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The biology of Aging in Insects From Drosphila to other insects and back.pptx
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- 4. The Biology of Aging in Insects: From Drosophila to Other Insects and Back DOCTORAL SEMINAR -III ARCHANA B R II Ph. D (Agricultural Entomology ) UAS Raichur 3
- 5. C O N T E N T S INTRODUCTION DEFINTION ORIGIN OF AGING RESEARCH DROSPHILLA AS MODEL ORGANISM MECHANISM UNDERLYING AGING – NON GENETIC AND GENETIC AGING IN NON DROSOPHILA INSECTS- EUSCOIAL INSECTS FLIGHT AND INSECT LIFESPAN DIAPAUSE AND LIFESPAN CONCLUSION AND PERSPECTIVES 4
- 6. “Aging is an extraordinary complex process with a time- dependent loss of structure, function, and physiological integrity” Accumulation of damage at the molecular and cellular levels which, over time, results in marked physiological impairments throughout the organism. SIGNS OF AGING • Physiology • Behaviour • Body structures • Molecular pathways 5
- 7. Research into the mechanisms underlying the process of aging is emerging as an exciting area of biomedical research CANONICAL MODEL ORGANISMS 6
- 8. we share 60 % of DNA 75% of known human disease genes have a recognisable match in fruit flies relatively short life span ease of maintenance environmental and genetic manipulations that alter life span already available information on aging powerful molecular genetic technique sequence of the full Drosophila genome DROSOPHILA AS MODEL ORGANISM 7 (Helfand and Rogina, 2003)
- 9. MANIPULATIONS THAT ALTER LIFE SPAN IN DROSOPHILA (a) ambient temperature/ stressors, (b) physical activity, (c) reproductive status, and (d) dietary status NONGENETIC GENETIC a) Oxidative stress, b) Contribution of chromatin structure. c) Life extending mutations d) Role of heat-shock proteins 8
- 10. temperature rate of chemical reaction “RATE OF METABOLISM THEORY” “longevity is inversely proportional to the level of the basal metabolic rate measured as oxygen consumption” Longevity Vantt hoff’s law RATE OF LIVING THEORY “the faster an organism's metabolism, the shorter its lifespan” Variations- geographical origin of species 9
- 11. Objective: investigate the relationship between the temperature, genetic background (fruit fly origin), and metabolic rate on lifespan. Experiments - wild type Drosophila melanogaster fruit flies originating from Australia, Canada, and Benin and the reference OregonR strain. The metabolic rate - measured at 20 ◦C, 25 ◦C, and 28 ◦C in an isothermal calorimeter 10 (Molon et al., 2020)
- 12. Aus>can>ben>ore Can> Aus>ben>ore Aus>Can>Ore>Ben Aus>Can=Ore>Ben Forecasting of impact of global warming on metabolic activity and lifespan of various insect 11
- 13. “Negative correlations, between these fitness traits, such as the cost- of-reproduction trade-off between fecundity and survival” Competitive resource allocation, Energy Reproduction Maintenance and survival SURVIVAL AND REPRODUCTION Individuals that reproduce more live shorter lives Reduced lifespan Physiological Trade off Evolutionary Trade off Antagonistic pleiotrophy 12 (Flatt, 2020)
- 14. 2 virgins of same sex for 5 days OM, allowed to copulate only once and immediately seperated SP, One male and one female placed together in culture tube and allowed to copulate over 5 days MP, flies given a new partner every day for 5 days 13 (Koliada et al., 2020)
- 15. Mating status affects the lifespan in Drosophila. Survival and reproduction as a function of time for female (A) and male (B) flies of different mating groups 14
- 16. 70–80% 40% 50% 60 % Effect of Mating status on reproduction and egg quality 15
- 17. In Drosophila, mating frequency may affect reproductive success by mediating survival maintenance and reproduction. long-term effects of mating is that this process leads to a reallocation of nutritional resources to reproduction at the expense of somatic maintenance, maximization of egg production and, thereby, female reproductive success risks of predation, disturbance of immune function, infection, enhanced susceptibility to stress and genital damage lead to immediate fitness costs and higher risk of early death 16
- 18. DIETARY RESTRICTION – LIFE EXTENDING THERAPY Maintain intestinal epithelial barrier, up-regulates lipid metabolic processes, and improves the ability of the gut to deal with damage or stress Intestinal dysplasia 17 (Piper and Partridge, 2007).
- 19. Intestine of elderly flies Increase stem proliferation Increase intestinal flora Activation of Inflamatory pathways Increase intenstinal permeability Diet restriction Regulate stem prolifertion Prevent microbial contamination Inhibition of aging related pathways Maintain intestinal permeability 18
- 20. Lifespan extension reported for food reduction – food dilution or nutrient manipulation Dilution of dietary protein Sugar, agar and casein or dried yeast - fecundity poor on all casein-based diets, but high with yeast addition - lifespan greatest on yeast based diets (casein poorly nutritious) - next longest lifespan on intermediate casein concentration (Min, 2006) Yeast component dilution Cornmeal, dried yeast, sugar, agar - fecundity not reported - longest lifespan at intermediate yeast concentration (Pearl, 2005) Dilution of added live yeast solution Sugar, charcoal, agar - increased fecundity with increased yeast - low yeast condition mostly longer-lived than controls (Partridge and piper, 2005) Dietary dilution Dried yeast, sugar, agar - optimum sugar concentration found by monitoring egg- laying - lifespan peak at intermediate yeast concentration - found one yeast better than others for DR with Drosophila (Simpson et al., 1989) 19
- 22. • genetics plays a major role in the process of aging and the determination of longevity • The fact that aging is hereditary, however, does not necessarily mean that a fixed genetic pathway determines aging • 25-30 % of the variation in human longevity is due to genetic factors, while the rest is due to individual behavior and environmental factors Role of Oxidative stress Contribution of chromatin structure. Life extending mutations Role of heat-shock proteins, GENETIC FACTORS IN ALTERING LIFESPAN 21
- 23. 23 Driving force behind the process of aging. ROS defense system superoxide dismutase (Sod), catalase (Cat) Superoxide Hydrogen peroxide Oxyzen and water One notable finding is that overexpression of human SOD in the motorneurons of the fly resulted in a 40–50% increase in life span 22 (Parks et al., 1998)
- 24. Life-extending mutations Single gene mutations can greatly enhance our understanding of complex biological processes such as aging To date, two different life-extending mutations methuselah (mth) and I’m not dead yet (Indy) mutants The mth gene, mutations of which increase mean life span by 35%, mediate most cellular response to hormones and neurotransmitters. In addition to long life, the mth mutant animals are resistant to heat stress, starvation, dessication 23
- 25. Indy gene (I am not dead yet) 50% similarity to human and rat responsible for the transporter of Krebs cycle intermediates Life-span extension in Indy mutants Control Indy 206 Indy 302 Indy 159 Mean life span 37 days 71 days 69 days 69 days Maximal life span - 92 87 87 24 (Rogina et al., 2000) Increase lifespan , without loss of fertility
- 26. AGING IN NON DROSOPHILLA INSECTS ignores the diversity of longevity and aging traits evolved in nature To study various regulators and mechanisms involved For deep understanding of aging biology SOCIAL INSECTS IN AGING Ideal model systems Effects of Social factors on aging Intraspecific variation 25
- 27. AGING RATE AND LIFESPAN IN WORKER TASK CHANGES Difference in the Vitellogenin level 26 (Amdam et al., 2005)
- 28. MECHANISMS REGULATING CASTE SPECIFIC AGEING 28 Vitellogenin level – protects organisms from oxidative stress Longevity QUEEN >>> WORKER NURSERS >>> FORAGERS DIFFERENCE IN ANTIOXIDANT CAPACITY ENDOCRINE FACTORS Insulin/ IGF signaling Juvenile harmone Vitellogenin Vg - Downregulate insulin –producing cells in brain or corpora allata Longevity EUSOCIALITY • Colonial life style • Division of labour 27
- 30. Worker Pseudoqueen High brain insulin MAPK ATK Lmp 2 protei n 29 Studies on Social insect – Conserved and species specific mechanism of aging
- 31. FLIGHT AND AGING IN INSECTS Longevity Cost in terms of increased level of • reactive oxygen species (ROS), • the by products of mitochondrial metabolism, accelerated aging through damaging macromolecules, including DNA, lipid, and proteins 30
- 32. (Yan and Sohal, 2000) 31
- 33. To understand the nature of the mechanisms underlying the relationship between physical activity and oxidative stress the rate of mitochondrial H2O2 release was lower and its age-related increase was slower in the LA flies than in the HA flies 32
- 34. 34 Mitochondria from flight muscles of the adult housefly were examined. 1. adenine nucleotide translocase (ANT) , 2. aconitase , age-related increase in Carbonyl content and a corresponding loss in function. Accumulation of oxidative damage to ANT and aconitase and the loss in their functional activity are retarded in the flies whose life span has been extended experimentally by prevention of flying 33
- 35. “How to extend lifespan has always fascinated people through out the human history” Hypometabolic states Cryonics 34
- 36. Slow aging during insect reproductive diapause 35 Adult- reproductive diapause arrests development of oogenesis, vitellogenesis Accesory gland activity Mating behaviour This implies slow aging during diapause Elevated somatic stress resistance Realllocation of resources to somatic maintainence DIAPAUSE AND AGING IN INSECTS (Dhillon and Hasan, 2018)
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- 38. 38
Editor's Notes
- 4 mating protocols
- Mating status significantly affected the lifespan of both female (Log rank, χ2 = 60.9, p < .0001) and male (Log rank, χ2 = 26.7, p < .0001) flies (Fig. 1A and B). Virgin female flies (V) had longest lifespan among the four female groups (Fig. 1A). A significantly reduced lifespan was observed for once-mated flies (OM) and flies mated only with a single partner (SP). The shortest lifespan was observed for female flies mated with multiple partners (MP) (Fig. 1A). Flies of all mated female groups had reduced mean lifespan in comparison to virgin flies (Fig. 1C) and maximum lifespan was also shorter in female flies of SP and MP groups, compared with virgin flies (Fig. 1D). The effect of mating status in males was less pronounced. There was significant difference in lifespan among males of virgin, once-mated or single partner groups (Fig. 1B). However, a decrease in mean lifespan was observed for males mated with multiple partners. Maximum lifespan was unaffected by mating status among males (Fig. 1E and F).
- This loss of intestinal homeostasis is considered as a hallmark of aging in both flies and humans, and is associated with the progression of other aging-related diseases [39–41]. Intestinal epithelial barrier dysfunction has served as a predictor of mortality, as flies that have permeable guts display a decrease in longevity [12,35,42]. Our current understanding of the underlying molecular mechanisms that regulate intestinal epithelia maintenance and the age-associated loss of barrier function is limited, and is an active field of study . Throughout aging, ISCs hyperproliferate and drive intestinal dysplasia [34]. In addition to intestinal dysplasia, a common hallmark of the aging gut is a progressive loss of barrier function, such that older guts lose the ability to selectively regulate nutrients and contain the microbiota in the intestinal lumen
- The intestines of elderly flies displa Mitogen-activated protein kinase (MAPK)- Abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis. The Imd pathway is a broadly-conserved NF-κB immune signalling pathway of insects and some arthropods that regulates a potent antibacterial defence response. The pathway is named after the discovery of a mutation causing severe immune deficiency (the gene was named "Imd" for "immune deficiency"). The Imd pathway is a broadly-conserved NF-κB immune signalling pathway of insects and some arthropods that regulates a potent antibacterial defence response. The pathway is named after the discovery of a mutation causing severe immune deficiency (the gene was named "Imd" for "immune deficiency"). The Insulin-like Receptor signaling pathway in Drosophila is initiated by the binding of an insulin-like peptides (ILPs) to the Insulin-like receptor (InR). ILPs are important regulators of metabolism, growth, reproduction and lifespan. In the fly, there is a progressive loss in the intestine’s ability to synthesize and store lipids with aging because of the decline in the number of ECs in the intestine, resulting in decreased ability to transport lipids or absorb lipids from the lumen into ECs. Restoration of intestinal lipid metabolism has been reported to extend lifespan in flies [88]. DR improves intestinal epithelia barrier function and also promotes a metabolic shift towards enhanced utilization of lipids and increased mitochondrial function
- The Drosophila and mammalian intestine are sharing many similarities at the molecular and cellular levels. Therefore, a more comprehensive understanding of Drosophila intestinal physiology and pathology in response to aging and different dietary interventions may translate into findings in higher order animals and humans.
- Eating well, not drinking too much alcohol, avoiding tobacco, and staying physically active enable some individuals to attain a healthy old age; genetics then appears to play a progressively important role in keeping individuals healthy as they age into their eighties and beyond. The study of longevity genes is a developing science. It is estimated that about 25 percent of the variation in human life span is determined by genetics, but which genes, and how they contribute to longevity, are not well understood. Some of the gene variants that contribute to a long life are involved with the basic maintenance and function of the body’s cells. These cellular functions include DNA repair, maintenance of the ends of chromosomes (regions called telomeres), and protection of cells from damage caused by unstable oxygen-containing molecules (free radicals).
- The oxidative stress hypothesis is presently the most prominent theory in the field of aging research. This hypothesis states that the imbalance between the formation and detoxification of reactive oxygen species generated during normal cellular metabolism results in the accumulation of oxidative damage to a variety of macromolecules, including DNA, proteins, and lipids” This theory proposes that highly reactive derivatives of oxygen, the free radicals, are produced during normal metabolism. The organism is then unable to counteract all the damage to macromolecules because the balance between oxidants and antioxidants, such as free radicals detoxifying enzymes, is in favor of oxidants. With time, unrepaired damage is expected to accumulate and put at risk the homeostasis of the organism, i.e. to provoke aging and death
- The mth gene predicted a protein with homology to several guanosine triphosphate-binding protein-coupled seven-transmembrane domain receptors. Thus, the organism may use signal transduction pathways to modulate stress response and life-span.
- Location of the INDY transporter in the fat body and oenocytes suggest a role in intermediary metabolism and expression in the gut suggests a role in uptake of nutrients. Reductions in INDY activity may alter uptake, utilization, or storage of important nutrients and affect normal metabolism. It has been hypothesized that reductions in Indy activity seen in Indy mutations might be altering the normal energy supply in flies resulting in life span extension through a mechanism similar to CR. CR has been shown to increase life span and delay the onset of age-related symptoms in a broad range of organisms
- . Phenotypes with different life expectancies emerge through social transfers and resource allocation between siblings (schematic depiction). Protein currency is transferred as jelly, where constituents of the yolk precursor vitellogenin are included. Larvae, callow nest bees (‘‘young”) and mature foragers are among the net receivers of jelly (bold red arrows). Nurse bees, with an intermediate average life expectancy (‘‘survival capacity”, y-axis) constantly produce large amounts of vitellogenin (indicated by the larger green lightning bolts) in their abdominal fat bodies and transfer jelly to the net receivers. In contrast, the net receivers have low nutrient stores (indicated by smaller filled red circles) and show low levels of vitellogenin production (smaller green lightning bolts). Accordingly, foragers also represent the shortest-lived phenotype that usually dies after some days (y-axis). However, if reverting to nurse tasks (slim red arrow), foragers can recover characteristics of the phenotype with an intermediate survival capacity. When brood load declines in autumn, bees transition to the long-lived winter state (slim blue arrow). While both, nurse and winter bees, have considerable vitellogenin storages (larger filled red circles), winter bees display greatly reduced sib care transfers and outlive nurse bees in summer by several months. These dynamics suggests that vitellogenin is the major currency of honey bee survival.
- In most organisms, reproduction is correlated with shorter life span. However, the reproductive queen in eusocial insects exhibits a much longer life span than that of workers. In Harpegnathos ants, when the queen dies, workers can undergo an adult caste switch to reproductive pseudo-queens (gamergates), exhibiting a five-times prolonged life span. To explore the relation between reproduction and longevity, we compared gene expression during caste switching. Insulin expression is increased in the gamergate brain that correlates with increased lipid synthesis and production of vitellogenin in the fat body, both transported to the egg. This results from activation of the mitogen-activated protein kinase (MAPK) branch of the insulin signaling pathway. By contrast, the production in the gamergate developing ovary of anti-insulin Imp-L2 leads to decreased signaling of the AKT/forkhead box O (FOXO) branch in the fat body, which is consistent with their extended longevity.
- . Noteworthy, diapause not only slows aging during diapause phase, but also has speciesdependent effects on adult longevity after diapause. For example, maize stalk borer (Busseola fusca) and spotted stem borer (Chilo partellus) have shortened adult lifespans after diapause (GebreAmlak, 1989; Dhillon and Hasan, 2018), but cotton bollworm (H. armigera) and multivoltine bruchid (Kytorhinus sharpianus) display extended lifespans after diapause (Ishihara and Shimada, 1995; Chen et al., 2014).