1. Theories of Aging Mary McDonald, MD Assistant Professor
Division of Geriatric Medicine and Palliative Care, Department of Family Medicine

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

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

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

5. Life Expectancy
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.

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

8. Source: U.S. Census Bureau

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

10. Wordrefernce.com English Dictionary
Lifespan
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

11. 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.

12. Characteristics of Aging (1 of 2)
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
Examples of changes in the biochemical composition of tissue with age are lipofuscin and extracellular matrix cross-linking, protein oxidation, and altered rates of gene transcription.
Topic

13. Characteristics of Aging (2 of 2)
Loss of physiologic reserve and decreased homeostatic control may result from:
Allostatic load (persistent activation of normal neuroendocrine, immune, and autonomic responses to stress)
Development of homeostenosis (altered response to physiologic stresses)
Changes are generally irreversible
Allostatic response includes changes in cortisol, epinephrine, and cytokines that are adaptive in the short run but may be harmful if prolonged.
Allostatic load refers to the effects of prolonged or overactive allostatic response. A possible example of allostatic load is the putative relationship between the subtle increase in cortisol levels seen in many older people and hippocampal damage and memory loss. Conversely, it has been hypothesized that brief or recurrent exposures to stress such that specific signaling pathways and gene expressions are stimulated may be beneficial and ultimately promote longevity of an organism. This phenomenon is known as hormesis and is likely to be found occurring alongside examples of allostatic load. Hormesis has been observed in a variety of organisms (yeast, flies, worms, rodents) and in human cells in vitro.
Examples of homeostenosis include decreased ability to manage fluid and electrolyte derangements, including diminished thirst perception, decreased glomerular filtration, and changes in the renin-aldosterone system, urinary concentrating, and dilutional capacity.
Topic

14. Developmental-Genetic Progeria
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).

15. 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

16. Werner’s Syndrome
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

17. 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.

18. Theories of Aging Molecular Theories Cellular Theories System Theories
Evolutionary Theories

19. Molecular Theories of Aging
Gene regulation
Codon restriction
Error catastrophe
Dysdifferentiation

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

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

22. Gene Expression (2 of 2) Primary changes in gene expression with age:
Decreased transcription rates for key genes
Decreased messenger RNA (mRNA) turnover
Decreased inducibility of genes, such as immediate early genes, acute phase reactants, and stress genes
Expression of genes related to stress response is up- regulated during senescence
Consequences unknown
May be adaptations to accumulated environmental or oxidative stress
There is no evidence that age leads to an increased error rate during transcription and translation.
Some of the most definitive age-dependent changes in gene expression are observed when aged donor cells are analyzed during different forms of physiologic stress. This observation is perhaps not surprising, given clinical observations that elderly persons often respond less well than young adults to physiologic stress, such as infections, environmental extremes, and hypoxic events. The inability of cells to withstand physiologic stress with age is the strongest evidence that changes in stress-related gene expression contribute to poor functional outcomes.
Of 6000 human genes analyzed, only 61 or 1% showed changes in expression between young and middle-aged donors. Most of these changes were reduced gene expression involving cell cycle progression and maintenance or repair of the extracellular matrix. The functional consequence of declining gene expression related to the cell cycle is possibly to predispose elderly individuals to increased DNA strand breaks and other chromosomal instabilities.
Topic

23. Codon Restriction Theory
Accuracy of mRNA translation is impaired due to inability to decode codons in mRNA

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

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

26. Molecular Theories of Aging
Synopsis: Age-acquired chromosomal instabilities contribute to gene silencing or expression of disease-related genes (eg, cancer genes)
In support:
Damage by reactive oxygen species causes mitochondrial DNA (mtDNA) mutations in muscle and brain
Defective mitochondrial respiration and further oxidant injury creates a cycle of damage
Mitochondrial mutations and defective respiration have been linked to neurodegeneration
In opposition: The practical impact on nondiseased aging appears to be minimal
Given maternal inheritance of mtDNA, human longevity potentially is linked to the maternal genome.
Topic

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

28. Cellular Theories of Aging
Cellular senescence theory
Oxidative stress theory
Apoptosis theory

29. Cellular Senescence Theory
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

30. Telomere

31. Telomeres
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
Telomeres are DNA sequences that cap off chromosome ends. They prevent chromosome degradation and inappropriate fusion or recombination. Telomerase is an enzyme that is involved in their formation and maintenance.
Targeted disruption of telomerase activity is a conceivable cancer therapy, whereas reactivation of this enzyme might reverse age- dependent changes in replicative potential. Such an approach would presumably have to be tumor specific, since some cancerous cells do not have telomerase.
Topic

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

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

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

35. Systems Theories of Aging
Neuroendocrine
Immune senescence

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

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

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

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

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

41. 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.

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

43. 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

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

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

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

47. Can all of this knowledge be used to extend lifespan?

48. Life Span Extension: Metabolic And Insulin Signaling
There appears to be endocrine regulation of aging
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
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)
Low-expressing IGF-1 receptor alleles are more highly represented among long-lived humans
These pathways are potential targets for drugs to delay or prevent age-related changes
Animals lacking expression of GHRH are long-lived, but are small and exhibit delayed puberty. Similarly, knockout of the GH receptor results in small, subfertile animals that are long lived. Growth hormone acts via the insulin or insulin-like growth factor 1 (IGF-1) pathway.
In worms, flies, and mice, mutations in insulin receptor substrate (IRS) genes, the insulin receptor, and the IGF-1 receptor enhance longevity.
The first single-gene mutation that was described in worms to extend life span is in the AGE-1 gene, which appears to code for the homologue of the human phosphoinositol-3-kinase gene, a downstream effector of IGF-1. In worms, a neuron-specific mutation in the insulin- signaling system extends life span. In addition, reducing the activity of HSF1 shortens life span, whereas overexpression of heat-shock protein 70F increases life span in worms. Interestingly, HSF1 is required for insulin–IGF-1 signaling.
Mice lacking the insulin receptor specifically in adipose tissue are longer lived. Furthermore, mice heterozygous for a knockout of the IGF-1 receptor (homozygous knockouts are lethal) are longer lived, while exhibiting normal fertility and essentially normal size. These mice display increased resistance to oxidative stress, as do many of the long-lived mutants noted above.
Topic

49. Life Span Extension: Caloric Restriction (1 of 2)
Caloric restriction increases average and maximum life spans in a variety of species
Impact of caloric restriction varies considerably in mice and flies
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
Species in which caloric restriction has been shown to increase life span include yeast, worms, flies, spiders, fish, hamsters, rats, and mice. Although calories are severely restricted (up to 40%), essential nutrients such as vitamins and minerals are maintained at levels equivalent to those found in ad libitum diets.
The diet-restricted animals exhibit a delay in the onset of physiologic and pathologic changes with aging. These include hormone and lipid levels, female reproduction, immune function, nephropathy, cardiomyopathy, osteodystrophy, and malignancies.
Caloric restriction in mice retards the age-associated accumulation of mtDNA mutations. Perhaps very importantly, caloric restriction reduces oxidative damage in flies, rodents, and primates.
Topic

50. Life Span Extension: Caloric Restriction (2 of 2)
Sir2, an enzyme in the sirtuin family of proteins, mediates the benefits of caloric restriction in yeast
Sirtuin-activating compounds (STACs) could conceivably enhance life span in humans
Resveratrol, a plant polyphenol in red wine, is a STAC that prolongs life span in fruit flies and worms
Resveratrol has anti-inflammatory, antioxidant, anticancer, and vasoactive effects on human cells
It might be possible to develop calorie restriction mimetics to increase human life span
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51. 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

52. Summary
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
Topic

53. © American Geriatrics Society
Acknowledgements
GRS6 Chapter Authors: Bruce R. Troen, MD
Donald A. Jurivich, DO
© American Geriatrics Society
National Vital Statistics systems
Stedman’s Concise Medical Dictionary. Third Edition
Wordreference.com English Dictionary
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54. Landon Center on Aging Photo Contest

55. Landon Center on Aging Photo Contest

56. Landon Center on Aging Photo Contest

57. Landon Center on Aging Photo Contest

58. Landon Center on Aging Photo Contest