Neurobiology of Brain and Spinal Cord Disorders - Introduction to Aging (A 780/410G) - January 16, 2025 - PDF

NEUROBIOLOGY Alexander the Great OF BRAIN AND SPINAL CORD DISORDERS INTRODUCTION TO...

NEUROBIOLOGY Alexander the Great OF BRAIN AND SPINAL CORD DISORDERS INTRODUCTION TO THEORIES AND CONCEPTS OF AGING ANA 780/410G JANUARY 16, 2025 Is there a “Fountain of Youth”? Greg A Gerhardt, Ph.D., Professor of Neuroscience, Neurosurgery, Neurology, Psychiatry & Professor College of Pharmacy and College of Electrical Engineering Oldest Animals John Tinniswood 112 UK Brain Restoration Center  Learning Objectives Aging of biological systems and why aging is not a disease. Major risk factors that possibly accelerate the aging process. Animal models of aging: strengths and weaknesses. Genes implicated in aging. Caloric restriction and its implications on aging. What is our life span vs. life expectancy?  Misconceptions about the Aging Brain 1) You loose 6-8% of your neurons per decade. Possibly 1-2 % per decade but mostly functional changes and not cell death (Hof and Mobbs, 2001). Often neuronal cell body size is smaller with fewer dendrites. Synapse loss is more common! 2) Aging of the brain is inevitable and there is nothing I can do to improve brain function in aging. Keeping your body and brain active throughout life can contribute to “synaptic reserve” and greatly reduce your odds of dementia in aging. (Snowden, Aging With Grace, 2001) 3) You only lose brain cells during life and you never grow new ones. Youactually grow some new neurons in select regions of the brain such as the sub- ventricular zone/hippocampus. (Gage and coworkers, Gage FH ,Science, 2019) 4) I will get a neurodegenerative disease if I live long enough. Notnecessarily. The Nuns Study from UK supports that a good environment removed from tobacco, excessive drinking, high caloric intake and ample exercise may prevent age-related brain disease, but many people live long healthy lives without brain or spinal cord diseases. 5) If you get a neurodegenerative disease, we have treatments that slow the progression of the diseases. Not true, most therapies only treat symptoms, but there is progress in MS  Questions about Aging of the CNS and Your Body What is aging (from a biomedical perspective)? Can you separate aging from disease? What causes aging? Arethere genes for aging? Are these exclusive for aging or do they have other functions? Is it possible to extend life span without altering development or increasing risk to disease? Are there any effective anti-aging medications today? Will there be a such a pill in the future? Is the power to manipulate the aging process a desirable goal? Would you like to live forever?  Successful Aging in Your Career: Keep your brain and body active, learn new things, but be safe! UK Brain Restoration Center Successful Aging: Keep your brain and body active, learn new things, but be safe!  What is Aging (and Senescence)? Aging: changes that make an organism more likely to die- “an unresolved question in biology” (Medawar, 1952) an intrinsic, inevitable, and irreversible age- related process accompanied by a loss of viability and increased vulnerability (Comfort, 1964) a gradual deterioration of physiological function with age leading to progressive functional decline (Partridge & Mangel, 1999) The genetic garbage that is left over after natural selection Senescence: Age-related changes that negatively affect vitality and function of an organism and exponentially increase the risk for dying Decrease in the “force of natural selection” Mechanisms of the Aging Process Metabolic factors (Environmental/ lifestyle factors) Maintenance and Rate Repair Pathways Genetic influences Kirkwood Examples of Random Molecular Damage See Cagan et al., Somatic mutation rates scale with lifespan across mammals, Nature, 604, 517-524, 2022. Functional Decline in Brain Aging During Activity Neuron. 2007 56:924-35  Young adult subjects: multiple brain areas simultaneously activated during task performance  Older subjects: less activation of posterior regions  Coordination of large-scale brain systems that support high-level cognition disrupted with aging  Degree of activation between anterior and posterior regions correlated  Models of Aging Humans preferred but often impractical Saccharomyces cerevisiae C elegans 3 days 2-3 weeks Choice of model Duration Controversial Economical: Small size Genome equivalency- 31 % 40 % Short life cycles 2-3 months 2 years Genetic manipulation 50 % >98 % Drosophila Muscalis de Magalhaes http://www.senescence.info/aging_models.html Aging Phenotypes Across Species The Father of Gerontology Nathan Shock First director of (National Institute on Aging) NIA: Head of intramural research for 35 years It was Dr. Shock's insistence on answering what he considered the discipline's critical questions that made an impact on the field of gerontology:  "What are the underlying biological factors that produce what we perceive as aging?"  "Whatare the mechanisms that produce impaired performance with age?" http://www.grc.nia.nih.gov/visitors/lectures.htm “Aging is not a disease.” BLSA: World’s longest running study of human aging Some results: Many changes in elderly are due to disease and not aging Poor performance on visual-recall tests may predict increased risk for dementia https://www.nia.nih.gov/research/labs/blsa Other notable longitudinal studies Framingham: identify factors contributing to CVD by following its development over time https://www.bumc.bu.edu/fhs-bap/  Baltimore Longitudinal Study of Aging (BLSA) Some key findings: Men who tended to live longer had: Lower body temperatures Lower insulin levels Higher DHEA levels (dehydroepiandrosterone) Precursor of testosterone and estrogen Adrenal glands These physiological changes are shared by long lived monkeys who are on calorically restricted diets. Caloric Restriction Extends Lifespan of Monkeys Biomarker: a test that can predict the life expectancy of an organism Restriction Caloric Life Span Roth et al., Science, August 2nd, 2002 Caloric Restriction Reduces Signs of Aging Mike Linksvayer, 36, on a low-calorie diet for six years, is 6 feet and 135 pounds, and his blood pressure is 112 over 63. 7 Years of Caloric Restriction Before: 180 lbs After: 134 lbs  We report here that a CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. 2009 Study 2012 Study 70% of ad lib intake 70% of control intake 30% calories from sucrose 4% calories from sucrose  death Did not reduce death  diabetes diabetes  cancer  cancer  cardiovascular disease Did not  cardiovascular  brain atrophy disease Control diet did not result in obesity Fontana et al. Nutrient-sensing pathways and aging Conserved anti-aging pathways developed to overcome periods of starvation? Relevance to Human Aging? Issues regarding Caloric Restriction Isthere a gene that mediates effects on longevity? Cana caloric restriction mimetic be developed?  Sirtuin Proteins (histone deacetylases) Sir2 gene- evolutionarily conserved longevity gene that mediates caloric restriction? Yeast- family of 5 genes Sir2 overexpression ↑lifespan in yeast, worms, flies Resveratrol Sirtuinactivator ↑lifespan in yeast, worms, flies Caloric Restriction ↑lifespanin yeast and flies appears to require Sir2  Sirtuin Proteins (histone deacetylases) Sir2 gene- evolutionarily conserved longevity gene that mediates caloric restriction? Mammals- 7 genes Sirt1 is mammalian homologue of yeast Sir2 Baur, Pearson et al., Nature 2006 Resveratrol Tx (sirtuin activator) ↑lifespan in mice fed high fat diet (HFD) Lifespan unchanged in mice on normal diets but mice “metabolically” healthier  Sirtuin Proteins (histone deacetylases) Sir2 gene- evolutionarily conserved longevity n=108/group gene that mediates caloric restriction? New Sirtuin drug (SRT-1720) ↑mean lifespan in mice on HFD (44%) ↓weight, ↓fatty liver, ↑insulin sensitivity SD HFD HFD + SRT 1720 Unraveling of the Sirtuin Story? Science, December 2nd, 2011 Linking Lifespan Prolonging Treatments to Autophagy Caloric Restriction, Resveratrol, Sirtuin overexpression, Rapamycin, p53 depletion- may promote autophagy  Prominent Scientists in Aging Research Leonard Hayflick Pioneer on aging research (BIOGERONTOLOGY) Veryfew advances have occurred in our understanding of the human aging process. Successonly in of age-related diseases (GERIATRIC MEDICINE). Leonard Hayflick, Dept Anatomy, UCSF Famous for discovering the May 20, 1928- August 1, 2024 “Hayflick limit” Haylflick Phenomenon/Cell Senescence Normal cells have a finite number of divisions Population doublings correlated with the lifespan of the organism from which cells were derived Hayflick also showed that older cells did not divide as many times as the younger cells. Cell senescence was considered a model for in vivo aging, but it now is thought to be a stress and tumor suppressive response  Distinguishing Between Disease and Aging Leonard Hayflick’s Assessment Agingis not a disease, however, it is a major risk factor that predisposes to disease and all of the neurodegenerative diseases! WHY ARE OLD CELLS MORE VULNERABLE TO DISEASE THAN ARE YOUNG CELLS? Leading cause of death in old age Cardiovascular disease/stroke Cancer Diabetes Prevention of these diseases: increase life expectancy by only ~15 yrs. When does age-related cognitive decline begin? Salthouse, Neurobiol Aging 2009 How to Differentiate Disease Processes from Aging Changes? Unlike disease… age changes occur in all members of a species only after the age of reproductive success agechanges occur in every animal that reaches a fixed size in adulthood age changes take place in virtually all species age changes occur in animals removed from the wild (Hayflick, Nature 408:267, 2000)  Life Expectancy vs Life Span Life Expectancy in US Life Expectancy: the expected age of death for a newborn infant -increased dramatically since 1900. 1990: 340 million people >65 yrs old 2050: 2.5 billion people >65 yrs old  Life Expectancy vs Life Span Life Expectancy: the expected age of death for a newborn infant Has increased dramatically particularly since 1900. Increase is due to Better hygiene Adventof antibiotics and vaccines Life Expectancy Over Time “Very long lives are the probable destiny of most people alive now in developed countries” How Long Can We Live? Can humans achieve an extraordinary increase in life? Recent estimates: ~50% of infants born after 2000 in developed countries, can expect to reach 100 years of age (The Lancet, 2009) Familial aggregation of longevity? Jeanne Calment died at age of 122 (1875-1997)  Life Expectancy vs Life Span Can we extend the limits achieved on human longevity? Life Span Maximum number of years that a human can live InSweden, life span increased from 101 to 108 from 1861-1999 Many believe that it can’t go much past ~110-120 yrs; some think it is possible to live to 1000yrs! Science 289:2366, 2000 Why Do We Age? Genetic Programs or Damage Accumulation Is aging: Programmed Large differences in life span between species must be genetically determined Single gene mutations can result in increases in life span …or is aging due to: Progressive wear-and-tear and random damage Much evidence supports evidence of DNA, protein and lipid damage accumulating with aging Mechanisms of the Aging Process Metabolic factors (Environmental/ lifestyle factors) Maintenance and Rate Repair Pathways Genetic influences Kirkwood  Why Do We Age? Evolutionary Theories of Aging Theories: Senescence is programmed to limit population size (and accelerate turnover of generations). Flaw: senescence doesn’t contribute to mortality in the wild. Most species die from extrinsic hazards: infection, predation, starvation, cold, etc Three Evolutionary Theories of Aging Mutation Accumulation Antagonistic Pleiotropy Disposable Soma  Evolutionary Theories of Aging Theories: late-onset 1. Mutation Accumulation: the mutations increased frequency of gene mutations that occurs with age Aging is the result of mutations that strike late in life, beyond the control of natural selection Because survival is so low in the wild, the force of “natural selection” is too weak to oppose these late-onset deleterious mutations  How does “Natural Selection” affect Mutation Accumulation? The force of “natural selection” on survival falls dramatically after the earliest age of reproduction is reached. Implication: deleterious gene mutations will accumulate over generations with little or no check These genes thus become rampant in the gene pool Aging evolved because genes that produce Examples of the Effect of Natural Selection on Mutation Accumulation Progeria (Hutchinson- Gilford): Very rare Affects1 in every 8 million children Only 100 reported cases in the last century Aging is accelerated ~7 times Symptoms appear ~2 years of age Sporadic mutation in a single  Evolutionary (continued) Theories of Aging Theories: 2. Antagonistic Pleiotropy / Trade-off Theory: natural selection favors genes with good early effects even if these genes have bad effects later in life. Native Americans have a very high incidence of diabetes. They have inherited genes that facilitate the storage of nutrients.  Role of Tumor Suppression in Aging An example of antagonistic pleiotropy Interpretation Under normal conditions, p53 activity is balanced to prevent cancer as well as premature aging If p53 is hyperactive, then there is cancer protection at the expense of developing an early aging phenotype If p53 is deficient, early cancer develops (lowering p53 in cancer deficient mice increases life span) Aging is the price we pay for protection from cancer during the young reproductive years  Evolutionary Theories of Aging Theories: 3. Disposable Soma Theory: reproduction and cellular maintenance/repair compete for energy resources Oncean organism has reproduced, it is viewed as being disposable.