Introduction Longevity - Lecture Notes PDF

Module 4073 „Autophagy & Longevity“ Lecture 1: Longevity Prof. Dr. Tassula Proikas-Cezanne 22nd April 2024 Twitter: @TassulaPC Introduction Longevity  Introduction Longevity The global market for healthy human longevity is enormous with total healthcare expenditures i...

Module 4073 „Autophagy & Longevity“ Lecture 1: Longevity Prof. Dr. Tassula Proikas-Cezanne 22nd April 2024 Twitter: @TassulaPC Introduction Longevity  Introduction Longevity The global market for healthy human longevity is enormous with total healthcare expenditures in those 65 and older running well over $7 trillion... Dr. Robert Hariri Human Longevity Inc. … Our goal is not necessarily lengthening life, but extending a healthier, high performing, more productive life span. Dr. J. Craig Venter Human Longevity Inc.  Introduction Longevity Health span The global market for healthy human longevity is enormous with total healthcare expenditures in those 65 and older running well over $7 trillion... Dr. Robert Hariri Human Longevity Inc. … Our goal is not necessarily lengthening life, but extending a healthier, high performing, more productive life span. Dr. J. Craig Venter Human Longevity Inc.  Introduction Longevity Health span The global market for healthy human longevity is enormous with total healthcare expenditures in those 65 and older running well over $7 trillion... Dr. Robert Hariri … Our goal is not necessarily lengthening life, but extending a healthier, high performing, more productive life span. Dr. J. Craig Venter  Introduction Longevity Life span Fontana et al. (2010) Science 328:321  Introduction Longevity Life span Fontana et al. (2010) Science 328:321  Introduction Longevity Longevity Longevity Maria Branyas Morera Olot, Catalonia, Spain Born 04.03.1907 117 years 49 days Fontana et al. (2010) Science 328:321 Photo: https://www.ndtv.com/feature/no-worries-no-regrets-worlds-oldest-person-117-shares-secret- of-her-long-life-5185927  Introduction Longevity Longevity Longevity Kane Tanaka, Japan 02.01.1903 – 19.04.2022 119 years and 107 days Photo: Fontana et al. (2010) Science 328:321 https://www.reddit.com/r/interestingasfuck/comments/h0tik7/this_woman_who_was_20_in_the_y ear_1923_is_still/  Introduction Longevity Longevity Kane Tanaka, Japan 02.01.1903 – 19.04.2022 119 years and 107 days Fontana et al. (2010) Science 328:321 Photo: https://www.nytimes.com/2022/04/27/world/asia/kane-tanaka-japan-worlds-oldest- person.html  Introduction Longevity Fiction Longevity Newborn today would live Kane Tanaka, Japan until 22.04.2143 02.01.1903 – 19.04.2022 plus 107 days 119 years and 107 days Photo by Filip Mroz on Unsplash  Introduction Longevity Supercentenarians Jeanne Louise Sarah DeRemer Knauss Kane Tanaka, Calment, France Knauss, USA Japan 21.02.1875 – 24.09.1880 – 02.01.1903 – 04.08.1997 30.12.1999 19.04.2022 122 years, 164 days 119 years, 97 days 119 years, 107 days  Introduction Longevity 1889 WWI WWII 1968 2002 2019 Influenza 1914- 1938- Influenza/H3N2 SARS/SARS-CoV-1 COVID-19/SARS-CoV-2 First peaked in Russia First identified in Hong Kong First identified in China First identified in China 1918 1945 > 1 million deaths 1-4 million deaths 774 deaths 7 million deaths 1875 1918 1957 1981 2009 2014 Measles Influenza/H1N1 Influenza/H2N2 AIDS/HIV-1 Influenza/H1N1 Ebola/EBOV in the Fiji Islands First identified in the USA First identified in East Asia First recognized in 1981 First identified in the USA First identified in Guinea 40.000 deaths 50 million deaths 1-2 million deaths 40 million deaths Up to 575.400 deaths 11.000 deaths 2015 MERS/ Time line of Pandemics MERS-CoV First identified in the Middle East 850 deaths Jeanne Louise Sarah DeRemer Kane Tanaka, Calment, France Knauss, USA Japan 21.02.1875 – 24.09.1880 – 02.01.1903 – 04.08.1997 30.12.1999 19.04.2022 122 years, 164 days 119 years, 97 days 119 years, 107 days  Introduction Longevity 1889 WWI WWII 1968 2002 2019 Influenza 1914- 1938- Influenza/H3N2 SARS/SARS-CoV-1 COVID-19/SARS-CoV-2 First peaked in Russia First identified in Hong Kong First identified in China First identified in China 1918 1945 > 1 million deaths 1-4 million deaths 774 deaths 7 million deaths 1875 1918 1957 1981 2009 2014 Measles Influenza/H1N1 Influenza/H2N2 AIDS/HIV-1 Influenza/H1N1 Ebola/EBOV in the Fiji Islands First identified in the USA First identified in East Asia First recognized in 1981 First identified in the USA First identified in Guinea 40.000 deaths 50 million deaths 1-2 million deaths 40 million deaths Up to 575.400 deaths 11.000 deaths 2015 MERS/ Time line of Pandemics MERS-CoV First identified in the Middle East 850 deaths Jeanne Louise Sarah DeRemer Maria Branyas Morera Calment, France Knauss, USA Olot, Catalonia, Spain 21.02.1875 – 24.09.1880 – Born 04.03.1907 04.08.1997 30.12.1999 122 years, 164 days 119 years, 97 days 117 years 49 days  Introduction Longevity 2019 COVID-19/SARS-CoV-2 First identified in China 7 million deaths Time line of Pandemics Newborn today would live until 22.04.2143 plus 107 days Photo by Filip Mroz on Unsplash  Introduction Longevity Longevity Life span Life expectancy Ageing  Introduction Longevity Longevity Latin: “long age”, ongus (long), aevum (age) 180 years 30 minutes Galápagos giant Some Mayfly tortoise species 5000 years immortal Yew tree Hydra Fabian & Flatt (2011). Nature Education Knowledge, 3(10):9.  Introduction Longevity Longevity Singh et al., (2019) Cell.  Introduction Longevity Life expectancy Average total number of years  Introduction Longevity Life expectancy Average total number of years Increasing life expectancy Introduction Longevity Introduction Longevity  Introduction Longevity Life span Maximum number of years (appr. 122 years)  Introduction Longevity Life span Maximum number of years (appr. 122 years) Not increasing  Introduction Longevity Life span Maximum number of years (appr. 122 years) Not increasing Ancient greek philosophers > 90 years  Introduction Longevity Life span Maximum number of years (appr. 122 years) Not increasing Ancient greek philosophers > 90 years Nonagenarians > 90 years Centenarians > 100 years Semi-Supercentenariens > 105 – 109 years Supercentenariens > 110 years (1/1000 centenariens)  Introduction Longevity Life span Maximum number of years (appr. 122 years) Not increasing Ancient greek philosophers > 90 years Nonagenarians > 90 years 2012 calculation by the UN: 316,600 Centenarians Centenarians > 100 years (0.004% of world population) UNFA report Semi-Supercentenariens > 105 – 109 years Supercentenariens > 110 years (1/1000 centenariens)  Introduction Longevity Life span Maximum number of years (appr. 122 years) Not increasing Ancient greek philosophers > 90 years Nonagenarians > 90 years 2012 calculation by the UN: 316,600 Centenarians Centenarians > 100 years (0.004% of world population) UNFA report Semi-Supercentenariens > 105 – 109 years Today: 7 Supercentenarians Supercentenariens > 110 years (1/1000 (validated)centenariens) https://en.wikipedia.org/wiki/List_of_the_verified_oldest_people  Introduction Longevity Aging Process  Introduction Longevity Aging Process Responsible for the increased risk of disease and death  Introduction Longevity Aging Process Responsible for the increased risk of disease and death Cancer Incidence rates by age at diagnosis, all cancer types. Source: SEER 21 2013–2017. Credit: National Cancer Institute  Introduction Longevity Aging Process Responsible for the increased risk of disease and death Neurodegeneration Hou, Y., Dan, X., Babbar, M. et al. Ageing as a risk factor for neurodegenerative disease. Nat Rev Neurol 15, 565–581 (2019). https://doi.org/10.1038/s41582-019-0244-7  Introduction Longevity Gewin, Nature (2013) News, 08. December 2013  Introduction Longevity Aging Process Responsible for the increased risk of disease and death Regulated by genes and environmental signals  Introduction Longevity Genetic switch model of aging Genetic switch, or switches, during or after reproduction Repair, maintenance, stress resistance and homeostasis pathways are turned down, while these pathways are still able to function optimally Decline resulting from the loss of these survival pathways increases susceptibility to disease and the chance of death, thereby causing aging. Van Raamsdonk. (2017) Exp Gerontol.  Introduction Longevity Biomarkers of ageing Epigenetic clock Horvath’s clock Age estimate method Epigenetic DNA markers (353) Methylation levels DNAm age estimator Read-out for innate ageing processes Horvath and Raj (2018) Nat Rev Genetics.  Introduction Longevity Hallmarks of Ageing The Aging Clock is regulated by interconnected hallmarks: Deregulated nutrient-sensing, altered intracellular communication, cellular senescence, stem cell exhaustion, genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of protein homeostasis The Aging Clock is also regulated by environmental signals: Diet, Exercise Pertubations in one hallmark could affect all other hallmarks Singh et al., (2019) Cell.  Introduction Longevity Life-span differences Singh et al., (2019) Cell.  Introduction Longevity The African Killifish Nothobranchius furzeri Zimbabwe and Mozambique Invertebrate model organism to study vertebrate ageing Short-lived Numerous progeny Rapid sexual maturity Efficient genome editing Singh et al., (2019) Cell.  Introduction Longevity Human genes associated with longevity Deregulated nutrient-sensing and altered intracellular communication, cellular senescence, stem cell exhaustion, genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of protein homeostasis APOE4 allele encodes the apolipiprotein E Risk factor for Alzheimer’s disease and associated with decreased lifespan Low frequencies of APOE4 found in centenarians Singh et al., (2019) Cell.  Introduction Longevity Human genes associated with longevity APOE function Fat-binding protein Transports lipids, fat-soluble vitamins, cholesterol Defects result in hyperlipiemia (abnormally elevated lipid/lipoproteins levels in the blood) APOE Receptor: Very-low-density lipoprotein (VLDL) Singh et al., (2019) Cell.  Introduction Longevity Environmental signals associated with longevity The Aging Clock is also regulated by environmental signals: Diet, Exercise Singh et al., (2019) Cell.  Introduction Longevity Environmental signals associated with longevity Fontana and Partridge (2015) Cell.  Introduction Longevity “hara hachi bu” “Eat until your stomach is 80 percent full” Practiced by Okinawans (appr. 1800 calories per day). http://ngm.nationalgeographic.com/2005/11/longevity-secrets/buettner-text  Introduction Longevity Environmental signals associated with longevity The Aging Clock is also regulated by environmental signals: Diet, Exercise Singh et al., (2019) Cell. Iris Apfel American businesswoman, 29. August 1921 interior designer, and fashion icon. † 01. March 2024 “…I hope I never have to retire.” DDP IMAGES https://www.youtube.com/watch?v=KP3YKJGu6ag Iris Apfel In 2011 (90 years), she became visiting 29. August 1921 professor at The University of Texas, USA. † 01. March 2024 “…I hope I never have to retire.” DDP IMAGES https://www.youtube.com/watch?v=KP3YKJGu6ag Iris Apfel In 2019 (97 years), she signed a 29. August 1921 modelling contract. † 01. March 2024 “…I hope I never have to retire.” DDP IMAGES https://www.youtube.com/watch?v=KP3YKJGu6ag Iris Apfel In 2019 (97 years), she signed a 29. August 1921 modelling contract. † 01. March 2024 “Only. One. Trip.” DDP IMAGES https://www.youtube.com/watch?v=KP3YKJGu6ag  Introduction Longevity Caloric restriction activates autophagy Escobar et al., (2018) Aging Cell.  Introduction Autophagy Autophagy is an intracellular degradation system Proteins Starvation Lipids response Organelles  Introduction Autophagy Macroautophagy is responsible for the stochastic and specific degradation of cytoplasmic constituents (organells, proteins, lipids, nucleic acids). Proteasome Autophagosome Sharon et al. (2006) JBC Fengsrud et al., (2000) Biochem J.  Introduction Autophagy The phagophore: an autophagic sequestering cisterna Eeva-Liisa Eskelinen, www.helsinki.fi/bioscience/biochemistry/eskelinen Introduction Autophagy  Introduction Autophagy Embryo L1 L2/3 L4 atg-18 Wild type (gk378) age: 14d 400 100 Progeny reaching L4 (%) 80 300 Eggs / animal 60 200 40 *** 100 *** 20 0 0 N2 atg-18 epg-6 atg-18(gk378); N2 atg-18 epg-6 atg-18(gk378); (gk378) (bp242) epg-6(bp242) (gk378) (bp242) epg-6(bp242) Takac et al. (2019) Cells.  Introduction Autophagy Embryo L1 L2/3 L4 Survival Recovery Starvation Feeding Count animals L1 ≥ L2 Starvation Feeding Count animals Eggs L1 progressed larvae to ≥ L2 (up to 29 days) (2 days) Movement assessment 100 recovery after starvation (%) 80 wild type 60 atg-18(gk378) 40 20 0 0 10 20 30 40 days of starvation Takac et al. (2019) Cells.  Introduction Autophagy Embryo L1 L2/3 L4 FUDR 48-72h L4 transfer Count Eggs surviving animals every 2-3 days Plates with Plates with Plates with extracted eggs L3/L4 animals 20x L4 animals 100 80 survival (%) + FUDR 60 wild type atg-18(gk378) 40 20 0 0 10 20 30 40 time (days) Takac et al. (2019) Cells. Thank you.