Author: David Sinclair
Topics: Longevity, cancer
All information is attributed to the author. Except in the case where we may have misunderstood a concept and summarized incorrectly. These notes are only for reference and we always suggest reading from the original source.
Contents
Part I: What We Know (The Past)
1. Viva Primordium
2. The Demented Pianist
3. The Blind Epidemic
Part II: What We’re Learning (The Present)
4. Longevity Now
5. A Bitter Pill to Swallow
6. Big Steps Ahead
7. The Age of Innovation
Part III: Where We’re Going (The Future)
8. The Shape of Things to Come
9. A Path Forward
Conclusion
Part I: What We Know (The Past)
1. Viva Primordium
Early Life
As the nucleic acids concentrate, they grow into polymers. These are the world’s first RNA molecules, the predecessors to DNA. When the pond refills, the primitive genetic material becomes encapsulated by fatty acids to form microscopic soap bubbles—the first cell membranes. Eventually the shallow ponds are covered with a yellow froth of trillions of tiny precursor cells filled with short strands of nucleic acids, which we now call genes.
Most of the protocells are recycled, but some survive and begin to evolve primitive metabolic pathways, until the RNA begins to copy itself. Now that life has formed, as fatty-acid soap bubbles filled with genetic material, they begin to compete for dominance (prey vs. predator).
The products of mutations, insertions, gene rearrangements, and the horizontal transfer of genes from one species to another—will create organisms with bilateral symmetry, stereoscopic vision, and even consciousness.
Repair and Survival Gene Circuits
The original circuit begins with gene A, which stops cells from reproducing when times are tough. On early planet Earth, most times are tough. The circuit also has gene B, which encodes for a “silencing” protein. This silencing protein shuts gene A off when times are good, so the cell can make copies of itself when, and only when, it and its offspring will likely survive. The genes themselves aren’t novel. Then, the gene B silencer mutates to give it a second function: it helps repair DNA. When the cell’s DNA breaks, the silencing protein encoded by gene B moves from gene A to help with DNA repair, which turns on gene A. This temporarily stops all sex and reproduction until the DNA repair is complete.
Cells that fail to pause while fixing a DNA break will almost certainly lose genetic material. This is because DNA is pulled apart prior to cell division from only one attachment site on the DNA, taking the rest of the DNA with it. If DNA is broken, part of a chromosome will be lost or duplicated. The cells will likely die or multiply uncontrollably into a tumor. Cosmic rays, which tear vulnerable DNA strands apart, will result in unmutated genes losing their genetic material.
Modern day humans carry an advanced version of the survival circuit that allows it to last for decades past the age of reproduction. While it is interesting to speculate why our long lifespans first evolved given the chaos that exists at the molecular scale, it’s a wonder we survive thirty seconds, our reproductive years, let alone reach the age of 80.
To Everything There Is a Reason
Immune T-cells continuously patrol our body, looking for rogue cells to identify and kill before they can multiply into a tumor. However, rogue cancer cells evolve ways to fool cancer-detecting T-cells so they can keep multiplying. The latest and most effective immunotherapies bind to proteins on the cancer cells’ surface. Although, fewer than 10 percent of all cancer patients currently benefit from immunotherapy.
Thanks to a combination of a BRAF inhibitor and immunotherapy, survival of melanoma brain metastases, one of the deadliest types of cancer, has increased by 91 percent since 2011. Between 1991 and 2016, overall deaths from cancer in the United States declined by 27 percent and continue to fall.
Medawar expounded on a nuanced theory called “antagonistic pleiotropy.” It says genes that help us reproduce when we are young don’t just become less helpful as we age, they can actually become detrimental when we age.
Thomas Kirkwood framed the question of why we age in terms of an organism’s available resources. Known as the “Disposable Soma Hypothesis,” it is based on the fact that there are always limited resources available to species—energy, nutrients, water. They therefore evolve to a point that lies somewhere between two very different lifestyles: breed fast and die young, or breed slowly and maintain your soma, or body.
Homo sapiens: Having capitalized on its relatively large brain and a thriving civilization to overcome the unfortunate hand that evolution dealt it—weak limbs, sensitivity to cold, poor sense of smell, and eyes that see well only in daylight and in the visible spectrum—this highly unusual species continues to innovate. It has already provided itself with an abundance of food, nutrients, and water while reducing deaths from predation, exposure, infectious diseases, and warfare. These were all once limits to it evolving a longer lifespan.
Crisis Mode
Peter Medawar and Leo Szilard proposed that aging is caused by DNA damage and a resulting loss of genetic information. Because of the fact that nuclear transfer works in cloning, we can say with a high degree of confidence that aging isn’t caused by mutations in nuclear DNA.
Leslie Orgel proposed the “Error Catastrophe Hypothesis,” which postulated that mistakes made during the DNA-copying process led to mutations in genes, including those needed to make the protein machinery that copies DNA. The process increasingly disrupts those same processes, multiplying upon themselves until a person’s genome has been incorrectly copied into oblivion.
Denham Harman came up with the “Free Radical Theory of Aging,” which blames aging on unpaired electrons that whiz around within cells, damaging DNA through oxidation, especially in mitochondria, because that is where most free radicals are generated.
Science has since demonstrated that the positive health effects attainable from an antioxidant-rich diet are more likely caused by stimulating the body’s natural defenses against aging, including boosting the production of the body’s enzymes that eliminate free radicals, not as a result of the antioxidant activity itself…
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