Lifespan by David Sinclair
A) Introduction: A Grandmother’s Prayer
A.1) We are living much longer than ever. But not much better.
As a species, we are living much longer than ever. But not much better. Not at all. Over the past century we have gained additional years, but not additional life—not life worth living anyway.
What those final decades look like:
Ventilators and drug cocktails. Broken hips and diapers. Chemotherapy and radiation. Surgery after surgery after surgery. And hospital bills; my God, the hospital bills. We’re dying slowly and painfully.
What if we could be younger longer? Not years longer but decades longer. What if those final years didn’t look so terribly different from the years that came before them?
A.2) David Sinclair's scientific background
I’m fortunate that after thirty years of searching for truths about human biology, I find myself in a unique position.
I’m a professor in the Department of Genetics and codirector of the Paul F. Glenn Center for the Biological Mechanisms of Aging.
In my labs, teams of brilliant students and PhDs have both accelerated and reversed aging in model organisms and have been responsible for some of the most cited research in the field, published in some of the world’s top scientific journals.
I am also a cofounder of a journal, Aging that provides space to other scientists to publish their research on one of the most challenging and exciting questions of our time, and a cofounder of the Academy for Health and Lifespan Research, a group of the top twenty researchers in aging worldwide.
A.3) Book's content (The Information Theory of Aging - aging as a disease)
In the coming pages, I will present a new idea about why aging evolved and how it fits into what I call the Information Theory of Aging.
I will also tell you why I have come to see aging as a disease—the most common disease—one that not only can but should be aggressively treated. That’s part I.
In part II, I will introduce you to the steps that can be taken right now—and new therapies in development—that may slow, stop, or reverse aging, bringing an end to aging as we know it.
in part III, I will acknowledge the many possible futures these actions could create
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B) Part I: What We Know (The Past)
B.1) Chapter 1. "Viva Primordium"
B.1.1) Our planet as it was 4 billion years ago
IMAGINE A PLANET ABOUT THE size of our own, about as far from its star, its atmosphere does not have the same mix of gases as ours. It is a humid, toxic blanket of nitrogen, methane, and carbon dioxide. There is no oxygen. There is no life. Because this planet, our planet as it was 4 billion years ago, is a ruthlessly unforgiving place. Hot and volcanic. Electric. Tumultuous. But that is about to change.
B.1.1) The first organic molecules (RNA, cell membrane and Genes)
Organic molecules cover all surfaces, these molecules will remain just molecules, but when dissolved in pools of warm water, through cycles of wetting and drying a special chemistry takes place.
As the nucleic acids concentrate, they grow into polymers, the way salt crystals form when a seaside puddle evaporates. These are the world’s first RNA molecules, the predecessors to DNA.
the primitive genetic material becomes encapsulated by fatty acids to form microscopic soap bubbles—the first cell membranes.
It doesn’t take long, a week perhaps, before the shallow ponds are covered with a yellow froth of trillions of tiny precursor cells filled with short strands of nucleic acids, which today we call genes.
Most of the protocells are recycled, but some survive and begin to evolve primitive metabolic pathways, until finally the RNA begins to copy itself. That point marks the origin of life.
B.1.2) The first challenge for life (a prolonged dry season)
Now that life has formed—as fatty-acid soap bubbles filled with genetic material—they begin to compete for dominance. There simply aren’t enough resources to go around. May the best scum win.
Along comes a new threat: a prolonged dry season.
It is an ecosystem defined not by the annual waxing and waning of the waters but by a brutal struggle for survival. And more than that: it is a fight for the future—because the organisms that survive will be the progenitors of every living thing to come: archaea, bacteria, fungi, plants, and animals.
B.1.3) The "Great Survivor" and the Gene Mutation Circuit to repair DNA
Within this dying mass of cells, there is a unique species. Let’s call it Magna superstes. That’s Latin for “great survivor.”
It does not look very different from the other organisms of the day, but M. superstes has a distinct advantage: it has evolved a genetic survival mechanism.
There will be far more complicated evolutionary steps in the eons to come, changes so extreme that entire branches of life will emerge. These changes—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.
By comparison, this early evolutionary step looks, at first, to be rather simple. It is a circuit. A gene circuit.
The circuit begins with gene A, a caretaker that stops cells from reproducing when times are tough.
The circuit also has a 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. All life in the lake has these two genes. But what makes M. superstes unique is that the gene B silencer has mutated 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. This makes sense, because while DNA is broken, sex and reproduction are the last things an organism should be doing.
In future multicellular organisms, for instance, cells that fail to pause while fixing a DNA break will almost certainly lose genetic material.
If DNA is broken, part of a chromosome will be lost or duplicated. The cells will likely die or multiply uncontrollably into a tumor.
With a new type of gene silencer that repairs DNA, too, M. superstes has an edge. It hunkers down when its DNA is damaged, then revives. It is superprimed for survival. And that’s good, because now comes yet another assault on life.
Summary
THE EVOLUTION OF AGING. A 4-billion-year-old gene circuit in the first life-forms would have turned off reproduction while DNA was being repaired, providing a survival advantage. Gene A turns off reproduction, and gene B makes a protein that turns off gene A when it is safe to reproduce. When DNA breaks, however, the protein made by gene B leaves to go repair DNA. As a result, gene A is turned on to halt reproduction until repair is complete. We have inherited an advanced version of this survival circuit.
B.1.4) The second challenge for life (a cosmic ray storm)
Powerful cosmic rays from a distant solar eruption are bathing the Earth, shredding the DNA of all the microbes in the dying lakes.
The vast majority of them carry on dividing as if nothing has happened, unaware that their genomes have been broken and that reproducing will kill them.
The cells all die, and nothing is left. Nothing, that is, but M. superstes.
By virtue of its defiance of the ancient imperative to reproduce, M. superstes has survived.
When the latest dry period ends and the lakes refill, M. superstes wakes up. Now it can reproduce.
B.1.5) The "Great Survivor" advantage and the new descendants of the gene circuit
Evolving. Creating generations upon generations of new descendants. They are our Adam and Eve.
The fossil record in our genes goes a long way to proving that every living thing that shares this planet with us still carries this ancient genetic survival circuit,
It is there in every plant. It is there in every fungus. It is there in every animal. It is there in us.
given the chaos that exists at the molecular scale, it’s a wonder we survive thirty seconds, let alone make it to our reproductive years, let alone reach 80 more often than not. But we do. Marvelously we do. Miraculously we do. For we are the progeny of a very long lineage of great survivors. Ergo, we are great survivors.
But there is a trade-off. For this circuit within us, the descendant of a series of mutations in our most distant ancestors, is also the reason we age.
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B.2) Chapter 1. To Everything There Is A Reason
B.2.1) Aging vs Cancer (treating the symptoms not the illness)
Even gerontologists, doctors who specialize in aging, often don’t ask why we age—they simply seek to treat the consequences.
As recently as the late 1960s, for example, the fight against cancer was a fight against its symptoms.
B.2.2) Chemotherapy vs Oncogenes and Immunotherapy (the shift in paradigm on cancer treatments)
Then, in the 1970s, genes that cause cancer when mutated were discovered by the molecular biologists Peter Vogt and Peter Duesberg.
These so-called oncogenes shifted the entire paradigm of cancer research. Pharmaceutical developers now had targets to go after: the tumor-inducing proteins encoded by genes, such as BRAF, HER2, and BCR-ABL. By inventing chemicals that specifically block the tumor-promoting proteins, we could finally begin to move away from using radiation and toxic chemotherapeutic agents to attack cancers at their genetic source, while leaving normal cells untouched.
One of the most promising breakthroughs in the past decade has been immune checkpoint therapy, or simply “immunotherapy.”
Immune T-cells continually patrol our body, looking for rogue cells to identify and kill before they can multiply into a tumor. If it weren’t for T-cells, we’d all develop cancer in our twenties. But rogue cancer cells evolve ways to fool cancer-detecting T-cells so they can go on happily multiplying.
The latest and most effective immunotherapies bind to proteins on the cancer cells’ surface. It is the equivalent of taking the invisible cloak off cancer cells so T-cells can recognize and kill them.
B.2.3) Aging vs Cancer (the current stage of aging reasearch)
Aging research today is at a similar stage as cancer research was in the 1960s. We have a robust understanding of what aging looks like and what it does to us and an emerging agreement about what causes it and what keeps it at bay. From the looks of it, aging is not going to be that hard to treat, far easier than curing cancer.
B.2.4) Why do we age? - Idea 1: Selfish genes only care about early reproduction (no longevity)
In the 1950s, three evolutionary biologists, J. B. S. Haldane, Peter B. Medawar, and George C. Williams, propose some important ideas about why we age. When it comes to longevity, they agreed, individuals look out for themselves. Driven by their selfish genes, they press on and try to breed for as long and as fast as they can,
If our genes don’t ever want to die, why don’t we live forever? The trio of biologists argued that we experience aging because the forces of natural selection required to build a robust body may be strong when we are 18 but decline rapidly once we hit 40 because by then we’ve likely replicated our selfish genes in sufficient measure to ensure their survival. Eventually, the forces of natural selection hit zero. The genes get to move on. We don’t.
B.2.5) Why do we age? - Idea 2: Our lifestyle is determined by the available resources (breed fast and die young, or breed slowly and maintain your body)
Twenty years later, Thomas Kirkwood at Newcastle University 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.
This explains why a mouse lives 3 years while some birds can live to 100. The mouse most reproduce as fast as possible before dying from a natural predator. While birds of prey benefit from a strong body that puts them at the top of the food chain.
B.2.6) Why do we age? - Idea 3: aging is caused by DNA damage and a resulting loss of genetic information (mutation accumulation from radiation or mistakes made during the DNA-copying)
CRISIS MODE
if we are to make real progress in the effort to alleviate the suffering that comes with aging, what is needed is a unified explanation for why we age, not just at the evolutionary level but at the fundamental level. But explaining aging at a fundamental level is no easy task.
One hypothesis, proposed independently by Peter Medawar and Leo Szilard, was that aging is caused by DNA damage and a resulting loss of genetic information.
The idea that mutation accumulation causes aging was embraced by scientists and the public alike in the 1950s
But although we know with great certainty that radiation can cause all sorts of problems in our cells, it causes only a subset of the signs and symptoms we observe during aging, 10 so it cannot serve as a universal theory.
In 1963, the British biologist Leslie Orgel threw his hat into the ring with his “Error Catastrophe Hypothesis,” which postulated that mistakes made during the DNA-copying process lead 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.
B.2.7) Why do we age? - Idea 4: “Free Radical Theory of Aging” (electrons damage DNA and mitochondria through oxidation)
Around the same time Denham Harman, a chemist at Shell Oil, was also thinking atomically,
he 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.
Professor Harman had been taking high doses of alpha-lipoic acid for most of his life to quench free radicals.
B.2.8) The dissapointing results of antioxidants (the real players for longevity are the body’s natural defenses)
Through the 1970s and 1980s, Harman and hundreds of other researchers tested whether antioxidants would extend the lifespan of animals. The results overall were disappointing.
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.
The theory was overturned by scientists within the cloisters of my field more than a decade ago, yet it is still widely perpetuated by purveyors of pills and drinks, who fuel a $ 3 billion global industry. With all that advertising, it is not surprising that more than 60 percent of US consumers still look for foods and beverages that are good sources of antioxidants.
B.2.9) Free radicals mutations don't cause aging
Free radicals do cause mutations. Of course they do. You can find mutations in abundance, particularly in cells that are exposed to the outside world and in the mitochondrial genomes of old individuals.
Mitochondrial decline is certainly a hallmark of aging and can lead to organ dysfunction. But mutations alone, especially mutations in the nuclear genome, conflict with an ever-increasing amount of evidence to the contrary. Arlan Richardson and Holly Van Remmen spent about a decade at the University of Texas at San Antonio testing if increasing free-radical damage or mutations in mice led to aging; it didn’t.
B.2.10) Cloning as proof that old cells don't lose crucial genetic information
Ironically, it was Szilard, in 1960, who initiated the demise of his own theory by figuring out how to clone a human cell. Cloning gives us the answer as to whether or not mutations cause aging. If old cells had indeed lost crucial genetic information and this was the cause of aging, we shouldn’t be able to clone new animals from older individuals. Clones would be born old.
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. Sure, it’s possible that some cells in the body don’t mutate and those are the ones that end up making successful clones, but that seems highly unlikely. The simplest explanation is that old animals retain all the requisite genetic information to generate an entirely new, healthy animal and that mutations are not the primary cause of aging.
B.2.11) Looking for a new aging model (old model in crisis mode)
In The Structure of Scientific Revolutions, Thomas Kuhn noted that scientific discovery is never complete; it goes through predictable stages of evolution. When a theory succeeds at explaining previously unexplainable observations about the world, it becomes a tool that scientists can use to discover even more.
Soon the model enters crisis mode and begins to drift as scientists seek to adjust it, as little as possible, to account for that which it cannot explain.
the aging field began to coalesce around a new model—
B.2.12) A new model - The Multiple “Hallmarks” of Aging
In this more nuanced view, aging and the diseases that come with it are the result of multiple “hallmarks” of aging:
• Genomic instability caused by DNA damage
• Attrition of the protective chromosomal endcaps, the telomeres
• Alterations to the epigenome that controls which genes are turned on and off
• Loss of healthy protein maintenance, known as proteostasis
• Deregulated nutrient sensing caused by metabolic changes
• Mitochondrial dysfunction
• Accumulation of senescent zombielike cells that inflame healthy cells
• Exhaustion of stem cells
• Altered intercellular communication and the production of inflammatory molecules
B.2.13) Slow down aging - Addressing these hallmarks
Researchers began to cautiously agree: address these hallmarks, and you can slow down aging. Slow down aging, and you can forestall disease. Forestall disease, and you can push back death.
B.2.14) Slow down aging - Stem Cell Therapy (arthritis, diabetes, Alzheimer’s and Parkinson’s)
Take stem cells, which have the potential to develop into many other kinds of cells: if we can keep these undifferentiated cells from tiring out, they can continue to generate all the differentiated cells necessary to heal damaged tissues
we’re improving the rates of acceptance of bone marrow transplants, which are the most common form of stem cell therapy, and using stem cells for the treatment of arthritic joints, type 1 diabetes, loss of vision, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s.
B.2.15) Slow down aging - killing senescent cells to keep healthy tissues
Or take senescent cells, which have reached the end of their ability to divide but refuse to die,
if we can kill off senescent cells or keep them from accumulating in the first place, we can keep our tissues much healthier for longer.
B.2.16) Slow down aging - Addressing these hallmarks for longevity (telomere loss, decline in proteostasis, etc... {research})
The same can be said for combating telomere loss, the decline in proteostasis, and all of the other hallmarks. Each can be addressed one by one, a little at a time, in ways that can help us extend human healthspans.
researchers have increasingly homed their efforts in on addressing each of these hallmarks.
There is little doubt that the list of hallmarks, though incomplete, comprises the beginnings of a rather strong tactical manual for living longer and healthier lives.
B.2.17) Pushing the maxiumum limit of age
As for pushing way past the maximum limit? Addressing these hallmarks might not be enough.
Although it is in its early days, a new shift in thinking is again under way.