Lifespan: The Revolutionary Science of Why We Age—and Why We Don't Have To

by David A. Sinclair

Cynthia Kenyon spoke about her landmark work on a single mutation in the IGF-1 receptor gene that had doubled the lifespan of roundworms by activating DAF-162—work that was first suggested by Partridge to be a worm-specific aberration3 but soon forced her and other leading researchers to confront long-held beliefs that aging could be controlled by a single gene.

Important gene

Brian Kennedy, a former Guarente student who was about to assume the presidency of the Buck Institute for Research on Aging, explained the ways in which genetic pathways that had been similarly conserved in a diverse array of species were likely to play similar roles in mammalian aging. Andrzej Bartke from Southern Illinois University, former PhD adviser to Michael “Marathon Mouse” Bonkowski, talked about how dwarf mice can live up to twice as long as normal mice, a record. Molecular biologist María Blasco explained how old mammalian cells are more likely than young cells to lose their identity and become cancerous. And geneticist Nir Barzilai spoke of genetic variants in long-lived humans and his belief that all aging-related diseases can be substantially prevented and human lives can be considerably extended with one relatively easy pharmaceutical intervention.

Interesting findings related to aging

seditiously: aging itself is a disease.

Girls who go through puberty earlier than normal, for example, have an accelerated epigenetic clock. At that age, we can’t hear the mistakes of the concert pianist.11 But they are there, even as a teenager.

Perhaps the contrapositive is true- my late onset of puberty kept my body in a cataclystic state, associated with neotony

For older diabetics, in particular, a small wound can be deadly: The five-year mortality rate for a foot ulcer in a diabetic is greater than 50 percent. That’s higher than the death rates for many kinds of cancer.13 Chronic foot wounds, by the way, are not rare; we just don’t hear much about them. They almost always begin with seemingly benign rubbing on increasingly numb and fragile soles—but not always. My friend David Armstrong, at the University of Southern California, a passionate advocate for increasing our focus on preventing diabetic foot injuries, often tells the story of one of his patients, who had a nail stuck in his foot for four days. The patient noticed it only because he wondered where the tapping sound on the floor was coming from.

Oh shit, I should keep note.

There’s almost nothing that can be done for them except to cut back the dead and dying tissue, then cut some more, and then some more. From there, robbed of upright mobility, misery is your bedfellow and thankfully death is nigh. In the United States alone, each year, 82,000 elderly people have a limb amputated. That’s ten every hour. All this pain, all this cost, comes from relatively minor initial injuries: foot wounds. The older we get, the less it takes for an injury or illness to drive us to our deaths. We are pushed closer and closer to the precipice until it takes nothing more than a gentle wind to send us over. This is the very definition of frailty. If hepatitis, kidney disease, or melanoma did the sorts of things to us that aging does, we would put those diseases on a list of the deadliest illnesses in the world. Instead, scientists call what happens to us a “loss of resilience,” and we generally have accepted it as part of the human condition. There is nothing more dangerous to us than age. Yet we have conceded its power over us. And we have turned our fight for better health in other directions.

observed that even though average lifespans in the United States have increased in recent decades, our healthspans have not kept up. “We have reduced mortality more than we prevented morbidity,” she wrote in 2015.

DALY, which measures the years of life lost from both premature death and poor state of health. The Russian DALY is the highest in Europe, with twenty-five lost years of healthy life per person. In Israel, it is an impressive ten years. In the United States, the number is a dismal twenty-three.

DALY concept

Heart disease and cancer. Arthritis and Alzheimer’s. Kidney disease and diabetes. Most patients have several additional undiagnosed diseases, including hypertension, ischemic heart disease, atrial fibrillation, and dementia.18 Yes, these are different ailments with different pathologies, studied in different buildings at the National Institutes of Health and in different departments within universities. But aging is a risk factor for all of them. In fact, it’s the risk factor. Truly, by comparison, little else matters.

Aging is the core problem

I also knew why: cigarette smoke contains a chemical called benzo(a)pyrene, which binds to guanine in DNA, induces double-strand breaks, and causes mutations. The repair process also causes epigenetic drift and metabolic changes that cancer cells thrive on, in a process we’ve called geroncogenesis.

Oh shitt, I must take note of this. Cigarettes and their efficacy relating to DNA damage in terms of casual smoking

But consider this: though smoking increases the risk of getting cancer fivefold, being 50 years old increases your cancer risk a hundredfold. By the age of 70, it is a thousandfold.21

Of course not. When we stay healthy and vibrant, as long as we feel young physically and mentally, our age doesn’t matter. That’s true whether you are 32, 52, or 92. Most middle-aged and older adults in the United States report feeling ten to twenty years younger than their age, because they still feel healthy. And feeling younger than your age predicts lower mortality and better cognitive abilities later in life.22 It’s a virtuous cycle, as long as you keep pedaling.

Neotony.

That’s what people have been doing for centuries—without even knowing it—in centenarian-heavy places such as Okinawa, Japan; Nicoya, Costa Rica; and Sardinia, Italy. These are, you might recognize, some of the places the writer Dan Buettner introduced to the world as so-called Blue Zones starting in the mid-2000s.

Blue zones

And overwhelmingly that advice comes down to eating more vegetables, legumes, and whole grains, while consuming less meat, dairy products, and sugar.

Luigi Cornaro, a fifteenth-century Venetian nobleman who could, and probably should, be considered the father of the self-help book.

Over the course of just three months, those who maintained the “fasting mimicking” diet lost weight, reduced their body fat, and lowered their blood pressure, too. Perhaps most important, though, the participants had lower levels of a hormone made primarily in the liver called insulin-like growth factor 1, or IGF-1. 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 100.15 Levels of IGF-1 have been closely linked to longevity. The impact is so strong, in fact, that in some cases it can be used to predict—with great accuracy—how long someone will live, according to Nir Barzilai and Yousin Suh, who research aging at the Albert Einstein College of Medicine at Yeshiva University in New York.

There isn’t much debate on the downsides of consumption of animal protein. Study after study has demonstrated that heavily animal-based diets are associated with high cardiovascular mortality and cancer risk. Processed red meats are especially bad. Hot dogs, sausage, ham, and bacon might be gloriously delicious, but they’re ingloriously carcinogenic, according to hundreds of studies that have demonstrated a link between these foods and colorectal, pancreatic, and prostate cancer.20 Red meat also contains carnitine, which gut bacteria convert to trimethylamine N-oxide, or TMAO, a chemical that is suspected of causing heart disease. That doesn’t mean a little red meat will kill you—the diet of hunter-gatherers is a mix of plants packed with fiber and nutrients, mixed with some red meat and fish in moderation21—but if you’re interested in a long and healthy life, your diet probably needs to look a lot more like a rabbit’s lunch than a lion’s dinner. When we substitute animal protein with more plant protein, studies have shown, all-cause mortality falls significantly.22 From an energy perspective, the good news is that there isn’t a single amino acid that can’t be obtained by consuming plant-based protein sources. The bad news is that, unlike most meats, weight for weight, any given plant usually delivers limited amounts of amino acids. From a vitality perspective, though, that’s great news. Because a body that is in short supply of amino acids overall, or any single amino aci...

It’s also increasingly clear that all essential amino acids aren’t equal. Rafael de Cabo at the National Institutes of Health, Richard Miller at the University of Michigan, and Jay Mitchell at Harvard Medical School have found over the years that feeding mice a diet with low levels of the amino acid methionine works particularly well to turn on their bodily defenses, to protect organs from hypoxia during surgery, and to increase healthy lifespan by 20 percent.24 One of my former students, Dudley Lamming, who now runs a lab at the University of Wisconsin, demonstrated that methionine restriction causes obese mice to shed most of their fat—and fast. Even as the mice, which Lamming called “couch potatoes,” continued to eat as much as they wanted and shun exercise, they still lost about 70 percent of their fat in a month, while also lowering their blood glucose levels.25 We can’t live without methionine. But we can do a better job of restricting the amount of it we put into our bodies. There’s a lot of methionine in beef, lamb, poultry, pork, and eggs, whereas plant proteins, in general, tend to contain low levels of that amino acid—enough to keep the light on, as it were, but not enough to let biological complacency set in. The same is true for arginine and the three branched-chain amino acids, leucine, isoleucine, and valine, all of which can activate mTOR. Low levels of these amino acids correlate with increased lifespan26 and in human studies, a decreased consumption of br...

Protein consumption msy be counter productive to longevity

There is a difference between a leisurely walk and a brisk run, however. To engage our longevity genes fully, intensity does matter. Mayo Clinic researchers studying the effects of different types of exercise on different age groups found that 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.

HITT for longevity, LITt fo ft burn

Cigarettes, for starters. There aren’t many legal vices out there that are worse for your epigenome than the deadly concoction of thousands of chemicals smokers put into their bodies every day. There’s a reason why smokers seem to age faster: they do age faster. The DNA damage that results from smoking keeps the DNA repair crews working overtime, and likely the result is the epigenetic instability that causes aging. And although I’m not likely to be the first person you’ll hear this from, it nonetheless bears repeating: smoking is not a private, victimless activity. The levels of DNA-damaging aromatic amines in cigarette smoke are about fifty to sixty times as high in secondhand as in firsthand smoke.58 If you do smoke, it is worth trying to quit. Don’t smoke? That’s great, but even without smoke there’s fire. In much of the developed world—and increasingly in the developing world as well—we’re practically bathing in DNA-damaging chemicals. In some places—cities with lots of people and lots of cars, especially—the simple act of breathing is enough to do extra damage to your DNA. But it would also be wise to be wary of the PCBs and other chemicals found in plastics, including many plastic bottles and take-out containers.59 (Avoid microwaving these; it releases even more PCBs.) Exposure to azo dyes, such as aniline yellow, which is used in everything from fireworks to the yellow ink in home printers, can also damage our DNA.60 And organohalides—compounds that contain substit...

Cigaretttes and BPA/BPS

Precise vibrating sockets on SIRT1 simultaneously clasp onto an NAD molecule and the protein it wants to strip the acetyls from, such as a histone or FOXO3. The two captured molecules immediately lock together, just before SIRT1 rips them apart in a different way, producing vitamin B3 and acetylated adenine ribose as waste products that are recycled back to NAD.

Differential between Niacin and Niacotinamide

It wasn’t long before researchers discovered that the compound was an effective suppressor of the immune system. That would end its potential as an antifungal—there are plenty of remedies for athlete’s foot that don’t come at the cost of lowered immunity—but it gave scientists a new attribute to study. Even in the 1960s, researchers knew that one of the most common reasons for an organ transplant to fail is that the recipient patient’s body rejects it. Could rapamycin lower the immune response enough to ensure the organ would be accepted? Indeed it could.

Check rapamycin's relationship as an anti inflamamatant (possibly) cellular autophagy and mTOR relationship.

Because in recent years it has become clear that rapamycin isn’t just an antifungal compound and it isn’t just an immune system suppressor; it’s also one of the most consistently successful compounds for extending life.

Check if it operates mTOR, SIRT path, epigenetic recession etc

Type 1 diabetes, which occurs when the pancreas doesn’t produce enough of the hormones needed to alert the body to sugar, is now widely treated by supplemental insulin. But the fight was not over. The type 2 version of the disease, so-called age-associated diabetes, occurs when the pancreas is able to make enough insulin but the body is deaf to it. The 9 percent of all adults globally with this disease need a drug that restores their body’s sensitivity to insulin so cells take up and use the sugar that’s coursing through their bloodstreams. That’s important for at least two reasons: it gives the overworked pancreas a rest, and it prevents spikes of freely floating sugar from essentially caramelizing proteins in the body. Recent results indicate high blood sugar can also speed up the epigenetic clock.

I'll Weed off the keto cycle soon: with a reduction of insulin sensitivity I'll switch to plant proteins to reintroduce carbs (50-75g) into my diet. Too much animal amino acids.

In 1957, Sterne published a paper demonstrating the effectiveness of oral dimethyl biguanide to treat type 2 diabetes. The drug, now most commonly called metformin, has since become one of the most widely taken and effective medicines on the globe. It’s among the medications on the World Health Organization’s Model List of Essential Medicines, a catalog of the most effective, safe, and cost-effective therapies for the world’s most prevalent medical conditions.

I believe metformin also doesn't significantly raise insulin levels

Like rapamycin, metformin mimics aspects of calorie restriction. But instead of inhibiting TOR, it limits the metabolic reactions in mitochondria, slowing down the process by which our cellular powerhouses convert macronutrients into energy.20 The result is the activation of AMPK, an enzyme known for its ability to respond to low energy levels and restore the function of mitochondria. It also activates SIRT1, one of my lab’s favorite proteins. Among other beneficial effects, metformin inhibits cancer cell metabolism, increases mitochondrial activity, and removes misfolded proteins.21 A

Metformin vs rapamycin

An admittedly small study of healthy volunteers claimed that the DNA methylation age of blood cells is reversed within a week and, astoundingly, only ten hours after taking a single 850 mg pill of metformin.

he found two chemicals that, rather than inhibiting SIRT1, stimulated or “activated” it, making it work ten times as fast. That was a serendipitous discovery, not only because he was expecting to find inhibitors but because activators are very rare in nature. They are so rare, in fact, that most drug companies don’t even bother following up when one is discovered, figuring it must be a mistake. The first SIRT1-activating compound, or STAC, was a polyphenol called fisetin, which helps gives plants such as strawberries and persimmons their color and is now known to also kill senescent cells. The second was a molecule called butein, which can be found in numerous flowering plants as well as a toxic plant known as the Chinese lacquer tree. Both had a significant effect on SIRT1, though not the sort of pedal-to-themetal reaction that might make them ripe for further research.

The three main pathways: mtor, ampk and sirt

life. We saw increases in maximum lifespan, too—on resveratrol, they kept going past 35. We tested resveratrol in yeast cells with no SIR2 gene, and there was no effect. We tested it on calorie-restricted yeast, and saw no further increase in lifespan, suggesting that the same pathway was being activated; this was how calorie restriction was working.

Resveratrol on sirt-2

Howitz and I were fascinated by the fact that resveratrol is produced in greater quantities by grapes and other plants experiencing stress.

How come japanese knotweed in the form or tras resveratrol wasn't mentioned here?

xenohormesis—the idea that stressed plants produce chemicals for themselves that tell their cells to hunker down and survive.

Ever wonder why organic foods, which are often grown under more stressful conditions, might be better for you?

Bit of a jump imo lol

This prompted a flood of research into other sirtuin-activating compounds, called STACs, that are many times more potent than resveratrol at stimulating the survival circuit and extending healthy lifespans in animals.

STACs more potent than resveratrol

Another STAC is NAD, sometimes written as NAD+.39 NAD has an advantage over other STACs because it boosts the activity of all seven sirtuins. NAD was discovered in the early twentieth century as an alcoholic fermentation enhancer.

That’s because Shin-ichiro Imai and Lenny Guarente showed that NAD acts as fuel for 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. And we sure wouldn’t have seen the lifespan-extending impact of the activator resveratrol. We and others also noticed that NAD levels decrease with age throughout the body, in the brain, blood, muscle, immune cells, pancreas, skin, and even the endothelial cells that coat the inside of microscopic blood vessels.

We first discovered a gene called PNC1, which turns vitamin B3 into NAD.

discovered in 2004 that a form of vitamin B3 called nicotinamide riboside, or NR, is a vital precursor of NAD. He later found that NR, which is found in trace levels in milk, can extend the lifespan of yeast cells by boosting NAD and increasing the activity of Sir2. Once a rare chemical, NR is now sold by the ton each month as a nutraceutical. Meanwhile, on a parallel path, researchers, including us, were homing in on a chemical called nicotinamide mononucleotide, or NMN, a compound made by our cells and found in foods such as avocado, broccoli, and cabbage. In the body, NR is converted into NMN, which is then converted into NAD. Give an animal a drink with NR or NMN in it,40 and the levels of NAD in its body go up about 25 percent over the next couple of hours, about the same as if it had been fasting or exercising a great deal.

Nr vs nmn

One more thing that is important to bear in mind: 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.44 Meanwhile, emerging research is demonstrating that the inhibition of mammalian target of rapamycin, or mTOR, may be able to preserve ovarian function and fertility during chemotherapy,45 while the same gene pathway plays an important role in male fertility, as a central player in the production and development of sperm.

Why short telomeres cause senescence has been mostly worked out. A very short telomere will lose its histone packaging, and, like a shoelace that’s lost an aglet, the DNA at the end of the chromosome becomes exposed. The cell detects the DNA end and thinks it’s a DNA break. It goes to work to try to repair the DNA end, sometimes fusing two ends of different chromosomes together, which leads to hypergenome instability as chromosomes are shredded during cell division and fused again, over and over, potentially becoming a cancer.

Short explanation of telomeric length

Small numbers of senescent cells can cause widespread havoc. Even though they stop dividing, they continue to release tiny proteins called cytokines that cause inflammation and attract immune cells called macrophages that then attack the tissue.

Understanding why senescence evolved is not just an academic exercise; it could help us design better ways to prevent or kill senescent cells. Cellular senescence is a consequence of our inherited primordial survival circuits, which evolved to stop cell division and reproduction when DNA breaks were detected. Just as in old yeast cells, if DNA breaks happen too frequently or they overwhelm the circuit, human cells will stop dividing, then sit there in a panic, trying to repair the damage, messing up their epigenome, and secreting cytokines. This is the final stage of cellular aging—and it’s not pretty.

A class of pharmaceuticals called senolytics may be the zombie killers we need to fight the battle against aging on this front.

That’s what the Mayo Clinic’s James Kirkland has done. He needed only a quick course of two senolytic molecules—quercetin, which is found in capers, kale, and red onions, and a drug called dasatinib, which is a standard chemotherapy treatment for leukemia—to eliminate the senescent cells in lab mice and extend their lifespan by 36 percent.4 The implications of this work cannot be overstated. If senolytics work, you could take a course of a medicine for a week, be rejuvenated, and come back ten years later for another course. Meanwhile, the same medicines could be injected into an osteoarthritic joint or an eye going blind, or inhaled into lungs made fibrotic and inflexible by chemotherapy, to give them an age-reversal boost, too. (Rapamycin, the Easter Island longevity molecule, is what’s known as a “senomorphic” molecule, in that it doesn’t kill senescent cells but does prevent them from releasing inflammatory molecules, which may be almost as good.5

Then, in 1996, Ian Wilmut and his colleagues at the University of Edinburgh replaced the chromosomes of a sheep’s egg with those from an udder cell. The result was Dolly, whose birth was met with a heated public debate about the purported dangers of cloning. The debate overshadowed the most important point: that old DNA retains the information needed to be young again.

I remember i used to think this technique would damage the dvd as if it were an analog device.

CLAUDE SHANNON’S 1948 SOLUTION TO RECOVERING LOST INFORMATION DURING DATA TRANSMISSIONS LED TO CELL PHONES AND THE INTERNET. It may also be the solution to reversing aging. Source: C. E. Shannon, “A Mathematical Theory of Communication,” Bell System Technical Journal 27, no. 3 (July 1948): 379–423 and 27, no. 4 (October 1948): 623–66. To end aging as we know it, we need to find three more things that Shannon knew were essential for a signal to be restored even if it is obscured by noise: An “observer” who records the original data The original “correction data” And a “correcting device” to restore the original signal I believe we may have finally found the biological correcting device.

In 2006, the Japanese stem cell researcher Shinya Yamanaka announced to the world that after testing dozens of combinations of genes, he had discovered that a set of four—Oct4, Klf4, Sox2, and c-Myc—could induce adult cells to become pluripotent stem cells, or iPSCs, which are immature cells that can be coaxed into becoming any other cell type. These four genes code for powerful transcription factors that each controls entire sets of other genes that move cells around on the Waddington landscape during embryonic development. These genes are found in most multicellular species, including chimpanzees, monkeys, dogs, cows, mice, rats, chickens, fish, and frogs. For his discovery, essentially showing that complete cellular age reversal was possible in a petri dish, Yamanaka won the Nobel Prize in Physiology or Medicine along with John Gurdon in 2012. We now call these four genes Yamanaka factors.

Yamanaka's experiments

Patients with an RPE65 mutation that causes blindness, for example, can now be cured with a simple injection of a safe virus that infects the retina and delivers, forever, the functional RPE65 gene.

Another gene

Yamanaka factors from birth; these can be turned on by injecting the mice with doxycycline. In a now-famous study from 2016, when Belmonte triggered the Yamanaka factors for just two days a week throughout the lifespan of a prematurely aging mouse breed called LMNA, the mice remained young compared to their untreated siblings and lived 40 percent longer.11 He’s shown that the skin and kidneys of regular old mice heal more quickly, too. The Yamanaka treatment, however, was highly toxic.

Yamanaka treatments and their risky toxicity, you must stay on the edge of life to prevent senescence.

the four-gene combo could induce teratomas, which are particularly disgusting tumors made up of several types of tissue, such as hair, muscle, or bone.

Wacky biology