Aging & Disease Introduction Lecture 1 PDF

Molecular basis of Aging: Introduction 2X: Fundamental Topics in Biology Aging & Disease (lecture 1) Prof. Iain Johnstone November 2023 Slides by Iain Johnstone and Dr The global population is aging For the first time in hist...

Molecular basis of Aging: Introduction 2X: Fundamental Topics in Biology Aging & Disease (lecture 1) Prof. Iain Johnstone November 2023 Slides by Iain Johnstone and Dr The global population is aging For the first time in history there are now more people over the age of 65 than there are under the age of 5 This gap is only set to widen Increase in age related diseases Aims of this lecture Understand what is meant by “aging” in biology Appreciate the relationship between aging and lifespan Appreciate how aging is a major contributor to the development of diseases such as diabetes, cancer, and neurodegeneration Describe how the study of genetics, animal models and progeroid syndromes provide insights into the biological mechanisms of aging  Aging? Meltzer et al. 2020 What is aging? Time related deterioration of the physiological functions necessary for fertility and survival Longevity- how long an organism lives Senescence- time-related deterioration Development of disease markers- age related diseases e.g. cancer Key Questions 1. Is aging a random inevitable process in multi-cellular organisms? 2. OR… Do genes and systems exist to delay time-related deterioration or promote senescence? 3. Why (and how) do biological systems deteriorate over time?  What does nature itself tell us? Different species have different lifespans – house mouse 1-2 years, Greenland shark >400 years. Different genomes generate different lifespans?? Do we think this statement is correct? House mouse Mus musculus Even within one order (Rodentia) lifespans can vary a lot – naked mole >30 years, house mouse 1-2 years. Naked mole rat: unusual physiology, can survive ~20 mins without oxygen, rarely get cancer, high levels of DNA repair and chaperones to maintain correct protein folding. Age- Naked mole rat specific mortality does not increase with age – even at Heterocephalus ages 25-fold past reproductive maturity. Lets think about glaber this. Ruby et.al., https://doi.org/10.7554/eLife.31157.001 Biotech company in the What can we learn from the naked mole rat and how field can this be applied to human aging and disease? https://www.calicolabs. Lets think a bit more about age- specific mortality. Mortality rate – the probability of death in a given period of time (death rate per year for humans, per month for mice, per day for Drosophila etc.) In the next few slides we will investigate patterns of age-specific mortality in three examples: Pacific salmon, fruit flies and then humans.  Semelparity - genetically programmed senility and death after reproduction Pacific salmon species (not Atlantic) Death a few days after spawning Is aging a random process in multi-cellular organisms? In a test to measure lifespan of Drosophila melanogaster, no flies lived beyond 75 days. If the mortality rate of Drosophila was constant, the survival graph would look like: This is a theoretical graph for constant mortality rate (chance of death on any day being equal). This might happen if death was a random process – like the probability of being eaten by a predator. A bird eating the fly. A survivorship curve in Drosophila actually looks like this… What can we take from this? Almost none die before 30 days Half are dead by 55 days None live beyond 75 days ~90% die between 45 and 65 days It is close to being a bi-phasic curve – low mortality then high mortality. (If we look closely, it is slightly more complex than biphasic).  It is the same for humans Our life is divided into four distinct mortality phases: A. Raised mortality in A infancy. B B. Low mortality until mid-life (~60 years of age) C. High mortality mid- life to old age. D. Reduced mortality C in extreme old age (relative to old age). Factors that prevent death early in life that then decline with age? What explains D – D Factorsold extreme that promote age? death (Next later in life? slide)  Possible explanations for the human data Reduced poverty, improved nutrition, sanitation – 1851 to 1931. Sulphonamides, antibiotics, childhood vaccination, the NHS and a welfare state – 1931 to 1951. Incremental improvements in modern medicine and lifestyle changes (people used to smoke in cinemas) – 1951 – now. Recent “improvements” are not decreasing the mortality rate in section C of the graph – they look to be delaying its onset. A longer mid-life. Is the mortality rate in section C genetically programmed – a less extreme version of the Pacific Salmon? People who survive to extreme old age probably have genetics that reduce this mortality rate a bit. By contrast some evidence suggests old mole rats are not more prone to dying than young ones. They are also resistant to diseases of ageing (cancer, heart disease). The relationship between aging and disease Senescence, aging, death Is there a relationship between aging and disease? Are disease rates also biphasic/ triphasic? Does senescence lead to diseases? Aging and Cancer 2 Phase? 3-Phases? % prevalence Coronary heart disease Age  Finally, the big one! Dementia Alzheimer’s is the most common form of dementia % prevalence Age Caution! Not all diseases are age related Epilepsy % prevalence age Key questions Which genes/proteins/systems protect against aging, death or damage early in life? Which genes/proteins/systems promote aging, death or damage late in life? GENETICS How can we find them (in humans)? 1. Genetic linkage studies: diseases of premature aging Monogenic, causal 2. GWAS: longevity complex trait, many SNPs, low effect size Still early days!! Multi- trait loci have been linked with several age- related diseases, suggesting shared ageing influences (Meltzer et al. 2020 Nature). TCF7L2 (T2D) also linked to lifespan Remember GWAS/genetics is “hypothesis generating”  Progeroid syndromes Progeroid syndromes constitute a group of genetic disorders characterized by clinical features mimicking physiological aging at an early age. MONOGENIC Segmental progeria Werner syndrome (gene: WRN) Cockayne syndrome (gene: ERCC6) Werner Syndrome: 1 in 200,000 (USA), 1 in 30,000 Multiple tissues affected (Japan) Autosomal recessive Transgenic Unimodal mice Familial Alzheimer’s Disease (gene: APP) Familial Parkinson’s Disease (gene: SNCA) One main tissue affected Autosomal dominant WT Mutant WRN Loss of genome integrity is the most common feature of accelerated aging in progeroid syndromes Molecular changes in normal ageing and human progeroid syndromes Similarities between molecular hallmarks of aged cells and the human progeroid syndromes are remarkable. Human progeroid syndromes do accelerate real ageing processes. Very powerful argument that the molecular defects caused by these syndromes are major causative agents of ageing. “The aging machine” The hallmarks of aging Interconnected processes Direct impact on the development of age related diseases Our next two lectures will cover some of these hallmarks in more depth and discuss their importance for aging and age-related disease  Thank you!  There's no time for us, There's no place for us, What is this thing that builds our dreams, yet slips away from us Who wants to live forever, Who wants to live forever? Queen (1986)