Saturday, April 7, 2018

Dementia is not a Normal Part of Aging

Dementia is not part of the normal aging process. Except that the main factor and predictor of dementia is age. Seeing my physician when I complain that I cannot walk/run/climb steps (choose your specific complaint here) the physician always says well “…its your age.”
And then with dementia, all of a sudden it becomes a disease. No one told me that my bad knee is due to a disease, they just put it down to age. But dementia, all of a sudden is not part of the normal aging process and yet age is the main contributory factor to dementia and Alzheimer’s disease.
As a scientist, I am perplexed.
How can one of the most prolific and frightening of disease not be due to old age and not part of the“normal aging process," when the main predictor is age?
Source: awareness_for_epilepsy/flickercreativecommons
Mission control: We are shutting down.
Brain: Shit.
Mission Control: We will start slow.
Brain: Do you have to?
Because it is time.
Time for what?
Time for other people to have a chance, it is our strategy to replace old generations with new ones
Perhaps a little bit longer
How long?
Shutting down
First we will close down recent memories
Make it easier to detach
I am worried, will it change me?
Yes. You are dying. You will no longer be.
Did you watch the Monty Python skit with the parrot?

Shutting down
Recent memory being erased
Any pain
No…but I am worried
Why? We are shutting down, there is no pain
I miss who I was
Who “were” you?
I don’t remember
You see, trust me, I know what I am doing, I am nature
Erasing further histories
More memories erased
Oh No…please stop
Stop What?
I do not know…but my wife/husband/daughter/son/lover/helper is worried…they keep asking me to return to who I was before
That is not possible
We are shutting down
Are you in Pain?
Shutting down
Please stop it is hurting THEM
Hurting whom?
Those that love me
Well, did you tell them that you are shutting down
Why not?
I did not want to hurt them
And they are hurting now because you did not tell them?
But it is reality, it is the truth and it is ordained by Nature
I know
So you didn’t tell them
They want me to be healthy
And alive?
Is that even possible
So why did they expect it with you?
Shutting down.
Removing social constraints
Wait wait
How do I deal with my family?
That is your domain…I deal with the timeline
Yes but can you help me?
Sure…ask many people have died before you? Does everyone expect you to die? How do they want you to die?
Shutting down

Note: A third of people with dementia regain their subjective quality of life, especially after settling into a nursing home. Main predictor of lowered quality of life is depression which is exacerbated by what Tom Kitwood calls  "malignant social psychology” where a caregiver’s relationship negatively affects the care-recipient. It is telling that  caregivers negatively evaluate the person with dementia's quality of life.

Some comparisons:
British Cancer Society Data:

 © USA Copyrighted 2018 Mario D. Garrett
Bosboom, P. R., Alfonso, H., & Almeida, O. P. (2013). Determining the predictors of change in quality of life self-ratings and carer-ratings for community-dwelling people with Alzheimer disease. Alzheimer Disease & Associated Disorders, 27(4), 363-371

Aging Is Not a Genetic Dustbin

Nature designed us to age for a reason.

Harmful genes that cause Huntington’s disease — a disease that attacks the neurons in the brain — only show up between ages 30 to 50, in some cases after the birth of offspring. There are many other diseases that accumulate later on in life, dementia being the main one. In 1952, Peter Brian Medawar tried to explain this by suggestion that older adults accumulate mutations and become a "genetic dustbin."

In Medawar's theory, there is no advantage to aging, nor are there any benefits for older people to live. Aging is simply the result of declining functions before death. This biological interpretation proved popular.

To explain aging, biologist George Williams in 1957 came up with the "antagonistic pleiotropy hypothesis" (named by Michael Rose in 1982). Pleiotropy is the phenomenon where one or a few genes control more than one trait. The antagonism part comes from the negative effect that emerges later on in life. As an example, testosterone in men might result in an attractive, muscular body in youth, as well as masculine features, such a deep voice and facial hair, but it also increases the likelihood of prostate cancer in older age, hence the antagonistic part of the pleiotropy. Although it is the positive aspects of the pleiotropic gene that are selected for in natural selection, the antagonistic aspect also sneaks into the gene pool. Aging is seen as an invisible cloak that sneaks bad genes into the gene pool by cloaking them under positive traits when young. Aging, in this view, has subverted the whole process of natural selection by disguising itself as a positive attribute in early life and then transforming — in a Jekyll-and-Hyde metamorphosis — into an aging liability. Somehow nature has been hoodwinked into allowing people to get old. Aging becomes a problem, a genetic dustbin of humanity. From here, it is fairly easy to see the approach: We need to cure aging, because nature made a mistake. The hubris of judging that nature made a mistake ignores that nature might have a different perspective from ours.

As a species, survival is nature's only ambition.

The only way that successive generations prosper is if they are a good fit with their environment. Each generation must survive long enough to create another generation. Nature keeps our genes immortal, and it has two extreme methods to achieve this single aim. One way is to produce an enormous number of offspring and hope that a few survive to then pass on their genes (known as r-selection). Another approach — one followed by humans — involves having few children whom we nurture until adulthood and beyond (known as K-selection). Therefore nurturing — protecting and supporting others — is our survival strategy, not competition.

Nurturing involves having things to teach and living long enough to be able to teach them. Which is why humans live long and have such a big brain; the two go together. Some 1.6 to 1.9 million years ago, our brain grew very fast; some say — not without contention — that brain expansion mirrors the development of cooking. Cooking, making food more easily digestible, resulted in greater availability of nutrients for the hungriest organ in our body — our brain. Nature engineered us to have both a big brain and longevity; they are intricately intertwined. We can see this through mathematical models that show a leap in predictive value when older people are included in the equation. Whether or not older people have a disease, the presence of older people in the family predicts longer-living children and grandchildren.

In the wild, most mammals die once they lose their ability to reproduce. Humans are different. We continue to live well past our capacity to reproduce, especially females. Is nature wrong again, or does nature have a special role for older people?

What the genetic dustbin proponents do not appreciate is that older people, especially grandmothers, have a statistically positive effect on their community. In 2004 while examining the “grandmother effect,” Mirkka Lahdenperä of the University of Turku, Finland, and her colleagues found statistical evidence that a grandmother has a decidedly beneficial effect on the reproductive success of her children and the survival of her grandchildren. Older adult humans promote the survival of the species. Unlike any other animal, we also transfer wealth, capital, and wisdom to our successive generations way past our reproductive period. When gene survival includes the broader community, then older people have a positive effect on their chances of survival.

By 1973, John Maynard Smith and George Price introduced game theory to evolutionary problems. While classic game theory sees players making rational choices on the basis of individual gain, evolutionary game theory posits an awareness of what others might do and the development of strategies to counter that decision. It is a social decision mode, not a purely individualist one. Maynard Smith argued that since everyone dies, evolution does not benefit individuals. Evolution is designed to benefit the community. In this interpretation, it explains that the strategy humans employ is based on benefits to the community, rather than benefits solely to the individual. Such a model fits the outcomes we see in reality. This insight was revolutionary and transformed the argument from one where aging is seen as a genetic dustbin to one where aging becomes part of a package for survival — a package that includes older adults contributing, in as yet unknown ways, to the promotion of our species.

There are instances where antagonistic pleiotropy of dementia has some really beneficial effects. For example, the Apolipoprotein E Variant 4 that is strongly associated with Alzheimer's disease might have beneficial aspects, such as reducing the rate of age-related macular degeneration, lower testosterone, and although there is no evidence of apoE isoform reducing infectious diseases, there is evidence that apoE could play a role in reducing our susceptibility to viruses, bacteria, and protozoan parasites. Such polymorphisms — having multiple expressions — are abundant in nature.

Despite this insight, in 2002, 51 renowned scientists — including such luminaries as Jay Olshansky, Leonard Hayflick, and Bruce  Carnes — published a position statement in Scientific American stating that “aging is a product of evolutionary neglect, not evolutionary intent.” Again, we are telling nature that it made a mistake, or at least was ignorant of the consequences. When Albert Einstein first confronted quantum physics, he said that “God does not play dice with the cosmos.” What is not reported frequently is the response from Danish physicist Niels Bohr: “Einstein, don't tell God what to do.” It seems that we are telling nature what it should do or how neglectful it is, rather than appreciating the biological system we call life as complete and perfect. We might guess at the intent of evolution — survival of our immortal genes — but we might not understand its methods.

Aging and having a big brain go hand-in-hand. It is nature’s plan for our survival. Older adults improve the survival of both their children and grandchildren. Looking at aging in a broader context allows us to view some of the wonders of nature. We have a lot to learn if we listen.

© USA Copyrighted 2018 Mario D. Garrett


Browning PJ, Roberts DD, Zabrenetzky V, Bryant J, Kaplan M, et al. (1994). Apolipoprotein E (apoE), a novel heparin-binding protein inhibits the development of Kaposi's sarcoma-like lesions in BALB/c nu/nu mice. J. Exp. Med. 180:1949–54

Bojanowski, C. M., Shen, D., Chew, E. Y., Ning, B., Csaky, K. G., Green, W. R., ... & Tuo, J. (2006). An apolipoprotein E variant may protect against age‐related macular degeneration through cytokine regulation. Environmental and molecular mutagenesis, 47(8), 594-602.

Hogervorst, E., Lehmann, D. J., Warden, D. R., McBroom, J., & Smith, A. D. (2002). Apolipoprotein E ε4 and testosterone interact in the risk of Alzheimer's disease in men. International journal of geriatric psychiatry, 17(10), 938-940.

Lahdenperä, M., Lummaa, V., Helle, S., Tremblay, M., & Russell, A. F. (2004). Fitness benefits of prolonged post-reproductive lifespan in women. Nature, 428(6979), 178.

Mahley, R. W., & Rall Jr, S. C. (2000). Apolipoprotein E: far more than a lipid transport protein. Annual review of genomics and human genetics, 1(1), 507-537.

Olshansky, S. J., Hayflick, L., & Carnes, B. A. (2002). Position statement on human aging. The Journals of Gerontology Series A: Biological Sciences and Medical Sciences, 57(8), B292-B297.

Pianka, E. R. (1970). On r-and K-selection. The American Naturalist, 104(940), 592-597.

Roselaar SE, Daugherty A. 1998. Apolipoprotein E-deficient mice have impaired innate immune responses to Listeria monocytogenes in vivo. J. Lipid Res. 39:1740–43

Smith, J. M., & Price, G. R. (1973). The logic of animal conflict. Nature, 246(5427), 15.

Williams, G. C. (1957). Pleiotropy, natural selection, and the evolution of senescence. evolution, 11(4), 398-411.

Tuesday, April 3, 2018

Jumping Genes and Longevity

We can see how genetics play a role in how long we live. Looking at different species and how long or short they live. But we do not know exactly how this works.
Alexander Graham Bell, the inventor of the telephone, was more passionate about aging. In 1900s he found that people that lived long had long-lived children. Whether this is due to genetics or to providing support to children, or both, remains undefined. But the connection is there. Sometimes despite having the best genes, bad luck just strikes. Take the example of Jeanne Louise Calment, who died at the age of 122 years in 1976. Despite having the best genes for longevity her family did not enjoy these positive attributes. Sometimes bad luck negates good genes when her daughter Yvonne, died at age 36 of pneumonia. Luckily, she left a son Frederic, who became a physician. He lived with his grandmother in her apartment. However, he also died early,  in a motorbike accident, at the same age as his mum 36 years old. Sometimes bad luck negates any genetic advantages.

Three classic experiments define how a genetic advantage results in living longer. The first experiment was conducted by Michael Rose who by allowing only eggs of older flies to hatch he found that the next generation lived longer. The new generation seemed to know that, similar to their parents, they need to live longer in order to reproduce. We also find this among humans. The older your mother was when she conceived you, the longer you will likely live. Unlike human, there is no nurturing for flies, so this effect is predominantly genetic.

The second type of experiment uses a naturally occurring disorder in a flatworm that produces less growth hormone which stunts their growth but they end up living much longer. Through a series of trial and errors Cynthia Kenyon at University California San Francisco managed to chemically knock out one of these genes in normal flatworms and in so doing nearly doubling their lifespan.

The third type of genetic observation is seen with mice, in particular the work done by Richard Miller and his infamous dwarf mouse called Yoda. Again, nature lead the way in showing us about the longevity advantage of having less growth hormones. In nature there are three types of dwarf mice that share this longevity characteristic: Snell, Ames and Laron dwarf mice. These mice live about three times longer than average.

By knocking out a gene to stop growing larger we could all live longer. Somehow the body knows that we need to live longer in order to be able to pass on its genes. Fortunately, we also have examples among humans as well. In a southern Ecuador community of 250 individuals that have Laron syndrome—causing a deficiency in primary growth hormone—although protecting them against disease, especially cancer, this apparent protection does not translate to living longer. This group unfortunately engage in risk behaviors in particular alcoholism that negate this genetic advantage.

No one wants to have a stunted growth in order to live longer. But what about having older parents to increased longevity? In biology, there is always a dark side—known scientifically as antagonistic pleiotropy.  This construct has plagued gerontological research since it posits when one gene controls for more than one trait (e.g. height) it is likely that one of these traits is beneficial (e.g. more athletic) while another side is detrimental (e.g. heart disease) to the individual later on in life.

The dark side is that we know that women having children at much older ages increases the risk of certain genetic problems. It has also been reported in 2018 by Boris Rebolledo-Jaramillo with Nottingham-Trent University UK, and his colleagues that children of older mothers face greater risk of developing diabetes, dementia and heart disease. As for older fathers, their kids are more likely to have dwarfism or Apert syndrome.  Newer research in 2012 by Augustine Kong at Reykjavik University, Iceland also suggest that there is an increased risk for autism and schizophrenia. There is a “goldilocks effect”, not too old and not too young, just right.

The surprising result in genetic research is the finding that as we age we are also changing our genes. It was always assumed that our genes unchanging and that they are given to us exclusively by our parents, period. But we are learning that we also add and modify our genes as we age. We acquire one percent of our genes from bacteria, fungi, viruses and archae—single cell micro-organisms.  Specifically, there are special molecules that reside in these cells that are there specifically to develop antibodies. They are not part of the cell but act as independent contractors. Known as “plasmids” they help us fight infections. If we are constantly being infected, in order to help us develop immunity, they somehow insert their antibodies-producing-genes into our DNA so we can develop this protection ourselves. Sometimes our own genes change position in our chromosomes so they gain higher priority. These genes are known as “jumping genes” or as “transposons.”

Such strange genetic behavior was first discovered by Barbara McClintock in the 1940s who was awarded the Nobel Prize for medicine in 1983. How plasmid and jumping genes do this remains an absolute mystery. Her work provided evidence that the composition of our genes—our genome—changes while we are living. The longer we live, the more likely that these new genetic improvements are transmitted to our children. So now we have figured out the method of how Michael Rose’s flies create a time stamp on their genes. Plasmids are at work throughout the aging process.

We develop immunity from the day we are born and some of these biological adaptations end up in our genes through the transfer of external genetic material. Our genes are more permeable than we once thought. We get genes not just from our parents but also from the environment. In addition, we also get genetic material from our twins in the womb and mothers get genes from their children. We find male chromosomes in mothers who had baby boys. We are a magnet for adaptive genetic material from our environment.

Barbara McClintock was also the first scientist to correctly speculate on the basic concept of how some genes can be switched on and off—known as epigenetics, epi meaning “above” controlling genes. Sometimes a defective gene (e.g. for diabetes or Alzheimer’s disease) can be switched off—through diet, exercise and mild trauma. As we age we pick up new genetic material and modify existing genes (epigenetics) before we pass these genes on to our children. Our lives are devoted to just this aim, making sure that our children are best prepared to the new world they face. As for bad luck, we have Pandora’s last remaining attribute: Hope.

© USA Copyrighted 2018 Mario D. Garrett

Bartke, A., Wright, J. C., Mattison, J. A., Ingram, D. K., Miller, R. A., & Roth, G. S. (2001). Longevity: extending the lifespan of long-lived mice. Nature, 414(6862), 412.

Garrett M (2017) Immortality With a Lifetime Guarantee. Createspace.
Kenyon, C., Chang, J., Gensch, E., Rudner, A., & Tabtiang, R. (1993). A C. elegans mutant that lives twice as long as wild type. Nature, 366(6454), 461.
McClintock, B. (1993). The significance of responses of the genome to challenge.
Rebolledo-Jaramillo, B., Su, M. S. W., Stoler, N., McElhoe, J. A., Dickins, B., Blankenberg, D., ... & Paul, I. M. (2014). Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA. Proceedings of the National Academy of Sciences, 111(43), 15474-15479.
Rose, M. R. (1984). Laboratory evolution of postponed senescence in Drosophila melanogaster. Evolution, 38(5), 1004-1010.