61 terms

Path 8 - Aging and Cell Senescence

Objectives 1.) The major trend in epidemiology of aging population - Aging, Life expectancy, Life span 2.) Causal relationship between age-associated, chronic diseases and organismal aging - Major causes of death in aged population 3.) Cell senescence in vitro and in vivo and its association with advancing age - Telomere and telomerase
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Aging
the accumulation of deleterious changes in a person over time. Age is measured chronologically.
Changes are progressive, unidirectional, irreversible, and result in death
- Chronological aging may also be distinguished from "social aging" (cultural age-expectations of how people should act as they grow older) and "biological aging" (an organism's physical state as it ages).
Biological Aging
defined by decline of physiological functions, decreased capacity to respond to stress, and exponential increase of age specific mortality rate.
- Differences are sometimes made between populations of elderly people.
- Divisions are sometimes made between the young old (65-74), the middle old (75-84) and the oldest old (85+).
Population Aging
the increase in the number and proportion of older people in society.
Aging and Disease
Aging is NOT a disease, but can make one more susceptible to disease
Life Expecancy
the expected (in the statistical sense) average number of years of life remaining at a given age.
This parameter can vary with age.
e.g. in a population with a high infant and childhood mortality the life expectancy would be low. However, the cohort that survives to early adulthood would have a significantly higher life expectancy. e.g., the best evidence indicates that life expectancy at birth in medieval Britain was 30 years; however, the cohort that survived age 21 the life expectancy increased to 43 years to a total age of 64.
Maximum Life Span (MLS)
has stronger genetic component than life expectancy and is determined by the rate of aging.
- Can be defined as the mean life span off the most long-lived 10% of a given cohort.
- Alternatively, has been defined by the age at which the oldest known member of a species or experimental group has died.
- In humans the MLS as defined by the former definition is somewhere between 100 and 110
120
Experimental Conditions that can Increase MLS
- caloric restriction
- pharmacologic or genetic activation or inactivation of metabolically critical genetic loci
- transgenic up regulation certain genes
Infant Mortality and Life Expectancy
Life expectancy is often confused with life span to the point that they are nearly synonyms; when people hear 'life expectancy was 35 years' they often interpret this as meaning that people of that time or place had short life spans. The life expectancy generally quoted is the at birth number which is an average that includes all the babies that die before their first year of life as well as people that die from disease and war. This parameter can vary with age. For example in a population with a high infant and childhood mortality the life expectancy would be low.

In this graph, infant mortality rates in 1900 are quite high; correspondingly, average life expectancy of newborns in 1900 is very low at 47.6 years. In 1992 infant mortality rate drops to < 1% and we find that life expectancy has risen by nearly 30 years compared to data from the year 1900.
Changes in Life Expectancy
Changes in Life Expectancy at specific ages decreases as the age gets closer to the MLS
- While Life Expectancy has increased in most developed countries, the Maximum Life Span has NOT changed.
Rectangularization
The change observed in the shape of survival curves, which has been termed rectangularization, shows that more and more individuals survive to very old age, and all of them die in a very narrow time window. It has been proposed that this "compression" is due the fact that, as human life approaches its absolute biologic limits, improvements in health will contribute mostly to a reduction of morbidity but very little to further increases in life expectancy.
Healthspan
the duration of good health - NOT the same as lifespan
Lifespan Increase
The issue has significant financial and therefore political implications; a one year increase in life expectancy is estimated to cost the U.S. Social Security Administration ~$50 billion.
Aging US Population
Average life span and life expectancy in the US since 1990 have grown dramatically
--> Overall increase in the proportion of older people in the society geometrical increase in survival of older ppl --> increased medical care and social needs
- This advance in age is mostly due to improvements in sanitation, the discovery of antibiotics, and medical care
- Growth of the older population mostly due to general increase in overall population size but also influenced by declines in leading causes of mortality
Overall Increased Life Expectancy due largely to decreased infant mortality and vaccines
Population Aging Worldwide
Population aging is taking place throughout the world.

Improved survival at older ages and a low birthrate have resulted in European countries having the oldest populations in the world. Italy and Germany are estimated to have the oldest populations in Europe and the second and third oldest in the world at approximately 19% each.
Diseases of Aging = (Conditions)
Conditions, not necessarily true diseases, with no associated mortality
- common ("senile", "age-related") cataract
- common "essential" hypertension
- osteoporosis
- osteoarthritis
- nodular prostate hyperplasia (men)
- wrinkled skin
- presbyopia (loss of vision)
- brain cell loss
- monoclonal gammopathy of uncertain significance (MGUS)
Age-Dependent Diseases
Certain diseases are inevitable if you live long enough
- "Diseases with prevalence increasing logarithmically with age"
- common ("senile", "age-related") cataract
- common "essential" hypertension
- osteoporosis
- nodular prostate hyperplasia (men)
- presbyopia (loss of vision)
- brain cell loss
Age-Related/Associated Diseases Definition
Diseases that tend to show up first in older people.There is very little Darwinian selection against these diseases.
Can be defined as those which display an exponential or near-exponential increase in incidence in the last 4 to 5 decades of life. By this definition 5 of the 6 of the leading causes of death in the population ≥65 years are age-associated.
Age-Related Diseases List
True diseases with mortality associated with them
- atherosclerosis (stroke, heart attack, etc.)
- calcific aortic stenosis
- temporal arteritis
- myelodysplastic syndrome
- chronic lymphocytic leukemia
- plasma cell ("multiple") myeloma
- type II diabetes
- Alzheimer's histologic changes
- idiopathic Parkinson's disease
- prostate cancer
- breast cancer
- colon cancer
- glaucoma
Degenerative Disease
If an age-related or age-dependent or age-associated disease is not obviously inflammatory or neoplastic, it is called DEGENERATIVE. This term is actually a confession of ignorance.
Age-Dependent vs Age-Related
Age Dependent = Logarithmic
Age Related = Exponential
Leading Causes of Death for ages >65
*1.) Heart Disease
2.) Cancer
3.) Cerebrovascular Disease
4.) Chronic Lower Respiratory Disease
(Infectious Disease/Pneumonia was #4 in 1980)
5.) Alzheimer's Disease*
Together account for 69.5% of all deaths
- The increased incidence in the mortality caused by chronic respiratory diseases and Alzheimer disease is most likely due to the increased size of the very elderly population (≥85).
Cause of Death in Older vs Younger Population
The causes of death in the older subjects are different than younger (25-44 yo) population. The increasingly greater life expectancy of the population has been driven in part by reduced mortality at older ages.
Younger Population Top Causes of Death:
1.) Accidents
2.) Pediatric Cancer
3.) Heart Disease (Congenital, not Ischemic)
4.) Homicide
5.) Suicide
6.) HIV
Senescence
the process of aging (in biology)
Cellular Senescence: a phenomenon where isolated cells demonstrate a limited ability to divide in culture
Organismal Senescence: the aging of organisms. The currently irreversible senescence inevitably ends in death.
Sensescence vs Aging
Aging is a general term and includes development
Senescence specifically refers to adult organism decline
Organismal senescence
The aging of organisms. The currently irreversible senescence inevitably ends in death.
Cellular Senescence - Definition
The phenomenon by which normal diploid cells lose the ability to divide, normally after about 50 cell divisions in vitro.
Idea of Cell Senescence: Cell Appearance
Old cells (i.e., the cells of the elderly, regardless of when they last underwent mitosis) look the same as young cells.
The older you get, the more lipofuscin you have in your heart muscle fibers, neurons, and liver cells (even babies have plenty in their hearts), but it seems doubtful that this sequestered pigment interferes with cell function.
Idea of Cell Senescence: Cell Durability
Old cells do not withstand a variety of challenges as well as younger cells
- Supposedly they are more likely to undergo apoptosis when stressed, though how (and when or whether) this happens remains difficult to study
In tissues in which cells normally undergo turnover, the rate decreases in the elderly
Much of this effect is attributed to methylation of cytosine bases near business genes
Organismal Senescence: Aging of Whole Organisms [KNOW THIS!!!!]
In general, aging is characterized by:
- declining ability to respond to stress
- increased homeostatic imbalance
- increased risk of aging-associated diseases
Aging Mechanisms
- Cumulative injury to cell membranes and DNA due to free radical injury
- Increased cross linking of proteins
- Accumulation of errors in protein synthesis
Accumulated DNA Damage
Appears to be a limiting factor in the determination of maximum life span.
The theory that DNA damage is the primary cause of aging, and thus a principal determinant of maximum life span, has attracted increased interest in recent years. This is based, in part, on evidence in human and mouse that inherited deficiencies in DNA repair genes often cause accelerated aging.
Hypotheses of the Mechanism of Aging
Stochastic:
- Crosslinking macromolecules
- Glycation (AGE's)
- Somatic (cell) mutations
- Free radical injury
Genetic
- Telomere shortening
- Modulation of metabolic and repair pathway
Multifactorial (Multiplex) vs Unifactorial (Unitarian)
- Mechanisms of aging appear to lie some where in between the 2 opposing hypotheses (Stochastic vs Genetic)
Stochastic Hypothesis
Predicts that the aged phenotype is caused by a series of random, injurious events, such genomic mutations and/or free radical induced injury
- Crosslinking macromolecules
- Glycation (AGE's)
- Somatic (cell) mutations
- Free radical injury
Genetic Hypothesis
Predicts that aging is a manifestation of the last segment of the developmental program
- Telomere shortening
- Modulation of metabolic and repair pathway
Random Damage "Theories" of Aging: Theories
- Free radical theory
- Post-translational protein modification theory
- Cross-linkage among connective tissue molecules
- Waste-products theory
- Error-catastrophe theory
- Somatic mutation theory
2 Ideas about why we age at cellular and molecular levels
1.) Random Damage "Theories" ("wear and tear theories", "stochastic theories", etc.)
2.) Programmed Self-Destruct "Theories"
- Not mutually exclusive
Random Damage "Theories" of Aging
focus on things that probably contribute both to early disease and death, and to some of the problems of old age. However, they probably can't explain the basic...?
Hayflick Finite Doubling Potential Phenomenon
the wearing-out of laboratory cell-lines that have undergone mitosis many times
Hayflick Limit
The number of times a normal human cell population will divide until cell division stops. Empirical evidence shows that the telomeres associated with each cell's DNA will get slightly shorter with each new cell division until they shorten to a critical length.
Does Number of Cell Divisions Control Lifespan?
No.
Most living species have at least one upper limit on the number of times cells can divide (unless cancerous or injected with a virus). For humans, this is the Hayflick limit, although number of cell divisions does not strictly control lifespan (non-dividing cells and dividing cells lived over 120 years in the oldest known human.
Human Fibroblast Cell Culture
Fibroblasts in culture will divide, at most, about 60 times; before that, after each generation, a smaller percentage of fibroblasts are willing to divide. This limited doubling capacity is the well-known HAYFLICK PHENOMENON ("finite doubling potential", "clonal senescence").

In other words, there is strong evidence that OUR BODIES ARE PROGRAMMED TO WEAR OUT (provided, of course, that we don't die of disease or accidents in youth).
Population Doubling Levels of Different Age Groups
Finite population doublings of primary human fibroblasts derived from a newborn, a 100-year-old person, and a 20-year-old patient with Werner syndrome (premature aging syndrome).
The ability of cells to grow to a confluent monolayer decreases with increasing population-doubling levels.
Telomeres and Aging
Rpetitive sequence of (TTAGGG)n at the ends of the chromosome
Much telomeric DNA is lost from human cells over the course of many cell divisions, in vitro and in vivo [Gamete telomeres are elongated during gametogenesis.]
- Unknown whether this loss is random or programmed
- Among rapidly-dividing cells, telomeres are shorter in the elderly than in the young
Shortened Telomeres
Shortened telomeres may reach a point where they cannot support normal division of chromosomes, resulting in cell senescence (replicative arrest) and abnormal chromosomal function
- can result in altered gene expression, cancer propagation, immune dysfunction, aging of tissues and the emergence of chronic disease
- Aging cells with shortened telomeres seem to be predisposed to "metabolic mistakes"
Telomerase
Enzyme (DNA polymerase) which extends telomeres when cells divide. Telomerase regulates the proliferative capacity of human cells.
- Telomerase uses Reverse Transcriptase activity to add 6nt repeating sequence (5'-TTAGGG) to the 3' end of chromosomes ==> Telomeres
- W/out telomerase, if a cell divides recursively, at some point all the progeny will reach their Hayflick limit.
- W/ telomerase, each dividing cell can replace the telomeres, and any single cell can then divide unbounded
Telomerase Structure
Pic: showing the protein component of telomerase (TERT) in grey and the RNA component in yellow.
- Human telomerase consists of (protein/ enzyme) telomerase reverse transcriptase (TERT) and telomerase RNA (TERC)
- TERT has a 'mitten' structure that allows it to wrap around the chromosome
Telomerase in Cells
1.) Somatic cells: don't usually have Telomerase
2.) Germ cells: lots of Telomerase
3.) Stem cells: low levels of telomerase
*Telomerase can be activated in Cancer cells
Premature Aging Syndromes
A variety of premature aging syndromes are associated with short telomeres. However, the genes that have been mutated in these diseases all have roles in the repair of DNA damage and the increased DNA damage may, itself, be a factor in the premature aging.
hTERT Gene Transduction
The absence of telomerase activity in most human somatic cells results in telomere shortening during aging.
Telomerase activity can be restored to human cells by hTERT gene transduction or potentially via drug therapy; such extended-lifespan cells could be useful in forms of cell therapy to be developed for age-related diseases.
On the other hand, the absence of telomerase acts as a limitation on cancer growth unless telomerase becomes reactivated.
Telomere Function
1.) DNA Protection
2.) Signaling to other pathways, including cell death
- shortened telomeres form sticky ends that stick and --> cell death
- shortened telomeres may "send" a signal to induce apoptosis
Telomere Synthesis
1.) Telomerase binds 3' flanking end of telomere that is complimentary to Telomerase RNA
2.) Bases are added using RNA as a template
3.) Telomerase relocates
4.) Second step is repeated
etc etc
Cellular Aging
- Cell functions decrease with age
- Cells have limited division potential, and may have a cellular clock (a way to count the # of divisions) leading to senescence, a terminally non-dividing state:
1.) Telomere shortening (telomerase stabilizes chromosome length, reactivated in immortalized cells)
2.) Clock genes (clk-1 in C. elegans)
Cell functions that decrease with age
- mitochondrial oxidative phosphorylation
- synthesis of nucleic acids, structural and enzymatic proteins
- capacity for DNA repair and nutrient uptake
Mechanisms of Cellular Aging
Cellular aging is the result of:
- progressive decline in the proliferative capacity and life span of cells
- effects of continuous exposure to exogenous influences that result in the progressive accumulation of cellular and molecular damage
- Genetic factors and environmental insults combine to produce the cellular abnormalities characteristic of aging
Calorie Restriction
How calorie restrictions prolong life span is not established. IGF, insulin-like growth factor.
Anti-Cancer Mechanism
In human cells the combination of short telomeres and suppression of TERT expression together provide an anti-cancer mechanism.
1.) (left) Oncogenic mutation can trigger senescence. Even if the cells divide some, they eventually stop and die.The end result is a benign lesion, such as a nevus.
2.) If the mutated cell slips past the checkpoints and continues dividing, eventually the cells reach a "Crisis Point" due to the lack of telomerase in human somatic cells, which brings the divisions to a halt.
State of Crisis
If oncogenic cells continue to divide telomeres progressively shorten until they become so short as to cause end-to-end fusions. Breakage-fusion-bridge cycles may ensue. This state (crisis) is a terminal one for the cell and the cell will eventually die.
Rise of the Immortal Cells
If either before crisis or during crisis telomerase becomes upregulated, then telomere erosion (due to replication) is stopped and an immortal cell clone arises
- Because of the many mutations that the cell has acquired by this time the cell may already be tumorigenic or may have acquired many of the mutations needed to reach that stage.
Antagonistic Pleiotropy
The same combination of short telomeres and lack of TERT expression that helps to protect against cancer could limit the ability of tissues to respond to injury and stress in old age.
If this is correct, the anti-cancer process may provide an example of antagonistic pleiotropy, the genetic event (repression of TERT) having beneficial effects in early life span and possibly negative effects in late life span.
Loss of Telomeric Sequences
Loss of telomeric sequences can be detected in vivo with advancing age. However, the decline is not linear; the most rapid losses are early and late in life.
Telomerase Theory
Telomerase activity is absent in most normal human somatic cells because of the lack of expression of TERT; TERC is usually present.
Without telomerase, telomere shortening eventually limits the growth of cells, either by senescence, in cells with intact cell cycle checkpoints (a G1 cell cycle block), or by crisis in cells with inactivated checkpoints (telomeric end-to-end fusions cause chromosome breakage and mitotic catastrophe).

In contrast, activity of this enzyme is readily detectable in germ cell and at lower levels in stem cells. Moreover, high levels of activity were detected in the majority immortal human cell lines that were derived from cancers or transformed in culture. These observations lead to the telomere hypothesis.