Increased Life Span Research Articles

Astrocytes: The Stars in Neurodegeneration?

Today, neurodegenerative disorders like Alzheimer's disease (AD), Parkinson's disease (PD), frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) affect millions of people worldwide, and as the average human lifespan increases, similarly grows the number of patients. For many decades, cognitive and motoric decline has been explained by the very apparent deterioration of neurons in various regions of the brain and spinal cord. However, more recent studies show that disease progression is greatly influenced by the vast population of glial cells. Astrocytes are traditionally considered star-shaped cells on which neurons rely heavily for their optimal homeostasis and survival. Increasing amounts of evidence depict how astrocytes lose their supportive functions while simultaneously gaining toxic properties during neurodegeneration. Many of these changes are similar across various neurodegenerative diseases, and in this review, we highlight these commonalities. We discuss how astrocyte dysfunction drives neuronal demise across a wide range of neurodegenerative diseases, but rather than categorizing based on disease, we aim to provide an overview based on currently known mechanisms. As such, this review delivers a different perspective on the disease causes of neurodegeneration in the hope to encourage further cross-disease studies into shared disease mechanisms, which might ultimately disclose potentially common therapeutic entry points across a wide panel of neurodegenerative diseases.

Would the mice’s memory of mitochondrial stress pass on to mice offspring

This study investigates whether the offspring of genetically modified mice with AD-induced UPRmt have genetic memory, which makes the offspring more likely to produce UPRmt or even with a more obvious effect. We first conducted biochemical studies using double transgenic mice of different ages to explore the expression levels of UPRmt-related proteins in hippocampal lysates. The two groups of mice were then mated to produce offspring, then the expression levels of UPRmt-related proteins in the offspring were explored. The offspring were tested for UPRmt characterization and physiological changes. Our analysis shows with inherited mtDNA and the consequent UPRmt, UPRmt can also communicate across tissues via intracellular signals; the cell-autonomous induction of UPRmt enables individuals to engage in global stress responses, whereby individuals exhibit greater resistance to adverse mitochondrial stresses, bacterial infections, and toxins, resulting in longer life. Due to the limitations of experimental materials, we propose more theories without a large amount of experimental data as support. We conclude that stress resistance can also develop in mammalian offspring due to mitochondrial stress-induced mitochondrial nuclear imbalance and the consequent increase in lifespan, thus increasing the survival advantage of the mammalian species.

Case-Based Reasoning in Achieving Sustainability Targets of New Products

Improving product sustainability is becoming an increasingly significant challenge for modern enterprises. A growing number of manufacturers are interested in enhancing product sustainability throughout the product life cycle. This study is concerned with using case-based reasoning to identify ways of improving product sustainability and select variables for model specification. Parametric models are applied to search for opportunities to improve product sustainability. This can be achieved through changes introduced at the product design stage. Simulations are performed using constraint-satisfaction modeling to identify conditions for achieving the sustainability targets of new products. Constraint-satisfaction modeling provides a suitable framework for finding all possible sustainability-enhancing changes (if any) during the new product development process. These changes may support R&D specialists in identifying opportunities to improve the sustainability of new products. We demonstrate the usefulness of the proposed approach with an example in which our method enabled a reduction in the product failure rate and an increase of battery lifespan for a robot vacuum cleaner line. We analyzed several factors affecting two targets of product sustainability: minimizing the product failure rate and maximizing battery lifespan. Our findings indicate that R&D staff size is the biggest factor in reducing the product failure rate, and that battery capacity is the most significant factor in battery lifespan.

Exploring the contributions of circular business models towards the transition of green economy in the Ghanaian construction industry

PurposeIn recent times, both academics and industrialists have undertaken research into various areas of circular business models (CBM) in a bid to promote a green economy. Yet despite numerous studies conducted, the ensuing discourse contains scant information regarding the contributions of CBM towards the transition of green economy in the construction industry. This present study therefore aims to explore the contributions of CBM in the transition towards a green economy in the Ghanaian construction industry.Design/methodology/approachA comprehensive literature review was first conducted to identify the contributions of CBM towards the transition towards a green economy. A quantitative research strategy was then adopted to collect primary questionnaire data from professionals with knowledge of CBM and the green economy from 104 participants for the study. The data gathered was analyzed using descriptive statistics and exploratory factor analysis viz. Principal component analysis.FindingsThe contributions of CBM towards the transition towards a green economy were found to be: value contributions (i.e. lower carbon footprint, lower emission of waste by the industry, value creation for clients, innovation in construction materials and methods, reduced maintenance cost, creation of energy efficient infrastructures, improved value proposition for firms, improved sustainability of the industry and reduced pressure on finite resource.); green contributions (i.e. recycling and reuse of construction waste, promotion of green building technology, increased potential for economic growth, increased resource efficiency and creation of green building market) and longevity contribution (i.e. increased life span of buildings). It was evident that CBM make significant contributions in the transition towards green economy and as such, policymakers and other stakeholders within the construction industry must adopt these models to maximize their green credentials and accrue inherent benefits associated with transitioning towards a green economy.Originality/valueThis paper presents a novel and comprehensive study that explores the contributions of CBM towards engendering a green economy. The study’s results provide construction industry stakeholders and policymakers with clear insight into the contributions of CBM towards the transition into a green economy. In practice, this study provides much needed guidance to support construction practitioners to transition towards a green economy in alignment with the United Nations' Sustainable Development Goals (SDGs).

Hyperacute Serum and Knee Osteoarthritis.

The knees are the most frequently affected weight-bearing joints in osteoarthritis (OA), impacting millions of people globally. With increasing life spans and obesity rates, the prevalence of knee OA will further mount, leading to a significant increase in the economic burden. The usual treatment modalities utilized to manage knee OA have shortcomings. Over the last decade, the field of regenerative medicine involving the use of biologics, such as autologous peripheral blood-derived orthobiologics, including hyperacute serum (HS), has evolved and shown potential for managing knee OA. In this manuscript, we qualitatively present the in vitro, pre-clinical, clinical, and ongoing studies investigating the applications of HS in the context of knee OA. Seven in vitro studies and one clinical study fit the scope of our manuscript. The results demonstrated that the administration of HS is potentially safe and efficacious in terms of increasing the viability of osteoarthritic chondrocytes, reducing pain and inflammation, and improving function in patients with knee OA. However, due to insufficient literature, pre-clinical studies to better understand the mechanism of action are required. In addition, adequately powered, multi-center, non-randomized, and randomized controlled trials with longer follow-up are warranted to establish the safety and efficacy of HS for the management of knee OA and to justify its clinical use.

Performance investigation of solar photovoltaic panels using mist nozzles cooling system

ABSTRACT Solar PV has a disadvantage over its many advantages that its electrical efficiency falls due to rise in surface/operating temperature of solar PV cells. Therefore, it is necessary to find a way to mitigate the efficiency loss due to rise in temperature as well as to increase life span of solar photovoltaics by lowering its cell temperature. In this research, the impact of mist cooling on output of PV panel is observed through experimental setup installed at rooftop of Postgraduate Department, Mehran University of Engineering and Technology, Jamshoro, Pakistan. The rear surface of PV module is cooled with designed mist nozzle assembly. The performance of modified mist cooled PV module is than compared with reference PV module. Experimental investigation is performed several days in different weather conditions with natural circulation and with forced circulations by using submerged pump. The maximum efficiency gains of 7% and average gain of 3.72% is observed with natural circulation, and maximum gain of 9.2% and average gain 1.72% are observed with forced circulated mist. The overall impact of proposed mist cooled system is positive on performance of PV panels.

Challenging pacemaker implantation in a patient with a large aortic aneurysm – a case report

With the increasing life span of the general population more cases of the aneurysms are being reported within cardiological patients with other vascular morbidities. A 75-year-old woman presented with syncope in the course of third-degree cardiovascular block. During the first day of hospitalization, the interventional cardiologist implanted the temporary endocavitary lead through the internal jugular vein. The following day, the implantation of a pacemaker was performed. During the procedure, it was revealed that the venous system on the left side of the patient’s chest is significantly modified by a large aortic arch aneurysm constricting the left brachiocephalic vein. Due to the usage of a hydrophilic guide wire, the cardiologist managed to gain access through the critically stenosed part of the vein and successfully implant the pacemaker.

Human lifespan and sex-specific patterns of resilience to disease: a retrospective population-wide cohort study

BackgroundSlower paces of aging are related to lower risk of developing diseases and premature death. Therefore, the greatest challenge of modern societies is to ensure that the increase in lifespan is accompanied by an increase in health span. To better understand the differences in human lifespan, new insight concerning the relationship between lifespan and the age of onset of diseases, and the ability to avoid them is needed. We aimed to comprehensively study, at a population-wide level, the sex-specific disease patterns associated with human lifespan.MethodsObservational data from the SIDIAP database of a cohort of 482,058 individuals that died in Catalonia (Spain) at ages over 50 years old between the 1st of January 2006 and the 30th of June 2022 were included. The time to the onset of the first disease in multiple organ systems, the prevalence of escapers, the percentage of life free of disease, and their relationship with lifespan were evaluated considering sex-specific traits.ResultsIn the study cohort, 50.4% of the participants were women and the mean lifespan was 83 years. The results show novel relationships between the age of onset of disease, health span, and lifespan. The key findings include: Firstly, the onset of both single and multisystem diseases is progressively delayed as lifespan increases. Secondly, the prevalence of escapers is lower in lifespans around life expectancy. Thirdly, the number of disease-free systems decreases until individuals reach lifespans around 87–88 years old, at which point it starts to increase. Furthermore, long-lived women are less susceptible to multisystem diseases. The associations between health span and lifespan are system-dependent, and disease onset and the percentage of life spent free of disease at the time of death contribute to explaining lifespan variability. Lastly, the study highlights significant system-specific disparities between women and men.ConclusionsHealth interventions focused on delaying aging and age-related diseases should be the most effective in increasing not only lifespan but also health span. The findings of this research highlight the relevance of Electronic Health Records in studying the aging process and open up new possibilities in age-related disease prevention that should assist primary care professionals in devising individualized care and treatment plans.

Phenolic-rich lees from Philippine rice wine (tapuy) increases Caenorhabditis elegans lifespan in spite of having low antioxidant activity

Tapuy is an indigenous wine produced in the Philippines. Rice wine fermentation produces a by-product of rice leftover and microbial biomass, collectively called lees, which usually is discarded as a waste product. However, studies have shown the potential value of lees as a healthy food source. We wanted to determine the nutritional profile of tapuy wine and its lees and their abilities to extend lifespan in Caenorhabditis elegans. Tapuy lees (7.65 g/100 g dry weight) was 18.5-fold greater in protein content compared to tapuy wine. Its sugar content (27.66 g/100 g dry weight) is similar to the tapuy wine’s sugar content (23.465 g/100 g dry weight). Through LC–MS/MS, 18.75% and 12.39% of spectral peaks in tapuy wine and lees were matched, respectively, to specific compounds, and several of them are associated with beneficial health effects. Furthermore, the phenolic content in tapuy lees (19,475.526 Gallic Acid Equivalent) is 6.5-fold greater compared to tapuy wine. Surprisingly, the DPPH and FRAP antioxidant assays show that tapuy lees had a lesser antioxidant ability compared to tapuy wine. However, C. elegans fed with supplementation of tapuy lees extract showed a 16.24% increase in mean lifespan, which is higher compared to the 6.10% increase in mean lifespan when supplemented with tapuy wine. Taking all these findings together, our study revealed that tapuy lees has a greater nutritional value than tapuy wine, and this underutilized and wastefully discarded product can be repurposed as a potential functional food.Graphical

Personalized medicine in old age psychiatry and Alzheimer's disease.

Elderly patients show us unfolded lives with unique individual characteristics. An increasing life span is associated with increasing physical and mental disease burden. Alzheimer's disease (AD) is an increasing challenge in old age. AD cannot be cured but it can be treated. The complexity of old age and AD offer targets for personalized medicine (PM). Targets for stratification of patients, detection of patients at risk for AD or for future targeted therapy are plentiful and can be found in several omic-levels.

Characterization of methionine dependence in melanoma cells.

Dietary methionine restriction is associated with a reduction in tumor growth in preclinical studies and an increase in lifespan in animal models. The mechanism by which methionine restriction inhibits tumor growth while sparing normal cells is incompletely understood. We do know that normal cells can utilize methionine or homocysteine interchangeably (methionine independence) while most cancer cells are strictly dependent on methionine availability. Here, we compared a typical methionine dependent and a rare methionine independent melanoma cell line. We show that replacing methionine, a methyl donor, with its precursor homocysteine generally induced hypomethylation in gene promoters. This decrease was similar in methionine dependent and methionine independent cells. There was only a low level of pathway enrichment, suggesting that the hypomethylation is generalized rather than gene specific. Whole proteome and transcriptome were also analyzed. This analysis revealed that contrarily to the effect on methylation, the replacement of methionine with homocysteine had a much greater effect on the transcriptome and proteome of methionine dependent cells than methionine independent cells. Interestingly, methionine adenosyltransferase 2A (MAT2A), responsible for the synthesis of S-adenosylmethionine from methionine, was equally strongly upregulated in both cell lines. This suggests that the absence of methionine is equally detected but triggers different outcomes in methionine dependent versus independent cells. Our analysis reveals the importance of cell cycle control, DNA damage repair, translation, nutrient sensing, oxidative stress and immune functions in the cellular response to methionine stress in melanoma.

Milk fat globule membrane and its polar lipids: reviewing preclinical and clinical trials on cognition.

In most parts of the world, life expectancy is increasing thanks to improved healthcare, public health policies, nutrition, and treatment. This increase in lifespan is often not accompanied by an increase in health span, which severely affects people as they age. One notable consequence of this is the increasing prevalence of neurodegenerative diseases such as mild cognitive impairment, dementia, and Alzheimer's disease. Therefore, dietary and pharmaceutical measures must be taken to reduce the burden of such pathologies. Among the different types of nutrients found in the diet, lipids and especially polar lipids are very important for cognition due to their abundance in the brain. Amid the most studied sources of polar lipids, milk fat globule membrane (MFGM) stands out as it is abundant in industrial by-products such as buttermilk. In this narrative review, we discuss the latest, i.e. less than five years old, scientific evidence on the use of MFGM and its polar lipids in cognitive neurodevelopment in early life and their potential effect in preventing neurodegeneration in old age. We conclude that MFGM is an interesting, abundant and exploitable source of relatively inexpensive bioactive molecules that could be properly formulated and utilized in the areas of neurodevelopment and cognitive decline. Sufficiently large randomized controlled trials are required before health-related statements can be made. However, research in this area is progressing rapidly and the evidence gathered points to biological, health-promoting effects.

Insulin Sensitizers as Anti-Aging Agents: Unveiling Synergies with Albumin, GLP-1RA, Klotho Protein, and Metformin in the Quest to Combat Aging

This study delves into the synergistic interplay among albumin, insulin, Klotho protein, and relevant medications in the pursuit of a concerted approach to halt aging. Emphasizing albumin's pivotal role in various physiological functions, including transportation and drug distribution, the research underscores its decline's correlation with aging-related cognitive implications. The intricate relationship between insulin and albumin, modulated by Foxo1, underscores its crucial significance. Groundbreaking experiments, utilizing unmodified serum albumin, demonstrate a remarkable increase in lifespan and enhanced physical capabilities, highlighting the potential of an integrative approach. The investigation extends to insulin sensitizers, Klotho protein, metformin, and SGLT2 inhibitors, collectively revealing promising anti-aging effects. The association between Klotho protein and albumin suggests a collaborative mechanism with implications for efficient transport and distribution. This research offers insights into a comprehensive, synergistic strategy harnessing the potential of these elements to counteract aging processes.

Walnuts for the eye and vision

The increase in lifespan with the consequent expansion of the aging of the world population has become an important challenge for public health. In recent decades, there has been a progressive increase in the incidence of debilitating diseases related to aging, including neurodegenerative disorders and eye diseases. Oxidative stress and inflammation are believed to play a critical role in several eye disorders, such as age‐related macular degeneration (AMD), diabetic retinopathy (DR), and cataracts, the leading causes of visual loss and blindness worldwide. Neurodegenerative events were also related to AMD and DR.Nutrients such as n‐3 polyunsaturated fatty acids (n‐3 PUFA) and antioxidants, specifically polyphenols, carotenoids, and vitamins C and E, may play a role in preventing both cognitive decline and retinal degenerative processes. Nuts have been described as a “superfood”, containing a notable variety of natural components that may have additive and/or synergistic properties for health and may prevent some pathologies. Nuts in general and walnuts in particular have a rich matrix of these bioactive components and through additive effects, have the potential to beneficially impact neuronal function in the brain and retina. Among different nuts, walnuts contain n‐3 PUFAs, specifically α‐linolenic acid (ALA; C18:3n‐3). It is believed that ALA may improve brain health indirectly through conversion to docosahexaenoic acid (DHA; C22:6n‐3), which has the ability to modulate brain plasticity and counteracts neuroinflammation in experimental studies. Other bioactive compounds in walnuts, such as arginine, tocopherols, folate, melatonin and polyphenols, also support neurological health and cognitive well‐being by modulating blood pressure, HDL function, glucoregulation, endothelial vasodilator function, oxidative status and vascular dysfunction. Polyphenols (including ellagitannins) have high antioxidant and prebiotic properties, which can regulate the gut microbiome, which is related to the increased risk of several inflammatory diseases. There is growing evidence that walnuts may contribute positively to eye disorders such as AMD, DR, and cataract prevention.

Green synthesis of silver/silver chloride nanoparticles derived from Elaeocarpus floribundus leaf extract and study of its anticancer potential against EAC and MCF-7 cells with antioxidant and antibacterial properties

In this study, the formation of Elaeocarpus floribundus leaf extract-mediated Ag/AgCl-NPs was ensured by color changes, UV–visible spectrum and it was characterized by scanning electron microscopy, transmitted electron microscopy, X-ray powder diffraction, thermal gravimetric analysis, and Fourier transform infrared spectroscopy. Synthesized Ag/AgCl-NPs scavenged DPPH and ABTS free radicals with the IC50 values of about 99.86 and 25.50 µg/ml, respectively. Among four pathogenic bacteria, Shigella dysenteriae was the most sensitive to Ag/AgCl-NPs with the lowest MIC value of 2 µg/ml. Besides, Escherichia coli failed to produce biofilm at 80 µg/ml of Ag/AgCl-NPs in a 24 to 96 h incubation period. Using MTT assay, 84.15 % EAC and 61.71 % MCF-7 cells growth inhibition caused at 32 µg/ml of Ag/AgCl-NPs. Moreover, Ag/AgCl-NPs inhibited 46.46 %, 54.54 %, and 71.28 % growth of EAC cells in mice at the doses of 1.5, 3, and 6 mg/kg/day after five consecutive days. Additionally, frequent apoptotic and altered morphological cells were found in Ag/AgCl-NPs treated groups during cellular morphological study. Moreover, incredible progress of hematological parameters (RBC, Hemoglobin, and WBC) with reduced average tumor weight and an increase in lifespan up to 73.82 % were observed in Ag/AgCl-NPs treated groups of mice and showed mild toxicity with an LC50 value of 138.56 µg/ml towards brine shrimp nauplii.

Computational insights into the binding modes, keto-enol tautomerization and stereo-electronically controlled decarboxylation of oxaloacetate in the active site of macrophomate synthase.

Oxaloacetic acid (OAA) is a β-ketocarboxylic acid, which plays an important role as an intermediate in some metabolic pathways, including the tricarboxylic acid cycle, gluconeogenesis and fatty acid biosynthesis. Animal studies have indicated that supplementing oxaloacetic acid shows an increase of lifespan and other substantial health benefits including mitochondrial DNA protection, and protection of retinal, neural and pancreatic tissues. Most of the chemical transformations of OAA in the metabolic pathways have been extensively studied; however, the understanding of decarboxylation of OAA at the atomic level is relatively lacking. Here, we carried out MD simulations and combined quantum mechanical/molecular mechanical (QM/MM) calculations as an example to systematically elucidate the binding modes, keto-enol tautomerization and decarboxylation of OAA in the active site of macrophomate synthase (MPS), which is a Mg(II)-dependent bifunctional enzyme that catalyzes both the decarboxylation of OAA and [4+2] cycloaddition of 2-pyrone with the decarboxylated intermediate of OAA (pyruvate enolate). On the basis of our calculations, it was found that the Mg2+-coordinated oxaloacetate may exist in enol forms and keto forms. The four keto forms can be transformed into each other by simply rotating the C2-C3 single bond, nevertheless, the keto-enol tautomerization strictly requires the assistance of pocket water molecules. In addition, the decarboxylation is stereo-electronically controlled, i.e., it is the relative orientation of the terminal carboxyl anion that determines the rate of decarboxylation. As such, the chemistry of oxaloacetate in the active site of MPS is complex. On one hand, the most stable binding mode (K-I) may undergo enol-keto tautomerization to isomerize to the enol form, which may further react with the second substrate; on the other hand, K-I may isomerize to another binding mode K-II to proceed decarboxylation to generate pyruvate enolate and CO2. Starting from K-I, the enol-keto tautomerization corresponds to a barrier of 16.2 kcal mol-1, whereas the decarboxylation is associated with an overall barrier of 19.7 kcal mol-1. These findings may provide useful information for understanding the chemistry of OAA and the catalysis of related enzymes, and they are basically in agreement with the available experimental kinetic data.

The Power of Emotional Engagement: Tamil Television Serials as a Trail to Enhance Well-being and Successful Ageing among Older Adults

Tamil television serials have the potential to elicit a wide variety of emotions in viewers. Emotional control and expression change as individuals age, and this change is interrelated in various ways. Positive or negative emotions, when put into practice by regulating the emotions associated with health, can result in an increase or decrease in lifespan during successful ageing. This study explores the relationship between emotional well-being and prosperous ageing in Tamil television serials among older adults. An exploratory method was adopted to understand the connection between Tamil television serials and emotional well-being for successful ageing in Tamil Nadu (a southern state of India). Fourteen older adults over 50 who watch Tamil television mega-serials from Tamil Nadu were recruited for in-depth interviews. Three themes emerged from the thematic analysis: emotional connection, life satisfaction, fortitude and ageism among older adults. The findings suggest that Tamil television serials provide emotional engagement, companionship and life satisfaction for older adults, contributing to successful ageing.

Effect of the LSD1 inhibitor RN-1 on γ-globin and global gene expression during erythroid differentiation in baboons (Papio anubis).

Elevated levels of Fetal Hemoglobin interfere with polymerization of sickle hemoglobin thereby reducing anemia, lessening the severity of symptoms, and increasing life span of patients with sickle cell disease. An affordable, small molecule drug that stimulates HbF expression in vivo would be ideally suited to treat the large numbers of SCD patients that exist worldwide. Our previous work showed that administration of the LSD1 (KDM1A) inhibitor RN-1 to normal baboons increased Fetal Hemoglobin (HbF) and was tolerated over a prolonged treatment period. HbF elevations were associated with changes in epigenetic modifications that included increased levels of H3K4 di-and tri-methyl lysine at the γ-globin promoter. While dramatic effects of the loss of LSD1 on hematopoietic differentiation have been observed in murine LSD1 gene deletion and silencing models, the effect of pharmacological inhibition of LSD1 in vivo on hematopoietic differentiation is unknown. The goal of these experiments was to investigate the in vivo mechanism of action of the LSD1 inhibitor RN-1 by determining its effect on γ-globin expression in highly purified subpopulations of bone marrow erythroid cells enriched for varying stages of erythroid differentiation isolated directly from baboons treated with RN-1 and also by investigating the effect of RN1 on the global transcriptome in a highly purified population of proerythroblasts. Our results show that RN-1 administered to baboons targets an early event during erythroid differentiation responsible for γ-globin repression and increases the expression of a limited number of genes including genes involved in erythroid differentiation such as GATA2, GFi-1B, and LYN.

Dhr96[1] mutation and maternal tudor[1] mutation increase life span and reduce the beneficial effects of mifepristone in mated female Drosophila.

Mating and receipt of male Sex Peptide hormone cause increased egg laying, increased midgut size and decreased life span in female Drosophila. Feeding mated females with the synthetic steroid mifepristone decreases egg production, reduces midgut size, and increases life span. Here, several gene mutations were assayed to investigate possible mechanisms for mifepristone action. Drosophila Dhr96 is a hormone receptor, and a key positive regulator of midgut lipid uptake and metabolism. Dhr96[1] null mutation increased female life span, and reduced the effects of mifepristone on life span, suggesting that Dhr96[1] mutation and mifepristone may act in part through the same mechanism. Consistent with this idea, lipidomics analysis revealed that mating increases whole-body levels of triglycerides and fatty-acids in triglycerides, and these changes are reversed by mifepristone. Maternal tudor[1] mutation results in females that lack the germ-line and produce no eggs. Maternal tudor[1] mutation increased mated female life span, and reduced but did not eliminate the effects of mating and mifepristone on life span. This indicates that decreased egg production may be related to the life span benefits of mifepristone, but is not essential. Mifepristone increases life span in w[1118] mutant mated females, but did not increase life span in w[1118] mutant virgin females. Mifepristone decreased egg production in w[1118] mutant virgin females, indicating that decreased egg production is not sufficient for mifepristone to increase life span. Mifepristone increases life span in virgin females of some, but not all, white[+] and mini-white[+] strains. Backcrossing of mini-white[+] transgenes into the w[1118] background was not sufficient to confer a life span response to mifepristone in virgin females. Taken together, the data support the hypothesis that mechanisms for mifepristone life span increase involve reduced lipid uptake and/or metabolism, and suggest that mifepristone may increase life span in mated females and virgin females through partly different mechanisms.

KYNURENINE PATHWAY INHIBITORS COMBINED WITH NAD+ PRECURSORS INCREASES LONGEVITY GENE EXPRESSION IN DROSOPHILA

Abstract With rates of aging-related functional decline rising, the need for novel intervention strategies to extend lifespan has increased. In humans, the kynurenine pathway (KP) metabolizes tryptophan and produces nicotinamide adenine dinucleotide (NAD+). KP is correlated negatively with longevity and increased KP metabolite concentrations decrease the average and maximum lifespans in flies. However, genetic and pharmacological inhibition of tryptophan metabolism and dietary supplementation of NAD+ precursors increase the average and maximum lifespans in flies. To comprehensively explore the effects of KP manipulation, we fed DGRP_229 Drosophila males diets infused with ⍺-MT (KP inhibitor), nicotinamide (NAM, an NAD+ precursor), or the combination of NAM and ⍺-MT. We found that all treatments resulted in increased average and maximum lifespans, with the combination treatment displaying the greatest increase compared to the control of 30% (P< 0.0001). The combination treatment resulted in an average lifespan increase of 15% in relation to ⍺-MT alone (P< 0.0001) and 18% in comparison to NAM alone (P< 0.0001). To gain more insight into the biological mechanisms through which different treatments affect lifespan, we performed qRT-PCR on 11 longevity genes in Drosophila. We found that the combination treatment significantly increased the expression of gigas (Gig) (P=0.03), which interacts with Tsc1 to control cellular growth by regulating insulin and TOR signaling pathways, and sirtuin 1 (Sirt1) (P=0.03), an NAD+-dependent histone deacetylase. Our results demonstrate that the combined treatment of KP inhibition and NAD+ precursor elicits a transcription response similar to other lifespan-enhancing treatments and could be used as an alternative intervention method.