2024 A&A Chapter 2 Notes_Bio of Aging.pptx

Chapter 2: Biological Theories of Aging Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Not All Organisms Experience Disease  Sequoia trees: Largest organism on Earth  Do not show signs of aging ‒ Appears to be immune from...

Chapter 2: Biological Theories of Aging Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Not All Organisms Experience Disease  Sequoia trees: Largest organism on Earth  Do not show signs of aging ‒ Appears to be immune from Senescence (internal biological clock for aging).  Die mainly from lightning strikes, fire, pest outbreaks, or humans.  Can live 3,000 years or Author photo more. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Telomeres  Lie at the ends of chromosomes and protect the ends, similar to the plastic coverings on the ends of shoelaces.  Serve at least three important functions: ‒ Prevent chromosome ends from degrading ‒ Prevent chromosome ends from being perceived as broken and in need of cessation of division or programmed cell death ‒ Prevent DNA repair mechanisms that could mistakenly cause problems such as chromosome fusions Copyright © Springer Publishing Company, LLC. All Rights Reserved. Telomeres (cont’d)  End replication problem: As cells reproduce by dividing multiple times over the life span, telomeres continue to shorten.  With each reproduction, telomeres become shorter and shorter, until a point at which cells are no longer able to divide (replicative senescence or replicative aging). Copyright © Springer Publishing Company, LLC. All Rights Reserved. Telomeres (cont’d)  This cessation has been called the Hayflick limit (Hayflick, 1965) and places a limit on the life span of mammals.  Once a cell can no longer divide, it can remain in a state of cell senescence for years, which can lead to telomere shortening, but it eventually goes through programmed cell death, or apoptosis. Hayflick, L. (1965). The limited in vitro lifetime of human diploid cell strains. Experimental Cell Research, 37, 614– 636. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Telomeres (cont’d)  Apoptosis is most common in cell types for which disposal is easy, such as skin or intestine cells.  Some cells remains in senescence for prolonged periods (e.g., skin moles) and can undergo major changes in physiology (e.g., become cancerous). Copyright © Springer Publishing Company, LLC. All Rights Reserved. Cell Senescence  Cannot create new cells needed for tissue health (e.g., Alzheimer’s disease)  Release senescence-associated secretory phenotype (SASP), which can stimulate growth of malignant cells (e.g., tumors) Copyright © Springer Publishing Company, LLC. All Rights Reserved. Antagonistic Pleiotropy  When genes that may cause harmful effects in late life are favored by natural selection if they have beneficial effects during reproductive years Copyright © Springer Publishing Company, LLC. All Rights Reserved. Telomerase  An enzyme that makes telomeres longer and adds DNA to them.  Most human tissue lacks enough telomerase to stop age-related loss of telomeres (Exceptions: Regenerative tissue in esophagus, intestines, hair, skin, uterus, and sperm).  Telomerase is found in 90% of malignant tumors and allows cancer cells to reproduce indefinitely.  Therefore, it is a common target for cancer treatments. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Limitations to Telomere Research  Most research is performed with leukocytes (white blood cells); leukocyte telomere length may not represent telomeres of other cells.  Techniques used to measure telomere length vary across studies.  Still unknown whether shortened telomeres lead to disease, or whether diseases shorten telomeres. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Telomere Length  Women have longer telomeres than men.  Many animals have longer telomeres than humans.  The leach petrel (small bird in the North Atlantic) has telomeres that actually get longer with age, and the life span for it is unusually long (up to mid-30s).  Mice have longer telomeres than humans.  Telomeres in humans may be short enough to inhibit growth of cancer while allowing enough cell replication to live long enough to reproduce. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Free Radicals (Harman, 1956)  Atoms or molecules that have at lease one unpaired electron, making them unstable.  Generated primarily in mitochondria, which make energy for cells.  Oxygen is required for energy creation.  Reactive oxygen species (ROS) are a by-product of energy production. Harman, D. H. (1956). Aging: A theory based on free radical and radiation chemistry. Journal of Gerontology, 11(3), 298–300. Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Free Radicals (Harman, 1956) (cont’d)  ROS are free radicals that contain oxygen molecules.  ROS production increases in disease or under high stress.  ROS damages cells, eventually leading to cell death. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Antioxidants  Chemicals that inhibit oxidation and thereby protect against free radicals.  Resveratrol is one common antioxidant and prompts other antioxidants.  A nutrient found in plants, especially plants going through environmental stress. Includes grapes (and red wine), raspberries, blueberries, peanuts, and some pine trees. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Antioxidants (cont’d)  “Hormesis”: Small levels of ROS may be healthy for organisms  This may be a mechanism of caloric restriction. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Caloric Restriction  A reduction in calories has been shown to increase life span in yeast, fruit flies, nematodes, fish, rats, mice, hamsters, and dogs.  How much reduction?  Reducing calories in numerous species by 30% to 60% increases the life span by 20% to 50%.  Reduces the incidence or delays the onset of diabetes, cancer, cardiovascular disease, and brain atrophy in rhesus monkeys, and is associated with improved cognitive functioning and decreased risk of Alzheimer’s disease in mice. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Caloric Restriction (cont’d)  May slow down the buildup of cells damaged by ROS with age.  May increase the expression of sirtuins.  Sirtuins have many beneficial effects related to aging, and caloric restriction increases the activity of sirtuins. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Sirtuins  Sirtuins are mammalian homologues of the yeast Silent Information Regulator 2 (Sir2).  Regulate systems associated with energy metabolism and cell longevity.  Seven sirtuins in the human body regulate various cellular functions such as apoptosis, tumor suppression, and responses to stress. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Sirtuins (cont’d)  Sirtuin activity depends on nicotinamide adenine dinucleotide (NAD).  NAD+ is an oxidizing agent, accepting electrons from other molecules, repairing the damage caused by free radicals. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Caloric Restriction  Ready to decrease your caloric intake by 30% to 60% for the rest of your life?  Not many other people are either….  Therefore, researchers are searching for ways to mimic the effects of caloric restriction, or to find mimetics.  Resveratrol is a mimetic. It increases Sirtuin 1 (SIRT1). Copyright © Springer Publishing Company, LLC. All Rights Reserved. Genetics of Aging Copyright © Springer Publishing Company, LLC. All Rights Reserved. Genes and Longevity  Does prolonging life simply lead to more people with age-related diseases like Alzheimer’s disease?  Actually, genetic mutations that extend life delay age- related diseases also. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Two Types of Genetics Studies  Quantitative: Include family, twin, and adoption studies ‒ Look for amount of heritability, or the proportion of variance explained by genetic factors ‒ Examples: Seattle Longitudinal Study, Swedish Adoption/Twin Study of Aging  Molecular: Investigate specific genetic variations related to specific traits Copyright © Springer Publishing Company, LLC. All Rights Reserved. Molecular Studies  Investigate whether particular polymorphisms are associated with specific phenotypes  Polymorphisms = a variation of a DNA sequence that one inherits  Phenotype = observable trait of someone encoded by genes (e.g., blue eyes, skin tone)  Single nucleotide polymorphism (SNP) = a variation of a single nucleotide present in part of the population Copyright © Springer Publishing Company, LLC. All Rights Reserved. Figure 2.2 Figure 2.2 A single nucleotide polymorphism (SNP). Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Single Nucleotide Polymorphisms (SNPs)  Can consist of substitutions, deletions, or insertions  1% to 2% of SNPs are found to be functional—to lead to changes in amino acid translation  Translation = production of proteins from DNA Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Genome-Wide Association Studies (GWAS)  Searching as much of the human genome as possible to find candidate genes related to particular phenotypes.  In the hundreds of thousands of statistical tests performed, statistically significant relationships are bound to be found.  Thus, researchers must look for large effect sizes to conclude an SNP is related to a trait. Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Genome-Wide Association Studies (GWAS) (cont’d)  Most traits related to psychology of aging are polygenic —related to multiple genetic and environmental factors, each with small effect sizes.  The amount of a gene also varies among people.  When the number of copies of a gene varies, they are known as copy number variants (CNVs).  CNVs may be more significant than SNPs in leading to genetic diversity. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Epigenetics  Study of chemical modifications of DNA that change gene activity without changing nucleotide sequences.  Includes attachment of additional material to DNA (e.g., DNA methylation). DNA methylation declines in the brain with age.  Epigenetics can explain how environmental factors like toxins and diet interact with physiology.  Some epigenetic changes can be passed to subsequent generations. Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Molecular Genetic Research Approaches  Reverse genetic method: Specific genes are knocked out and researcher determines the effect on the organism ‒ Used with yeast, fruit flies, and nematodes (worms), all of which have short lives.  Forward genetic method: Uses natural genetic variation among populations to identify candidate genes ‒ Used with mammals, including humans Copyright © Springer Publishing Company, LLC. All Rights Reserved. Genes Related to Aging Copyright © Springer Publishing Company, LLC. All Rights Reserved. Apolipoprotein E (APOE)  Encodes an apolipoprotein that is a large component of very low density lipoproteins (VLDLs), which remove excess cholesterol from blood. The protein directs the delivery of lipids from one cell type to another.  Three possible alleles, ε2, ε3, and ε4, thus leading to six genotypes that one can inherit: ε2/ε2, ε2/ε3, ε2/ε4, ε3/ε3, ε3/ε4, and ε4/ε4. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Apolipoprotein E (APOE) (cont’d)  The ε3/ε4 and ε4/ε4 genotypes have been found to be associated with increased risk of myocardial infarction, whereas the ε2/ε3 genotype is associated with decreased risk.  Apolipoprotein is expressed in many organs and is expressed the most in the liver, followed by the brain. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Apolipoprotein E (APOE) (cont’d)  A presence of one ε4 allele increases one’s risk for developing Alzheimer’s disease, and inheriting two alleles causes even greater risk  The ε2 allele, on the other hand, may protect against Alzheimer’s disease Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Catechol-O- Methyltransferase (COMT)  The COMT enzyme inactivates catecholamines (norepinephrine, epinephrine, and dopamine) in neuronal synapses, particularly dopamine in the frontal lobes.  One common SNP, rs4680 G/A, makes this gene exist in two different forms, or alleles.  One allele (“VAL”) encodes the amino acid VAL at position 158 of the amino acid sequence, and the other allele (“MET”) encodes the amino acid MET at the same location. Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Catechol-O- Methyltransferase (COMT) (cont’d)  The enzyme produced by the MET allele catalyzes much less than the VAL allele, so that catecholamine neurotransmitters linger longer at synapses.  This increase in dopamine availability caused by the MET allele may increase the efficiency of information processing, but  May also lead to more experience of negative affect, though this may not be true for older adults. Copyright © Springer Publishing Company, LLC. All Rights Reserved.  Brain-Derived Neurotrophic Factor (BDNF)  Increases synaptic plasticity and facilitates learning and memory with the hippocampus.  The common polymorphism of this gene (rs6265 G/A) causes MET to replace VAL at location 66 (VAL66MET).  The MET allele leads to less secretion of BDNF and lower neuronal survival and synaptic plasticity. Copyright © Springer Publishing Company, LLC. All Rights Reserved. Resource Modulation Hypothesis  Genetic variation may cause stronger effects on cognition as anatomical and neurochemical brain resources decline in old age.  Genes related to higher cognitive ability may have stronger effects for older adults than younger adults.  Papenberg et al. (2015). Papenberg, G., Lindenberger, U., & Bäckman, L. (2015). Aging-related magnification of genetic effects on cognitive and brain integrity. Trends in Cognitive Sciences, 19(9), 506–514. doi:10.1016/j.tics.2015.06.008 Copyright © Springer Publishing Company, LLC. All Rights Reserved.