Medicine and Long Life

Why do we have medicine?

The answer is obvious that a child can answer. It is to help people. To help them live long and healthy lives.

 

But does medicine help us live long?

Some medicines do, like some vaccines, and most interventions help people live slightly longer.

 

But people still die. In the last hundred years, we have only improved life expectancy at older age by 6 years. The great improvement in medicine has been in helping children survive childhood. And this was not just medicine it was because of public health. We made great progress in getting clean fresh water to communities and an efficient sewage system. Laws that protect the air we breathe, the hours worked, and age restrictions. It is these factors that have improved life the most rather than medicine.

 

For older people medicine performs invasive treatment like heart operations, setting bone fractures, and through medication like controlling blood pressure, cholesterol, and diabetes. These help some older people live slightly longer and in better health. But only slightly.

 

Two researchers examined what happens if we completely cure some chronic diseases.

Like a magician with their magic wand, they eliminate all diseases. This can only be done statistically. Kenneth Manton eliminated one disease at a time. By eliminating all of these killer diseases at 87 years of age, people live an additional 5.7 years for males and 6.5 years for females.

 

Another researcher eliminated one disease at a time and saw the effect this had on people’s lives. Again, they did this using statistics. Douglas G. Manuel reported that by eliminating cancer they predicted that one fifth of the years of life gained would be spent in poor health—and increased cost. This is because living longer results in these people getting dementia or other chronic disease such as atherosclerosis. On the other hand, eliminating musculoskeletal conditions would result in a year of good health for women and under half a year for men.

 

Many diseases are waiting for us in older age. The healthiest people on earth, like the Blue Zone people, one of which is in Okinawa, tend to live a long life. They only get sick for a few days before they die. There is no long period of sickness. In the end, it is best to be healthy as death comes quickly and our bodies seem to know how to shut down effectively when we are healthy.

 

We need to understand why our bodies are designed to shut down. We need to study aging not just specific diseases.

 

Then I return the question. Does medicine help people live long and healthy lives?

 

The answer might be that medicine allows us to believe we can change our nature. But as yet we do not understand “aging” enough to be able to change very much, but we all take what we can get right now.

 

Don’t Blame the Chickens or the Foxes

I have been teaching a university course on programs for older people for ten years. Every year I get some of my bright students come back to tell me that the program does not run as it was intended. The program that they interned in (clinical experience) operated differently from how it should have operated. Most reduced their services to make a larger profit. At first, I thought that this was an anomaly, infrequent events. But it happened with many of my students across a broad range of services. At one time one of my students, an ex-military intelligence in his previous life, wrote a critique of hospice services. I thought it was intriguing so I followed up and did my own research. What I found was that not only was he right, but there were other ways that he missed that hospices use to increase their profit and unfortunately reduce their care to older adults that are dying. How can this be?

I then decided to research all services to older adults. The results were devastating but informative. In the United States, every service that is provided for older adults is designed to increase profit generation. Every single one and it did not matter if they were “for-profit”, or “not-for-profit.” There are only two ways to increase your profit, you either increase prices for your services, reduce the number of services, and/or reduce their costs. What I found is that across a broad range of services, the preferred method was to reduce services. This had the direct effect of causing harm to the older client. It is predictable institutional abuse at a level that is difficult to comprehend in a developed and rich country. But my task was not simply to document these abuses, but to find a solution. That is when I came up with a parable.

A farmer has a brood of hens, he sells their eggs. Next to the farm there were a couple of foxes with their own small family to feed. They often got into the chicken coop and helped themselves to some of the chickens. This continued to happen year after year. I ask my students, who is at fault? Are the chickens at fault as they remain defenseless? Are the foxes at fault since they attempt to feed themselves and their families? Or is it the farmer who is incompetent at protecting the chickens? You cannot blame the chickens or the foxes which is what the media does. They blame people for not doing their homework and checking up on nursing homes, or hospices when they are at their most vulnerable stage in their life. Others blame the medical and pharmaceutical companies for their greedy behavior as they need to make a profit to survive. No one seems to blame the farmer, the government. We have regulatory agencies that are designed to safeguard our citizens, but they are not doing their job. Like the farmer they are incompetent, but unlike the farmer who loses the sale of his eggs, these administrators still get a hefty paycheck every month. When I figured that the solution was to enhance and strengthen government regulatory agencies, I formulated a theory that explains all of this and predicts that these abuses will continue to increase unless we enhance oversight. The book was published as Critical Age Theory on Kindle an Amazon company. It was generating some interest, but not a blockbuster, but then one day my account on Kindle was deleted. No explanation was given and no apology for deleting more than 12 books I had online.

I remember a friend of mine Allen Smith, a Professor of Economics at Eastern Illinois University, who published about similar institutional abuse this time on social security. He published The Alleged Budget Surplus, Social Security, and Voodoo Economics and in 2000, The Looting of Social Security. All of these books were critical of what the government was doing. Strangely, the last of these books was stopped from being published. Someone bought the rights and stopped printing it. At the end of his life Professor Smith bought the rights back and made it public again. I distribute it free to my students.

Basically, he is saying the same thing, don’t blame the chickens or the foxes.

We must hold our government to a higher standard as their only job, their sole reason for existing, is to better the lives of its constituents, the chickens. If they are not doing that then they have relinquished their right to govern. Most radical governments now, the populists, want to overthrow all our institutions and start again. But that is wrong; these institutions developed for a reason. Just because they are not functioning properly does not mean that they cannot be fixed. Look at the motive for their inception and you will find the answer of how to fix them. Perhaps we can regain a system of care that promotes health and dignity in our last stages of life.

Many Dementias

My mother, of 86 years of age, has dementia. But we do not really know what that means. At first, she was slow and fragile; her short-term memory was shot. The doctors found high calcium in her blood and diagnosed a benign tumor in the hyperthyroid. They operated and she came back energetic, hyperactive, and hallucinating and talking with her dead mother and sister. Then she stopped eating and only drank when directed. She shrank in weight and became nearly catatonic. I met with the family as I predicted a quick death. I made the family take uncomfortable decisions.  We admitted her to a nursing home, and when my sister visited her four hours later and saw how anxious she was, mum came back home. She had an infection, ended up in hospital, and came back with a bloody nose. This abuse further solidified the primary caregiver, my younger brother's determination to protect mum by keeping her home. Then she started independently eating and drinking and while still looking for her dead relatives, she was getting more exercise than anyone else. She was physically getting stronger. She is in constant motion and repeats nonsensical words as though she is praying. From the moment she wakes up to the last breath at night she is in motion and vocal.

It seems there are layers of diseases, one waiting for the other to emerge and take priority, or both acting at the same time. Our categorization of diseases is not designed for older people with multiple diseases. Especially in psychiatric nosology, the idea of identifying specific diseases as distinct and independent diseases is nonsensical. As we get older the body ages across the board. A weaker heart, lung, muscles, skeleton, joints,  everything is diminished, some more than others. An emerging disease is not independent but can be an expression of all of these small deteriorations. My mother had a hyperthyroid tumor that created a calcium imbalance that slowed her cognition and body down, and she also had Lewy Bodies Dementia that created the hallucinations, and ontop of these she also must have Vascular dementia or Alzheimer’s disease that destroyed her memory. All of these were acting upon her at the same time. Then there are other neurological diseases that we still have not identified. Her improved eating habits cannot be explained by the dementia diagnosis alone. There are other changes that are hidden from us. Among 90-year-olds half of the cause of their dementia is unknown as there are so many other biological changes happening. When there are neurological deficits you can be certain that other diseases will emerge at the same time. Aging might be the most obvious factor, but that does not inform us on how to prevent or delay dementias as we cannot stop aging, but we can improve how we age.  Psychiatric nosology will eventually be dragged kicking and screaming through this terrain of older patients’ maladies until we finally admit that unless we start looking at the whole person, studying aging and not just diseases, we will never get a handle on dementia.

 

 

The Sixth Scientific Revolution Transforming Humans as Context Bound

All scientific discoveries contribute towards a better understanding of the universe that we live in. All of this knowledge reinforces our belief that the universe is orderly and that we are at the center. In contrast, there are some scientific revolutions that change how we think about ourselves, as humans. There are some discoveries that shake up our complacency about our importance in the grand scheme of the universe. Such scientific revolutions deserve special merit since by removing our self-centered bias, we get closer to a more universal truth about us and the universe we inhabit. Since our bias for self-centeredness is strong, so are these scientific revolutions. This paper examined five such scientific revolutions and postulates a sixth one that is emerging.

It is easy to define the first of such revolutionary thinking. Thales of Miletus 6th century BCE argued that we should observe physical events without assigning the cause to "god." He argued that there is an underlying process that causes the world to behave the way it does and that we need to work out these hidden processes rather than simply call it the will of god. This revolutionary thinking caused the birth of science. 

The second scientific revolution was by the 16th  century Nicolaus Copernicus., who in astronomy, removed the earth from the center of the universe and placed it among other planets revolving around the sun. By doing this Copernicus also moved humankind, and not just Earth, from being at the center of the universe and we attained a more peripheral place in the universe.

The third revolution that continued to move humans away from being the center of the universe was by the 19th century Charles Darwin. By publishing his The Origin of Species, Darwin pushed humans off the throne of superior beings and back into our mammalian lineage. The theory asserts that like all other beings, we evolved and share lineage with lower primates and other living things. Like all other animals, we are a work in progress. 

The 20th century brought the fourth revolution with Sigmund Freud who emphasized the concept of an unconscious mind. The notion of the unconscious can be traced back to ancient civilizations when dreams were considered to be messages from the gods. Even early philosophers like Plato and Aristotle explored the idea of unconscious mental processes. At the turn of the century, scientists such as Franz Anton Mesmer, Pierre Janet, Alfred Adler, and Carl Jung all worked on this unconscious mind that hid thoughts and decisions from consciousness and therefore from us. But it was Freud that took this concept further and developed a theory of the mind that argued that the unconscious mind is the primary motivator for behavior. The theory put forward the interpretation that we are not in conscious control of our actions.

The later part of the 20th century brought us the fifth revolution with Albert Einstein and his colleagues who developed the idea that the matter is relative. This theory of relativity postulated that gravity and acceleration are indistinguishable, that mass and energy cause gravity and time to curve, and that the acceleration of massive objects causes ripples in spacetime. All of this makes our natural world less rigid, and our reality is determined by context by the locality of the event. 

These theories have one thing in common, what we believe about who we are, as humans on Earth, is not true. That we are part of a larger universe, that we evolved from other life forms, and that how we see the world is relative to our position in the universe. There is a locality in our reality. Where we are is important. The sixth revolution takes all these concepts of moving humankind away from being to the center of the universe as it argues that even our body is part of such a locality. That the biological and chemical context that we reside in determines how we function and behave. This environmental physiology, where the environment changes our physiology proposes that although we see ourselves as sovereign entities we are in reality a conglomerate of different processes that are influenced by the world we live in. As such, under this environmental physiology, there is no “us” and “them”, no “me” and the “environment”, as both converge. Environmental physiology highlights the malleability of our physiology. Richard Rorty said this beautifully: “…had physiology been more obvious psychology would never have arisen…if the body had been easier to understand, nobody would have thought that we had a mind.” (p 239). 

Most of the developments in environmental physiology highlight human intervention in modifying the body. However, equally impressive, and more instructive, is the evidence showing how nature itself manipulates our bodies. By observing how nature manipulates and modifies our bodies, scientists have learned new techniques that emulate nature. Despite the impressive nature of these technological advances, the underlying theme is how nature has such a powerful force on us by constantly changing and modifying our bodies. 

Technological advancements include: 

Genetic Engineering and Recombinant DNA technology led to the creation of genetically modified organisms (GMOs); 

Polymerase Chain Reaction (PCR) amplified specific DNA segments, making it possible to study and analyze genes and their functions more easily;

Gene Sequencing has led to insights into genetic variations, disease mechanisms, and personalized medicine; Stem Cell Research that promoted regenerative medicine, and tissue engineering; 

CRISPR-Cas9 Gene Editing technology allows precise modification of DNA sequences, making gene editing faster, and more accessible; 

Synthetic Biology of new biological components, systems, and even entire organisms, with varied applications; 

Omics Technologies advancements in how molecules interact within living organisms resulting in contributions to genomics, proteomics, and metabolomics; 

Human Embryonic Stem Cells that repair specific damaged organs; 

Induced Pluripotent Stem Cells (iPSCs) takes adult cells and reprogram them to an embryonic stem cell-like state; Immunotherapy such as immune checkpoint inhibitors and CAR-T cell therapy, harness the immune system to target and eliminate cancer cells; 

Microbiome Research that evaluates the bacterial makeup of the stomach enabling the development of probiotics; 

Nanobiotechnology that promotes targeted drug delivery, biosensors, and imaging technologies; 

Neuroscience and Brain Imaging such as functional MRI (fMRI), provide insights into the brain's structure and function; and 

Artificial Intelligence and Machine Learning in Biology accelerate data analysis, drug repurposing, protein folding predictions, and diagnostics.

Such advancements, impressive as they may seem, are just a small insight into the way that nature itself behaves. Scientists have used this limited knowledge about what we know about how the environment influences our bodies to experiment with coming up with technologies in a short span of time. But it would express a special kind of hubris if we forget to add how nature itself manipulates “us.” There is a vast number of unknown-unknowns, but what we have learned provides enough substantiating evidence to affirm that our context, our environment, changes us. This knowledge has taught us that we are more malleable and receptive than we believe. Nature manipulates our bodies on a daily basis. The sixth revolution in science is knowledge about how nature influences and changes our genes, how genes are expressed, how our body processes food, how we uptake nutrients, how we age, how we think, and how we behave.

Natural influences on the body include: 

Epigenetic modifications that determine the expression of specific genes, subdue some and excite others without altering the underlying genetic sequence. Environmental factors, such as diet, stress, and exposure to toxins, can lead to epigenetic modifications, influencing health outcomes; 

Plasmids, are small, circular DNA molecules in humans that come from bacteria and archaea and become inserted in human cells. They often carry genes that provide selective advantages, such as antibiotic resistance, leading to the spread of antibiotic resistance genes; 

Horizontal Gene Transfer (HGT) is the transfer of genetic material between different organisms, typically bacteria can exchange genetic material-- share beneficial genes, such as antibiotic resistance genes--through processes like conjugation, transformation, and transduction; 

Jumping Genes (Transposons) are segments of DNA capable of moving within a genome. They can "jump" from one location to another, potentially affecting gene regulation and function, playing a significant role in shaping the human genome's evolution and diversity; 

Retroviruses are individual strands of RNA viruses that can multiply into human cell DNA by integrating their genetic material into the host genome; 

Human endogenous retroviruses (HERVs) are remnants of ancient retroviral infections in our ancestors' germ cells; MicroRNAs (miRNAs) play a crucial role in post-transcriptional gene regulation by binding to messenger RNAs (mRNAs) and either degrade them or inhibit their translation into proteins;

Dysregulation of miRNAs has also been linked to the progression of diseases, such as cancer and neurodegenerative disorders; 

Prions are misfolded proteins that can induce the misfolding of other normal proteins, leading to a chain reaction that can propagate disease in the brain and nervous system, such as Creutzfeldt-Jakob disease in humans and bovine spongiform encephalopathy (mad cow disease) in cattle; 

Endocrine Disruptors such as Bisphenol A (BPA) are chemicals that can interfere with the endocrine system, disrupting hormonal regulation reproductive and developmental abnormalities; 

Gut bacteria break down complex carbohydrates, producing essential vitamins, and regulating immune responses affecting weight, inflammatory bowel disease, and allergies. which can influence our metabolism, immune system, and overall health; 

RNA editing such as Adenosine-to-inosine (A-to-I),  is a process that alters the nucleotide sequence of RNA after transcription. It is modified by enzymes called ADARs (adenosine deaminases acting on RNA and can impact gene expression, particularly in the nervous system, and is essential for normal brain function;

Genetic recombination is the process of exchanging genetic material between two DNA molecules during meiosis (cell division), homologous chromosomes exchange genetic material through crossing over. It occurs during sexual reproduction and contributes to genetic diversity; 

DNA Repair Mechanisms correct errors that arise during replication or as a result of external factors. For example,  Nucleotide excision repair (NER) is a DNA repair pathway that removes and replaces damaged nucleotides caused by exposure to ultraviolet radiation;

Hormesis where exposure to low or moderate levels of a stressor or toxin can result in a beneficial or stimulatory response, leading to improved health, resilience, or longevity. In other words, "What doesn't kill you makes you stronger." Hormesis can occur in various biological contexts such as Radiation Hormesis, Exercise Hormesis, Caloric Restriction Hormesis, and Phytochemical Hormesis.

All of these processes, and many others that we still have not discovered, interact. For example, exposure to low or moderate stressors that trigger hormetic responses may lead to epigenetic modifications. A hormetic response could activate specific cellular pathways that, in turn, influence epigenetic modification that changes how some genes are expressed (Vaiserman, 2011). The relationship can also be reciprocal where epigenetic modifications can regulate genes involved in stress response pathways or cellular repair mechanisms. Specific epigenetic changes may enhance or dampen hormetic responses, affecting the magnitude of the beneficial effect elicited by the stressor. In some cases, epigenetic changes induced by hormetic responses may be heritable. Offspring could inherit the altered epigenetic marks from their parents, potentially passing on the beneficial effects of hormesis to subsequent generations (Xavier, et al, 2019). Both hormesis and epigenetics have been linked to aging and longevity (Vaiserman, 2011). Moderate stressors that induce hormetic responses are believed to contribute to lifespan extension in various organisms. Epigenetic changes, on the other hand, can influence the aging process by regulating genes involved in cellular senescence and age-related diseases.

The Sixth Revolution in science moves humans from a homo-centric view of the world to one that places humans as more malleable and porous, allowing for the context, and the environment, to influence and change us.

REFERENCES

Rorty, R. (1979). Transcendental arguments, self-reference, and pragmatism. Transcendental arguments and science: Essays in epistemology, 77-103.

Vaiserman, A. M. (2011). Hormesis and epigenetics: is there a link?. Ageing research reviews, 10(4), 413-421.

Xavier, M. J., Roman, S. D., Aitken, R. J., & Nixon, B. (2019). Transgenerational inheritance: how impacts to the epigenetic and genetic information of parents affect offspring health. Human reproduction update, 25(5), 519-541.

TECHNOLOGICAL INNOVATIONS

Genetic Engineering and Recombinant DNA Technology:

Watson, J. D., & Crick, F. H. (1953). Molecular structure of nucleic acids: A structure for deoxyribose nucleic acid. Nature, 171(4356), 737-738.

Cohen, S. N., Chang, A. C., Boyer, H. W., & Helling, R. B. (1973). Construction of biologically functional bacterial plasmids in vitro. Proceedings of the National Academy of Sciences, 70(11), 3240-3244.

Polymerase Chain Reaction (PCR):

Mullis, K. B. (1986). The unusual origin of the polymerase chain reaction. Scientific American, 262(4), 56-61.

Saiki, R. K., Scharf, S., Faloona, F., Mullis, K. B., Horn, G. T., Erlich, H. A., & Arnheim, N. (1985). Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for diagnosis of sickle cell anemia. Science, 230(4732), 1350-1354.

Gene Sequencing:

Sanger, F., Nicklen, S., & Coulson, A. R. (1977). DNA sequencing with chain-terminating inhibitors. Proceedings of the National Academy of Sciences, 74(12), 5463-5467.

Venter, J. C., Adams, M. D., Myers, E. W., Li, P. W., Mural, R. J., Sutton, G. G., ... & Zhu, X. (2001). The sequence of the human genome. Science, 291(5507), 1304-1351.

Stem Cell Research:

Evans, M. J., & Kaufman, M. H. (1981). Establishment in culture of pluripotential cells from mouse embryos. Nature, 292(5819), 154-156.

Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663-676.

CRISPR-Cas9 Gene Editing:

Doudna, J. A., & Charpentier, E. (2014). Genome editing. The new frontier of genome engineering with CRISPR-Cas9. Science, 346(6213), 1258096.

Jinek, M., Chylinski, K., Fonfara, I., Hauer, M., Doudna, J. A., & Charpentier, E. (2012). A programmable dual-RNA–guided DNA endonuclease in adaptive bacterial immunity. Science, 337(6096), 816-821.

Synthetic Biology:

Gibson, D. G., Glass, J. I., Lartigue, C., Noskov, V. N., Chuang, R. Y., Algire, M. A., ... & Venter, J. C. (2010). Creation of a bacterial cell controlled by a chemically synthesized genome. Science, 329(5987), 52-56.

Khalil, A. S., & Collins, J. J. (2010). Synthetic biology: applications come of age. Nature Reviews Genetics, 11(5), 367-379.

Omics Technologies:

Aebersold, R., & Mann, M. (2003). Mass spectrometry-based proteomics. Nature, 422(6928), 198-207.

Lander, E. S., Linton, L. M., Birren, B., Nusbaum, C., Zody, M. C., Baldwin, J., ... & Bouvrette, S. (2001). Initial sequencing and analysis of the human genome. Nature, 409(6822), 860-921.

Human Embryonic Stem Cell Research:

Thomson, J. A., Itskovitz-Eldor, J., Shapiro, S. S., Waknitz, M. A., Swiergiel, J. J., Marshall, V. S., & Jones, J. M. (1998). Embryonic stem cell lines derived from human blastocysts. Science, 282(5391), 1145-1147.

Yu, J., Vodyanik, M. A., Smuga-Otto, K., Antosiewicz-Bourget, J., Frane, J. L., Tian, S., ... & Thomson, J. A. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science, 318(5858), 1917-1920.

Immunotherapy:

Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., ... & Urba, W. J. (2010). Improved survival with ipilimumab in patients with metastatic melanoma. New England Journal of Medicine, 363(8), 711-723.

Maude, S. L., Laetsch, T. W., Buechner, J., Rives, S., Boyer, M., Bittencourt, H., ... & Wood, P. (2018). Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine, 378(5), 439-448.

Microbiome Research:

Turnbaugh, P. J., Ley, R. E., Hamady, M., Fraser-Liggett, C. M., Knight, R., & Gordon, J. I. (2007). The human microbiome project. Nature, 449(7164), 804-810.

Qin, J., Li, R., Raes, J., Arumugam, M., Burgdorf, K. S., Manichanh, C., ... & Wang, J. (2010). A human gut microbial gene catalogue established by metagenomic sequencing. Nature, 464(7285), 59-65.

Nanobiotechnology:

Farokhzad, O. C., & Langer, R. (2009). Impact of nanotechnology on drug delivery. ACS Nano, 3(1), 16-20.

Sweeney, S. M., & Wooley, K. L. (2005). Self-assembling polymers for gene delivery: from laboratory to clinical trial. Advanced Drug Delivery Reviews, 57(15), 2075-2087.

Neuroscience and Brain Imaging:

Ogawa, S., Lee, T. M., Nayak, A. S., & Glynn, P. (1990). Oxygenation-sensitive contrast in magnetic resonance image of rodent brain at high magnetic fields. Magnetic Resonance in Medicine, 14(1), 68-78.

Kandel, E. R., Schwartz, J. H., & Jessell, T. M. (2000). Principles of neural science (Vol. 4). McGraw-Hill, Health Professions Division.

Artificial Intelligence and Machine Learning in Biology:

Alipanahi, B., Delong, A., Weirauch, M. T., & Frey, B. J. (2015). Predicting the sequence specificities of DNA- and RNA-binding proteins by deep learning. Nature Biotechnology, 33(8), 831-838.

Topol, E. J. (2019). High-performance medicine: the convergence of human and artificial intelligence. Nature Medicine, 25(1), 44-56.

NATURAL INFLUENCES

Epigenetics

Jirtle, R. L., & Skinner, M. K. (2007). Environmental epigenomics and disease susceptibility. Nature Reviews Genetics, 8(4), 253-262.

Plasmid 

Modi, S. R., Lee, H. H., Spina, C. S., & Collins, J. J. (2013). Antibiotic treatment expands the resistance reservoir and ecological network of the phage metagenome. Nature, 499(7457), 219-222.

Horizontal Gene Transfer

Thomas, C. M., & Nielsen, K. M. (2005). Mechanisms of, and barriers to, horizontal gene transfer between bacteria. Nature Reviews Molecular Cell Biology, 6(9), 711-721.

Jumping Genes

Chuong, E. B., Elde, N. C., & Feschotte, C. (2017). Regulatory evolution of innate immunity through co-option of endogenous retroviruses. Science, 351(6277), 1083-1087.

Retroviruses

Grandi, N., & Tramontano, E. (2018). Human endogenous retroviruses are ancient acquired elements still shaping innate immune responses. Frontiers in Immunology, 9, 2039.

MicroRNAs

Bartel, D. P. (2009). MicroRNAs: target recognition and regulatory functions. Cell, 136(2), 215-233.

Prions

Prusiner, S. B. (1998). Prions. Proceedings of the National Academy of Sciences, 95(23), 13363-13383.

Endocrine Disruptors

Diamanti-Kandarakis, E., Bourguignon, J. P., Giudice, L. C., Hauser, R., Prins, G. S., Soto, A. M., ... & Zoeller, R. T. (2009). Endocrine-disrupting chemicals: an Endocrine Society scientific statement. Endocrine Reviews, 30(4), 293-342.

Gut Bacteria

Sender, R., Fuchs, S., & Milo, R. (2016). Revised estimates for the number of human and bacteria cells in the body. PLOS Biology, 14(8), e1002533.

RNA Editing

Nishikura, K. (2010). Functions and regulation of RNA editing by ADAR deaminases. Annual Review of Biochemistry, 79, 321-349.

Genetic Recombination

Hunter, N. (2015). Meiotic recombination: The essence of heredity. Cold Spring Harbor Perspectives in Biology, 7(12), a016618.

DNA Repair

Lehmann, A. R., & McGibbon, D. (2006). Xeroderma pigmentosum. Orphanet Journal of Rare Diseases, 1(1), 27.

Radiation Hormesis, 

Macklis, R. M., & Beresford, B. (1991). Radiation hormesis. Journal of Nuclear Medicine, 32(2), 350-359.

Exercise Hormesis, 

Ji, L. L., Kang, C., & Zhang, Y. (2016). Exercise-induced hormesis and skeletal muscle health. Free Radical Biology and Medicine, 98, 113-122.

Caloric Restriction Hormesis, 

Turturro, A., Hass, B. S., & Hart, R. W. (2000). Does caloric restriction induce hormesis?. Human & experimental toxicology, 19(6), 320-329. 

Phytochemical Hormesis

Son, T. G., Camandola, S., & Mattson, M. P. (2008). Hormetic dietary phytochemicals. Neuromolecular medicine, 10, 236-246.

Summary of "Politics of Anguish" (book)

Chapter 1 : The Creation of a New Disease

Feared more than cancer or heart attack, Alzheimer’s disease has now capture people’s fears and worries. But finding how the disease develops and then progresses has eluded scientists. Going back in time when Dr. Alois Alzheimer observed the new disease provides some evidence and clues to why we have failed to control this disease. 

Finding that there were some clamping of neurons, plaques and tangles, in the brain was not a new discovery. But the creation of this new disease relied on other issues at the time. It relied on a belief that certain people are inferior, that politically it was beneficial for the Munich clinic to define this new disease to compete with the Prague clinic, and the belief that old age is a dustbin of medical problems. The motivation for creating this new disease was not only scientific but also political in 1900 Germany.

Alzheimer’s disease stayed dormant until the 1950s when American scientists started looking at diseases of older age and searching for cures. By the 1970’s the zeal of searching for a pill to cure all maladies, including Alzheimer’s disease, blinded researchers and they lost focus on how the disease develops and progresses.

The foundation of the science is however unstable. The initial observations that Alzheimer observed, the plaques and the tangles, were common, not just for Alzheimer’s disease but also for many other diseases including neurosyphilis (Dr. Alzheimer’s speciiality.) The plaques and the tangles did not directly cause the disease as many people had these in their brain but never developed the disease. This is a story of how the most frightening disease in the world was created by a perfect storm. Today we are left with disorganized research and a 100% failure of finding a cure or a way of slowing the disease. The future looks bleak and we can only understand this present situation by looking back in history. 

Chapter 1: The Creation of a New Disease 

What Alois Alzheimer identified more than a century ago was an early onset dementia that was important, but not for the reasons he and his clinic director Emil Kraepelin presumed. Initially Alzheimer saw a pattern that fit the biological proof in support of the clinical observations—plaques and tangles and early-age of onset. Subsequent researchers fell into the same pattern: a habitual research method of finding proof.  We now know that these criteria are not discrete enough to both define and predict Alzheimer’s disease. 

And we know this because of the ambivalence of the neurobiology, of how the plaques and tangles relate to the disease. Questions arose from the beginning, which to this day we still cannot answer, because there is a problem with what we are trying to explain. Other than familial Alzheimer’s disease, the remaining paths of the disease  are random and cannot be measured reliably. 

Clinicians remain dependent on prognostic tools that are unreliable. There remains a healthy discussion about the validity of the diagnosis. Research on the clinical features of Alzheimer’s disease is based on combining many short–term, specific, small, cross-sectional study samples. As a result research is fragmented and confusing. Whether by choice or chance we are told that the salvation to this disease will come from a cure. But this construct contains a falsehood. A similar search for laboratory proof is currently being undertaken for Alzheimer’s disease. But how did this state of disorganization in research come about? To find an answer we have to move away from science and look closer at the politics of the disease.

Chapter 2: Politics 

Only tenuous evidence existed that separate Alzheimer’s disease from senile dementia. The current consensus among researchers is that Alzheimer’s disease and senile dementia are indistinguishable in contrast to Alzheimer’s belief. 

The imperative to promote a more biological psychiatry was a paradigm-changing endeavor in the 20th century. Alzheimer’s disease played a major role in contributing to psychiatry’s reliance on neurobiology, biology, chemistry and genetics. Because of its prominence, Alzheimer’s disease will likely play a large role in the future of psychiatry. This prediction is being realized with the introduction in 2010 of the NIH-sponsored Research and Domain Criteria (RDoC) which integrates biomarkers, genomics and clinical observations to define both normal and abnormal behavior. Alzheimer’s disease is the proving concept for this new U.S. federally-funded nosology.

The fact that in the 1900s the Munich laboratory competed with the Prague laboratory was also a factor. Even today, biomedical research remains a highly competitive field. Nowadays biomedical research seems particularly prone to fraud because of the level of competition among clinics. Back in the 1900s Kraepelin understood this competition which played a significant role in the scramble to be the first to define Alzheimer’s disease. The belief that some people are different from others because of genetics may have also helped Kraepelin assert the distinction between Alzheimer’s disease and senile dementia. The eugenics argument is rarely mentioned in the literature despite the importance of the philosophy in academic circles at the turn of the 20th century. The fact that most of Kraepelin’s perceived competitors were Jewish—at a time when Jews were considered inferior by some groups—could not have been a small consideration. As an example, Fischer’s obscurity and his early demise in prison because of his Jewish beliefs, is another indication of the strong undercurrent of racist beliefs at the time. Although Fischer’s insights into dementia have now been vindicated his legacy remains obscured.  But of all these factors, the central issue was—and still is—ageism. If Alzheimer could not argue that this new disease was not just for older people, there would be no classification of a new disease. 

Diseases of old age are not news. For most of the past century, it was assumed that old age is a stage of dying and therefore associated with decrepitude. Older adults were meant to have diseases and die. No medical interest exists to subvert  such inevitability. The reason why Alzheimer’s disease gained traction is because, for the first time, the disease was affecting younger people. The importance of these prejudices are present with us today.  

The birth of Alzheimer’s disease as we know it today, was more than simply a new clinical observation it also had political overtones. It reflected the stereotypes of the time. In 2011, the NIA changed the definition of Alzheimer’s disease to allow the pharmaceutical industry to experiment with a clinical disease before it becomes diagnosed (pre-clincial). But this is creating costly and divergent research. After a century of research we are still unclear about the diseases that come under Alzheimer’s diseases and sadly, we are not closer to understand what causes Alzheimer’s disease or its many variants. 

Chapter 3: Disorganized research

Several major sources of confusion remain in Alzheimer’s disease research. The primary confounder comes from the fact that we do not know what Alzheimer’s disease is, and even if we did, we cannot reliably diagnose it, either clinically or neurobiologically. Even if we accept the NIA’s pre-clinical stage of Alzheimer’s disease, the validity and reliability of pre-clinical data is poor at best, and contradictory at worst.  

The varied causes of cognitive diseases are not well understood. Gaining knowledge about chemical, neurological and biological pathways and processes does not directly contribute to our understanding of behavioral or clinical disorders. After more than a hundred years of research, there remains a lack of understanding of whether one disease has different expressions—Alzheimer’s disease, Lewy Body Dementia, Vascular dementia—or whether different disease processes lead to the same pathway of expression—Alzheimer’s disease caused by physical trauma, bacteria, virus or vascular disease.  Therefore, it is difficult to make distinct and accurate diagnoses. 

The concept that Alzheimer’s disease is not a disease but a syndrome provides an impetus for more research by examining the process of the disease, rather than investing all research efforts in finding a cure. The cause/s of the disease are still unknown. Correlational studies might imply causation but this is psychology, not science. Researchers need to admit that the results are puzzling because we are working from an incomplete theory—one that we need to update.

The second source of confusion comes from the great variance among older adults—heteroscidasticity. Even among identical twins, this drift can result in one twin getting Alzheimer’s while the other escapes. This relates to epigenetic changes that influence both brain plasticity and neurogenesis. This variance, that increases among individuals as they age, will continue to dilute the linear association between a specific neuropathology and its expression, especially among older adults. 

Although researchers look for genetic markers that will eliminate all these epigenetic or environmental factors, so far The Alzheimer’s forum has identified more than 1,395 studies working on 695 genes that account for up to 0.5 percent of Alzheimer’s disease. If 695 genes account for half of one percent of Alzheimer’s disease, then even if researchers can identify and manipulate all of these genes the disease will not be cured. This criticism, that genetic studies cannot explain all the variance of Alzheimer’s disease, can be applied to the search for biomarkers, both biological and chemical. The only challenge to the current expression of biological determinism is the fact that there is no competing paradigm to guide research. 

The deduction is that confusion becomes a ploy, not a failure or an expression of incompetence. Confusion as a method allows a small research group connected with the NIA to dictate and continuously change the meaning of the disease. Regardless of the intention, the result is obvious. Confusion and uncertainty have created great fear. This confusion unfortunately spills over into clinical practice as well, affecting patients, their families and their rights as citizens. Alzheimer’s disease is over-registered and over-diagnosed with consequential wasted health care costs and undue stress to the family. Perhaps the confusion is that we did not understand that our fear of Alzheimer’s disease has become a neurobiolgical playground where we have feverishly worked ourselves into a research cul de sac. 

Chapter 4: Research cul de sac

The inductive method of observing a disease to learn what people have in common creates a false syllogism—a fallacy. Just because everyone with dementia has the neuropathology, we cannot logically argue that everyone with the neuropathology will have dementia.  Because science should also be based on a deductive model, where theory directs the line of investigation, researchers need to conduct more theory-driven hypothesis testing. A mounting body of evidence does not support the theoretical construct that a linear causal pathway exists between a biomarker, causing MCI that then matures into a dementing illness. Infact a systematic review of the literature agues for broad use of techniques to counter MCI. Partly for this reason, we see very little deductive reasoning in research on Alzheimer’s disease, although it is evident in neurobiological studies. The two worlds of neuroscience and clinical services that are evident in Alzheimer’s disease remain distinct, separate and divorced. 

The lack of validity, across a whole spectrum of issues in Alzheimer’s disease research is a negative statement. The anomalies point to the necessity of expanding the concept of biomarkers to explain how they might be moderated or mediated by other, as of yet unexplored factors. It could be that the plaques and tangles are like scarring on a wound—indicative of a trauma but serving as a protective feature. Clearing the scab will not change the underlying trauma and might even be detrimental to the healing process. We are leading to potential situations where despite being competent and having normal memory and behavior, a patient might still be diagnosed with dementia. Such is the mission of the Research Domain Criteria. We need to resist this biological determinism mode of thinking, which is becoming more and more prevalent, and which has negative repercussions on our relationship with our medical and legal institutions. Alzheimer’s disease is playing a major role in persuading researchers to adopt such a system of biological determinism. 

The relationship between Alzheimer’s disease and changes in the normal aging processes need to be distinguished. One possible clue could be the speed of attrition. Even though we still do not know enough about normal aging processes, sudden attrition might be indicative more of disease pathology. A longitudinal perspective is crucial for elucidating such a distinction. Despite all the ambiguity surrounding the disease, we see the disease as very real and very frightening. We remain fixated on it because it feeds a very personal and intimate fear. We accept a fanciful process of causation because it is safe to assume that we know how to approach the problem and possibly find a cure. But if we reinterpret the philosophy behind our fear of Alzheimer’s disease we might arrive at some basic understanding that might help in defining a new, badly-needed research paradigm. 

Chapter 5: Philosophy of Alzheimer’s disease

People need a consistent, stable sense of self throughout their lifetimes, including when they self-project into future situations. This is the essence of being, of Dasein. A purely neurobiological model of cognition cannot explain some basic anomalies in research. For example, a woman misdiagnosed with Alzheimer’s disease nevertheless makes herself believe that she has the disease; men who pretend to be 20 years younger become younger; and clusters of people who have very long lives age well without Alzheimer’s disease but these clusters are found only in small geographic areas. All these events can help us understand the dynamics of our reality, our being. This is the study of ontology. Such preoccupations have also received validation from neurological studies. The next frontier involves accepting a broader definition of being—of Dasein—that includes others, the environment and our geography. It is not biological determinism, because the biology/genetics is determined by the environment and our interpretation of that environment. We own the biology as well as the environment.

There is a cultural condition of the fear of Alzheimer’s disease. That there is an element of self–limitation, of  a self-fulfilling prophecy and it may be time to question our own mindsets. Older adults report that their fear of Alzheimer’s disease has increased from the second most feared disease to the most feared disease. Fear of dementia is now so strong that there is a new term: “Dementiaphobia”. This alone represents significant condition of our Dasein—both in terms of what we care about (gaining ownership of beliefs and ideas), the Facticity (we have no control over whether we get Alzheimer’s disease), and also in our personal projections of the future (the likelihood that we are going to get Alzheimer’s disease). 

In this context, fear has already limited our ability to deal with negative cognitive episodes. This is a constant in our lives. Many opportunities exist to misinterpret cognitive decline as both long-term and Alzheimer’s disease-related. Fear is nuanced. A family member suffering Alzheimer’s disease creates a template for us to follow, a mindset, especially if we provide care for them. There is significant deterioration in the health of caregivers when compared to a similar group of non-caregivers. Caregiving becomes more stressful the longer one does it. The stress does not stop when the care recipient dies. Also seen in the  “widowhood effect”—where the surviving spouse dies soon after their partner—exemplifies how intimate relationships define what is important in life. Death following spousal death among older adults has been estimated at between 30 percent and 90 percent in the short term, and around 15 percent in the long term. 

Not only are we led to believe that Alzheimer’s disease is random without any control, caring for a loved one with Alzheimer’s disease magnifies this as a likelihood in our future. This association might contribute more to familial dementia then genetic factors. Because we learn by experience we are sensitized to look for “signs” of the disease that we then use to promote the likelihood that we will get the disease. “We have nothing to fear but fear itself” is the new watchword for Alzheimer’s disease. 

Chapter 6: Complexity Theory of Dementias

The brain is the most complex organ in the universe. Nothing else is more complex. The simple theory that two misfolded proteins by themselves create a breakdown of thinking is not accurate. Theories based on the Amyloid Cascade hypothesis are incomplete. Emerging evidence points to a more complex process. There are many possible causes of dementia. The initial injury might or might not progress.  The neurological disease might or might not affect cognition. 

These considerations are valid and have been left out of the new research agenda. Our conventional reliance on genetic causes is similarly simplistic. Accepting the evidence that external injury (viral, bacterial, biological, chemical, environmental, behavioral) can initiate dementia reframes the disease as a public health issue. In this case, we can alleviate or minimize some of these causes. We are already doing this with head trauma in sports with new protocols for diagnosis and treatment. Other injuries that are shown to contribute to dementias should be similarly addressed. By addressing potential traumas, perhaps we could eventually prevent most of the initial causes of the disease. Such an approach opens the door to positive, creative prevention. Adjusting the focus to include the study of multiple causes also brings the disease squarely into the public health field. 

A central puzzle of dementias is the penumbra. Also, a feature of stroke, the penumbra or shadow that accompanies the surrounding dead tissue in the brain might explain why some stroke victims experience the growth of the penumbra that eventually leads to dementia. The process of penumbra raises radical scientific questions about the progression of dementias and whether or not the neuropathology can be contained. 

Perfusion (blood circulation) and the role of vascular conditions play a major role in dementias. Emphasizing the roles of an active lifestyle, healthy diet, and awareness of vascular issues moves the discussion further into the public health realm. Within Complexity Theory, the concept of the brain functioning as a machine is incorrect. Even dementia patients learn new things, and they sometimes forget things then remember them, or have episodes of clarity. How can we explain this fluctuation through neuronal death? Appreciating that parts of the brain can continue to grow, switch capacity from left to right and back to front, and vice versa, and acknowledging that cognition might be an assimilation of different systems within the same brain, will help researchers ask more incisive questions about the role of the brain. 

Acknowledging that the brain is always changing, neurons and glial cells constantly die and get replaced, where more than 30,000 proteins constantly misfold and get degraded, where constant injuries to the brain are accommodated, where memories are constantly re-imaged and prioritized, where cognitive functions are shifted from one area of the brain to another, all of these events define the daily functioning of our brain. The question that needs to be asked is why does this constant maintenance stops or becomes overwhelmed?

Science will benefit from a resurgence of sociological and philosophical discussion about the role of cognition in the mind, the distinction between mind and brain, and the concept of self. All these broad discussions have been rejected in preference for the more simplistic explanation. So far, after a century of confusion, it is time to stop repeating the same mistakes in the hope of coming up with new results. We need a new methodology that might provide different results. 

Chapter 7: Synthesis

A more inclusive approach allows diverse literature to be included rather than ignored. The body as a sovereign entity a self-willed, independent, exclusive and free agent is an illusion. Ample evidence now shows that our body—meaning our brain and body—not only respond to external activity but also mirrors these activities. External influences—of which we are unaware most of the time—affect how we think, behave and feel. Social constructs, memes, and stereotypes affect us because we internalize and operationalize them within us.  There is no impermeable barrier between our external environment and our body; an illusion of the mind creates this duality. No better example exposes this illusion than dementias and aging. The crescendo of fear of dementias affects us. We often live trapped in a world where fear dictates our future.  Fear of dementia as represented by Alzheimer’s disease now represents perhaps the penultimate disease meme of the 21st century.  To combat this we need to expand our study of dementias to include social and psychological factors, otherwise, we will remain in our current research cul de sac. We need to shift from a hypercognitive model to a caring model. Care might lead to a cure. 

Chapter 8: Epilogue

This is as far as science can take us. Criticism of dementia research dictates a number of changes that need to be made at the Federal level to promote a healthier and more inclusive scientific debate. Scientists need to be very sure of what they are studying and to emphasize the validity and reliability of their subject matter. Such recommendations are necessarily abstract, nuanced, and academic. But on a more personal level, I can identify the basic parameters of the data and conjecture how I see this Complexity Theory apply at an individual level. This is not prescriptive in any way but the start of a discussion away from the neurobiology. 

Recommendation for self-help

Summary and Class Discussion Points

Older Smell

On their return from visiting a nursing home, my children when we were in kindergarten happily shared with me their impression that the residents “smell.” A nursing home is not the best place to get to know older adults, but the stereotype remains. There are even some fancy scientific theories to explain why this is so. We know that taste and smell diminish with age, but that older people also have a distinct odor is worth exploring.

Visiting Japan, one is immediately faced with the strict culture of washing and bad odor is frowned upon. The Japanese even have a distinct name for the body odor of older people Kareishu. After conducting a poll of 150 men and women, the Japanese Shiseido Group found that odor from older people is the second most offensive scent behind bad breath. We will return to this study later on. 

Body odor in humans is determined by various factors, including genetic background, physiological conditions, behavioral patterns, food ingestion, and disease types, but most often there is a stereotype that it relates to getting old. The theory is that older people smell because of their aging biology. One theory suggests that aging causes hormonal imbalances resulting in more lipid acid in our skin. And as skin matures, its natural antioxidant protection decreases, resulting in greater oxidation of this lipid acid resulting in Nonenal. The smell of this chemical compound is similar to oil that goes rancid when left out. This chemical is more common among people over 40 years of age. Another biological theory is that the major contributor is the bacterial activity in skin gland secretions. Numerous skin bacteria help produce smelly substances and as we get older this bacteria seems to be more common. 

It could also be related to diet. In 2017 Jun Nishihira with Hokkaido Information University and his colleagues reported that eating a mushroom extract (Champignon) was found to improve body smell, as well as bad breath and smelly poo. The idea that perhaps we can counteract this Kareishu was explored by Dae Youn Hwang with Pusan National University, Republic of Korea, and his colleagues. They found that extracts of Spiraea Japonica—a deciduous, perennial shrub native to Japan—reduced the odor of older adults. 

Developing products to counteract Kareishu opens the market to businesses making money off older people’s fears and stereotypes. Shiseido Group at one point developed a perfume "Harmonage Fragrance" specifically formulated to neutralize older people’s body odor. Then there is the line of anti-age-stench soaps by Mirai Clinical that this time uses persimmon extract as a natural deodorizer. The issue is not that body odor changes with age, it does, the issue is whether this smell is bad. 

Researchers have shown that the body odors of some animals—including mice, black-tailed deer, otters, owls, and rabbits—change with age and that animals can distinguish their young and old peers by smell. Even people can tell the difference between old and young otters and rabbits by how they smell. 

Older people might smell differently from younger people, but this is not always a bad smell. We know for example, that some frail older people experience difficulties in mobility and getting washed, but those that are still functional and maintain good hygiene might be different.

Johan Lundström and his colleagues at the University of Pennsylvania stitched absorbent pads into the armpits of T-shirts and asked volunteers of different ages to sleep in the shirts for five consecutive nights. During the day, the volunteers stored the T-shirts in sealed plastic bags; avoided spicy foods, cigarettes, and alcohol; and showered with odorless shampoo and soap. After the fifth night, blindfolded volunteers rated the pads and found elderly people's odors both less intense and less unpleasant than odors from young and middle-aged people. Middle-aged men had the most unpleasant odor while the odors of middle-aged women were judged to be the most pleasant. Old people's smell was often instantly recognizable and not necessarily in a bad way. The result from this study is different from the earlier study by the Shiseido Group. But then again if I am selling a fragrance I want to create a market of smelly older adults so that they will buy my fragrance. In reality, older adults might smell differently but not in a bad way. The lesson is how easily we accept the negative stereotype of older people smelling.

Kenkou to Yoi Tomodachi  4

References

Nishihira, J., Nishimura, M., Tanaka, A., Yamaguchi, A., & Taira, T. (2017). Effects of 4-week continuous ingestion of champignon extract on halitosis and body and fecal odor. Journal of Traditional and Complementary Medicine, 7(1), 110-116.

Kim, J. E., Choi, Y. J., Lee, S. J., Gong, J. E., Seong, J. E., Park, S. H., & Hwang, D. Y. (2022). Evaluation of Deodorizing Effects of Saccharina japonica in 10-Month-Old ICR Mice Using a Novel Odor Marker Associated with Aging. Evidence-Based Complementary and Alternative Medicine, 2022.

https://www.scientificamerican.com/article/old-person-smell/

Mitro, S., Gordon, A. R., Olsson, M. J., & Lundström, J. N. (2012). The smell of age: perception and discrimination of body odors of different ages. PloS one, 7(5), e38110.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038110