1/ Lifespan: Why We Age—and Why We Don't Have To (Sinclair and LaPlante)
"In my labs, we have both accelerated and reversed aging in model organisms and have been responsible for some of the most cited research published in top scientific journals."
amazon.com/Lifespan-Why-A…
"In my labs, we have both accelerated and reversed aging in model organisms and have been responsible for some of the most cited research published in top scientific journals."
amazon.com/Lifespan-Why-A…
2/ "I have come to see aging as a disease—one that not only can but should be aggressively treated.
"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." (p. 10)
"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." (p. 10)
3/ "Increasing free-radical damage or mutations in mice didn't lead to aging.
"It has proven simple to restore the function of mitochondria in old mice, indicating that a large part of aging is not due to mutations in mitochondrial DNA, at least not until late in life.
"It has proven simple to restore the function of mitochondria in old mice, indicating that a large part of aging is not due to mutations in mitochondrial DNA, at least not until late in life.
4/ "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.
5/ "It’s a misconception that cloned animals age prematurely, one perpetuated in the media; even the NIH website says so.
"The first cloned sheep lived half a normal lifespan and died of a progressive lung disease. Extensive analysis of her remains revealed no premature aging.
"The first cloned sheep lived half a normal lifespan and died of a progressive lung disease. Extensive analysis of her remains revealed no premature aging.
6/ "The list of cloned species that proven to live a normal, healthy lifespan now includes goats, sheep, mice, and cows.
"Because nuclear transfer works in cloning, we can say with a high degree of confidence that aging isn’t caused by mutations in nuclear DNA." (p. 14)
"Because nuclear transfer works in cloning, we can say with a high degree of confidence that aging isn’t caused by mutations in nuclear DNA." (p. 14)
7/ "A decade ago, the ideas of leading scientists in the aging field began to coalesce around a new model involving multiple causes.
"In this more nuanced view, aging and the diseases that come with it are the result of multiple “hallmarks” of aging." (p. 16)
"In this more nuanced view, aging and the diseases that come with it are the result of multiple “hallmarks” of aging." (p. 16)
8/ "The science is moving faster now than ever before, thanks to robots that analyze tens of thousands of potential drugs each day, sequencing machines that read millions of genes a day, and computing power. Theories are now more easily tested and refuted.
9/ "Once again, we find ourselves in a period of chaos: still quite confident that the aforementioned hallmarks are accurate indicators of aging and its myriad symptoms but unable to explain why the hallmarks occur in the first place." (p. 18)
10/ "I believe an answer exists: a singular cause of aging upstream of all the hallmarks.
"Aging, quite simply, is a loss of information.
"But there are two types of information in biology, and they are encoded entirely differently.
"Aging, quite simply, is a loss of information.
"But there are two types of information in biology, and they are encoded entirely differently.
11/ "Digital information is based on a finite set of possible values. Because DNA is digital, it is a reliable way to store and copy information.
"Analog information is in the epigenome (traits that are heritable but aren't transferred by genetic means)." (p. 20)
"Analog information is in the epigenome (traits that are heritable but aren't transferred by genetic means)." (p. 20)
12/ "Analog data can be changed whenever the environment demands it. They can store an almost unlimited number of possible values.
"But analog information degrades over time, falling victim to cosmic rays and oxygen. Analog information can be lost as it's copied." (p. 21)
"But analog information degrades over time, falling victim to cosmic rays and oxygen. Analog information can be lost as it's copied." (p. 21)
13/ "The longevity genes I work on are called sirtuins. They're enzymes that remove acetyl tags from histones and other proteins, changing the packaging of the DNA, turning genes off and on. These critical epigenetic regulators control our reproduction and our DNA repair.
14/ "They require a molecule called nicotinamide adenine dinucleotide (NAD). The loss of NAD as we age, and the resulting resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.
15/ "Trading reproduction for repair, the sirtuins order our bodies to “buckle down” in times of stress and protect us against the major diseases of aging: diabetes and heart disease, Alzheimer’s disease and osteoporosis, even cancer.
16/ "They mute the chronic, overactive inflammation that drives atherosclerosis, metabolic disorders, ulcerative colitis, arthritis, and asthma. They prevent cell death and boost mitochondria. They go to battle with muscle wasting, osteoporosis, and macular degeneration.
17/ "In studies on mice, activating sirtuins can improve DNA repair, boost memory, increase exercise endurance, & help the mice stay thin, regardless of what they eat.
"Scientists have established this in peer-reviewed studies published in the journals Nature, Cell, & Science.
"Scientists have established this in peer-reviewed studies published in the journals Nature, Cell, & Science.
18/ "Sirtuins aren’t the only longevity genes. Two other very well-studied sets of genes perform similar roles, which also have been proven to be manipulable in ways that can offer longer and healthier lives." (p. 24)
19/ "There are plenty of stressors that will activate longevity genes without damaging the cell, including certain types of exercise, intermittent fasting, low-protein diets, and exposure to hot and cold temperatures.
20/ "Complementing these approaches are hormesis-mimicking molecules. Drugs in development and at least two drugs on the market can turn on the body’s defenses without creating any damage, mimicking the benefits of exercise and intermittent fasting." (p. 26)
21/ "Among monozygotic human twins, epigenetic forces can drive two people with the same genome in vastly different directions. It can even cause them to age differently. You can see this clearly in side-by-side photographs of the faces of smoking and nonsmoking twins.
22/ "Smokers have bigger bags under their eyes, deeper jowls below their chins, and more wrinkles around their eyes and mouths. They are not older, but they’ve aged faster.
"Studies of identical twins place genetic influences on longevity at 10%-25% (surprisingly low)." (p. 37)
"Studies of identical twins place genetic influences on longevity at 10%-25% (surprisingly low)." (p. 37)
23/ "Youth → broken DNA → genome instability → disruption of DNA packaging and gene regulation (the epigenome) → loss of cell identity → cellular senescence → disease → death
"If we could intervene in all of these steps, could we stop aging?" (p. 40)
"If we could intervene in all of these steps, could we stop aging?" (p. 40)
24/ "Malign chemicals, radiation, and normal DNA copying cause DNA damage.
"It’s not that the sirtuins are overwhelmed; the sirtuins and their coworkers that control the epigenome don’t always find their way back to their original gene stations after being called away.
"It’s not that the sirtuins are overwhelmed; the sirtuins and their coworkers that control the epigenome don’t always find their way back to their original gene stations after being called away.
25/ "Wherever epigenetic factors leave the genome to address damage, genes that should be off switch on and vice versa. Wherever they stop on the genome, they do the same, altering the epigenome in ways that were never intended when we were born.
26/ "Cells lose their identity and malfunction. The ensuing chaos materializes as aging. This is the epigenetic noise that is at the heart of our unified theory.
"The cell doesn’t make enough Sir2 protein to simultaneously silence the mating-type genes and repair broken DNA.
"The cell doesn’t make enough Sir2 protein to simultaneously silence the mating-type genes and repair broken DNA.
27/ "It has to shuttle Sir2 between the various places on an “as-needed” basis. This is why adding an extra copy of the SIR2 gene extends lifespan and delays infertility: cells have enough Sir2 to repair DNA breaks and enough Sir2 to silence the mating-type genes." (p. 46)
28/ "It doesn't so much matter where DNA damage occurs. Sirtuins rush all over the place to address that damage, leaving their responsibilities and sometimes returning to other places along the genome where they are silencing genes that aren’t supposed to be silenced." (p. 48)
29/ "We could age mice without affecting commonly assumed causes of aging (mutations, telomeres, mitochondria, stem cells). They suffered from loss of body mass, mitochondria, and muscle strength and an increase in cataracts, arthritis, dementia, bone loss, and frailty." (p. 52)
30/ "Between young (23+) and old (up to 4,713) bristlecone trees, there were no meaningful differences in chemical transportation systems, rate of shoot growth, quality of pollen, size of their seeds, the way seeds germinated. No deleterious mutations were found." (p. 53)
31/ "When calories are restricted, MSN2 extends yeast lifespan by turning up genes that recycle NAD, giving the sirtuins a boost." (p. 55)
"Every time there’s a radical adjustment to the epigenome (e.g., after DNA damage from the sun or an X-ray), a cell’s identity changes.
"Every time there’s a radical adjustment to the epigenome (e.g., after DNA damage from the sun or an X-ray), a cell’s identity changes.
32/ "A skin cell starts turning on genes that were shut off in the womb. Now it is 90% a skin cell and 10% other cell types, with properties of neurons and kidney cells. It becomes inept at normal tasks, such as making hair, keeping skin supple, and healing when injured." (p. 58)
33/ "When elderly mice were treated with an NAD-boosting molecule that activated the SIRT1 enzyme, new capillaries were formed, supplying oxygen, removing lactic acid & toxic metabolites from muscles, and reversing one of the most significant causes of frailty in mice and humans.
34/ "Because the sirtuins had been activated, the mice’s epigenomes were becoming more stable. The lining of the capillaries was responding as if the mice were exercised. It was the first exercise mimetic, a sure sign that some aspects of age reversal are possible." (p. 63)
35/ "Simple tests to determine how biologically old you probably are: If you are over 45 and can do more than twenty push-ups, you are doing well.
"Sit on the floor, barefooted, with legs crossed. Lean forward quickly and see if you can get up in one move. A young person can.
"Sit on the floor, barefooted, with legs crossed. Lean forward quickly and see if you can get up in one move. A young person can.
36/ "A middle-aged person typically needs to push off with one hand. An elderly person often needs to get onto one knee.
"A study of people 51 to 80 years found that 157 of 159 people who passed away in 75 months had received less than perfect sit-rise-test scores." (p. 73)
"A study of people 51 to 80 years found that 157 of 159 people who passed away in 75 months had received less than perfect sit-rise-test scores." (p. 73)
37/ "Stopping one disease doesn’t make it less likely a person will die of another. Sometimes, the treatment for one disease can even be an aggravating factor for another.
"Chemotherapy can cure some forms of cancer but also increases susceptibility to other forms of cancer.
"Chemotherapy can cure some forms of cancer but also increases susceptibility to other forms of cancer.
38/ "Something as seemingly routine as orthopedic surgery can make patients more susceptible to heart failure.
"Surviving cancer or heart disease doesn’t substantially increase the average human lifespan, it just decreases the odds of dying of cancer or heart disease.
"Surviving cancer or heart disease doesn’t substantially increase the average human lifespan, it just decreases the odds of dying of cancer or heart disease.
39/ "The U.S. spends hundreds of billions/year fighting cardiovascular disease. But if we could stop it completely, the average lifespan would gain only 1.5 years.
"Stopping all cancer would give us just 2.1 more years of life; other causes of death still increase exponentially.
"Stopping all cancer would give us just 2.1 more years of life; other causes of death still increase exponentially.
40/ "Focusing individual diseases is very expensive and ineffective when it comes to prolonging our health-spans. What we need are medicines that knock down *all* the hurdles." (p.76)
The authors of Superfreakonomics make a similar case in multiple areas:
The authors of Superfreakonomics make a similar case in multiple areas:
https://twitter.com/ReformedTrader/status/1382183569397719043
41/ "Even though average lifespans in the U.S. have increased in recent decades, our healthspans have not kept up.
"The disability-adjusted life year (DALY), which measures years of life lost from both premature death and poor state of health (including brain-related disease).
"The disability-adjusted life year (DALY), which measures years of life lost from both premature death and poor state of health (including brain-related disease).
42/ "The Russian DALY is the highest in Europe, with 25 lost years of healthy life per person. In Israel, it is an impressive 10 years. In the U.S., the number is 23.
"Even the more optimistic assessments suggest that the numbers have largely been static in recent years." (p.77)
"Even the more optimistic assessments suggest that the numbers have largely been static in recent years." (p.77)
43/ "We’ve always thought of aging as an inevitable part of life.
"That’s what we used to say about pneumonia, influenza, tuberculosis, and gastrointestinal conditions. In 1900, those accounted for half of deaths in the U.S.—one of them would get you if you lived long enough.
"That’s what we used to say about pneumonia, influenza, tuberculosis, and gastrointestinal conditions. In 1900, those accounted for half of deaths in the U.S.—one of them would get you if you lived long enough.
44/ "Today, deaths among people suffering from tuberculosis and gastrointestinal conditions are exceedingly rare. Pneumonia and influenza claim less than 10% of the lives taken by those conditions a century ago—with most of those deaths now among individuals weakened by aging.
45/ "What changed? In no small part, it was framing. Advances in medicine, innovations in technology, and better information to guide our lifestyle decisions resulted in a world in which we didn’t have to accept the idea that these diseases were “just the way it goes.” " (p. 88)
46/ "After twenty-five years of researching aging and having read thousands of scientific papers, if there is one piece of advice I can offer, one surefire way to stay healthy longer, one thing you can do to maximize your lifespan right now, it’s this: eat less often.
47/ "Yeast fed with lower doses of glucose live longer. Their DNA is exceptionally compact—delaying inevitable ERC accumulation, nucleolar explosion, & sterility.
"In animals, the key to engaging the sirtuin program appears to be just enough food to function healthily; no more.
"In animals, the key to engaging the sirtuin program appears to be just enough food to function healthily; no more.
48/ "In 2017, a Duke research team sought to limit 145 adults to a diet of 25% fewer calories than typically recommended. The actual restriction achieved was 12% over two years. That was enough, however, for improved health and slower aging based on changes in blood biomarkers.
49/ "A long-term study of calorie restriction in rhesus monkeys produced compelling results. Before the study, the maximum known lifespan was 40 years. But of 20 monkeys that lived on calorie-restricted diets, 6 reached that age (roughly 120 years in human terms).
50/ "To hit that mark, the monkeys didn’t need to live on a calorie-restricted diet for their entire lives. Some of the test subjects were started on a 30% reduction regimen when they were middle-aged monkeys.
51/ "Calorie restriction works to extend the lifespan of mice, even when initiated at 19 months of age, the equivalent of a 60- to 65-year-old human, but the earlier the mice start, the greater the lifespan extension.
52/ "Calorie restriction has also been shown to forestall cardiac disease, diabetes, stroke, and cancer.
"In one study, people ate a normal diet most of the time but had a restricted diet consisting primarily of vegetable soup, energy bars, and supplements five days each month.
"In one study, people ate a normal diet most of the time but had a restricted diet consisting primarily of vegetable soup, energy bars, and supplements five days each month.
53/ "Over the course of three months, those who maintained the “fasting mimicking” diet lost weight, reduced their body fat, and lowered their blood pressure. They also had lower levels of a hormone made primarily in the liver called insulin-like growth factor 1, or IGF-1.
54/ "Mutations in IGF-1 and the IGF-1 receptor gene are associated with lower rates of death and disease and found in abundance in females whose families tend to live past 100. IGF-1 levels can sometimes be used to predict how long someone will live.
55/ "A popular method is to skip breakfast and have a late lunch (the 16 hour:8 hour diet).
"However, almost any periodic fasting diet that does not result in malnutrition is likely to put your longevity genes to work in ways that will result in a longer, healthier life." (p.97)
"However, almost any periodic fasting diet that does not result in malnutrition is likely to put your longevity genes to work in ways that will result in a longer, healthier life." (p.97)
56/ "Animal-based diets (esp. processed red meats) are associated with high cardiovascular mortality and cancer risk.
"When we substitute plant protein, all-cause mortality falls.
"A body that is in short supply of amino acids is under the stress that engages survival circuits.
"When we substitute plant protein, all-cause mortality falls.
"A body that is in short supply of amino acids is under the stress that engages survival circuits.
57/ "When the mTOR enzyme is inhibited, it forces cells to spend less energy dividing and more energy in the process of autophagy, which recycles damaged and misfolded proteins. That act of hunkering down ends up being good for prolonged vitality in every organism we’ve studied.
58/ "mTOR isn’t impacted only by caloric restriction. If you want to keep mTOR from being activated too much or too often, limiting your intake of amino acids is a good way to start, so limit your intake of meat and dairy.
59/ "Feeding mice a diet with low levels of the amino acid methionine protects organs from hypoxia during surgery & increases healthy lifespan by 20%. Even obese mice who eat as much as they want & shun exercise lose 70% of their fat in a month & lower their blood glucose levels.
60/ "There’s a lot of methionine in beef, lamb, poultry, pork, & eggs. Plant proteins contain low levels—enough to keep the light on but not for biological complacency.
"Low levels of arginine & the branched-chain leucine, isoleucine, * valine correlate with increased lifespan.
"Low levels of arginine & the branched-chain leucine, isoleucine, * valine correlate with increased lifespan.
61/ "In human studies, a decreased consumption of branched-chain amino acids has been shown to improve markers of metabolic health.
"We can do this by lowering our consumption of foods that many people consider to be the “good animal proteins:” chicken, fish, and eggs." (p. 101)
"We can do this by lowering our consumption of foods that many people consider to be the “good animal proteins:” chicken, fish, and eggs." (p. 101)
62/ "Leucine is found in large quantities in protein drinks. But that muscle building is coming in part because leucine is activating mTOR, which calls out to your body, “Times are good right now: let’s disengage the survival circuit.”
63/ "In the long run, protein drinks may prevent the mTOR pathway from providing its longevity benefits.
"For mice, just one week with no leucine reduces blood glucose levels.
"This may help explain why vegetarians suffer lower rates of cardiovascular disease & cancer." (p.101)
"For mice, just one week with no leucine reduces blood glucose levels.
"This may help explain why vegetarians suffer lower rates of cardiovascular disease & cancer." (p.101)
64/ "Individuals who exercise more—the equivalent of at least a half hour of jogging five days a week—have telomeres that appear to be nearly a decade younger.
"Exercise applies stress to our bodies. It raises NAD levels, which then activate the survival network...
"Exercise applies stress to our bodies. It raises NAD levels, which then activate the survival network...
65/ "turning up energy production and forcing muscles to grow extra capillaries. The longevity regulators AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise.
"People who self-reported as runners were far less likely to die of heart disease.
"People who self-reported as runners were far less likely to die of heart disease.
66/ "Even when the researchers adjusted for obesity and smoking, the runners were less likely to have died during the years of the study. The big shock was that the health benefits were remarkably similar no matter how much running the people had done.
67/ "Even ten minutes of moderate exercise a day added years to their lives.
"There is a difference between a leisurely walk and a brisk run, however. To engage our longevity genes fully, intensity does matter.
"There is a difference between a leisurely walk and a brisk run, however. To engage our longevity genes fully, intensity does matter.
68/ "Although many forms of exercise have positive health effects, it’s high-intensity interval training (HIIT)—the sort that significantly raises your heart and respiration rates—that engages the greatest number of health-promoting genes (and more of them in older exercisers).
69/ "Your breathing should be deep and rapid at 70-85% of your maximum heart rate. You should sweat and be unable to say more than a few words without pausing for breath. This induces just enough stress to activate your body’s defenses against aging without doing permanent harm.
70/ "When you give rats a high-calorie diet & allow them to burn off the energy, lifespan extension is minimal.
"If you make food filling but not as calorific, some of the health benefits are lost. Hunger helps turn on genes in the brain that release longevity hormones." (p.104)
"If you make food filling but not as calorific, some of the health benefits are lost. Hunger helps turn on genes in the brain that release longevity hormones." (p.104)
71/ "Less-than-comfortable temperatures can also turn on your longevity genes.
"Female (male) mice genetically engineered to live a half degree cooler than normal have a 20% (12%) longer life.
"You can try is activating the mitochondria in your brown fat by being a bit cold.
"Female (male) mice genetically engineered to live a half degree cooler than normal have a 20% (12%) longer life.
"You can try is activating the mitochondria in your brown fat by being a bit cold.
72/ "A brisk walk in a T-shirt on a winter day in a city like Boston will do the trick. Exercising in the cold especially appears to turbocharge the creation of brown adipose tissue. Leaving a window open overnight or not using a heavy blanket while you sleep could also help.
73/ "As for fasting, the greatest benefits are likely to come for those who get close to, but not beyond, the edge. Hypothermia is not good for our health. Neither is frostbite. But goose bumps, chattering teeth, and shivering arms aren’t dangerous." (p. 109)
74/ "DNA damage from smoking keeps the DNA repair crews working overtime, and likely resulting in epigenetic instability that causes aging.
"The levels of DNA-damaging aromatic amines in cigarette smoke are about fifty to sixty times as high in secondhand as in firsthand smoke.
"The levels of DNA-damaging aromatic amines in cigarette smoke are about fifty to sixty times as high in secondhand as in firsthand smoke.
75/ "Be wary of the PCBs and other chemicals found in plastics, including plastic bottles and take-out containers. (Microwaving them even more PCBs.)
"Azo dyes, such as aniline yellow, used in everything from fireworks to yellow ink in printers, can also damage DNA.
"Azo dyes, such as aniline yellow, used in everything from fireworks to yellow ink in printers, can also damage DNA.
76/ "Organohalides—in solvents, degreasers, pesticides, & hydraulic fluid—can also wreak havoc on our genomes.
"N-nitroso compounds are in food treated with sodium nitrite, including some beers, most cured meats, & especially cooked bacon. These compounds are potent carcinogens.
"N-nitroso compounds are in food treated with sodium nitrite, including some beers, most cured meats, & especially cooked bacon. These compounds are potent carcinogens.
77/ "Cancer is just the start of our nitrate-treated woes, as nitroso compounds can inflict DNA breakage as well.
"Radiation, such as UV light, X-rays, gamma rays, and radon (the second most frequent cause of lung cancer) can cause additional DNA damage." (p. 112)
"Radiation, such as UV light, X-rays, gamma rays, and radon (the second most frequent cause of lung cancer) can cause additional DNA damage." (p. 112)
78/ "In 1957, Sterne published a paper demonstrating the effectiveness of metformin to treat type 2 diabetes. It’s on the WHO’s Model List of Essential Medicines for the most effective, safe, and cost-effective therapies.
"As a generic medication, it costs less than $5 a month.
"As a generic medication, it costs less than $5 a month.
79/ "A small study of healthy volunteers claimed that the DNA methylation age of blood cells is reversed within ten hours after taking a single 850 mg metformin pill. But clearly, work is needed with a larger sample to see if metformin can delay the aging clock over the long run.
80/ "If Barzilai and his colleagues can show metformin has measurable benefits in the ongoing Targeting Aging with Metformin (TAME) study, the US Food and Drug Administration has agreed to consider aging as a treatable condition." (p. 127)
81/ "NAD boosts the activity of all seven sirtuins.
"Without sufficient NAD, the sirtuins don’t work efficiently: they can’t remove the acetyl groups from histones, they can’t silence genes, and they can’t extend lifespan. NAD levels decrease with age throughout the body.
"Without sufficient NAD, the sirtuins don’t work efficiently: they can’t remove the acetyl groups from histones, they can’t silence genes, and they can’t extend lifespan. NAD levels decrease with age throughout the body.
82/ "A form of vitamin B3 called nicotinamide riboside, or NR, is a vital precursor of NAD.
"Nicotinamide mononucleotide (NMN) is made by our cells and found in avocado, broccoli, and cabbage. In the body, NR is converted into NMN, which is then converted into NAD.
"Nicotinamide mononucleotide (NMN) is made by our cells and found in avocado, broccoli, and cabbage. In the body, NR is converted into NMN, which is then converted into NAD.
83/ "Give an animal NR or NMN, and its NADlevels go up 25% over the next couple of hours, about the same as if it had been fasting or exercising.
"Shin-ichiro Imai demonstrated in 2011 that NMN could treat the symptoms of type 2 diabetes in old mice by restoring NAD levels.
"Shin-ichiro Imai demonstrated in 2011 that NMN could treat the symptoms of type 2 diabetes in old mice by restoring NAD levels.
84/ "Our own lab was able to make the mitochondria in old mice function just like mitochondria in young mice after a week of NMN injections.
"We found that NMN could give old mice more endurance than young mice.
"We found that NMN could give old mice more endurance than young mice.
85/ "For balance, coordination, speed, strength, and memory, the difference between the mice that were on NMN and the mice that were not was astounding.
"NMN can protect against kidney damage, neurodegeneration, mitochondrial diseases, and Friedreich’s ataxia.
"NMN can protect against kidney damage, neurodegeneration, mitochondrial diseases, and Friedreich’s ataxia.
86/ "We find NMN to be more stable than NR and see health benefits in mouse experiments that aren’t seen for NR. But it’s NR that's been proven to extend mice's lifespan. NMN is still being tested.
"Human studies with NAD boosters are ongoing - so far, with no toxicity." (p.136)
"Human studies with NAD boosters are ongoing - so far, with no toxicity." (p.136)
87/ "NMN is able to restore the fertility of old mice that have had *all* their eggs killed off by chemotherapy or have gone through “mousopause.”
"Though our results were reproduced in two different labs, they're so controversial that no one on the team voted to publish them.
"Though our results were reproduced in two different labs, they're so controversial that no one on the team voted to publish them.
88/ "SIRT2 controls the process by which an immature egg divides so that only one copy of the mother’s chromosomes remain in the final egg in order to make way for the father’s chromosomes. Without NMN or additional SIRT2 in old mice, their eggs were toast.
89/ "Pairs of chromosomes were ripped apart from numerous directions, instead of exactly two. But if the old female mice were pretreated with NMN for a few weeks, their eggs looked pristine, identical to those of young mice.
90/ "NMN is hardly the only longevity molecule showing promise in this area. Metformin is already widely used to improve ovulation in women with infrequent or prolonged menstrual periods as a result of polycystic ovary syndrome." (p. 141)
91/ "Although telomerase can extend telomeres, it is switched off to protect us from cancer, except in stem cells. But if you put telomerase into cultured skin cells, they don’t ever senesce.
"Senescent cells are often referred to as “zombie cells,” because they refuse to die.
"Senescent cells are often referred to as “zombie cells,” because they refuse to die.
92/ "Senescent cells can cause havoc. Even though they stop dividing, they release cytokines that cause inflammation and attract macrophages that then attack the tissue. Chronically inflammation is unhealthy: consider multiple sclerosis, inflammatory bowel disease, or psoriasis.
93/ "All these diseases are associated with excess cytokine proteins. Inflammation is also a driving force in heart disease, diabetes, and dementia.
"Cytokines don’t just cause inflammation; they also cause other cells to become zombies, like a biological apocalypse.
"Cytokines don’t just cause inflammation; they also cause other cells to become zombies, like a biological apocalypse.
94/ "When this happens, they can even stimulate surrounding cells to become a tumor and spread.
"Destroying senescent cells in mice can give them substantially healthier and significantly longer lives." (p. 150)
"Destroying senescent cells in mice can give them substantially healthier and significantly longer lives." (p. 150)
95/ "A dab of senescent cells under a young mouse’s skin fills the entire mouse with zombie cells that cause premature signs of aging.
"Senolytics are small molecules designed to specifically kill senescent cells by inducing the death program that should already have happened.
"Senolytics are small molecules designed to specifically kill senescent cells by inducing the death program that should already have happened.
96/ "The first human trials of senolytics were started in 2018 to treat osteoarthritis & glaucoma, conditions in which senescent cells can accumulate. It will be a few more years before we know enough about the effects and safety of these drugs to give them to everyone." (p. 153)
97/ "LINE-1 genes are bundled up and rendered silent by sirtuins. But as mice age, these sirtuins become scattered all over the genome, having been recruited away to repair DNA breaks elsewhere, and many of them never find their way home.
"This exacerbated by a drop in NAD.
"This exacerbated by a drop in NAD.
98/ "Without sirtuins to spool to silence the transposon DNA, cells start to transcribe these endogenous viruses.
"Over time, as mice age, once silent LINE-1 prisoners are turned into RNA, and the RNA is turned into DNA, which is reinserted into the genome at a different place.
"Over time, as mice age, once silent LINE-1 prisoners are turned into RNA, and the RNA is turned into DNA, which is reinserted into the genome at a different place.
99/ "Besides creating genome instability and epigenomic noise that causes inflammation, LINE-1 DNA leaks from the nucleus into the cytoplasm, where it is recognized as a foreign invader. In response, cells release immunostimulatory cytokines that cause inflammation in the body.
100/ "Retroviral hellhounds have no leash, causing numerous DNA breaks and the epigenome to degrade rapidly instead of slowly. Experiments show that antiretrovirals, the same kinds used to fight HIV, extend the lifespan of SIRT6 mutant mice about twofold." (p. 153)
101/ "Cloning shows that old DNA retains the information needed to be young again.
"The fact that Barbra Striesand's dog was 14 when she died—that’s somewhere in the range of 75 in human years—and still donated cells didn’t impact the dog's clones one bit." (p. 160)
"The fact that Barbra Striesand's dog was 14 when she died—that’s somewhere in the range of 75 in human years—and still donated cells didn’t impact the dog's clones one bit." (p. 160)
102/ "We know that cloning a new tadpole or a mammal from an old one is possible. So even if a lot of the epigenetic information is lost in old age, obscured by epigenetic noise, there must be information that tells the cell how to reset." (p. 162)
103/ "A set of four genes—Oct4, Klf4, Sox2, c-Myc—can induce adult cells to become pluripotent stem cells (immature cells that can be coaxed into becoming any other type).
"For showing complete cellular age reversal to be possible in a petri dish, Yamanaka shared a Nobel Prize.
"For showing complete cellular age reversal to be possible in a petri dish, Yamanaka shared a Nobel Prize.
104/ "The implications are profound, and not only because he paved the way for us to grow entirely new populations of blood cells, tissues, and organs in the dish that can be and are being transplanted into patients.
105/ "In our lab, we use these and other switches not just to reset cells but to reset an entire body’s epigenetic landscape—sending sirtuins back to where they came from, for instance. Cells that have lost their identity during aging can be led back to their true selves.
106/ "There are approved gene therapies and hundreds of clinical trials under way. Patients with a mutation that causes blindness can be cured with a safe virus that delivers the functional RPE65 gene. (The eye is used for trials because it is immunologically isolated)." (p. 163)
107/ "As I write this, while everyone else is working on the *progression* of glaucoma, we have *restored* vision in old mice.
"If adult cells, even old nerves, can be reprogrammed to regain a youthful epigenome, the information to be young cannot all be lost." (p. 168)
"If adult cells, even old nerves, can be reprogrammed to regain a youthful epigenome, the information to be young cannot all be lost." (p. 168)
108/ "By infecting mice with reprogramming genes Oct4, Sox2, and Klf4, the age of cells is reversed by the TET enzymes, which remove just the right methyl tags on DNA, reversing the clock of aging and allowing the cells to survive and grow like a newborn’s."
109/ "We may be on the verge of understanding what makes biological time tick and how to wind it back.
"If we can fix the toughest-to-fix and regenerate the toughest-to-regenerate cells, there’s no reason to suspect we cannot regrow any type of cells our bodies need." (p. 170)
"If we can fix the toughest-to-fix and regenerate the toughest-to-regenerate cells, there’s no reason to suspect we cannot regrow any type of cells our bodies need." (p. 170)
110/ "CAR-T therapy and checkpoint inhibition are less than a decade old. There are hundreds of other immuno-oncology clinical trials under way. Results are promising, with remission rates of >80% in some studies. Doctors say this is the revolution they’ve been waiting for.
111/ "Through sequencing, we can see what kinds of bacteria have made their way into a tumor. Bacteria can protect tumors from anticancer drugs. We can identify which bacteria are present & predict which antibiotics will work against those single-celled tumor protectors." (p.177)
112/ "Today, I can read an entire human genome in a few days for <$100 on a sequencer that I plug into my laptop.
"Targeted sequencing aimed at answering a specific question—“What kind of cancer is this?” or “What infection do I have?”—can now be done in less than 24 hours.
"Targeted sequencing aimed at answering a specific question—“What kind of cancer is this?” or “What infection do I have?”—can now be done in less than 24 hours.
113/ "Drug developers are using genomic information to find new and revive failed drugs for people with specific genetic variations.
"This can markedly affect drug efficacy and patient survival, including the efficacy of what are thought of as well-understood chemotherapies.
"This can markedly affect drug efficacy and patient survival, including the efficacy of what are thought of as well-understood chemotherapies.
114/ "Superfocused DNA testing can offer us early and accurate diagnoses, detecting the genetic signature of cancer and other illnesses years before they can normally be detected.
"Many diseases, after all, are genetically detectable long before they are symptomatic." (p. 186)
"Many diseases, after all, are genetically detectable long before they are symptomatic." (p. 186)
115/ "Rhonda Patrick, a longevity scientist turned health and fitness expert, has been using a continual blood glucose–sensing device to see what foods give her body a major sugar spike. She’s seen that, at least for her, white rice is bad and potatoes aren’t so bad.
116/ "Researchers have been developing sensors that can identify diseases, diet changes, injuries, and stress through sweat. A few companies are developing handheld breath analyzers that can diagnose cancer, infectious diseases, and inflammatory diseases.
117/ "Biotracking and computer-generated food recommendations reduce blood sugar levels as efficiently as the leading diabetes drug, while optimizing other health biomarkers, too." (p. 188)
118/ "By the latter part of the century, the business model that long sustained vaccine research and development was broken. The cost of testing new vaccines had risen exponentially, thanks in large part to increasing public concerns about safety & risk-averse regulatory bodies.
119/ "The “low-hanging fruit” of the inoculation world had already been picked. Now a simple vaccine can take more than a decade to produce and cost more than half a billion dollars, and there is still the chance it won’t be approved for sale.
120/ "Even some vaccines that have worked well and been critical for the prevention of epidemics, such as GlaxoSmithKline’s Lyme disease vaccine, have been taken off the market because the unfounded backlash against vaccines made continuation of the product “just not worth it.”
121/ "The good news is we are experiencing a mini-renaissance in vaccine development, which has tripled from 2005-15, now accounting for a 1/4 of all biotech products being developed.
"We're also learning how to quickly grow vaccines in human cells, mosquito cells, & bacteria.
"We're also learning how to quickly grow vaccines in human cells, mosquito cells, & bacteria.
122/ "One Boston-based research consortium was able to get a vaccine for Lassa fever, a disease similar to Ebola, all the way to the animal-testing stage in just four months and for about $1 million, cutting many years and many millions of dollars from the usual process." (p.204)
123/ "Yang used gene editing to eliminate retroviral genes from pigs that prevent them from donating organs.
"Scientists have been working toward using 3-D printing to create living tissue. They have implanted printed ovaries into mice and spliced printed arteries into monkeys.
"Scientists have been working toward using 3-D printing to create living tissue. They have implanted printed ovaries into mice and spliced printed arteries into monkeys.
124/ "In the future, when we need body parts, we might very well print them, perhaps by using our own stem cells or even reprogrammed cells taken from blood or a mouth swab.
"Any one technology might lead to a dead end. But there is simply no way that all of them will fail.
"Any one technology might lead to a dead end. But there is simply no way that all of them will fail.
125/ "Separately, any of these innovations in pharmaceuticals, precision medicine, emergency care, and public health would save lives, providing extra years that would otherwise have been lost. Taken together, they would provide decades of longer, healthier life." (p. 207)
126/ "Though there are many examples of false predictions, it is far more common *not* to see something coming. We extrapolate linearly. More people, more horses, more horse manure. More cars, more pollution, more climate change." (p. 215)
Thread on this:
Thread on this:
https://twitter.com/ReformedTrader/status/1381686597842657280
127/ "That’s not how it works. When technologies go exponential, experts can be blindsided.
"Albert Michelson, who won a Nobel Prize for measuring the speed of light, declaring in 1894 that there was probably little else to discover in physics besides additional decimal places.
"Albert Michelson, who won a Nobel Prize for measuring the speed of light, declaring in 1894 that there was probably little else to discover in physics besides additional decimal places.
128/ "He died in 1931 as quantum mechanics was in full swing.
"In his 1995 book, Bill Gates made no mention of the internet, though he substantially revised it a year later.
“Embrace things rather than fighting them. Work with things rather than running from/prohibiting them.”
"In his 1995 book, Bill Gates made no mention of the internet, though he substantially revised it a year later.
“Embrace things rather than fighting them. Work with things rather than running from/prohibiting them.”
129/ "Humankind is far more innovative than we give it credit for. Over the past two centuries, every generation has seen new technologies: steam engines, metal ships, horseless carriages, skyscrapers, planes, computers, the internet, mobile devices, and gene-edited babies.
130/ "At first we are shocked; then we barely notice. We find it hard to predict what will happen when complex technologies suddenly merge.
"If we continue on the path we’re on, some estimates suggest half of all children born in the U.S. today will live past 104." (p. 215)
"If we continue on the path we’re on, some estimates suggest half of all children born in the U.S. today will live past 104." (p. 215)
131/ "The question is not whether the Earth can currently sustain 8 billion, 16 billion, or 20 billion people. The question is whether humans continue to develop the technologies that permit us to stay ahead of the curve and even make the planet a better place for all creatures.
132/ "If we were to stop *all* deaths (however unlikely), we would add 150,000 people to our planet each day: less than 1%/year, still considerably slower than the rate the last few billion have come along and easily countered by the global decline in family sizes." (p. 244)
133/ "In the past 200 years—with the most explosive population growth in human history—we transformed from a world in which nearly everyone but monarchs & their viceroys lived in poverty to a global society in which the rate of extreme poverty is now below 10% & rapidly falling.
134/ "Meanwhile, in a century in which we added billions to the global population, we also improved educational access. In 1800, the global literacy rate was 12%, by 1900 it was 21%, and today it’s 85%. The majority has instant access to essentially all the world’s knowledge.
135/ "Child mortality fell from >36% in 1900 to <8% in 2000.
"There is no evidence in modern times that population levels correlate with, let alone cause, misery. Our world is more populated today than it ever has been—and it’s a better place for more people, too." (p. 248)
"There is no evidence in modern times that population levels correlate with, let alone cause, misery. Our world is more populated today than it ever has been—and it’s a better place for more people, too." (p. 248)
136/ "Paradoxically, no public funding agency around the world classifies aging as a disease.
"For now, the pool of public funding available for research on prolonged vitality is paltry; the biggest checks are still written to support initiatives aimed at *recognized* diseases.
"For now, the pool of public funding available for research on prolonged vitality is paltry; the biggest checks are still written to support initiatives aimed at *recognized* diseases.
137/ "There are several ways to innovate and prolong healthy lifespans, but the easiest is also the simplest: define aging as a disease. Labs like mine would no longer be rare. There are far more people who want to work on aging than there are labs they can work in." (p. 267)
138/ "In 2005, Dana Goldman estimated how much it would cost for new discoveries to extend a human life by one year.
Diabetes medication: $147,199
Cancer treatment: $498,809
Pacemaker: $1,403,740.
Anti-aging compound: $8,790
Diabetes medication: $147,199
Cancer treatment: $498,809
Pacemaker: $1,403,740.
Anti-aging compound: $8,790
139/ "There is no cheaper way to address the health care crisis than to address aging at its core.
"What will be left: medical maintenance (very cheap), emergency medicine (rare), and communicable diseases (which we’ll be able to track, treat, and prevent efficiently)." (p. 271)
"What will be left: medical maintenance (very cheap), emergency medicine (rare), and communicable diseases (which we’ll be able to track, treat, and prevent efficiently)." (p. 271)
140/ "The longer we make rodents live, the faster they tend to die. They still die of the same diseases, but, perhaps because they are very old, and the animals are on the brink anyway, they tend to suffer for days rather than months, then keel over." (p. 280)
141/ "I don’t want unlimited years, just ones filled with less sickness and more love.
"For most researchers, the fight against aging isn’t about ending death; it’s about prolonging healthy life and giving more people the chance to meet death on far better terms." (p. 282)
"For most researchers, the fight against aging isn’t about ending death; it’s about prolonging healthy life and giving more people the chance to meet death on far better terms." (p. 282)
142/ "There is nothing wrong with skepticism, but after thousands of studies, the evidence is irrefutable: if you believe climate change is a threat, you can’t say GMOs are, because the evidence that GMOs are safe is stronger than the evidence that climate change is occurring.
143/ "GMOs could be feed the billions of people who are already going hungry and the additional billions who will be born in coming years.
"We need to figure out how to satiate the global demand for protein without the tremendous environmental costs of farmed animal meat.
"We need to figure out how to satiate the global demand for protein without the tremendous environmental costs of farmed animal meat.
144/ "Made with 99% less water, 93% less land, and 90% fewer greenhouse gases, innovations that are giving us close-to-meat products—with plant “leghemoglobin” that “bleeds” and some good old-fashioned mad science—are booming." (p. 286)
145/ "The 2018 EU ruling was not intended to protect consumers from GMO; it was part of a trade war to keep US-patented products out of the EU.
"Today’s LED lights use 75% less energy than incandescents and last 50x as long.
"Human ingenuity is not a zero-sum game." (p. 286)
"Today’s LED lights use 75% less energy than incandescents and last 50x as long.
"Human ingenuity is not a zero-sum game." (p. 286)
146/ " 'Retirement' today involves ever-skyrocketing insurance premiums and pyramid-scheme pensions.
"Labor leaders are locked in a futile fight for retirement and benefits for workers who, in the past, would have labored for 40-50 years, retired briefly, and then promptly died.
"Labor leaders are locked in a futile fight for retirement and benefits for workers who, in the past, would have labored for 40-50 years, retired briefly, and then promptly died.
147/ "Almost no one is fighting over what the world of work will look like when age is truly nothing more than a number.
"We are going to have to “touch the third rail”—Social Security—adjusting our expectations about work, retirement, and who deserves what and when." (p. 293)
"We are going to have to “touch the third rail”—Social Security—adjusting our expectations about work, retirement, and who deserves what and when." (p. 293)
148 / More on the history of pensions in the U.S.:
https://twitter.com/ReformedTrader/status/1111357546848120832
149/ "Every country in the entire world is encouraged to start reporting using ICD-11 on January 1, 2022. What this means is that it will finally be possible to be diagnosed with a condition called “old age.” " (p. 302)
150/ Author's habits (p.303)
1000mg NMN, 1g resveratrol in yogurt, 1g metformin
Vits D, K2, aspirin
Avoids sugar, bread, pasta, mammal meat, smoking, microwaved plastic, excessive UV/X-rays/CT scans, daytime/nighttime warmth
Skips one meal/day
Biomarker analysis
Exercise/weights
1000mg NMN, 1g resveratrol in yogurt, 1g metformin
Vits D, K2, aspirin
Avoids sugar, bread, pasta, mammal meat, smoking, microwaved plastic, excessive UV/X-rays/CT scans, daytime/nighttime warmth
Skips one meal/day
Biomarker analysis
Exercise/weights
151/ Andrew Steele interview
* New book: Ageless (amazon.com/Ageless-Scienc…)
* Genomic instability, cellular senescence, and mitochondrial dysfunction
* Chronic inflammation
* What is cancer?
* Biology of aging
* Hair loss
* Gum disease and dementia
trendfollowing.com/2021/03/14/ep-…
* New book: Ageless (amazon.com/Ageless-Scienc…)
* Genomic instability, cellular senescence, and mitochondrial dysfunction
* Chronic inflammation
* What is cancer?
* Biology of aging
* Hair loss
* Gum disease and dementia
trendfollowing.com/2021/03/14/ep-…
152/ “Despite concerns about hype, scientists are hopeful of finding a way forward by relying on hard evidence.
“Finding drugs that work in people doesn’t involve sales pitches. It involves the long, laborious process of actually doing research.”
khn.org/news/a-fountai…
“Finding drugs that work in people doesn’t involve sales pitches. It involves the long, laborious process of actually doing research.”
khn.org/news/a-fountai…
153/ Melanie Avalon interview
* What is biohacking?
* Blue light blocking glasses
* Near-Infrared Light Therapy
* Hormetic stress and cold therapies
* Apollo Neuro device for sound wave therapy
* Quality of sleep
* Supplements
* NAD+
* Vitamin D
….mindsharecollaborative.libsynpro.com/ep-143-biohack…
* What is biohacking?
* Blue light blocking glasses
* Near-Infrared Light Therapy
* Hormetic stress and cold therapies
* Apollo Neuro device for sound wave therapy
* Quality of sleep
* Supplements
* NAD+
* Vitamin D
….mindsharecollaborative.libsynpro.com/ep-143-biohack…
154/ "In general, the evidence for vitamin B3 derived compounds to increase NAD+ in older people is good, while the evidence for that increase to then produce benefits to health is mixed at best. Regular exercise appears to be better at increasing NAD+."
fightaging.org/archives/2021/…
fightaging.org/archives/2021/…
155/ "Forces from walking/running are transmitted from bone surfaces along arteriolar blood vessels into marrow. Bone-forming cells sense these forces, proliferate, and secrete a growth factor that increases the frequency of cells that form lymphocytes."
utsouthwestern.edu/newsroom/artic…
utsouthwestern.edu/newsroom/artic…
156/ "Intermittent fasting reduces inflammation and oxidative stress, leads to increased numbers and quality of mitochondria, and increases autophagy.
"Many of the beneficial effects are entwined with lower insulin levels."
roguehealthandfitness.com/sweet-spot-int…
"Many of the beneficial effects are entwined with lower insulin levels."
roguehealthandfitness.com/sweet-spot-int…
157/ "Occupational physical activity is associated with higher life expectancy after controlling for confounding factors (birth cohort, education, income, ethnicity, prevalent cardiovascular disease, smoking, leisure-time physical activity, BMI)."
fightaging.org/archives/2021/…
fightaging.org/archives/2021/…
159/ "The right amount of stress (not too much and not too little) can make us stronger, biologically impacting our cells in very beneficial ways."
* Intermittent fasting
* Exercise
* Foods
* Traditional and infrared sauanas
* Cold therapy
* Sleep
cynthiathurlow.com/ep-145-stress-…
* Intermittent fasting
* Exercise
* Foods
* Traditional and infrared sauanas
* Cold therapy
* Sleep
cynthiathurlow.com/ep-145-stress-…
160/ "Scientists removed senescent cells by using lipid antigens to activate iNKT cells. When they treated mice with diet-induced obesity, blood glucose levels improved, while mice with lung fibrosis had fewer damaged cells and also lived longer."
eurekalert.org/pub_releases/2…
eurekalert.org/pub_releases/2…
161/ ...
* Intermittent fasting
* Exercising while in a fasted state
* Boosting autophagy
* Different kinds of exercise
* Detoxing
* Common fasting mistakes
* Fasting variations (especially for women)
...
….mindsharecollaborative.libsynpro.com/ep-146-fasting…
* Intermittent fasting
* Exercising while in a fasted state
* Boosting autophagy
* Different kinds of exercise
* Detoxing
* Common fasting mistakes
* Fasting variations (especially for women)
...
….mindsharecollaborative.libsynpro.com/ep-146-fasting…
162/ Matthew Walker
Poor sleep: Alzheimer’s risk, mental health, memory consolidation
peterattiamd.com/matthewwalker1/
Sleep disruption & heart disease, cancer, sexual function
peterattiamd.com/matthewwalker2/
Effects of poor sleep; impacts of caffeine, alcohol, THC, CBD
peterattiamd.com/matthewwalker3/
Poor sleep: Alzheimer’s risk, mental health, memory consolidation
peterattiamd.com/matthewwalker1/
Sleep disruption & heart disease, cancer, sexual function
peterattiamd.com/matthewwalker2/
Effects of poor sleep; impacts of caffeine, alcohol, THC, CBD
peterattiamd.com/matthewwalker3/
163/ "The Conboys replaced half of mice’s plasma with saline + albumin. The dilution of pro-aging factors activated molecular changes that unleashed age-defying factors, leading to cognitive improvements and reduced inflammation in the brain."
smithsonianmag.com/innovation/in-…
smithsonianmag.com/innovation/in-…
166/ Lifespan Succeeds in Crowdfunding a 200-Person Rapamycin Study
"Much of the cost of formal clinical trials is unrelated to the essentials."
NOTE: This seems well within the reach of philanthropy, which makes me wonder what the real barriers are.
fightaging.org/archives/2021/…
"Much of the cost of formal clinical trials is unrelated to the essentials."
NOTE: This seems well within the reach of philanthropy, which makes me wonder what the real barriers are.
fightaging.org/archives/2021/…
167/ "Bioprinting uses cells that are genetically identical the recipient's. Scientists harvest these cells from a transplant recipient and grow them in the lab. They then use a 3D printer to arrange those cells to create the tissue the patient needs."
statnews.com/2021/06/18/3d-…
statnews.com/2021/06/18/3d-…
168/ "A number of papers in recent years have suggested there to be a link between gum disease and neurodegeneration. Some epidemiological data suggests that the effect size is modest at best, however - a 6% increase in risk in one cohort, for example."
fightaging.org/archives/2021/…
fightaging.org/archives/2021/…
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