Biomedical Perspective of Aging

Neurobiology of Brain and Spinal Cord Disorders: Introduction to Theories and Concepts of Aging

• The lecture introduces theories and concepts of aging, covering aging of biological systems, risk factors accelerating aging, animal models, genes, caloric restriction, lifespan, and life expectancy

Learning Objectives

• Understand aging in biological systems and why it not considered a disease
• Learn about major risk factors potentially accelerating the aging process.
• Evaluate the strengths and weaknesses of animal models used in aging research.
• Identify genes implicated in aging
• Understand the implications of caloric restriction on aging
• Differentiate between lifespan and life expectancy

Misconceptions about the Aging Brain

• Losing 6-8% of neurons per decade is a misconception
• The actual loss is closer to 1-2% - mainly functional changes, not cell death, with smaller neuron size and fewer dendrites; synapse loss is more common
• Aging of the brain is somehow inevitable, and it is possible to improve brain function during aging by keeping your body and brain active
• Staying active contributes to "synaptic reserve" and reduces dementia risks
• Losing brain cells is not the only factor
• The brain grows new neurons in areas like the sub-ventricular zone/hippocampus
• Getting a neurodegenerative disease is not inevitable with old age if living a long life
• A good environment, free from tobacco and heavy drinking, plus healthy exercise, can prevent age-related brain diseases
• Treatments for neurodegenerative diseases do not slow the progression, but treat the symptom, yet progress is being shown in MS and AD

Questions about Aging

• What defines aging from a biomedical perspective?
• Is it possible to separate aging from disease?
• What are the root causes of aging?
• Identify genes associated with aging and determine if they exclusively affect aging, or if they have other functions.
• Is it possible to extend life span without causing developmental alterations or increasing disease risk?
• Are there any existing anti-aging medications, and is developing such a pill a future possibility?
• Is actively manipulating the aging process a desirable goal?
• Would living forever hold appeal?

Successful Aging

• Successful aging involves keeping the brain and body active and continuing to learn new things, all while staying safe.

Defining Aging and Senescence

• Aging includes the changes that make an organism more susceptible to death, or, an unresolved question in biology (Medawar, 1952)
• Aging is an inherent, inevitable, and irreversible process accompanied by decreased viability and increased vulnerability (Comfort, 1964)
• Aging is a gradual decline of physiological functions with age, leading to progressive decline (Partridge & Mangel, 1999)
• Aging includes the the genetic remnants left after natural selection.
• Senescence includes age-related declines of organism vitality, increasing the risk of death
• Senescence has a decreasing "force of natural selection"

Mechanisms of the Aging Process

• The rate of age-related frailty, disability, and disease is influenced by the accumulation of cellular defects and random molecular damage
• Maintenance and repair pathways as well as metabolic factors and genetic influences modulate this rate.

Random Molecular Damage Contributing to Aging

• Damage to DNA(genome instability) includes somatic mutations (copying errors/imperfect repair), telomere shortening, chromosome rearrangements, mitochondrial DNA mutations, gene disruption by viruses/transposons or aberrant epigenetic modifications
• RNA damage comes from transcription or aberrant splicing errors
• Protein damage is derived from misfolding, synthesis errors, aberrant post-translational modifications, aberrant aggregation, or impaired turnover (catabolism)
• Membrane damage can come from oxidation.
• Gene expression, cell-fate determination, differentiation or damage segregation during cell division plus cell migration and cell death can disrupt things

Functional Decline in Brain Aging

• Young adults activate multiple brain areas for tasks
• Older adults have lower activated posterior regions
• Coordination of large-scale brain systems for high-level cognition becomes disrupted.
• The degree of activation between anterior and posterior brain regions can be correlated

Models of Aging

• Humans are preferred but often impractical for aging models
• Model choice depends on the study's duration and potential controversies.
• Economical models include small size and short life cycles
• Genetic manipulation is also a critical choice for aging models
• Yeasts as a model has a genome equivalency of 31% compared humans
• C. elegans has a genome equivalency of 40% to humans
• Drosophila has a genome equivalency of 50% compared to humans
• Muscalis has a genome equivalency of 98% compared to humans

Aging Phenotypes Across Species

• Conserved aging phenotypes across species include decreased cardiac function, apoptosis/senescence, cancer/hyperplasia, genome instability, macromolecular aggregates, and reduced memory/learning
• Additional phenotypes encompass declines in GH, DHEA, testosterone, IGF, thyroid function and innate immunity with increased inflammation, changes in skin/cuticle, decreased function of mitochondria.
• Other phenotypes include sarcopenia, osteoporosis, abnormal rest/sleep plus impairments vision, demyelination and fitness with arteriosclerosis and changes in fat content

The Father of Gerontology

• Nathan Shock, first director of the NIA - intramural research for 35 years
• Shock wanted to answer what the underlying biological factors that produce the perception of aging or identify the mechanisms causing impaired performance with age
• Aging is not a disease

Baltimore Longitudinal Study of Aging (BLSA)

• The BLSA is world's longest-running study of human aging
• Results suggest changes in elderly are due to disease, not aging.
• Visual-recall performance predicts dementia risk

Baltimore Longitudinal Study of Aging (BLSA) Key Findings

• Men who tended to live longer had lower body temperatures and insulin levels, plus higher DHEA levels (dehydroepiandrosterone)
• Changes are shared by long-lived monkeys on low caloric diets.

Caloric Restriction

• Caloric restriction is when caloric intake is reduced without malnutrition
• Biomarkers of caloric restriction are a test that can predict the life expectancy of an organism
• The NIA Primate Aging Study showed that the caloric restriction male rhesus monkeys had better survivability

Caloric Restriction Benefits

• Decreases signs of aging in rhesus monkeys.
• Improves biomarkers like blood pressure and insulin levels in humans.

Caloric Restriction Limitations

• A 2009 NIA study of rhesus monkeys indicated CR did not improve outcomes
• Monkeys on 70% of the ad lib intake saw 30% of calories from sucrose plus potential death, diabetes or cancer and cardiovascular disease plus brain atrophy
• The 2012 Study of control intake with 4% calories from sucrose, there were not reduced deaths or cancer
• 2012 study did show no cardiovascular disease and the control group saw no obesity

Caloric Restriction And Memory

• Caloric restriction improves memory in the elderly humans
• Restriction must still be an adequate, healthy diet

Life Span Increase and Beneficial Health Effects Chart

• Life span can increase from 3-fold in yeast with starvation/DR, or, 2-3 fold increase in worms with 10-fold increase from DR
• Flies can see a 2-old increase from a 60-70% improvement in DR
• Mice can an improve 30-50% and 30-50% respectively with a 100% improvement in DR combination
• Monkeys show a trend, yet there is no testing and humans show no determining indicators on deficiency

Nutrient-Sensing Pathways and Aging

• Anti-aging pathways that are conserved are developed to overcome periods of starvation.
• These pathways are linked to lifespan through the TOR.
• TOR shows glycolysis and glycogen accumulation

Relevance to Human Aging

• Aging is human condition
• There are functionally significant insulin-like growth factor I receptor mutations in centenarians

Issues Regarding Caloric Restriction

• Does a gene mediate the lifespan effects of caloric restriction?
• Is the development of a caloric restriction mimetic possible?

Sirtuin Proteins (Histone Deacetylases)

• Histone deacetylases can mediate the function of the Sir2 gene and also have a high level of genetic conservation
• Having 5 genes that that increase lifespan in yeast, worms and flies
• Resveratrol can activate Sirtuin and increase lifespan in yeast, worms and flies
• Lifespan can also be dependent on Sir2 in yeast and flies

The Function of 7 Genes in Mammals

• Sirt1 is the mammalian version of Sir2 in yeast
• Resveratrol can increase lifespan in activated mice with HFD - high fat diet
• Lifespan is not changed for normal diets, but the mice are metabolically healthier b eating healthier

New Sirtuin Drug (SRT-1720)

• Has increased survivability in mice with (44%)
• Causes a lower weight with less fatty liver and more insulin sensitivity

Unraveling the Sirtuin Story Timeline

• 1999: MIT's Kaeberlein and Guarente show that the SIR2 gene extends lifespan in yeast.
• 2001: Others show the protein responds to calorie restriction in worms.
• 2002: Kaeberlein completes his Ph.D. and works at a biotech company.
• 2004: Helfand repeats the SIR2 finding in flies at Brown University.
• 2004-2005: Sinclair, a Guarente lab alum, creates Sirtris to develop drugs for diseases, including resveratrol in red wine. Kaeberlein and Kennedy find yeast resveratrol doesn't effect SIR2 lifespan in the lab
• 2007: Guarente's paper showed that expressing SIRT1 helped mice doesn't help them live longer, though they are healthier
• 2008: GlaxoSmithKline buys Sirtris for $720 million.
• 2011: Kaeberlein and British colleagues publish saying SIR2 doesn't extend life in worms or flies.

Linking Lifespan Prolonging Treatments to Autophagy

• Caloric restriction, resveratrol, Sirtuin overexpression, Rapamycin, p53 depletion promotes autophagy

Prominent Scientists in Aging Research

• Leonard Hayflick is a pioneer in aging research
• Few advances have been made in the human aging processes
• There is better success in age-related diseases (geriatric medicine)
• Hayflick is famous for discovering the "Hayflick limit,"

Hayflick Phenomenon/Cell Senescence

• Normal cells have a finite division count
• Population doublings correlated with the lifespan of the source organism from which cells were derived
• Older cells divide less than younger ones.
• Cell senescence was a model for in vivo aging is thought to be a stress and tumor suppressor

Distinguishing Between Disease and Aging

• Aging is not considered a disease, it is a major risk factor for diseases plus neurodegeneration

Age-Related Cognitive Decline Begin?

• Cognitive functions such as memory, reasoning, spatial visualization, and speed all decline with age

Differentiating Disease from Aging

• Aging changes occur in all species members exclusively after reproductive success and in every animal reaching adult size
• Aging happens if virtually all species, as well as those removed from nature, have all seen it

Life Expectancy vs Life Span

• Life expectancy is the expected age of death for a newborn infant
• Life expectancy has dramatically risen since 19