Lifespan: Why We Age – and Why We Don’t Have To

David Sinclair’s Book Review and Summary

Little by little, millenia by millenia, we’ve been adding years to the average human life through access to stable food sources and clean water.
But although the average moved up, the limit did not.

As long as we’ve been recording history, we have known people, who have reached their 100th year and who might have lived beyond that mark. But we rarely reach 110. Almost no one reaches 115.

Measuring Biological Age

To put yourself into an aged mind-set, try this little experiment.
Using your nondominant hand, write your name, address, and phone number while circling your opposite foot counterclockwise.

Different functions peak at different times for different people, but physical fitness, in general, begins to decline in our 20s and 30s.

There are some simple tests to determine how biologically old you probably are.

Push-Ups
The number of push-ups you can do is a good indicator.
If you are over 45 and can do more than twenty, you are doing well.

Sitting-Rising Test (SRT)
The other test of age is the sitting-rising test (SRT).
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.
A middle-aged person typically needs ato push off with one of their hands.
An elderly person often needs to get onto one knee.
A study of people 51 to 80 years found that 157 out of 159 people who passed away in 75 months had received less than perfect SRT scores.

Horvath Clock
Named after Steve Horvath from UCLA, Horvath Clock is an accurate way of estimating someone’s biological age by measuring thousands of epigenetic marks on the DNA, called methylation.

Hallmarks of Aging

1. Genomic instability caused by DNA damage;
2. Attrition of the protective chromosomal endcaps, the telomeres;
3. Alterations to the epigenome that controls which genes are turned on and off;
4. Loss of healthy protein maintenance, known as proteostasis;
5. Deregulated nutrient sensing caused by metabolic changes;
6. Mitochondrial dysfunction;
7. Accumulation of senescent zombielike cells that inflame healthy cells;
8. Exhaustion of stem cells;
9. Altered intercellular communication and the production of inflammatory molecules.

Lifespan vs. Healthspan

There is the difference between extending life and prolonging vitality.

Addressing hallmarks of aging could vastly increase average lifespan, but it might not be enough for pushing past the maximum limit.

Treating one disease at a time has little impact on lifespan.
Your chance of developing a lethal disease increases by a thousandfold between the ages of 20 and 70, so preventing one disease makes little difference to lifespan.

Even though average lifespans in the US have increased in recent decades, our healthspans have not kept up.

Hallmarks are accurate indicators of aging and its myriad symptoms but unable to explain why hallmarks occur in the first place.

Aging results in physical decline.
It limits the quality of life.

DALY, or disability-adjusted life year,
measures the years of life lost from both premature death and poor state of health.
The Russian DALI is highest in Europe, with 25 lost years of healthy life per person.
The US DALI is 23.
In Israel DALI is 10.

We can get to an increased lifespan through an ever-rising healthspan, the portion of our lives spent without disease or disability.

What is the upward limit? The author, David Sinclair, doesn’t think that there is one.
Many of his colleagues agree.
There is no biological law that says we must age.

We have found genes that impact the symptoms of aging.

We have found longevity genes that control the body’s defenses against aging and thus offer a path to slowing down aging through natural, pharmaceutical, and technological interventions.

But we haven’t identified a singular gene that causes aging.

And we won’t.

Because our genes did not evolve to cause aging.

From the looks of it, aging is not going to be that hard to treat, far easier than curing cancer.

Inspiring Examples from Nature

Bristlecone Pine Trees of California White Mountains
Over the course of many thousands of years, their cells do not appear to have undergone any decline in function. Scientists call this “negligible senescence”.

Hydra Vulgaris
This freshwater polyp also evolved to defy senescence.

“Immortal Jellies”
A couple of species of jellyfish can completely regenerate from adult body parts, earning them the nickname “immortal jellies”, e.g., Aurelia aurita from the US West Coast and Turritopsis dohrnii from the Miditerranian.

These biological equivalents of F. Scott Fitzgerald’s backward-aging Benjamin Button teaches us: that cellular age can be fully reset without losing our wisdom, our memories, or our souls.

The Theories of Aging

David Sinclair feels that there has never been a unified theory of aging.
The author is confident he can provide one.

Mutation Accumulation as a Cause of Aging (independently proposed by Peter Medawar and Leo Szilard)

Aging is caused by DNA damage and a resulting loss of genetic information.

This theorie was embraced during 1950s and 1960s, when the effects of radiation on human DNA were on a lot of people’s minds.

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, so it cannot serve as a universal theory.

“Error Catastrophe Hypothesis” by Leslie Orgel, 1963

Mistakes made during the DNA-Copying process lead to mutation of genes, including those needed to make the protein machinery that copies DNA.

The process increasingly multiplies upon itself until a person’s genome has been incorrectly copied into oblivion.

“Free Radical Theory of Aging” by Denham Harman

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.

Harman was taking high doses of alpha-lipoic acid for most of his life to quench free radicals.

Although there was some success in increasing the average lifespan of rodents, the overall results of testing if antioxidants would extend the maximum lifespan of animals were disappointing.

Although advertised by the pills and drinks industry, this theory was overturned by scientists almost a decade ago.

Aging isn’t caused by mutations in nuclear DNA.

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.

Restoration of the Function of Mitochondria
Free radicals do cause mutations. However testing showed that increasing free-radical damage or mutations in mice does not lead to aging.
It has proven surprisingly 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.

Cloning
If mutations cause aging, we shouldn’t be able to clone new animals from older individuals. Clones would be born old. But cloned animals don’t age prematurely. E.g., although Dolly, the first cloned sheep, died prematurely of a progressive lung disease, her remains showed no sign of premature aging. Since then there have been a lot of cloned goats, sheep, mice, and cows that lived a normal lifespan.

The Information Theory of Aging by David Sinclair

The Survival Circuit

Ancient Survival Gene Circuit
We have inherited an advanced version of a 4-billion-year-old survival gene circuit.

The first life-forms would have turned off reproduction while DNA was being repaired, providing a survival advantage.

When DNA breaks, gene A turns off reproduction.
The protein made by gene B leaves to go repair DNA.
When repair is complete and it is safe to reproduce, gene B makes a protein that turns gene A back off and the cell can reproduce.

Cells that fail to pause while fixing a DNA break will almost certainly lose genetic material. Such cells will likely die or multiply uncontrollably into a tumor.

Human Survival Gene Circuit
Our DNA is constantly under attack.

On average, each of our forty-six chromosomes is broken in some way every time a cell copies its DNA, amounting to more than 2 trillion breaks in our bodies per day.
And that’s just the breaks that occur during replication.

Others are caused by natural radiation, chemicals in our environment, and the X-rays and CT scans that we’re subjected to.

If we didn’t have a way to repair our DNA, we wouldn’t last long.
We evolved to sense DNA damage, slow cellular growth, and divert energy to DNA repair until it was fixed – the survival circuit.

Mammals don’t just have a couple of genes that create a survival circuit.
Scientists have found more than two dozen of them within our genome, called:

• “longevity genes” because of the ability to extend both average and maximum lifespans;
• “vitality genes” because of the ability to make life healthier.

Together, these genes form a surveillance network within our bodies, communicating with one another between cells and between organs by releasing proteins and chemicals into the bloodstream, monitoring and responding to what we eat, how much we exercise, and what time of day it is.

But there is a trade-off. For this circuit within us is also the reason we age.

Digital and Analog Information in Biology

According to the Information Theory of Aging, aging, quite simple, is a loss of information.

But there are two types of information in biology, and they are encoded differently:

1. Digital information – based on a finite set of possible values, quaternary (base 4), coded as adenine, thymine, cytosine, and guanine, the nucleotides A, T, C, G of DNA.

2. Analog information – epigenome, meaning traits that are heritable that aren’t transmitted by genetic means.

   Every one of our cells has the same DNA, so what differentiates a nerve cell from a skin cell is epigenome.

   Epigenome is the collective term for the control systems and cellular structures that tell the cell which genes should be turned on and which should remain off.

   DNA in a cell isn’t flailing around disorganized.
   Epigenome consists of strands of DNA wrapped around tiny balls of spooling proteins called histones
   (these beads on a string self-assemble to form loops – imagine looping your garden hose into a pile),
   which are bound up into even bigger loops called chromatin,
   which are bound up into bigger loops called chromosomes.

If the genome were a computer, the epigenome would be the software.

Digital chemical system was the best way to store long-term genetic data.

But information storage was also needed to record and respond to environmental conditions, and this was best stored in analog format.

Analog data are superior for this job because they can be changed back and forth with relative ease whenever the environment within or outside the cells demands it, and they can store an almost unlimited number of possible values, even in response to conditions that have never been encountered before.

But even though analog devices have their advantages, they have a major disadvantage – analog information degrades over time and information is lost as it’s copied.

DVD Player Analogy
We are the biological equivalent of an old DVD player. And this is actually good news.

If mutations caused aging, we would not be able to easily address it, because when information is lost without a backup, it is lost for good.

You can not play or restore content from a broken DVD.

But we can usually recover information from a scratched DVD.
The same kind of process is what it will take to reverse aging.

As cloning beautifully proves, our cells retain their youthful digital information even when we are old.

To become young again, we just need to find some polish to remove the scratches.

Foundation for Understanding The Survival Circuit and Its Role in Aging

Cell Ex-differentiation

Epigenome instructs the newly divided cells on what type of cells they should be and what they should remain (sometimes for decades, as in the case of individual brain neurons and certain immune cells).

That’s why a neuron doesn’t one day behave like a skin cell and a dividing kidney cell doesn’t give rise to two liver cells.

Without epigenetic information, cells would quickly lose their identity
and new cells would lose their identity, too.
If they did, tissues and organs would eventually become less and less functional until they failed.

At the molecular level, what’s really going on is that different genes are being switched on and off, guided by transcription factors, sirtuins and other enzymes such as DNA methyltransferases (DNMTs), which mark the DNA and its packing proteins with chemical tags that instruct the cell and its descendants to behave in a certain way.

As we age, broken DNA activates the curvival circuit and rejiggers DNA in small ways.

When you disrupt the epigenome by forcing it to deal with DNA breaks, you introduce noise, leading to an erosion of the epigenetic landscape.

Every time there’s a radical adjustment to the epigenome (e.g., DNA damage from the sun or an X-ray), a cell’s identity changes.
A skin cell starts behaving differently, turning off genes that were shut off in the womb and were meant to stay off.

Over time, cells progressively lose their original identity,
eventually transforming into zombielike senescent cells in old tissues.
Now it is 90% a skin cell and 10% other cell types, all mixed up, with properties of neurons and kidney cells.
The cell becomes inept at the things skin cells must do, such as making hair, keeping the skin supple, and healing when injured.
We say the cell has ex-differentiated.

Each cell is succumbing to epigenetic noise.
The tissue made up of thousands of cells is becoming a melange, a medley, a miscellaneous set of cells.
The body turns into chimeras of misguided, malfunctioning cells.

That’s aging.
This loss of analog information is what leads each of us into a world of heart disease, cancer, pain, frailty, and death.

The Demented Pianist Analogy

Think of our genome as a grand piano.
Each gene is a key.
Each key produces a note.

And from instrument to instrument,
depending on the maker, the materials, and the circumstances of manufacturing,
each will sound a bit different, even if played the exact same way.

These are our genes.
We have about 20,000 of them, give or take a few thousand.

Each key can also be played pianissimo (soft) or forte (with force).

The notes can be tenuto (held) or allegretto (played quickly).

For master pianists, there are hundreds of ways to play the keys together,
in chords and combinations that create music we know as jazz, rock, waltzes etc.

The pianist that makes this happen is the epigenome.

Through a process of revealing our DNA or bundling it up in tight protein packages, and by marking genes with chemical tags called methyls and acetyls composed of carbon, oxygen, and hydrogen, the epigenome uses our genome to make the music of our lives.

Sometimes the size, shape, and condition of a piano dictate what a pianist can do with it. Likewise, the genome certainly dictates what the epigenome can do.

But our DNA is not our destiny.

Now imagine you’re in a concert hall.
The music is perfect.
But then, a few minutes into a piece, the pianist misses a key.
The first time it happens, it’s almost unnoticeable.
But then, a few minutes later it happens again.
And then, with increasing frequency, again and again and again.

It’s important to remember that there is nothing wrong with the piano.
Indeed, we’d assume that there was something wrong with the pianist.
And the pianist is playing most of the notes prescribed by the composer,
but also playing some extra notes.

Epigenetic noise causes the same kind of chaos.

It is driven in large part by highly disruptive insults to the cell, such as broken DNA, as it was in the original 4-billion-year-old survival gene circuit.

And this, according to the Information Theory of Aging, is why we age.
Moreover, it’s why each one of the hallmarks of aging occurs, from stem cell exhaustion and cellular senescence to mitochondrial dysfunction and rapid telomere shortening.

Information Theory of Aging. Universal Model Of Life And Death:
Youth =>
=> broken DNA =>
=> genome instability =>
=> disruption of gene packaging and gene regulation (the epigenome) ->
=> loss of cell identity =>
=> cellular senescence =>
=> disease =>
=> death

Longevity Genes Classification

1. Sirtuins
2. Rapamycin or TOR/mTOR
3. AMPK

Sirtuins

The longevity genes the author works on are called “sirtuins”, named after the yeast SIR2 gene.

Sirt2 gene in yeast and SIRT genes in mammals are all descendants of gene B.
It’s original job was to silence a gene that controlled the reproduction.
In mammals, the sirtuins have since taken on a variety of new roles, not just as controllers of fertility (which they still are).

After a few billion years of advancements since the day of the yeast, they have evolved to control our health, our fitness, and our very survival.

These critical epigenetic regulators sit at the very top of cellular control systems, controlling our reproduction and our DNA repair.

There are seven sirtuins in mammals, SIRT1 to SIRT7, and they are made by almost every cell in the body:

1. SIRT1, SIRT6, and SIRT7, are critical to the control of the epigenome and DNA repair.
2. SIRT3, SIRT4, and SIRT5, reside in mitochondria, where they control energy metabolism.
3. SIRT2 buzzes around the cytoplasm, where it controls cell division and healthy egg production.
4. SIRT1 in mammals moves from silent genes to help repair broken DNA in mammal and human cells.

Sirtuins instruct the histone spooling proteins to bind up DNA tightly, while they leave other regions to flail around.

In this way some genes stay silent, while others can be accessed by DNA-binding transcription factors that turn genes on.

Accessible genes are said to be in “euchromatin”, while silent genes are in “heterochromatin”.

Sirtuins are enzymes that remove acetyl tags from histones and other proteins (e.g. those controlling cell division, survival, DNA repair, inflammation, glucose metabolism, mitochondria etc.).

By removing chemical tags on histones,
sirtuins help prevent transcription factors from binding to genes,
converting euchromatin (accessible) into heterochromatin (silent).

By doing so, sirtuins change the packaging of the DNA, turning genes on and off when needed.

Sirtuins also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD.
The loss of NAD as we age, and the 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.

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.

They mute the chronic, overactive inflammation that drives such as atherosclerosis, metabolic disorders, ulcerative colitis, arthritis, and asthma.

They prevent cell death and boost mitochondria, the power packs of the cell.
They go to battle with muscle wasting, osteoporosis, and macular degeneration.

In studies on mice, activating the sirtuins can improve DNA repair, boost memory, increase exercise endurance, and help the mice stay thin, regardless of what they eat.

Sirtuin Emergency Teams
Sirtuins are the directors of the specialized emergency teams that address DNA instability, DNA repair, cell survivability, metabolizm, and cell-to-cell communication.

When sirtuins shift from their typical priorities to engage in DNA repair, their epigenetic function at home ends for a bit.

Then, when the damage is fixed and they head back to home base, they get back to doing what they usually do: controlling genes and making sure the cell retains its identity and optimal function.

But what happens when there’s one emergency after another to tend to?
The repair crews are away from home a lot.
The work they normally do piles up.
And most of all, one of the most important things they do while at home – reproducing – doesn’t get done.

This form of hormesis, the original survival circuit, works fine to keep organisms alive in the short term.

But unlike longevity molecules that simply mimic hormesis by tweaking sirtuins, mTOR, or AMPK, sending out the troops on fake emergencies, these real emergencies create life-threatening DNA damage (from malign chemicals, radiation, DNA copying).

It’s not so much that the sirtuins are overwhelmed, what’s happening every day is that the sirtuins and their coworkers that control the epigenome don’t always find their way back to their original gene stations after they are called away.

Sometimes they return to other places along the genome.
Wherever they stop on the genome, sirtuins are silencing genes that aren’t supposed to be silenced.

Wherever the epigenetic factors leave the epignome to address damage, genes that should be off, switch on and vice versa.

All of this is altering the epigenome in ways that were never intended when we were born.
Cells lose their identity and malfunction.

This is a cellular equivalent of destructing the cellular pianist.

This is the epigenetic noise that is at the heart of the unified aging theory.

AMPK

AMPK is a metabolic control enzyme, which evolved to respond to low energy levels.

Rapamycin or TOR/mTOR

Rapamycin or TOR (called mTOR in mammals) – a complex of proteins that regulates growth and metabolism.

Like that of sirtuins, mTOR activity is exquisitely regulated by nutrients.
And like that of sirtuins, mTOR can signal cells in stress to hunker down and improve survival by boosting such activities as DNA repair, reducing inflammation caused by senescent cells, and, perhaps its most important function, digesting old proteins.

When all is well and fine, TOR is a master driver of cell growth.
It senses the amount of amino acids that is available and dictates how much protein is created in response.

When it is inhibited, though, it forces cells to hunker down, dividing less and reusing old cellular components to maintain energy and extend survival – sort of like going to the junkyard to find parts with which to fix up old car rather that buying a new one, a process called autophagy.

When our ancestors were unsuccessful in bringing down a woolly mammoth and had to survive on meager rations of protein, it was the shutting down of mTOR that permitted them to survive.

Longevity Genes and Hormesis

The defense systems based on longevity genes are all activated in response to biological stress.

Some stressors are simply too great to overcome – acute trauma and uncontrollable infections will kill an organism without aging that organism.

Important point is that there are plenty stressors that will activate longevity genes without damaging the cell, including:

1. certain types of exercise;
2. intermittent fasting;
3. low-protein diets;
4. exposure to hot and cold temperatures.

That is called hormesis.
Hormesis is generally good for organisms, especially when it can be induced without causing any lasting damage.

When hormesis happens all is well.
And, in fact, all is better than well, because the little bit of stress that occurs when the genes are activated prompts the rest of the system to hunker down, to conserve, to survive a little longer.

That’s the start of longevity.

Complementing these approaches are hormesis-mimicking molecules, drugs that can turn on the body’s defenses without creating any damage.
In this way we can mimic the benefits of exercise and intermittent fasting with a single pill.

It’s like a prank call on a Pentagon: the troops and the Army Corps are sent out, but there is no war.

A bit of adversity or cellular stress is good for our epigenome because it stimulates our longevity genes.
It activates AMPK, turns down mTOR, boosts NAD levels, and activates sirtuins – the disaster response teams – to keep up with the normal wear and tears that comes from living on planet Earth.

Hormesis vs. DNA Damage

When it comes to aging, “normal” is bad enough.
When our sirtuins have to respond to many disasters – especially those that cause double-strand DNA breaks – these epigenetic signalers are forced to leave their posts and head to other places on the genome where DNA breaks have occurred.
Sometimes they make their way back home. Sometimes they don’t.

The natural and necessary act of replicating DNA causes DNA breaks, trillions of them throughout your body every day.
Embryos and babies experience aging.

We can’t prevent all DNA damage – and we wouldn’t want to because it’s essential for the function of the immune system and even for consolidating our memories – but we do want to prevent extra damage:

• Cigarettes. There’s a reason why smokers seem to age faster: they do age faster.
• We’re particularly bathing in DNA-damaging chemicals: mercury, PCBs, PBDEs, dioxins, and chlorinated pesticides.
  In some cities the simple act of breathing is enough to do extra damage to your DNA.
• PCBs and other chemicals found in plastic.
• Azo dyes, such as aniline yellow, which is used in everything from fireworks to the yellow ink in home printers.
• Organohalides – compounds that contain substituted halogen atoms and are used in solvents, degreasers, pesticides, and hydraulic fluid.
• N-nitroso compounds that are present in food treated with sodium nitrite, including some beers, most cured meats, and especially cooked bacon.
• Radiation. Any source of natural or human-inflicted radiation, such as UV light, X-rays, gamma rays, and radon in homes (which is the second most frequent cause of lung cancer besides smoking.)

Xenohormesis

Many health-promoting molecules, and chemical derivatives of them, are produced by stressed plants, we get:

• resveratrol from grapes;
• aspirin from willow bark;
• metformin from lilacs;
• epigallocatechin gallate from green tea;
• quercetin from fruits;
• and allicin from garlic.

This is the evidence of xenohormesis – the idea that stressed plants produce chemicals for themselves that tell their cells to hunker down and survive.

This means that when we search for new drugs from the natural world we should be searching the stressed-out ones: in stressed plants, in stressed fungi, and even in the stressed microbiome populations in our guts.

The theory is also relevant to the foods we eat; plants that are stressed have higher concentrations of xenohormetic molecules that may help us engage our own survival circuits.

Look for the most highly colored ones because xenohormetic molecules are often yellow, red, orange, or blue.

One added benefit: they tend to taste better.
The best wines in the world are produced in dry, sun-exposed soil or from stress-sensitive varieties such as Pinot Noir; as you might guess, they also contain the most resveratrol.
The most delectable strawberries are those that have been stressed by periods of limited water supply, the best heads of lettuce come when the plants are exposed to a one-two combo punch of heat and cold.
Ever wonder why organic foods, which are often grown under more stressful conditions, might be better for you?

Lessons from Yeast About Why We Age

In young yeast cells, male and female “mating-type information” (gene A) is kept in the “off” position by the Sir2 enzyme (encoded by a descendant of gene B).

With time, the instability of the highly repetitive ribosomal DNA (rDNA) causes toxic DNA circles to form.
DNA was recombining and amplifying, showing up as dark spots and wispy circles, depending on how coiled up and twisted they are.
These loops were called extrachromosomal ribosomal DNA circles, or ERCs, and they are accumulating as the mutants age.

These recombine and eventually accumulate to toxic levels in old cells, killing them.

In response to DNA circles and the perceived genome instability, Sir2 moves away from silent mating-type genes to help stabilize the genome.

Redistribution of Sir2 to the nucleus is a response to numerous DNA breakages, which happen as a result of ERCs multiplying and inserting back into the genome or joining together to form super large ERCs.

When Sir2 moves to combat DNA instability, it causes sterility in old bloated yeast cells.

Both male and female genes turn on, causing infertility, the main hallmark of yeast aging.

It is epigenomic noise in its purest form.

If the aging was induced, we would see the same pattern emerge in yeast cells that had aged normally.

Experiment 1 – Werner’s Syndrome in Yeast

Understanding of aging by studying Werner’s Syndrome, caused by WRN gene mutation, symptoms of which include a loss of body strength, wrinkles, gray hair, hair loss, cataracts, osteoporosis, heart problems, and many other telltale signs of aging among people in their 30s and 40s. Life expectancy for someone with Werner is 46 years.

In experiments with yeast, broken DNA causes genome instability, which distracts Sir2 protein, which changes epigenome, causing the cells to lose their identity and become sterile while they fixed the damage.Those were the analog scratches on the digital DVDs. Epigenetic changes cause aging. There is a singular process that controls them all.

Nucleus exploding -> sirtuins moving toward it as the cells grew older

In yeast, the equivalent of WRN gene is Slow Growth Suppressor 1, or SGS1.
After the swap of the functional SGS1 gene with a mutant version, the yeast cell’s lifespan was cut in half after a precipitous decline in health and function.

In the aged SGS1 cells, the nucleolus looked as if it had exploded.
The rDNA of the yeast cells looked like a vacuum-sealed bag of yarn that had been ripped open.

In response to the damage, Sir2 (descended from gene B) moved away from the mating genes (descended from gene A) that control fertility and into the nucleolus.

Sir2 is an epigenetics factor, an enzyme that sits on genes, bundles up the DNA, and keeps them silent.
At the molecular level, Sir2 achieves this via its enzymatic activity, making sure that chemicals called acetyls don’t accumulate on histones and loosen the DNA packaging.

When sirtuins left the mating genes, the mutant cells turned on both male and female genes, causing them to lose their sexual identity much earlier than in normal old cells.

Experiment 2 – putting ERC into young yeast cells

If we put an ERC into young yeast cells, ERCs would multiply and distract the sirtuins, and the yeast cells age prematurely, go sterile, and die young.
This is evidence that ERCs don’t just happen during aging, they cause it.

Experiment 3 – putting SIR2 into a cell

Inserting an extra copy of SIR2 into the genome of yeast cells stabilizes the yeast genome and delays aging, causing a 30% increase in the yeast cell’s lifespan.
Adding extra copies of the dSir2 gene to fruit flies suppresses epigenetic noise and extends their lifespan.

Are Findings in Yeast Relevant to More Complex Organisms?

In 2017 Eva Bober’s team at the Max Planck Institute for Heart and Lung Research reported that sirtuins stabilize human rDNA.

In 2018 Katrin Chua at Stanford University found that, by stabilizing human rDNA, sirtuins prevent cellular senescence – essentially the same antiaging function as were found for sirtuins in yeast twenty years earlier.

Longevity Now

Fasting

There is widespread disagreement, even among the best nutritionists in the world as to what constitutes the “best” diet for H. sapiens. That’s likely because there is no best diet; we’re all different enough that our diets need to be subtly and sometimes substantially different, too. But we’re also all similar enough that there are some very broad commonalities: more veggies and less meat; fresh food versus processed food.

One surefire way to stay healthy longer, one thing you can do to maximize your lifespan right now is to eat less often.
Not malnutrition. Not starvation. But fasting.

Caloric Restriction
Yeast, rodents, fruit flies and our close genetic cousins rhesus monkeys lived longer when their food was restricted.

In animal studies, the key to engaging the sirtuin program appears to be keeping things on the razor’s edge through calorie restriction – just enough food to function in healthy ways and no more.

It engages the survival circuit, telling longevity genes to do what they have been doing since primordial times: boost cellular defenses, keep organisms alive during times of adversity, ward off disease and deterioration, minimize epigenetic change, and slow down aging.

Longevity gene MSN2 in yeast stands for “multicopy suppressor of SNF1 (AMPK in humans) epigenetic regulator”.
It’s job in yeast is to turn on genes that push cells away from cell death and toward stress resistance.
When calories are restricted MSN2 extends lifespan by turning up genes that recycle NAD, thereby giving the sirtuins a boost.

FOXO3 varians in humans (analogies of yeasts’ MSN2) likely turn on the body’s defenses against diseases and aging, not just when times are tough but throughout life.

But this has proven a challenge to test on humans in a controlled scientific setting.
It would be a challenge to keep a test group of humans on the razor’s edge for long periods of time.

There are observational studies that strongly suggest long-term calorie restriction could help humans live longer and healthier lives, too.

• In 1978 on the island of Okinawa, framed for its large number of centenarians, bioenergetics researcher Yasuo Kagawa learned that the total number of calories consumed by schoolchildren was less than two-thirds of what children were getting in mainland Japan. Adult Okinawans were also leaner, taking in about 20 percent fewer calories than their mainland counterparts.
• The Biosphere 2 research: from 1991 to 1993, eight people lived inside a three-acre, closed ecological dome in southern Arizona, where they were expected to be reliant on the food they were growing inside. The amount of food they farmed was not sufficient, it wasn’t bad enough to cause malnutrition, but it did mean that the team members were frequently hungry.

CR hasn’t been demonstrated only to lengthen life but also to forestall cardiac disease, diabetes, stroke, and cancer. It’s not just a longevity plan; it’s a vitality plan.

Research is increasingly demonstrating that many of the benefits of a life of strict and uncompromising calorie restriction can be obtained in another way. In fact, that way might be even better.

Intermittent fasting
Eating normal portions of food but with periodic episodes without meals – is often portrayed as a new innovation in health.

In 1946, University of Chicago researchers Anton Carlson and Frederick Hoelzel subjected rats to periodic food restrictions and found that those that went hungry every third day lived 15 to 20 percent longer than their cousins on a regular diet.

At the time it was believed that fasting provided the body with a “rest”.
That’s very much the opposite of what we know about what happens at a cellular level when we subject our bodies to the stress of going without food.

Today, human studies are confirming that once-in-a-while calorie restriction can have tremendous health results, even if the times of fasting are quite transient.

In one such study, participants ate a normal diet except restricting their diet to vegetable soup, energy bars, and supplements for five days each month. 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.
Most importantly, the participants had lower levels of a hormone made primarily in the liver called insulin-like growth factor 1, or IGF-1.
Levels of IGF-1 have been closely linked to longevity and can be used to predict how long someone will live.

Geneticists Nir Barzilai and Yousin Suh from Albert Einstein College of Medicine at Yeshiva University in New York focus their research on centenarians who have made it to 100 – and beyond – without suffering from age-related diseases.
In some cases it doesn’t actually matter what they put into their bodies. They carry gene variants that seem to put them into a state of fasting no matter what they eat.

Some people are simply winners in the genetic lottery.
The rest of us have some extra work to do.
But the good news is that the epigenome is malleable.
Since it’s not digital, it’s easier to impact.
We can control the behavior of this analog element of our biology by how we live our lives.

The important thing is not just what we eat but the way we eat.
There is a strong correlation between fasting behavior and longevity in Blue Zones such as Ikaria, Greece. On many days, that means no meat, dairy products, or eggs and sometimes no wine or olive oil. Additionally, many Greeks observe periods of total fasting before taking Holy Communion.

Many centenarians of Bama County in southern China generally eat their first small meal of the day around noon, then share a larger meal with their families at twilight.
In this way, they typically spend sixteen hours or more each day without eating.

There are numbers of ways to calorie restrict that are sustainable, and many take the form of what has to come to be known as periodic fasting – not being hungry all the time but using hunger some of the time to engage our survival circuit:

• A popular method is to skip breakfast and have a late lunch (the 16:8 diet).
• Another is to eat 75 percent fewer calories for two days a week (the 5:2 diet).
• You can try skipping food a couple of days a week (Eat Stop Eat).
• The health pundit Peter Attia goes hungry for an entire week every quarter.

The permutations of these various models for extending life and health are being worked out in animals. The short-term studies are promising.
Over time, some of these ways of limiting food will prove to be more effective than others.

Amino Acids
We are engaging the survival circuit by limiting how much we eat, but what we eat is also important.

We’d die quite quickly without amino acids, the organic compounds that serve as the building blocks for every protein in the human body.
Without them – and in particular the nine essential amino acids that our bodies cannot make on their own – our cells can’t assemble the life-giving enzymes needed for life.

Meat contains all 9 of the essential amino acids, but it doesn’t come without a cost.

Study after study has demonstrated that heavily animal-based diets are associated with high cardiovascular mortality and cancer risk.
Red meat also contains carnitine, which gut bacteria convert to trimethylamine N-oxide, or TMAO, a chemical that is suspected of causing heart disease.

When we substitute animal protein with more plant protein, studies have shown, all-cause mortality falls significantly.

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 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 acid for a spell, is a body under the very sort of stress that engages our survival circuits.

You’ll recall that when the enzyme known as mTOR 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.

What we’re coming to learn is that 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 inhibiting this particular longevity gene is really as simple as limiting your intake of meat and dairy.

Essential amino acids aren’t equal.

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 lifespan by 20 percent. Methionine restriction causes obese mice to shed most of their fat – and fast.

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 is 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.

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 lifespan and human studies, a decreased consumption of branched-chain amino acids has been shown to improve markers of metabolic health significantly.

We can’t live without them, but can get less of them by lowering our consumption of animal proteins, chicken, fish, and eggs – particularly when those foods aren’t being used to recover from physical stress or injury.

Leucine is well known to boost muscle, which is why it’s found in protein drinks.
But that muscle building is coming in part because leucine is activating mTOR, which essentially calls out to your body, “Times are good right now, let’s disengage the survival circuit”.
In the long run however, protein drinks may be preventing the mTOR pathway from providing its longevity benefits.
Studies in which leucine is completely eliminated from a mouse’s diet have demonstrated that just one week without this particular amino acid significantly reduces blood glucose levels, a key marker of improved health.

Additionally to the inhibition of mTOR, the lower calorie content and increased polyphenols are also helpful.

Sugar
Yeast cells fed with lower amounts of sugar were not just living longer, but their DNA was exceptionally compact – significantly delaying the inevitable ERC accumulation, catastrophic numbers of DNA breaks, nucleolar explosion, sterility, and death.

Exercise

Exercise improves our blood flow.
It improves lung and heart health.
It gives us bigger, stronger muscles.

But what is responsible for much of that is a simple thing that happens at a much smaller scale: the cellular scale.
Exercise turns on the genes to make us young again at a cellular level.

When researchers studied the telomeres in the blood cells of thousands of adults with all sorts of different exercise habits, they saw a striking correlation: those who exercised more had longer telomeres.

According to a study funded by Center for Disease Control and Prevention in 2017, individuals that exercised the equivalent of at least half hour of jogging five days a week had telomeres a decade younger than those who didn’t.

Exercise, by definition, is the application of stress to our bodies.
It raises NAD levels, which in turn activates the survival network, which turns up energy production and forces muscles to grow extra oxygen-carrying capillaries.

The longevity regulators AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise, irrespective of caloric intake.

The longevity genes that are turned on by exercise are responsible for:

• building new blood vessels that deliver oxygen to cells;
• boosting the activity of mitochondria, which burn oxygen to make chemical energy;
• improving heart and lung health;
• making people stronger;
• and extending telomeres
  (SIRT1 and SIRT6 help extend telomeres, then package them up so they are protected from degradation.)

What puts these genes into action is the hormesis program governed by the survival circuit, the mild kind of adversity that wakes up and mobilizes cellular defenses without causing too much havoc.

The good news is that we don’t have to exercise for hours on end.
One recent study found that those who ran four to five miles a week – for most people, that’s an amount of exercise that can be done in less than 15 minutes per day – reduce their chance of death from a heart attack by 40 percent and all-cause mortality by 45 percent.

There is a difference between a leisurely walk and a brisk run, however.
To engage our longevity genes fully, intensity does matter.
Your breathing should be deep and rapid at 70 to 80 percent of your maximum heart rate.
You should sweat and be unable to say more than a few words without pausing for breath.
This is the hypoxic response, and it’s great for inducing just enough stress to activate your body’s defenses against aging without doing permanent harm.

Mayo Clinic research study on different kinds of exercise shows that high-intensity interval training (HIIT) – that significantly raises your heart and respiration rates – engages the greatest number of health-promoting genes, and more of them in older exercisers.

“Can I just eat what I want and run off the extra calories?”
Unlikely as on rats the lifespan extension in these conditions is minimal.
A combination of fasting and exercise lengthens your lifespan.

Cold and Heat

Cold

Exposing your body to less-than-comfortable temperatures is another very effective way to turn on your longevity genes.

Being out of the thermoneutral zone changes our breathing patterns, blood flow to and through our skin, our heart rates speed up or slow down.

Homeostasis – the tendency for living things to seek a stable equilibrium – is the guiding force of the survival circuit.

Calorie restriction has the effect of reducing core body temperature.
It wasn’t at first clear whether this contributes to prolonged vitality or was simply a by-product.

In 2006 Scripps Research Institute genetically engineered mice (by inserting copies of UCP2 gene into hipotalamus) to live their lives with a body temperature a half degree Celsius cooler than normal, which resulted in a 20% longer life for female and 12% for male mice.
This gene also has a human analog and is connected to longevity.

In 2001 researchers from Beth Israel Deaconess Medical School and Harvard Medical School showed that mice age faster when their UCP2 gene is nullified.

In 2005 Stephen Helfand at University of Connecticut Health Center demonstrated that targeted upregulation of an analogous gene could extend the lifespans of fruit flies by 28 percent in females and 11 percent in males.

In 2017 researchers from Universite Laval in Quebec demonstrated that colder temperatures could change the way the gene operated, too – through its ability to rev up brown adipose tissue known as “brown fat”.

This mitochondria-rich substance was, until recently, thought to exist only in infants.
In adults, brown fat decreases with age.
It “hangs out” in different areas in different people, sometimes in the abdomen, sometimes across the upper back.

Rodent studies provided significant insights into the correlation between brown fat and longevity.
Animals with abundant brown fat or subjected to shivering cold for three hours a day have much more of the mitochondrial UCP-boosting sirtuin, SIRT3, and experience significantly reduced rates of diabetes, obesity, and Alzheimer’s disease.

That is why we need to learn more about how to chemically substitute for brown adipose tissue thermogenesis.
Chemicals called mitochondrial uncouplers can mimic the effects of UCP2.

In 1933, doctors Windsor Cutting and Maurice Tainter, from the Stanford University School of Medicine, summarized a series of papers showing that a mitochondrial uncoupler called 2,4-dinitrophenol (DNP) markedly increases metabolic rate.
Over 1 million capsules were sold.
Three pounds of weight per person per week were reportedly being shed.
People began to die from overdoses, and other long-term side effects showed up.
DNP was declared “extremely dangerous” and was banned for human consumption in the US.
DNP continued to be prescribed to Russian Soldiers during WWII to keep them warm.

Cold Activates Longevity Genes
Sirtuins are switched on by cold, which in turn activates protective brown fat in our back and shoulders.

And when we experience these conditions often enough, our longevity genes get the stress they need to order up some additional healthy fat.

You can try to activate the mitochondria in your brown fat by being a bit cold – a brisk walk in a T-shirt on a winter day in a city such as Boston will do the trick.
Exercising in the cold, in particular, appears to turbocharge the creation of brown adipose tissue.
Leaving a window open overnight or not using a heavy blanket while you sleep could help, too.
It’s probably best to change your lifestyle when you are young, because making brown fat becomes harder as you get older.

If you choose to expose yourself to the cold, moderation will be key. Neither hypothermia or frostbite are good for our health.

Cryotherapy – a few minutes in a box superchilled to -110C or -166F – is very “hot” now.

Heat

Raising the temperature of yeast – from 30C to 37C, just below limits of what those single-celled organisms can sustain – turns on the PNC1 gene and boosts their NAD production, so their Sir2 proteins can work that much harder. Mechanism that led to a 30% lifespan increase was the same as that evoked by calorie restriction.

Continuing an ancient Roman tradition, many northern and eastern Europeans regularly partake in “sauna bathing”, the Finns report using a sauna once a week, year round.

A study following more than 2,300 middle-aged men from eastern Finland for more than 20 years concluded that those who used sauna with great frequency – up to 7 times a week – enjoyed a twofold drop in heart disease, fatal heart attacks, and all-cause mortality events over those who heat bathed once per week.

There is no data in humans that explains why heat exposure may be good for us.
By analogy with yeast, we can assume that it is due to NAMPT, the gene in our bodies that recycles NAD.
NAMPT is turned on by a variety of adversity triggers, including fasting and exercise, which makes more NAD so the sirtuins can work hard at making us healthier.

Anti-Aging Supplements

When we toast to life, we really should be toasting to enzymes.
Every second you are alive, thousands of glucose molecules are captured within each of your trillions of cells by an enzyme called glucokinase, which fuses glucose molecules to phosphorus atoms, tagging them for energy production.
Most of the energy created is used by a multicomponent RNA and protein complex called a ribosome, whose primary job is to capture amino acids and fuse them with other amino acids to make fresh proteins.

Precise vibrating sockets on SIRT1 simultaneously clasp onto an NAD molecule and the protein it wants to strip the acetyls from, such as 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.
More important is the fact that the target protein has now been stripped of the acetyl chemical group that was holding it at bay.
Now the histone can pack DNA more tightly to silence genes, and FOXO3 has had its shackles removed, allowing it to go turn on a defense program of protective genes.

Yes, aging is an increase in entropy, a loss of information leading to disorder.
But living things are not closed systems.
Life can potentially last forever,a s long as it can preserve critical biological information and absorb energy from somewhere in the universe.

We have discovered ways to chemically modulate enzymes with molecules we call medicines.

Rapamycin – The Easter Island Longevity Molecule

Rapamycin isn’t just an antifungal compound and isn’t just an immune system suppressor used in organ transplants; it’s also one of the most consistently successful compounds for extending life.

It was successful in yeast, fruit flies and rodents.
Longer lived animals might not fare as well on it as shorter-lived ones do; it’s been shown to be toxic to kidneys at high doses over extended periods of time; and it might suppress the immune system over time.

That doesn’t mean TOR inhibition is a dead end, though.
It might be safe in small or intermittent doses – that worked in mice to extend lifespan and in humans dramatically improved the immune responses of elderly people to a flu vaccine.

There are hundreds of researchers working to identify “rapalogs” – compounds that act on TOR in ways similar to rapamycin but have greater specificity and less toxicity – as a pathway to greater human health and vitality.

Metformin

In the 1920s, doctors began to prescribe guanidine (found in Goat’s rue, or French lilac) as a way to lower blood glucose levels in patients with diabetes.
Type 2 diabetes occurs when the pancreas is able to make enough insulin but the body is deaf to it.
Oral dimethyl biguanide, now most commonly called metformin, is a drug for treatment of type 2 diabetes. It restores the body’s sensitivity to insulin so cells take up and use 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.

Metformin is 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. As a generic medication, it costs patients less than $5 a month in most of the world.
Except for an extremely rare condition called lactic acidosis, the most common of the side effects is some stomach discomfort. Many people mitigate that side effect by taking the medication as a coated tablet or with a glass of milk or a meal.

Researchers noticed a curious phenomenon: people taking metformin were living notably healthier lives – independent of its effect on diabetes.
In mice, even a very low dose of metformin has been shown to increase lifespan by nearly 6 percent.
In 26 studies of rodents treated with metformin, twenty-five showed protection from cancer.

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.
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.

The beauty of metformin is that it impacts many diseases. Through the power of AMPK activation, it makes more NAD and turns on sirtuins and other defenses against aging as a whole – engaging the survival circuit upstream of these conditions, ostensibly slowing the loss of epigenetic information and keeping metabolism in check, so all organs stay younger and healthier.

Among other beneficial effects, metformin inhibits cancer cell metabolism, increases mitochondrial activity, and removes misfolded proteins.
A study of more than 41,000 metformin users between the ages of 68 and 81 concluded that metformin reduced the likelihood of dementia, cardiovascular disease, cancer, frailty, and depression.
In one group of already frail subjects, metformin use over the course of nine years reduced dementia by 4 percent, depression by 16 percent, cardiovascular disease by 19 percent, frailty by 24 percent, and cancer by 4 percent.

An admittedly small study of health 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.

Sirtuin-Activating Compounds, or STACs

The three main longevity pathways, mTOR, AMPK, and sirtuins, evolved to protect the body during times of adversity by activating several mechanisms.
When they are activated, either by low-calorie or low-amino-acid diets, or by exercise, organisms become healthier, disease resistant, and longer-lived.
Molecules that tweak these pathways, such as rapamycin, metformin, resveratrol, and NAD boosters, can mimic the benefits of low-calorie diets and exercise and extend the lifespan of diverse organisms.

Fisetin

The first SIRT1-activating compound, or STAC, was a polyphenol called fisetin, which helps to give plants such as strawberries and persimmons their color and is now known to also kill senescent cells.

Butein

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.

Resveratrol

Fisetin and butein have an overlapping structure: two phenolic rings connected by a bridge.
Resveratrol, a natural molecule that is found in wine and that many plants produce in times of stress, also has this structure.
Resveratrol has a similar effect as fisetin and butein.

In fact, in yeast, it actually outperforms the other two molecules to the human equivalent of extra 50 years of life.
In fruit flies the effect was similar to 14 additional years in human terms.
Resveratrol also worked in roundworms.
When resveratrol was given to human cells in culture dishes, they became resistant to DNA damage.
When fed to obese mice for a year, the mice stayed fat.
But when they opened up the mice, the resveratrol mice looked identical to mice on a normal diet, with healthy hearts, livers, arteries, and muscles. They also had more mitochondria, less inflammation, and lower blood sugar levels.
The ones they didn’t dissect wound up living about 20% longer than normal.
In mice, when combined with intermittent fasting, resveratrol was able to greatly extend both average and maximum lifespan even beyond what fasting alone accomplishes.

When testing resveratrol in yeast cells with no SIR2 gene, there was no effect.
When testing it on calorie-restricted yeast, there was no further increase in lifespan, suggesting that the same pathway was being activated; this was how calorie restriction was working.

Resveratrol is a calorie-restriction mimetic that could extend longevity without hunger.

As it turned out, resveratrol wasn’t very potent and wasn’t very soluble in the human gut, two attributes that most medicines need to be effective at treating diseases.
Despite its limitations as a drug, it did serve as an important first proof that a molecule can give benefits of calorie restriction without the subject having to go hungry and that it is possible to activate sirtuins with a chemical.

In animals, STACs such as SRT1720 and SRT2104 are many times more potent than resveratrol.

NAD/NAD+

Another STAC is NAD, sometimes written as NAD+.
NAD has an advantage over other STACs because it boosts the activity of all seven sirtuins.
NAD is a product of the vitamin niacin.
A severe lack of NAD causes inflamed skin, diarrhea, dementia, skin sores, and ultimately death.
NAD is used by over five hundred different enzymes.
NAD is a central regulator of many major biological processes, including aging and disease.
It 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.
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.

When bioengineering yeast to make extra NAD, those yeast cells lived 50% longer than normal.
Could we do this in humans? Theoretically, yes. We already have the technology to do it using viruses to deliver the human gene called NAMPT.
We are also searching for safe molecules that would achieve the same result.

Human studies with NAD boosters are ongoing.
Emerging research strongly suggests NAD boosters could have a similar effects on human health.
So far, there has been no toxicity, not even a hint of it.

Some people have suggested NAD boosters could be taken with a compound that provides cells with methyl groups, such as trimethylglycine, also known as betaine or methylfolate.
Conceptually this makes sense – the “N” in NR and NMN stands for nicotinamide, a version of vitamin B3 that the body methylates and excretes in urine when it is in excess, potentially depleting cells of methyls – but this remains a theory.

Nicotinamide Riboside, or NR
A form of vitamin B3 called nicotinamide riboside, or NR, is a vital precursor of NAD.
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.

Nicotinamide mononucleotide, or NMN
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.
NMN could treat the symptoms of type 2 diabetes in old mice by restoring NAD levels.
Mitochondria in old mice starts functioning just like mitochondria in young mice after just a week of NMN injections.
NMN gives old mice the endurance of young mice and can even turn them into ultramarathoners.
NMN can protect against kidney damage, neurodegeneration, and mitochondrial diseases.

NR vs. NMN
Give an animal a drink with NR or NMN in it, and the levels of NAD in its body go up about 25% over the next couple of hours. about the same as if it had been fasting or exercising a great deal.

Which is the superior molecule: NR or NMN?
NMN is found to be more stable than NR.
There are some health benefits in NMN mouse experiments that aren’t seen when NR is used.
But it’s NR that has been proven to extend the lifespan of mice.
NMN is still being tested.
So there’s no definitive answer yet.

Nicotinamide riboside (NR) is converted to NMN, so some people take NR instead of NMN because it’s cheaper.
Cheaper are niacin and nicotinamide, but they don’t seem to raise NAD levels as NMN and NR do.

Senolytics

One of the key hallmarks of aging is the accumulation of senescent cells.
These are the cells that have permanently ceased reproduction.

Young human cells taken out of the body and grown in a petri dish divide about forty to sixty times until their telomeres become critically short.

Although the enzyme known as telomerase can extend telomeres, it is switched off to protect us from cancer, except in stem cells.
If you put telomerase into cultured skin cells, they don’t ever senesce.

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.

The other, safer solution to a short telomere is to shut the cell down by permanently engaging the survival circuit.
The exposed telomere, seen as DNA break, causes epigenetic factors such as sirtuins to leave their posts permanently in an attempt to repair the damage, but there is no other end to ligate it to. This shuts cell replication down.

Triggering the DNA damage response and major alterations to the epigenome are well known to occur in human senescent cells.
Senescence in nerve and muscle cells, which don’t divide much or at all, might be the result of epigenetic noise that causes cells to lose their identity and shut down.

This once-beneficial response, which evolved to help cells survive DNA damage, has a dark side: the permanently panicked cell sends out signals to surrounding cells, causing them to panic, too.

Senescent cells are often referred to as “zombie cells”, because even though they should be dead, they refuse to die, in some cases sitting in our tissues for decades.

Small number 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.
Being chronically inflamed is unhealthy: just ask someone with multiple sclerosis, inflammatory bowel disease, or psoriasis.
All these diseases are associated with excess cytokine proteins.
Inflammation is also a driving force in heart disease, diabetes, and dementia.
It is central to the development of age-related diseases.
And cytokines don’t just cause inflammation; they also cause other cells to become zombies, like a biological apocalypse. When this happens, they can even become a tumor and spread.

If zombie cells are so bad for our health, why doesn’t our body just kill them off?
It might be that we evolved senescence as a rather clever trick to prevent cancer when we are in our 30s and 40s.
Senescent cells don’t divide, which means that cells with mutations aren’t able to spread and form tumors.

Senescent cells are hard to reverse aging in, so the best thing to do is to kill them off.
Small-molecule drugs called senolytics are designed to specifically kill senescent cells by inducing the death program that should have happened in the first place.

Destroying senescent cells in mice can give them substantially healthier and 20 to 30% longer lives.

Quercetin
Quercetin is a senolytic molecule found in capers, kale, and red onions.

Dasatinib
Dasatinib is a senolytic molecule, which is a standard chemotherapy treatment for leukemia.

Senomorphic vs. Senolytic; Rapamycin
Rapamycin, the Easter island longevity molecule, is a “senomorphic” molecule, meaning it doesn’t kill senescent cells but does prevent them from releasing inflammatory molecules, which might be almost as good.

Retrotransposon suppressors

The selfish genes that are called LINE-1 retrotransposons, and their fossil remnants, make up about half of the human genome, what is often referred to as “junk DNA”.

It’s a lot of genetic baggage, and they are sneaky buggers.
In young cells, these ancient “mobile DNA elements”, also known as retrotransposons, are prevented by chromatin from jumping out of the genome, then breaking DNA to reinsert themselves elsewhere.
LINE-1 genes are bundled up and rendered silent by sirtuins.
But as mice age, and possibly as we do as well, 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 loss is exacerbated by a drop in NAD levels.
Without the sirtuins to spool the chromatin and silence the transposon DNA, cells start to transcribe these endogenous viruses.

This is bad. And it only gets worse.
Over time, as mice age, the once silent LINE-1 prisoners are turned into RNA and the RNA turned into DNA, which is reinserted into the genome at a different place.
Besides creating genome instability and epigenomic noise that causes inflammation, LINE-1 DNA leaks from the nucleus into cytoplasm, where it is recognized as a foreign invader.
In response, the cells release even more immunostimulatory cytokines that cause inflammation throughout the body.

It may turn out that, as NAD levels decline with age, sirtuins are rendered unable to silence retrotransposon DNA.
Perhaps one day, antiretroviral drugs (the same kind used to fight HIV) or NAD boosters will be used to keep these jumping genes silent.

David Sinclair’s Longevity Regimen

1. 1 gram (1,000 mg) of NMN every morning,
   along with 1 gram of resveratrol (shaken into homemade yogurt),
   1 gram of metformin;
2. a daily dose of vitamin D, vitamin K2, and 83 mg of aspirin;
3. keep sugar, bread, and pasta intake as low as possible;
4. skip one meal a day or at least make it really small;
5. take a lot of steps each day and walk upstairs,
   go to the gym to lift weights, jog a bit, and hang out in the sauna before dunking in an ice-cold pool;
6. eat a lot of plants and try to avoid eating other mammals,
   eat meat after a work out;
7. don’t smoke, avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans;
8. try to stay on the cool side during the day and when sleeping at night;
9. keep body weight or BMI in the optimal range;
10. practice mindfulness and positive thinking.

Gender Differences

For most of medical history, our treatments and therapies have been based on what is best for males.
Ever since female mice have been regularly included in lifespan experiments, large gender differences in effects of longevity genes and molecules have been seen.

Treatments that work through insulin or mTOR signaling typically favor females, whereas chemical therapies typically favor males, and no one really knows why.

If females and males are in the same environment, in general, females live longer.
Scientists have tested whether it is the X chromosome or the ovary that is important.
They created mice with one or two Xs, with either ovaries or testes.
Those with a double dose of the X lived longer, even if they had testes and especially if they didn’t.

Preserving and Restoring Female Fertility

We are still working to understand how epigenetic noise is dampened at a molecular level, but we know in principle how it works.
When we give silencing proteins such as sirtuins a boost, they can maintain the youthful epigenome even with DNA damage occurring.
Somehow they can cope with it.
Perhaps they are just superefficient at repairing DNA breaks and head home before they get lost, or if half the sirtuins head off, the remaining enzymes can hold down the fort.

One of David Sinclair’s students reported that his postmenoposal mother started having her cycle again after taking NMN.
A trial in 2018 to test whether an NAD booster could restore the fertility of old horses was successful.
NMN was able to restore the fertility of old mice that had all their eggs killed off by chemotherapy or have gone through “menopause”.
These might be interesting indicators that NAD boosters might restore failed or failing ovaries.

In 2004, Jonathan Tilly – a highly controversial figure in the reproductive biology community – claimed that human stem cells that can give rise to new eggs, late in life, exist in the ovaries.
Controversial though this theory is, it would explain how it is possible to restore fertility even in mice that are old or have undergone chemotherapy.

Ovary is an organ that has a day-to-day function, both holding on to eggs that were created during embryonic development and potentially being a repository for additional eggs derived from precursor cells later in life.
The ovary also is the first major organ to break down as a result of aging, in humans and animal models alike.
NMN boosts NAD, and this boosts the activity of the SIRT2 enzyme.
SIRT2 controls the process by which an immature egg divides so that only one copy of the mother’s chromosomes remains 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.
But if the old female mice were pretreated with NMN for a few weeks, their eggs looked pristine, identical to those of young mice.

Metformin is already widely used to improve ovulation in women with infrequent or prolonged menstrual periods as a result of polycystic ovary syndrome.

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

Cellular reprogramming

What if we could reset the aging clock and prevent cells from ever losing their identity and
becoming senescent in the first place?

Jellyfish have been shown by using small body fragments to regenerate polyps that spawn a dozen new jellies.

The DNA blueprint to be young, after all, is always there, even when we are old.
So how can we make the cell reread the blueprint?

Here it’s helpful to return to the DVD metaphor.
There are two ways to play an old, scratched DVD with fidelity.
You could buy a better DVD player, one with a more powerful laser that could reveal the data under scratches. Or you could polish the disc to expose the information again, making the DVD as good as new.

In 1958, Oxford University professor John Gurdon removed the chromosomes from a frog’s egg and replaced them with chromosomes from an adult frog and obtained living tadpoles.

In 1996 sheep’s egg chromosomes were replaced with those from an udder cell. The result was Dolly, which proved that the old DNA retains the information needed to be young again.

But how might we reset the body without becoming a clone?
Claude Shannon’s 1948 “A Mathematical Theory of Communication” which is relevant to the “Information Theory of Aging”, says that the best way is to store a backup set of data.
That way, even if some primary data are lost, an “observer” can send this “correcting data” to a “correcting device” to recover the original message.
This is how the internet works.
If data packets are lost, they are recovered and sent moments later, all thanks to TCP/IP (Transmission Control Protocol/Internet Protocol.)

The “source” of the information is the egg and sperm, from your parents.
The “transmitter” is the epigenome, transmitting analog information through space and time.
The “receiver” is your body in the future.

To end aging we need to find three more things:
An “observer” who records the original data
The original “correction data”
And a “correcting device” to restore the original signal.

We may have finally found the biological correcting device.
In 2006, the Japanese stem cell researcher Shinya Yamanaka won the Nobel Prize for the discovery that showed that complete cellular age reversal was possible in a petri dish.
He found that a set of four genes – Oct4, Klf4, Sox2, and c-Myc – could induce adult cells to become pluripotent stem cells, or iPSCs, which can be coaxed into becoming any other cell type. We now call these four genes Yamanaka factors.
Yamanaka 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.
We can use this and other switches to reset an entire body’s epigenetic landscape, sending sirtuins back where they came from. Cells that have lost their identity during aging can be led back to their true selves.
This is the DVD polish we’ve been looking for.

At age 30, you would get a week’s course of three injections that introduce a specially engineered adeno-associated virus, or AAV, which causes a very mild immune response, less even than what is commonly caused by a flu shot.
The virus, which has been known to scientists since the 1960s, has been modified so it doesn’t spread or cause illness.
The virus would carry a small number of genes – some combination of Yamanaka factors, and a fail-safe switch that could be turned on with a well-tolerated molecule such as doxycycline, an antibiotic that can be taken as a tablet.
Nothing, at that point, would change in the way your genes work.
But when you begin to see and feel the effects of aging, like sometime in your mid-40s, you would be prescribed a month’s course of doxycycline.
When you are 25 again, the prescription would be discontinued, the AAV would switch off.
Then, a few more decades down the road, when gray hairs begin showing up again, you’d start another cycle of the prescribed trigger.
This has been shown to work in mice experiments, where mice lived 40% longer compared to untreated siblings.
With the pace at which biotech is advancing, we may be able to move away from using viruses and simply take a month’s course of pills.

There was a mice experiment, where a mouse’s optic nerve was used to test age reversal and rejuvenation.
The eye is the organ of choice to trial gene therapies because it is immunologically isolated.
This was also one of the hardest problems in biology to solve, because optic nerves don’t regenerate unless you are a newborn.
Peripheral nerves, like those in our arms and legs, can grow back, albeit very, very slowly.
The nerves of the central system, though – optic nerves and the nerves of the spinal cord – never grow back.
The result was that the OSK reprogramming virus had restored vision.

Epigenetic reprogramming showed to regrow optic nerves and to restore eyesight in old mice.
By infecting mice with reprogramming genes called Oct4, Sox2, and Klf4, the age of cells was reversed by the TET (ten-eleven translocation) enzymes, which removed just the right methyl tags on DNA, reversing the clock of aging.

If adult cells in the body, even old nerves, can be reprogrammed to regain a youthful epigenome, the information to be young cannot be all lost.
There must be a repository of correction data, a backup set of data that cells retain over a lifetime that somehow directs a reboot.

The methyl tags on DNA, removed by TET enzymes, mark the passage of the Horvath aging clock. This points to the DNA methylation clock as not just an indicator of age but a controller of it.

How the enzymes know which tags are the youthful ones is a mystery. Solving that mystery would be the equivalent of finding the “observer” that holds the original data.
When the correcting device is switched on by infecting cells with OSK genes, the cell somehow knows how to contact the observer and use the correction data to restore the original signal to that of a young cell.

One day it might be possible to reprogram cells via pills that stimulate the activity of the OSK factors or the TETs.

Natural molecules stimulate the TET enzymes, including vitamin C and alpha-ketoglutarate, a molecule made in mitochondria that is boosted by CR and, when given to nematode worms, extends their lifespan.

DNA-Based Treatments and Therapies

DNA can tell you what foods to eat, what microbiomes to cultivate in your gut and on your skin, and what therapies will work best to ensure that you reach your maximum potential lifespan.
The same is true of medical interventions: our genes can tell us which are better for us and which could do more harm than good.
Same is true of medical interventions. We don’t all respond to drugs the same way. Our genes can tell which are better for us and which could do more harm than good.

We are also learning to read the entire human proteome – all of the proteins that can be expressed by every type of cell. Each protein can tell a story about the kind of cell from which it came, a story we can use to understand what diseases are in our bodies long before they are detectable any other way.

DNA testing can offer us early and accurate diagnoses of a vast range of ailments and even estimate our rate of biological aging.

Xenotransplantation
Luhan Yang and her colleagues at Harvard Medical School demonstrated that they could use gene editing to eliminate dozens of retroviral genes from pigs that currently prevent them from donating organs, which is one of the big obstacles to xenotransplantation.

3D Printing Living Tissue
Today scientists have implanted printed ovaries into mice and spliced printed arteries into monkeys. In the future we might expect printing skeletal tissue to fix broken bones, printed skin and organs. In the future, when we need body parts, we might print them using our own stem cells or using reprogrammed cells taken from blood or mouth swab.

Ethics of Immortality

The time to talk about ethics and how personal privacy will be impacted by coming technologies is now.

DNA-based technologies that enable the detection of specific pathogens, for example, could also be used to search for specific people.

Technology now exists to create humans that are stronger and longer lived.

One report, which examined sixty-five different scientific projections, concluded that the most common estimated “carrying capacity” of our planet is 8 billion.
That’s just about where we’re at right now.

What would happen if we had a few more years?
A few more decades?
A few more centuries?
Will we follow the perilous path that ultimately leads to dystopian doom?
Will we band together to create a world that exceeds our wildest utopian dreams?