Mary Mc Donald MD Assistant Professor Division of

Mary Mc. Donald, MD Assistant Professor Division of Geriatric Medicine and Palliative Care, Department of Family Medicine

Learning Objectives Every student should be able to. . . n Differentiate chronological age from biological age. n Explain what is meant by the heterogeneity of aging in humans and describe its clinical implications. n Discuss the multiple coexisting forces which may work in concert to affect the aging process. n Compare life expectancy and lifespan. n Describe the general characteristics of aging n Describe what is meant by homeostenosis. n Evaluate theories of aging presented and outline supporting and opposing evidence of each. n Compare and contrast the two theories of lifespan extension and describe their clinical implications.

CHRONOLOGICAL AGE How long have You lived? VS BIOLOGICAL AGE How old is Your body?

CLINICALLY, WE SEE GREAT VARIATION WITHIN THE BIOLOGICAL AGE OF OUR OLDER ADULT PATIENTS

Life Expectancy n the average number of years remaining for a living being (or the average for a class of living beings) of a given age to live.

Life Expectancy at Birth, 65 and 85 Years of Age, by Sex & Race: United States, Selected Years 1900 -2002 Source: U. S. Census Bureau

Source: U. S. Census Bureau

Life Expectancy Improved public hygiene and the discovery of antibiotics in the early to mid 1900 s led to significantly prolonged lifespan n Further prolongation occurred in 1970’s and 1980’s with improved treatments for cardiovascular disease n

Lifespan - The duration of life of an individual Average Lifespan - The normal or average duration of life of members of a given species. Wordrefernce. com English Dictionary

Lifespan Jeanne Calment of Southern France died in 1997 at the age of 122 years and 164 days. Very active. Took up fencing at age 85 and was still riding a bicycle at age 100.

Characteristics of Aging (1 of 2) n n n Mortality increases exponentially Biochemical composition of tissue changes Physiologic capacity decreases Ability to maintain homeostasis diminishes Susceptibility and vulnerability to disease increases Environmental and genetic factors influence the rate of aging

Characteristics of Aging (2 of 2) n Loss of physiologic reserve and decreased homeostatic control may result from: Ø Allostatic load (persistent activation of normal neuroendocrine, immune, and autonomic responses to stress) Ø Development of homeostenosis (altered response to physiologic stresses) n Changes are generally irreversible

Developmental-Genetic Progeria n n Progeria is a disease of premature aging Death typically by age 13 and usually due to atherosclerotic disease, stroke, heart attack. Hutchinson-Gilford Progeria linked to mutations in the nuclear structural protein lamin A. caused by a tiny, point mutation in a single gene, known as lamin A (LMNA).

Werner’s Syndrome Disease of premature aging. Patients appear normal for first two decades of life but develop arteriosclerosis, malignant neoplasms, DMII, osteoporosis, cataracts very young

Werner’s Syndrome n n n Disorder isolated to a single gene on chromosome 8 which encodes for a DNA helicase This gene has been cloned and is an area of great research DNA helicases are involved in the repair, replication and expression of genetic material

Aging research has turned away from a single gene answer to the cause of aging. Increasing understanding that aging is a consequence of complex interactions within differing systems of the body and the surrounding environment.

Theories of Aging § § Molecular Theories Cellular Theories System Theories Evolutionary Theories

Molecular Theories of Aging Gene regulation n Codon restriction n Error catastrophe n Dysdifferentiation n

Gene Regulation Theory n Aging is caused by changes in gene expressions, affecting both aging and development

Gene Expression (1 of 2) n Compared with younger adults, the elderly can have decreased, unchanged, or increased rates of gene expression n Mechanisms that influence gene expression with aging: Ø Mutations in DNA sequences in/around certain genes Ø Latent viral infections (eg, herpes viruses) Ø Accumulation of environmentally induced cell damage n It is unknown whether age-related changes in gene expression are functionally significant

Gene Expression (2 of 2) n Primary changes in gene expression with age: Ø Decreased transcription rates for key genes Ø Decreased messenger RNA (m. RNA) turnover Ø Decreased inducibility of genes, such as immediate early genes, acute phase reactants, and stress genes n Expression of genes related to stress response is upregulated during senescence Ø Consequences unknown Ø May be adaptations to accumulated environmental or oxidative stress

Codon Restriction Theory n Accuracy of m. RNA translation is impaired due to inability to decode codons in m. RNA

Error Catastrophe Theory n Decline in fidelity of gene expression over time resulting in increased portion of abnormal proteins

Dysdifferentiation n A gradual accumulation of random molecular damage over time impairs regulation of gene expression

Molecular Theories of Aging n n Synopsis: Age-acquired chromosomal instabilities contribute to gene silencing or expression of diseaserelated genes (eg, cancer genes) In support: Ø Damage by reactive oxygen species causes mitochondrial DNA (mt. DNA) mutations in muscle and brain Ø Defective mitochondrial respiration and further oxidant injury creates a cycle of damage Ø Mitochondrial mutations and defective respiration have been linked to neurodegeneration n In opposition: The practical impact on nondiseased aging appears to be minimal

Molecular Theories of Aging n n mt. DNA also undergoes age-related changes Ø Mutation rate 10, 000 -fold greater in elderly than in younger adults Ø Up to 10% of very old adults have mt. DNA deletions However, mitochondrial and mt. DNA are amply redundant Ø Age-related changes in respiratory chain activities are subtle, if detectable at all Ø Most likely effect of age-related mt. DNA changes is reduced functional reserve of energy production

Cellular Theories of Aging n n n Cellular senescence theory Oxidative stress theory Apoptosis theory

Cellular Senescence Theory n n n Each cell has a maximum number of divisions before it enters senescence The length of the telomere end of the DNA chain shortens with each division and less telomerase activity is observed A telomere is a region of highly repetitive DNA at the end of a chromosome that functions as a disposable buffer

Telomere

Telomeres n n n Aged cells with proliferative potential exhibit telomere shortening and loss of telomerase activity Conversely, telomerase hyperactivity is linked to cellular transformation and cancer Telomere length and telomerase activity might be clinical markers of human aging and oncogenesis

Oxidative Stress Theory Oxidative metabolism produces reactive oxygen species which damage protein, lipids and DNA

Oxidative Stress Theory n In support: Ø Mutations in oxidative stress pathway can extend life span Ø Mutations in other pathways that increase longevity resist oxidative damage n In opposition: Antioxidants do not delay human senescence or disease

Apoptosis Theory Genetically determined, programmed cell death. “Genome Crisis”

Systems Theories of Aging n n Neuroendocrine Immune senescence

Neuroendocrine Theory n Changes in the neuroendocrine control of homeostasis result in aging-related physiologic alterations

Neuroendocrine Theory n Synopsis: Hypothalamic and pituitary responses are altered (TRH, GNRH, GHRH, TSH, LH, FSH, GH, ACTH) n In support: No direct support as causative of healthy aging, and supplementation does not alter aging in humans

Immune Senescence Theory n Changes in the immune system with aging lead to increases in infectious disease and increase in autoimmune disease in older adults.

Theories of Aging: Immune Senescence n Synopsis: Time-acquired deficits, primarily in Tcell function, increase susceptibility to infections and cancer Ø Slower onset of lymphocyte proliferation Ø Diminished cloning efficiency of individual T cells Ø Fewer population doublings of fibroblasts n In support: Some diseases are associated with aging n In opposition: Immunologic function is apparently not directly related to healthy aging

Evolutionary Theories of Aging results from a decline in the force of natural selection 1. 2. Mutation accumulation Antagonistic Pleiotropy

Mutation Accumulation Mutations that affect health in older ages are not selected against and therefore accumulate in a population Supported by diseases like Huntington’s Disease. An autosomal dominant, terminal, neurodegenerative disease that typically presents at age 30 -45, after childbearing age.

Mutation Accumulation Diseases that are lethal in childhood or early adulthood are not passed to further generations and do not accumulate in a population

Antagonistic Pleiotropy Some genes that code for beneficial effects in early life may then be detrimental in later years Discussed as the conflict between fecundity (reproductive ability) and longevity

Antagonistic Pleiotropy and Testosterone production in young men supports reproductive potential This same hormone in older adults contributes to the development of prostate cancer

Antagonistic Pleiotropy Studies have revealed that destroying germ line cells in both Drosophila and C. elegans can extend lifespan

Antagonistic Pleiotropy Insert picture of drosophila Drosophila Insert picture of elegans C. elegans

Can all of this knowledge be used to extend lifespan?

Life Span Extension: Metabolic And Insulin Signaling n There appears to be endocrine regulation of aging Ø In a range of species, mutations in certain genes, especially those that appear to play roles in metabolic and insulin signaling (eg, GH, IGF-1), extend life span Ø In contrast, life span is shorter in humans with untreated isolated GH deficiency (but normal age-related GH decline may have little to do with healthy aging) Ø Low-expressing IGF-1 receptor alleles are more highly represented among long-lived humans n These pathways are potential targets for drugs to delay or prevent age-related changes

Life Span Extension: Caloric Restriction (1 of 2) n Caloric restriction increases average and maximum life spans in a variety of species n Impact of caloric restriction varies considerably in mice and flies n Two robust markers of caloric restriction in rodents (reduced body temperature, reduced plasma insulin) have been observed in older men and in caloric-restricted rhesus monkeys

Life Span Extension: Caloric Restriction (2 of 2) n Sir 2, an enzyme in the sirtuin family of proteins, mediates the benefits of caloric restriction in yeast n Sirtuin-activating compounds (STACs) could conceivably enhance life span in humans Ø Resveratrol, a plant polyphenol in red wine, is a STAC that prolongs life span in fruit flies and worms Ø Resveratrol has anti-inflammatory, antioxidant, anticancer, and vasoactive effects on human cells n It might be possible to develop calorie restriction mimetics to increase human life span

What does aging mean to the physician? § § § Great heterogenicity in the older population Increased attention to biological age versus chronological age No “one size fits all” approach to treating older adults

Summary n n There are large interindividual variations in the rate of physiologic aging Aging appears to have multiple causes, including genetic and environmental factors Genetic factors may regulate aging or life span through a variety of mechanisms (eg, insulin signaling, control of oxidative damage, DNA maintenance, and altered gene expression) It might be possible to extend human life span with caloric restriction mimetics or drugs targeting the GH/IGF-1 pathway

Acknowledgements GRS 6 Chapter Authors: Bruce R. Troen, MD Donald A. Jurivich, DO © American Geriatrics Society National Vital Statistics systems Stedman’s Concise Medical Dictionary. Third Edition. 1997 Wordreference. com English Dictionary

Landon Center on Aging Photo Contest

Landon Center on Aging Photo Contest

Landon Center on Aging Photo Contest

Landon Center on Aging Photo Contest

Landon Center on Aging Photo Contest