 4 or 8 µg/g of a miR-146a-5p mimetic, respectively. Effects of miR-146a-5p overexpression were also evaluated in 3T3-L1 cells cultured under high and normal glucose conditions. Treatment with miR-146a-5p mimetic increased cellular senescence and inflammation and decreased pro-apoptotic factors in visceral adipose tissue of df/df mice. The miR-146a-5p mimetic induced similar effects in 3T3-L1 cells cultivated at normal but not high glucose levels. Importantly, 3T3-L1 HG cells in high glucose conditions showed significantly higher expression of miR-146a-5p than 3T3-L1 grown in normal glucose conditions. These results indicate that miR-146a-5p can be a marker for cellular senescence. This miRNA represents one of the significant SASP factors that if not precisely regulated, can accentuate inflammatory responses and stimulate senescence in surrounding non-senescent cells. The role of miR-146a-5p is different in healthy versus stressed cells, suggesting potential effects of this miRNA depend on overall organismal health, aging, and metabolic state.

James L. Kirkland

Papers

Different fat depots are distinct mini-organs

New Scanning Electron Microscopic Method for Determination of Adipocyte Size in Humans and Mice

Accelerated aging in older cancer survivors.

Aging and Adipose Tissue

miR-146a-5p modulates cellular senescence and apoptosis in visceral adipose tissue of long-lived Ames dwarf mice and in cultured pre-adipocytes