Lecture 2 PAD - Biological Ageing PDF

L E C T U R E 2 – B IO LO G IC A L AGEING (PS Y C 5 9 1 0 M ) Dr Melanie Burke SCHOOL OF PSYCHOLOGY UNIVERSITY OF LEEDS  LECTURE OUTLINE Dat Lectu Details Theme e re 1 Introduction to Ageing a...

L E C T U R E 2 – B IO LO G IC A L AGEING (PS Y C 5 9 1 0 M ) Dr Melanie Burke SCHOOL OF PSYCHOLOGY UNIVERSITY OF LEEDS  LECTURE OUTLINE Dat Lectu Details Theme e re 1 Introduction to Ageing and Dementia 2 Biological Ageing “HEALTHY 3 Cognitive Ageing AGEING AND THE BRAIN” 4 Psychosocial Ageing “Talking about Healthy Ageing” discussion 5 MCI – Diagnosis / Research “AGE-RELATED 6 MCI – Treatment DISEASES AND PATHOLOGY” 7 Dementia – Diagnosis / Research 8 Dementia – Treatment “Talking about Dementia” discussion 9 Living with Dementia “THE INTRA- 10 Dementia friendly INDIVIDUAL PERSEPCTIVE” 11 Revision Lecture and Module  LEC T U R E 2 BIOLOG I C A L AG E I N G LECTURE 2 – LEARNING OUTCOMES 1. TO KNOW THE MAIN THEORIES OF BIOLOGICAL AGEING 2. TO UNDERSTAND THE SUB-CATEGORIES OF BIOLOGICAL AGEING THEORIES AND EVIDENCE. 3. HIGHLIGHT POTENTIAL PRO’S AND CON’S OF EACH THEORY 4. CONSIDERATION OF HOW THIS FITS INTO THE BIGGER PICTURE OF AGEING.  LAYOUT FOR TODAY’S LECTURE: THERE ARE 2 MAIN CATEGORIES IN THE THEORIES OF BIOLOGICAL AGEING. THE LECTURE IS SPLIT INTO TWO AND EACH SECTION WILL FOCUS ON EACH MAIN THEORY. PART ONE: The programmed or genetic theory PART TWO: The damage or error theory  PART ONE: THE PROGRAMMED THEORY OF AGEING A. The Programmed Theory of Aging The programed theory of ageing outlines that cells have a finite lifespan that follows a timeline and results in death. This implies that we have pre- programmed changes in our genes possibly from childhood that cause senescence. Programmed Theory: 3 Lines of Evidence 1) PROGRAMMED LONGEVITY - Certain genes switch “on” and “off” over time, all of which are pre-programmed. 2) ENDOCRINE THEORY - Regular changes in hormones control ageing. 3) IMMUNOLOGICAL THEORY - Immune system is programmed to decline over time, leaving us more susceptible to diseases.  1. PROGRAMMED LONGEVITY E(z) histone methyltransferase This theory suggests our heterozygous mutation genes are pre-programmed to change over time and the result of these changes causes the symptoms we associate with the ageing process. Evidence comes from lifespan studies in animals where genetic modifications have prolonged life. “Longevity gene” as children of centurions are more likely to live to 100.  CHALLENGES TO PROGRAMMED LONGEVITY THEORY Twin studies: Herskind et al (1996) studied 2872 Danish twin pairs and only 0.26-0.24 hereditary factor i.e. 25% of age at death was explained by genetics/hereditary factors, the rest was environmental/other factors. Most gene manipulation evidence comes from animal studies and has limitations when translated into human genetic homologs. However research on centenarians i.e. extreme old age (0.1% males and 1% females) offers a different picture ! Sebastiani, P., & Perls, T. T. (2012). The genetics of extreme longevity: lessons from the new England centenarian study. Frontiers in genetics, 3, 277.  2. ENDOCRINOLOGY IN AGEING This is where biological clocks act via hormones in the body in a certain ways to control how fast you age. Developed by Vladimir Dilman (1954). The hypothalamus controls various chain-reactions within the body to release hormones. Sensitivity of this structure declines with age. The Hypothalamic Pituitary Axis (HPA) regulates homeostasis loses efficiency with ageing.  EVIDENCE FOR ENDOCRINE THEORY Powers, Harrisons and Flurkey (2006) removed the pituitary gland of mice. They found a 15% and 21% increase in lifespan when it was removed at 1 and 9 months respectively. In addition, genetically engineered mice show increase in GH and insulin-like growth factor, delay puberty, reduce size and ageing, and increase lifespan (see Ames dwarf mouse).  3. THE IMMUNE THEORY OF AGEING As we age our immune responses decline. This theory posits that immune dysfunction may explain the ageing process. Devised by Roy Walford (1969). A decrease in immunity can lead to our susceptibility to various chronic diseases especially with an inflammatory component (e.g. arthritis), cancer, and Alzheimer's. The mechanism is believed to emerge from decreased naive T-cells and increased memory T-cells i.e. wrong identification of foreign cells/virus. IMMUNOSCENESCE NCE Immunological changes known as immunoscenescence was coined by Walford in 1969. Shrinking of the Thymus and increased fat with decreased IL- 7 cells = reduced naïve T cells and increase memory T cells in the blood. Increased IgA and IgB in the blood = autoimmune disorder where body attacks it’s own cells. Chronic low grade inflammation and poor response to new invading antigens (i.e. vaccines).  EVIDENCE FOR IMMUNE THEORY Apoptosis is programmed cell death, and is part of normal growth and development and is used to maintain correct number of T-cells. Apoptosis is important in the immune system, and plays significant roles in the control of the immune response, the deletion of immune cells (mature T-cells) recognising self-antigens, and cytotoxic killing. New evidence suggests altering pathways could prolong life. Soto-Gamez & Demaria (2017). Drug Discovery Today, 22(5):786-795  INTERACTIVE TASK !! IN GROUP’S DISCUSS: IS IMMUNOSENESCENCE THE RESULTS OF PRIMARY AGEING OR CAN SECONDARY FACTORS EXPLAIN THIS RESPONSE ? HINT: CONSIDER DIFFERENCES INDIVIDUAL DIFFERENCES !!! https://www.sciencedirect.com/science/ article/pii/S1568163721001690  PART TWO: THE DAMAGE OR ERROR THEORY OF AGEING  B. Damage or Error Theories of Biological Ageing: Lines of evidence There are 4 main theories in the Damage Theory of Ageing: 1) Wear and Tear Theory - Our cells and organs response to age by simply wearing out, like in any machine over repeated use, the mechanisms start to deteriorate. 2) Rate of Living Theory - This suggests that our basal (at rest) metabolism influences how fast we age with those that have a higher basal metabolism ageing faster. 3) Cross-linking Theory -Accumulation of cross-linked proteins in our body damages cells and tissue slowing down our body and resulting in ageing 4) Free Radicals Theory - Superoxide and free radicals in the body cause damage to cells and eventually organs. This results in accumulated damage and reduction in functioning.  1. WEAR AND TEAR Cells wear out and this results in poorer functioning as we age. Devised by August Weismann (1882). In essence, reduced cellular metabolism means the cells are unable to repair themselves and cells in the heart, brain and muscle cannot replace themselves as effectively. This is also linked to stress and autoimmune inflammation making it harder to heal from injury (NB: linked to Immunological Theory of Ageing). CHALLENGES TO WEAR AND TEAR EVIDENCE FOR EVIDENCE AGAINST Matches common Cells can repair themselves and perceptions of aging and some continue to divide in older age. easy to understand the logic. Organisms build strength and Fits with the law of resilience over life, and rather than starting at peak entropy. performance i.e. develop Agrees with evidence that strength over time. the body declines with Organisms vary widely in lifespan and do not follow the age. same pattern. Cannot explain all ageing effects.  2. RATE OF LIVING THEORY The rate of living theory suggests the faster the metabolic rate of an animal, the faster it ages. Devised by Max Rubner (1908). Evidence comes from Kleiber’s Law (1932) where he suggests ¾ of a species body mass dictates it’s metabolic output and ultimately how long it lives. It can explain why the giant tortoise lives 150 years and also why women live longer than men.  EVIDENCE FOR RATE OF LIVING Evidence for the rate of living in animals is good, but in human’s is limited. Then a study came out in 2011 by Jumpertz et al. They found higher endogenous metabolic rate, that is how much 652 non-smoking Pima Indians are energy the body uses for normal body Native Americans living in Southern functions (at rest), is a risk factor for Arizona. earlier mortality. This increased metabolic rate (ATP Body composition was analysed and a turnover) may lead to earlier organ glucose tolerance test (insulin levels) damage (in effect accelerated aging) for obesity and diabetes. possibly by accumulation of toxic substances produced with the Sleep energy expenditure (EE) and increase in energy turnover." resting Metabolic Rate (RMR) R. Jumpertz, et al (2011). Higher Energy Expenditure in Humans Predicts Natural Mortality. Journal of Clinical Endocrinology & Metabolism, 96(6):E972-E976  3. CROSS- LINKING THEORY Cross linking is when protein cells in our body link to other cells or proteins = fuse. This results in a structural change and a chemical release resulting damaged functionality. Devised by Johan Bjorksten (1942). One example is collagen cross-linking in the cornea resulting in corneal rigidity and reduction in elastic properties to react to near and far images.  EVIDENCE FOR CROSS- LINKING Bjorkstein and Tenhu (1990) took protein samples from the post-mortem brains of younger and older adults. They tested cross- linking by measuring the amount of non- freezing water in macromolecules. Low amount of non-freezing aggregates means more cross-linkage. Young brains (o) bind more non-freezing water than old brains (X) meaning less cross- linkage in young brains. When Glutar Aldehyde (GA) or Dipotassium peroxysulfate (K2S2O8) is applied to young brains causing more cross-linkage in the proteins the results look like old brain structures. Bjorkstein & Tenhu (1990) The cross-linking theory of ageing – added evidence. Experimental Gerontology, 25: 91-95.  4. FREE- RADICAL THEORY Free radicals are unstable atoms present in our tissues that can damage our healthy cells and cause illness and ageing. Devised by Deham Harman (1956). Free radicals have unpaired electrons in their atomic structure which seek other atoms to attach to. Sources of free radicals -> Anti-oxidants (via food sources) can attach to these free radicals and neutralizing them. Hence the need for increasing anti-oxidant consumption as we age (found in Broccoli, spinach  EVIDENCE FOR FREE- RADICAL In the 1980’s many papers produced clear relationships between higher oxidant production and longevity i.e. are ability to remove oxidants (i.e. free radicals) from our system means we live longer. Evidence comes from increasing the proteins in mice that detect and eliminate cellular damage (such as Arf/p53) Mitochondria from young (left) and old (right) rats = Mice with the extra gene dose of Arf and p53 more heterogeneity, proteins (a = with tumors), b = without) show disrupted cristae and around a 16 % increase in lifespan. bigger size = damaged.  SUMMARY OF ERROR THEORIES It's been estimated that genes can explain a maximum of 35 percent of lifespan. Overall, it's likely that aging is a multifactorial process, meaning that it is probably a combination of several of the theories. It's also important to note that the theories discussed here are not mutually exclusive. The concept of epigenetics, or whether or not a gene that is present is "expressed" can further muddy our understanding. In addition to genetics, there are other determinants of aging such as our behaviors, exposures, and just plain luck. You are not doomed if your family members tend to die young, and you can't ignore your health even if your family members tend to live long. MANY STUDIES GIVE THE SAME MESSAGE FOR DECREASING IMPACT OF BIOLOGICAL AGEING … Anti-tumor and Lower blood sugar immunosuppression druglevels - Polyphenol = antioxidant diabetes Nicotinamide Adenine Dinucleotide = increases Reduce LDLs inand metabolism thecell liver = lower function. cholesterol. Thins the blood = reduced blood clotting Lowers blood pressure Reduces auto-immune Increaseseffects good enzymes and bacteria in the gut = good gut health Magda R. Hamczyk et al. J Am Coll Cardiol 2020; 75:919-930. OPTIMISING GENETIC EFFECTS IN AGEING Some practices which seem to keep the organs and tissues of our bodies healthy may also keep our genes and chromosomes healthy. Exercise - Studies have found that physical activity not only helps your heart and lung function well, but exercise lengthens telomeres.16 “Optimisation and Eat a healthy diet - A diet high in fruits and vegetables is associated with greater preservation of genes telomerase activity (in effect, less shortening of the telomeres in your cells). A diet high in omega-3-fatty acids is associated with longer telomeres but a diet high in is NOT a PASSIVE omega-6-fatty acids is the opposite and associated with shorter telomeres. In addition, fizzy drinks intake is linked with shorter telomeres. Reservatrol, the process, ingredient responsible for the excitementbut rather over drinking red wine (but also found in 1) is a gene whichan ACTIVE pursuit stress (NAD). of non-alcoholic red grape juice) appears to activate the longevity protein SIRT (Sirtuin protects against oxidative Reduce stress and maintaining avoid carcinogens a healthy Maintain a healthylifestyle throughout weight - Not only is obesity linked with some of the genetic mechanisms associated with aging noted above (such as increased shortening of telomeres), but repeated studies have caloric restriction. life.” found longevity benefits associated with  INTERACTIVE SESSION 1) Individually, or in groups, write a summary of the (i) programmed theories of ageing and (ii) wear and tear theories. 2) Discuss potential pro’s and cons of each theory, noting down any potential critical points. 3) Consider what lifestyle factors could effect Biological Ageing. Note these down ! 4) Report back to the whole group on (i) pro’s and con’s, and (ii) lifestyle factors. BIOLOGICAL THEORIES OF AGEING PROGRAMMED WEAR AND TEAR THEORIES THEORIES Insert your summaries here … READING LIST FOR TODAYS LECTURE: Sebastiani, P., & Perls, T. T. (2012). The genetics of extreme longevity: lessons from the new England centenarian study. Frontiers in genetics, 3, 277. Jumpertz, et al (2011). Higher Energy Expenditure in Humans Predicts Natural Mortality. Journal of Clinical Endocrinology & Metabolism, 96(6):E972-E976: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100751/?report=reader (link to paper) Bjorkstein & Tenhu (1990) The cross-linking theory of ageing – added evidence. Experimental Gerontology, 25: 91-95. Hamczyk M, Nevado R, Barettino A, et al. Biological Versus Chronological Aging. J Am Coll Cardiol. 2020 Mar, 75 (8) 919–930.