Selective ablation of primary and paracrine senescent cells by targeting iron dyshomeostasis.

Senescent cells can spread the senescent phenotype to other cells by secreting senescence-associated secretory phenotype factors. The resulting paracrine senescent cells make a significant contribution to the burden of senescent cell accumulation with age. Previous efforts made to characterize paracrine senescence are unreliable due to analyses being based on mixed populations of senescent and non-senescent cells. Here, we use dipeptidyl peptidase-4 (DPP4) as a surface maker to isolate senescent cells from mixed populations. Using this technique, we enrich the percentage of paracrine senescence from 40% to 85%. We then use this enriched culture to characterize DPP4+ primary and paracrine senescent cells. We observe ferroptosis dysregulation and ferrous iron accumulation as a common phenomenon in both primary and paracrine senescent cells. Finally, we identify ferroptosis induction and ferrous iron-activatable prodrug as a broad-spectrum senolytic approach to ablate multiple types of primary and paracrine senescent cells.

Enhanced co-culture and enrichment of human natural killer cells for the selective clearance of senescent cells.

In the context of aging and age-associated diseases, Natural Killer (NK) cells have been revealed as a key cell type responsible for the immune clearance of senescent cells. Subsequently, NK cell-based therapies have emerged as promising alternatives to drug-based therapeutic interventions for the prevention and treatment of age-related disease and debility. Given the promise of NK cell-mediated immunotherapies as a safe and effective treatment strategy, we outline an improved method by which primary NK cells can be efficiently enriched from human peripheral blood across multiple donors (ages 20-42 years old), with a practical protocol that reliably enhances both CD56dim and CD56bright NK cells by 15-fold and 3-fold, respectively. Importantly, we show that our co-culture protocol can be used as an easily adaptable tool to assess highly efficient and selective killing of senescent cells by primary NK cells enriched via our method using longer co-culture durations and a low target to effector ratio, which may be more physiological than has been achieved in previous literature.

Aging of the Immune System: Focus on Natural Killer Cells Phenotype and Functions.

Aging is the greatest risk factor for nearly all major chronic diseases, including cardiovascular diseases, cancer, Alzheimer's and other neurodegenerative diseases of aging. Age-related impairment of immune function (immunosenescence) is one important cause of age-related morbidity and mortality, which may extend beyond its role in infectious disease. One aspect of immunosenescence that has received less attention is age-related natural killer (NK) cell dysfunction, characterized by reduced cytokine secretion and decreased target cell cytotoxicity, accompanied by and despite an increase in NK cell numbers with age. Moreover, recent studies have revealed that NK cells are the central actors in the immunosurveillance of senescent cells, whose age-related accumulation is itself a probable contributor to the chronic sterile low-grade inflammation developed with aging ("inflammaging"). NK cell dysfunction is therefore implicated in the increasing burden of infection, malignancy, inflammatory disorders, and senescent cells with age. This review will focus on recent advances and open questions in understanding the interplay between systemic inflammation, senescence burden, and NK cell dysfunction in the context of aging. Understanding the factors driving and enforcing NK cell aging may potentially lead to therapies countering age-related diseases and underlying drivers of the biological aging process itself.

A small-molecule Psora-4 acts as a caloric restriction mimetic to promote longevity in C. elegans.

In populations around the world, the fraction of humans aged 65 and above is increasing at an unprecedented rate. Aging is the main risk factor for the most important degenerative diseases and this demographic shift poses significant social, economic, and medical challenges. Pharmacological interventions directly targeting mechanisms of aging are an emerging strategy to delay or prevent age-dependent diseases. Successful application of this approach has the potential to yield dramatic health, social, and economic benefits. Psora-4 is an inhibitor of the voltage-gated potassium channel, Kv1.3, that has previously been shown to increase longevity and health span in the nematode Caenorhabditis elegans (C. elegans). Our recent discovery that Psora-4 lifespan benefits in C. elegans are synergistic with those of several other lifespan-extending drugs has motivated us to investigate further the mechanism by which Psora-4 extends lifespan. Here, we report that Psora-4 increases the production of free radicals and modulates genes related to stress response and that its effect intersects closely with the target set of caloric restriction (CR) genes, suggesting that it, in part, acts as CR mimetic. This effect may be related to the role of potassium channels in energy metabolism. Our discovery of a potassium channel blocker as a CR mimetic suggests a novel avenue for mimicking CR and extending a healthy lifespan.

Dissecting primary and secondary senescence to enable new senotherapeutic strategies.

Cellular senescence is a state of stable cell cycle arrest that is known to be elicited in response to different stresses or forms of damage. Senescence limits the replication of old, damaged, and precancerous cells in the short-term but is implicated in diseases and debilities of aging due to loss of regenerative reserve and secretion of a complex combination of factors called the senescence-associated secretory phenotype (SASP). More recently, investigators have discovered that senescent cells induced by these methods (what we term "primary senescent cells") are also capable of inducing other non-senescent cells to undergo senescence - a phenomenon we call "secondary senescence." Secondary senescence has been demonstrated to occur via two broad types of mechanisms. First, factors in the SASP have been shown to be involved in spreading senescence; we call this phenomenon "paracrine senescence." Second, primary senescent cells can induce senescence via an additional group of mechanisms involving cell-to-cell contacts of different types; we term this phenomenon "juxtacrine senescence." "Secondary senescence" in our definition is thus the overarching term for both paracrine and juxtacrine senescence together. By allowing cells that are inherently small in number and incapable of replication to increase in number and possibly spread to anatomically distant locations, secondary senescence allows an initially small number of senescent cells to contribute further to age-related pathologies. We propose that understanding how primary and secondary senescent cells differ from each other and the mechanisms of their spread will enable the development of new rejuvenation therapies to target different senescent cell populations and interrupt their spread, extending human health- and potentially lifespan.

Effect of habitual consumption of Ethiopian Arabica coffee on the risk of cardiovascular diseases among non-diabetic healthy adults.

BACKGROUND: Globally, coffee is one of the most consumed beverages and recently, it has been a target of researchers to understand its effect on human health whether good or bad. Even though there is controversy on coffee consumption effect in cardiovascular diseases, several reports pointed out that coffee has a positive effect on the occurrence and progression of chronic non-communicable diseases including cardiovascular diseases. However, the impact of Ethiopian coffee Arabica consumption on cardiovascular diseases has not been well investigated thoroughly. OBJECTIVE: The aim of the present study was to investigate the effect of habitual consumption of Ethiopian Arabica coffee on the risk of cardiovascular diseases among non-diabetic individuals in Addis Ababa. MATERIALS AND METHODS: A cross-sectional study was conducted in 70 healthy individuals in Addis Ababa. The participants were 35 coffee drinkers (16 males; 19 females) and 35 non-drinkers (15 males; 20 females). Coffee consumption and demographic data were obtained by using questionnaires. Anthropometric measurements were measured according to World Health Organization standards. Blood samples were collected by trained laboratory technicians through aseptic and sterile techniques for the analysis of biochemical parameters. Serum was separated via centrifugation and transported to Addis Ababa University, College of Health Sciences, Biochemistry laboratory with an ice pack for analysis or stored at -80 °C. Results were compared between coffee consumers and non -consumers using appropriate statistical parameter. RESULT: The main finding of this study was that consumption of Ethiopian origin Arabica coffee leads to a significant increase in serum free fatty acids (FFAs) and high density lipoprotein (HDL) as well as a significant decrease in triacylglycerides (TAGs) but has no significant effect in both total cholesterol (TC) and low density lipoprotein (LDL). The magnitude of the effect is similar in both sexes. CONCLUSION: The present study demonstrated that Ethiopian coffee Arabica consumption significantly affected most serum lipid levels and so it may be possible to say it has a protective effect against risks of cardiovascular diseases (CVDs). However, the correlations between coffee consumption habits and serum lipid levels require further investigation through experimental and epidemiological studies with larger sample size, including different age groups and nutritional habits.

Caspase-1 as a regulatory molecule of lipid metabolism.

Caspase-1 is an evolutionarily conserved inflammatory mediated enzyme that cleaves and activates inflammatory cytokines. It can be activated through the assembly of inflammasome and its major effect is to activate the pro-inflammatory cytokines; interleukin 1ß (IL-1ß) and interluekine-18 (IL-18). In addition to IL-1ß and IL-8, several lines of evidence showed that caspase-1 targets the substrates that are involved in different metabolic pathways, including lipid metabolism. Caspase-1 regulates lipid metabolism through cytokine dependent or cytokine independent regulation of genes that involved in lipid metabolism and its regulation. To date, there are several reports on the role of caspase-1 in lipid metabolism. Therefore, this review is aimed to summarize the role of caspase-1 in lipid metabolism and its regulation.

Drug Synergy Slows Aging and Improves Healthspan through IGF and SREBP Lipid Signaling.

There is growing interest in pharmacological interventions directly targeting the aging process. Pharmacological interventions against aging should be efficacious when started in adults and, ideally, repurpose existing drugs. We show that dramatic lifespan extension can be achieved by targeting multiple, evolutionarily conserved aging pathways and mechanisms using drug combinations. Using this approach in C. elegans, we were able to slow aging and significantly extend healthy lifespan. To identify the mechanism of these drug synergies, we applied transcriptomics and lipidomics analysis. We found that drug interactions involved the TGF-ß pathway and recruited genes related with IGF signaling. daf-2, daf-7, and sbp-1 interact upstream of changes in lipid metabolism, resulting in increased monounsaturated fatty acid content and this is required for healthy lifespan extension. These data suggest that combinations of drugs targeting distinct subsets of the aging gene regulatory network can be leveraged to cause synergistic lifespan benefits.

Lipid profiling of C. elegans strains administered pro-longevity drugs and drug combinations.

We report the effect of four lifespan modifying drugs and of synergistic combinations of these drugs on lipid profile in Caenorhabditis elegans. We employ ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) to compare the abundance of lipid species in treated and control animals. Adult nematodes were treated with rapamycin, rifampicin, psora-4 and allantoin and combinations of these compounds and the resulting change in lipid profiles, specifically in those of triacylglycerol (TAG), phosphatidylcholine (PC) and phosphatidylethanolamine (PE) were determined. We quantified changes resulting from treatment with the drug combinations relative to untreated controls and relative to animals treated with each constituent single drugs. We further determined the dependence of changes in lipid profiles on genes known to affect lipid metabolism using strains carrying mutations in these pathways. In particular, we determined lipid profiles in a genetic model of caloric restriction (eat-2), a strain lacking homolog of TGFß (daf-7) and in a strain lacking the SREBP/sbp-1 transcription factor.