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| Notes on the Nobel Conference 2004, St. Peter, MN | | Date Created: Oct 26, 2004, 03:09 PM |
 40th Nobel Conference Oct 5,6 2004
Gustavus Adolphus, St. Peter
The Science of Aging
Day One morning:
Speaker One: Dr. S. Jay Olshansky - "Human by Design" U of Ill. Chicago
Has a 1.5 million dollar bet with Dr. Steven Austin (began at $150, but by the time collected interest will have increased it 10,000 times) that someone alive in 2000 will be alive in 2150. "Nothing in biology makes sense except in the light of evolution" ( T. Dozhensky??)
Topic: Why, when, and how do we age?
Aging is defined as the passage of chronological time.
Senescence defined as the passage of biological time. Showed photograph of twins with different senescence.
Life-span is defined as the observed duration of life for an individual.
Life expectancy defined as the average of number of years of life remaining for a population.
Maximum life-span defined as the longest lived member of a species. The world record for life-span has been increasing. In the age of pestilence and famine there were oscillating birth and death rates. But in the last 100 years lower mortality rate at birth. Ref to his article in 1993.
Distribution of death of females in 1900 contrasted with 2000. Presently no one is older than 122. The maximum age has increased about 7 years in the last 100 yrs.
DNA is immortal (germ lines, that is), but evolution determined that its carriers became mortal.
Note - there is a graphic symbol for immortality - similar to infinity symbol
Starting from the work of Darwin, senescence theory was started by Sir Peter Medawar (based upon mutation accumulation), George Williams (antagonistic pleiotropy) Tom Kirkwood (disposable soma). Senescence is only found in animals that we protect, or us. Otherwise animals die from predators or environmental causes. All organisms have genetic programs for growth, development and reproduction, but none have programs for death (see C. Kenyon for biomolecular view). Life-span sectored by pre-reproductive period, reproductive period, and post reproductive period. Natural selection is only active in the reproductive period. Duration of life is calibrated to the onset and length of a species' reproductive window. Life-span of a mouse is 1,000 days, dog 5,000, elephant 26,000, human 29,000, sea turtle, 55,000, bowhead whale 77,000. Aging or senescence is an accident of surviving beyond the warranty period for living machines. Senescence is a byproduct not a program. Surgery, chemotherapy, etc. puts light on the "shadow of senescence". It lengthens life but doesn't change the nature of senescence. You have to modify the bedrock (the DNA) to change senescence.
The next longevity revolution will focus upon two forces. His book, "Redesigning humans" depicts how he would redesign the morphology of humans to last into longer years of wear. The article in Scientific American "If humans were built to last" appeared in 2001 and 2003. "Human by Design" is forthcoming in American Scientist Jan. or Feb. of 2005 and revised his vision. Two views of body design: 1) Michelangelo - perfection, 2) Darwin - anatomical oddities. Both agree that time reveals the "flaws" in a body design that was not intended for long-term use. Species that share so many common characteristics in terms of genetics, physiology and morphology have life expectancies and maximum life-spans that differ so widely.
Project Life-quest. Dan Buttoner (from MN). It is an educational program for Children. He and a team are going internationally to evaluate centenarians and super centenarians. You can extend life, but he says the process of aging has never been modified. He asks, "As long as we can make people live longer, why should anyone care whether life extension occurs by slowing aging or reducing fatal illness?" Jay says the difference is critical. If we only address fatal manifestations of aging, we may see a dramatic rise in frailty and disability among the elderly. You only add years to the end of a life span, not to the beginning or earlier (again, see Kenyon).
Q&A:
What is the difference between aging and disease? Alzheimer's has an ICD code doctors use for categorizing illness to the government, suggesting it is a disease? On average, humans would only gain 10-15 years to their lives if stroke, cardiac/heart ailments, and cancer were eliminated completely. Alzheimer's elimination would gain only 19 days of longevity!
- If we're programmed for reproduction why do females live longer than males? 75% of reproduction accomplished by humans by age 32. Actually most males and females have similar in reproductive success and mortality before middle age.
- Does oxidation affect aging? Body sows the seeds of its own destruction as soon as life begins.
- In senescence does the 2nd law of thermodynamics apply? No, we are open systems, not closed systems.
- What about studying the mitochondrial haplotypes (gene in mitochondria) in Italian and Sweden populations? We really don't have fundamental knowledge about the nature of longevity.
- Can you predict age? A 90 year old ran 3:40 in the recent Twin Cities marathon. So who knows?
- In his new article in Scientific American he redesigned the human knee to bend backwards and added a tail for balance. Someone asked what would a chair look like then? You just lean back on your tail, no need for chair!
Day One afternoon:
Speaker Two: Dr. Leonard Hayflick, U of California, San Francisco. "Hay-flick Limiting" is rule that cells can replicate 50 times or so, then they die. Cells are not immortal. Lineage of cells eventually dies. Interestingly, normal cells frozen then thawed remember how many times they divided (or doubled) before freezing. He also developed human cell strains. This strain WIi38 made possible billions of immunizations without the risk of developing vaccines contaminated with virus strains from animals. His papers are some of the most referenced in all of biology.
There are four aspects of the finitude of life. He will discuss key terms, 3 major concepts, why aging occurs, why it's not a disease, role of genes, what research on aging is and is not.
Four aspects : determinants of longevity, aging, age-associated diseases, death. The first 3 are often confused. Confusion results in missfunding, public policy disputes, and misinterpretation of research findings. Trees are often cited as the oldest organisms on earth, but he contends humans are older. In redwood trees (3K years old) or bristle-cone pine (5K years old) only its dead cells are that old. Their live cells are less than 30 years old, so anyone over 30 is older than the living parts of those trees. But we slough away our dead cells and trees keep them as their architecture.
Since only protected animals age, aging is a sociological phenomenom. Biological aging is the random, systemic, loss of molecular fidelity that eventually exceeds repair or maintenance capacity and occurs after reproductive maturity in animals that reach a fixed size in adulthood. Alligators, deep sea fish, etc. age so slowly it's almost imperceptible. This progressive loss of molecular fidelity increases vulnerability to age-associated diseases. Miss-folded proteins give rise to age related diseases. Some are subtle such as cataracts, hearing loss, loss of muscle mass, etc. and are not life threatening. But immune system losses, and amyloid fibrils cause Alzheimer's, Huntington's and Parkinson's. These are fatal.
All complex biological molecules have evolved energy states sufficient to maintain fidelity until most of the animals they constitute reach reproductive success. If not, the species would vanish. All molecules include those that compose repair, turnover and maintenance processes. Mean time to failure of humans is 78 yrs. Molecules change because some of their properties are thermodynamically unstable. E.g., the effect of hydrogen, covalent and Van der Waals bond twisting, angle bending, and bond lengthening. Examples of damage include glycation, inactivity due to conformational alterations, aggregation, precipitation and denaturation, amyloid formation, rate changes in degradation, synthesis, etc.
Premises for longevity:
1) Energy for fidelity must be retained from conception to reproductive success.
2) Selection for redundant physiological capacity in vital organs. More redundancy means more resiliency.
3) Excess physiological capacity gained after reaching the age of reproductive success is what indirectly determines longevity.
Conclusions:
1) Redundancy at sexual maturation governs potential additional survival time.
2) Genome directly determines events from conception to sexual maturation. Post reproductive longevity is determined indirectly.
3) Potential longevity is determined by fidelity of molecules.
4) ?
5) Molecules must first exist free of age (they start at zero age).
6) ?.
Why aging is not a disease:
1-3) ?
4) Aging happens only in feral animals protected by humans,
5) Aging increase the vulnerability to death.
6) At molecular levels, gradual deterioration occurs similarly in animate (organisms) and inanimate objects (like cars).
Longer age can be attained if diseases can be resolved: Removing specific causes of death adds specific number of years to life: cardiovascular: 6.73 years, cancer: 3.4 years, accidents: 0.92 yrs. All of these are years added at birth. Slightly less # of years added at age 65. Hayflick doesn't believe genes determine aging. Aging is spontaneous and genes are unnecessary to drive a spontaneous process. Aging is not a disease, but the process increases vulnerability to disease. What is research on aging? It embraces all aspects of the finitude of life. Biogerontologists do research on the fundamental biology of aging which is only one small part of longevity. No large research effort is directed toward the understanding of fundamental biology of human aging. The greatest risk factor for the leading causes of death is the aging process.
Q&A - Only recently have we paid attention to animals that don't reach a fixed size in adulthood. Sea Bass is a patagonian tooth fish. We don't know their age, but 100 years or older is frequent for the ones that are sold at the fish market. They are endangered.
- Cancer cells are immortal, unlike normal cells. Due to telemers being sealed. Cancers use telemerase and replace that end section at end normally lost during replication. Normal cells lose a layer of telemers during each replication.
- No evidence that antioxidants pass the gut to reduce "rusting" in the cells. So taking antioxidants have limited positive affect. Vitamin E does get to the brain, but no antioxidants have been shown to retard the aging process.
- Stem cells may replace organs, but are not a fountain of youth.
Speaker Three: Dr. Dennis Selkoe - Harvard Medical School
Alzheimer's can be treated as a disease. Other protein folding diseases like Huntington's and Parkinson's and Lou Gherig's can also be treated, though progress is slow. Alzheimer's is the most common cause of dementia. It affects 3-4 million Americans, over 20M worldwide, all races and ethnic groups. It accounts for over $100B in annual cost in the U.S. alone, and there is no effective treatment. Senility is senile dementia. It is a progressive mental failure after age 65. AD is the most common of over 20 causes for dementia. AD accounts for ~60% of dementia in US. Progresses over 5-20 years and is fatal. It shortens life expectancy by some 30-60%. At age 75, 4.3% of the population have AD, 8.5% at age 80, 16% at age 85, 28.5% at age 90. 360,000 new cases per year. 1.14 million cases by 2050. AD causes inflammation (microgliosis and astrocytosis), degenerates selectively, and creates deficits in acetylcholine, glutamate, somatostatin, serotonin, GABA, dopamine, norepenephrine, etc.
We have no idea why neurons next door to fibroid tangles and dead axons are unaffected. Tangles inside neurons are composed of altered forms of the microtubule-associated protein called "tau". Amyloid plaques outside cells are composed of the 40-42 long amino chain amyloid beta proteins. 12 year olds with Downs also have amyloid deposits. APP is beta-amyloid precursor protein. Long and stick like.
Alpha-beta (?ß) is the damaging section cut from APP and this may be a normal process, not a disease. What causes the problem is an imbalance between ?ß production and clearance (removing them). Four genes are related to AD predilection. All are related to increased ?ß peptide production. APP and Presenilin (gamma-secratase) come together in the cell. Presenilin threads its way in and out of the neuron membrane 8 times. Every cross causes potential for problems. ?ß production decreases when the Presenilin aspirates are mutated. Presenilin does the final cut of APP. There are antibodies to ?ß and an ?ß vaccine has made it into trials. Immunizing animal with the peptides that create the plaques keep the plaques from forming. It slows cognitive decline but a series side effect is that it causes inflammation in 6% of the patients, so trials were halted a year ago. But a new version of the vaccine understands why the inflammation was caused. Trials of this new vaccine started Nov 03.
Q&A - Counter-viewpoint is the "Taoist" (tau protein) persuasion. Neuron causes it, but ?ß required. Suggests a stronger role for tau.
- What makes AD a disease and not part of aging? Some indication shows a buildup of protein causes a precursor to AD and this might trigger a cascade effect.
- Aluminum as a contributing cause to AD? Aluminum does not induce tangles, but might cause another aggregate. In some patients, Aluminum was found to be elevated, but upon replicating the study it didn't pan out. There is currently little evidence that aluminum is involved in AD.
- Lesions occur more often in cognitive areas of the brain than in motor function areas. Thus cognitive function more effected than motor skills. A MRI will show shrinkage in motor areas, but that is not specific to AD.
- AD is being seen as a mix of genetics and environment. Inheriting 1 allele heightens chances of getting it greatly, 2 or more increases that risk greatly. Prevention: select your parents carefully (!), take vitamin E, possibly ibuprofen to reduce inflammation (breaks the cycle of protein aggregation somewhat). Epidemical studies say exercise and mental activity hold it off. See the study by Shodden and the Mankato nuns.
Day Two morning:
Speaker Four: Laura Carstensen - Stanford University School of Geriatric Psychology. Adding 30 years to life-span over the past 150 years is one of the greatest achievements of humankind. How to keep ourselves mentally, emotionally and physically fit into old age is a discussion worth having. Implicit theory of gerontology is that things get worse or decline as you age. Processing capacity does decrease as the mind ages (this can be measured several different ways). However, world knowledge increases or at least stays stable. This can be shown through studies of patients recalling Shipley vocabularies, antonym vocabularies and synonym vocabularies.
"Testing the limits paradigm". Young people outperform elders on memory tests. But both improve with practice, though younger people improve faster. When you emphasize that "this is a MEMORY test" in your instructions, this results in a bigger young/old difference, but when instructions given describe tasks as "learning" there is only a small difference. In positive conditions people do better than when negative conditions are given in instructions. So motivation counts. Likely due to self-image of the elderly.
Motivation affects perception of time. Socio-emotional Selectivity Theory. Because chronological age is associated with time left in life, goals change across the life span. Goals are always set in temporal contexts. When focusing on the present and your time is known to be limited, people invest in sure things, deepen relationships, savor life. They know what's important in life and live in the moment. In these situations the future becomes irrelevant. So time perception rather than age is the most important factor.
Theoretical postulates:
1) Perceived constraints on time motivate people to pursue emotionally meaningful goals.
2) Goals influence cognitive processing.
3) Pursuing emotional goals is good for emotional health.
Social partner options (given the choice of whether to spend time with the author of book you just read, or a recent acquaintance, or a member of your immediate family). Older people choose familiar social partners if time is open ended. If time is constrained (e.g. you're about to move away to another state) both old and young choose familiar partners highly. If its found that you could live for another 20 years (no time constraint) older people choose familiar partners less often than young. (Forget my family, I'm going to try new experiences!).
Memory for emotional narrative increases as you get older, because it's more relevant to them. Older people strongly prefer emotional print and TV ads (text referencing ones you love or "special moments") But this goes away if the timeframe is open ended. Elders remember emotionally meaningful slogans much better than knowledge-related slogans. Positive images (warm and fuzzy) and negative images (snakes, slime) are recalled equally by youth and elders, but positive images are remembered more strongly than negative images. So is this visual information not encoded or not perceived in the first place? With MRIs they found that brain activation when first shown positive images were recalled with the same results. But scans show elders don't really think about negative images. They just don't register. Amygdala scans show they attend to positive images, not to negative images (actually there is negative activity for both neutral or negative images). Elders also orient toward positive faces (smiles), and away from negative faces (fear or disgust). When people of any age try to recall their past more accurately (going for informational content), their recollections are more negative than the real event. When they try to recall it emotionally, they're more positive. Elders remember positive emotional images better than the young do. From age 12-34 negative emotions in day-to-day life slide downward. From 35-64 there is a minimum frequency of negative emotions in day-to-day life. Above 65 the frequency of negative emotions go up.
Q&A - Longitudinal studies are less misleading than cross-sectional studies. In other words, you should study the same people at age 20 and at age 70. More accurate than studying people of different ages at the same time. E.g. With cross-sectional studies it would be accurate to report that: In Florida, most people are born hispanic and die Jewish. Kind of funny but you get the idea.
- Her new book about increasing life-span over the past century, "The Unexpected Years"
- Call for scientific effort on later years.
- Compared to younger people, elders have lower rates of all other mental afflictions like phobias, except for dementia.
- Because of their preference to positive images, elders are less likely to respond to negative political ads.
Day Two afternoon :
Speaker Five: Dr. Cynthia Kenyon - U of San Francisco. Genes that establish longevity. Nematode "C. elegans" used for study. Adults have 957 cells in body. Found three (possibly four) pathways that influence longevity.
These are the genes that control aging (note that the other speakers used the term aging differently and Hayflick claimed that aging isn't controlled, it just happens). Life-spans: mouse 2 years, canary 15 years, bat 50 years. Similar animals like gray squirrels, 25 years. yet the rat is only 3 years.
Michael Class found a mutant worm that lived 50% longer than others. So first they changed the genes at random. Found that mutations that damage a gene called daf-2 double the worm's life-span. Nematodes have 20,000 genes (humans have 30,000). This added longevity was not just time tacked on to the end of their lives, but they seems to age more slowly. Seems to be an evolutionary traits to deal with times when food is in short supply. Worms raised with little food enter a "dauer" state where they don't eat. To enter this state they must be before adulthood. If no daf-2 gene they become dauer even if food is present. When does daf-2 activity act to promote dualism? To damage action of the gene they use RNAi. Gene acts on the worm soon after hatching (whether dauer conditions or not) then again in the adult to control rate of aging. Daf-2 encodes a hormone receptor. When hormones are placed at the receptor it tells the cell to age. Aging is therefore controlled, it doesn't just happen.
This hormone receptor is very similar to receptors for insulin and IGF-1 (insulin-like growth factor). When the hormone receptor is removed for nematodes, fruit flies and mice they all live longer. When removing the insulin receptor for fat tissue mice lived longer and stayed thin. The same genes aren't active in all tissue. The genes for the eyes that let you see aren't active in the heart, and vice versa. In same way these control genes affect the activities of many genes but may be more or less active. Are these genes contributing to the life span of daf-2 changed animals? Looking at the mutant worms, their activity is increased in long-lived animals. They really look youthful. Many genes less active in the long-lived mutants also influence longevity but are not control genes - they are more "downstream" from the control genes and influenced by them.
What do these "downstream genes" do? Some produce antioxidants, or chaperones (helper proteins), or antimicrobial, or metabolic genes, or novel genes. Worms have better protection against infection with chaperones. Daf-2 "conducts" other components that all work together. This system evolved from response to harsh environmental conditions. Dauer worms are also less sensitive to heat, radiation, etc. Huntington's protein put into normal C. elegens forms aggregates, but formation of aggregation is delayed in long-lived mutants. Long-lived mutant mice are more resistant to cancer as well. Long-lived flies are more resistant to heart failure. Animals are biologically younger, so therapeutic applications are possible. In other words, you can treat them after birth. To test this they added chemicals that inhibit the chaperone proteins. Inhibiting the chaperones caused aggregates to form in younger animals and to form in longer-lived mutants. So absence of these downstream genes can accelerate disease in normal or mutant animals.
Reproduction and aging: These studies show that life-span can be extended without inhibiting reproduction. Upcoming article in Nature on guppies. No tradeoff between life-span and reproduction. If one alters daf-2 gene plus you remove the reproductive system in the same animals, the worms live 6 times as long. Some super-long lived worms are ten times as long-lived.
Human longevity: changes in genes during the evolution from single celled animals have increased life-span by >1000 fold. Rates of damage and deterioration versus rates of maintenance and repair probably determine the rate of aging (remember, the germ lineage is immortal). We probably live so long because elders are wise; possibly also to help take care of grandchildren. Probably not much selective value in living much longer. Lack of role models if you live too long!
- Ethical implications: Living longer could result in overpopulation, too many elderly, no room in job market?
Q&A - They've tested many of the genes and some affect mitochondria by inhibiting respiration. But altering that gene must be done in childhood, so unlike daf-2 it changes the hormone system in adults. This mitochondrial gene operates differently from those affected by food restriction (caloric restriction) in adults. There are perhaps 4 systems (upstream controllers) for controlling long-livedness.
- Environmental triggers (expression of genes)? Those triggers affect smell and taste. If you knock out those olfactory genes they live longer. Implication is that if you have no smell or taste you could live longer!
Speaker Six: Dr. Peter J. Whitehouse, Department of Cognitive Science at Case Western Reserve U. -
Personally, he abandoned the distinction between work and play. He loves his work. Is an ethicist and a theologian. Gave a disclosure about his grants and funding and consulting fees from over the years. The language we use and the social, political and economic forces associated with our words are powerful. Integrating liberal arts and sciences (mentions a program called SAGES0). Says the university circle is the world's most powerful learning environment. Also has a focus on reinventing aging, that is, life span perspective.
Co-gnos "together knowledge". Unity of knowledge.
- Dementia ("impaired mind"). Alzheimer's (AD) named in 1906. In standard medical/scientific view, AD is not normal aging. Believes that genetic approaches to AD will be most effective. Conceptions of AD:
1) Biological - strongly genetic condition.
2) Clinical - a part of the narrative of the affected individual's life linked to the healer through relationship based care.
3) Cultural - AD is a cultural concern.
Have we created a terror in our society around AD? When labeled with AD we put those patients in another box. Would we all develop AD if we lived long enough? There are different levels of impairment. Mild cognitive impairment has no dementia, but is at-risk for AD. Such mild impairment exhibits relatively intact activities, yet they rate below the standard deviation for impairment for the same age group. What are the clinical implications of MCI: (mild cognitive impairment). Person says: I may or may not have it, may or may not get it. Partner says: I care for them, am cared by them, or, I do not and will not give care to them. Society says: this means we are going to have more impaired elderly. Technically, before MCI there is a pre-MCI. There is also "Aging Associated Memory Impairment" (pre-pre MCI). How do you talk about these states outside of our culture? Some languages can make the distinctions, but some don't. If you take MCI, translate it to Chinese, then back translate it from Chinese you get "loss of wisdom".
Wisdom can be seen as "executive functions" with a special dose of emotions and values, including purpose, planning, monitoring. Wisdom is both collective and individual. Everyone has it to one degree or another and can enhance it in themselves and others.
Bioethics was invented in 1970 by Dr. V.R. Potter. It is a bridge between science and humanities. It is an interdisciplinary profession emergent from biology, law, humanities. Focus is upon the goal of world-wide sustainable quality of life (QOL). It is a search for necessary wisdom and contains a personal ethical credo.
He posits a transformative power of therapy. Electronic reminiscence therapy (??). Memories of the theatre (??). NIA funded book club. The Intergenerational School is a school he helped develop has an Intergenerational Literature Collection, and staffs elderly as reading mentors for kids. Intergenerational Storytelling is a program within the school. It is another method for creating collective wisdom.
Overstated and provocative conclusion - the most important cognitive challenge is to recognize that experts may divide the world of AD into boxes that have the potential to terrorize people. Wiser solution is to realize that AD is a form of brain aging which will affect us all.
Q&A - Try aromatherapy, touch therapy. Many different ways to stimulate the brain. Some evidence that AD patients can recognize and read the faces of others. Some evidence that community volunteerism also delays onset.
- Unfortunately, not all caregivers are equally competent at giving care and even trained doctor are capable of ignoring the patient and addressing caregiver even with the patient in the room.
- Children of AD patients tend to have phobias about AD. When tested objectively and found to not have impairment, they are still concerned about impairment. If they are still concerned he asks them to take away 5% of what they do to reduce their anxiety about AD.
- Jay Olshansky doesn't take vitamins. The randomness of the aging process made him realize that length of life is less important than how he feels. He has a moderate diet and exercises daily.
- Hayflick: none of the experts know of any intervention to slow or stop aging. But many things can be done to delay or postpone aging.
- Jay: if Cynthia (Kenyon) is right, modifying a gene may cascade into both desirable effects like longer life, but also undesirable effects like forced retirement, housing shortage, etc. But in the absence of an aging "magic bullet", interventions like activity and exercise appear to help.
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