Lifespan - David Sinclair

Why We Age - and Why We Don't Have To

[bq] "Do your part to make humanity be the best it can be. Don't waste a moment. Embrace your youth, hold on to it for as long as you can. Fight for it."

We have dramatically increased lifespan, but our healthspan has not changed that much, and many spend their last years or even decades in very unpleasant conditions.

But this can change very soon. We're now in a position where we can extend actual healthspan, dramatically.

[bq] "I have come to see ageing as a disease - the most common disease - one that not only can but should be aggressively treated."

I. What We Know (The Past)

1. Viva Primordium

The earliest living cells probably quickly developed a very particular survival mechanism: stop cell reproduction when DNA damage occurs and focus all energy on repair until the damage is fixed.

Ageing research today is where cancer research was in 1960s.

[bq] "From the looks of it, ageing is not going to be that hard to treat, far easier than curing cancer."

It seems like there generally is a trade-off between longevity and reproduction. Animals at the bottom of the food chain put lots of energy into reproducing, having a large number of offspring, but live fairly short lives.

For decades people where searching for a single cause of ageing, from mutations to free radicals, but the current consensus is that it's an accumulation of factors.

Have nine "hallmarks" of ageing:

• DNA instability/damage

• Deregulated nutrient sensing

• Loss of proteostasis

• Altered intercellular communication

• Stem cell exhaustion

• Telomere attrition

• Mitochondrial dysfunction

• Cellular senescence

• Epigenetic alterations

[bq] "Address one of these, and you can slow down aging. Address all of them, and you might not age."

But there might still be some upstream cause responsible for all these hallmarks.

[bq] "Aging, quite simply, is a loss of information."

Two types of biological information:

• Digital: genetics stored in DNA

• Analog: epigenetics stored in chromatin

Sirtuin genes are particularly important in longevity since they switch on and off many other gene expressions, especially when it's time to use energy for cell protection/repair.

Two other similar systems are the gene mTOR and the enzyme AMPK.

Hormesis, the right kind of stressors, triggers these mechanisms, activating the longevity genes without damaging cells.

2. The Demented Pianist

Each of our cells has the same DNA. What differentiates one type of cell from another is the epigenome, the control system that determines which genes are turned on or off.

DNA is like a piano, and the epigenome is the pianist who actually plays it. Despite all the attention on DNA, the epigenome actually has a greater influence in controlling our lives.

Aging is really noise in the epigenome. It's not the piano that breaks, it's the player that adds in more and more random notes until the music becomes just noise. That's essentially the "Information Theory of Aging."

The sirtuin genes are there to combat that noise and restore any damage that might cause further noise, but they can get overwhelmed or distracted.

[bq] "I've come to think of sirtuins as the directors of a multifaceted disaster response corps, sending out a variety of specialized emergency teams to address DNA stability, DNA repair, cell survivability, metabolism, and cell-to-cell communication."

However, if there are too many emergencies and too much constant DNA repair required, the sirtuins are too busy with that to focus on their other duties of controlling the genes and ensuring optimal cell function. That's when problems start.

More sirtuin would help, and in yeast experiments adding extra sirtuin genes has shown much greater longevity/health. But for evolution, longevity was only relevant up to a certain point, and the extra sirtuin genes cost energy. So evolution didn't go that route. But we can.

Experiments in mice showed that just cutting the DNA, without altering anything, calls sirtuins from all over the body to the cut site for repair, leaving their original sites changed, as well as the new places they showed up at, both in ways not originally intended. This epigenetic noise led to premature aging.

Some organisms, like bristlecone pines and some jelly fish, seem to show no signs of aging. And some sharks, and even some mammals like certain whales, live extremely long, several hundred years.

Some longevity genes, like FOXO3, can make sure that defences against disease and aging are higher even in good times.

Epigenetics also control the development of stem cells into the different cell types. But even a fully developed cell can still change. Their stability is extremely important, but a changed epigenome can disrupt this. A skin cell may turn 10% neuron, or kidney cell, and become inept at some of its original tasks. And that's essentially the process of aging.

Stabilizing the cells, and the epigenome, is the biggest key to slow, or even reverse, aging.

3. The Blind Epidemic

In a certain way of thought, cancer, heart disease, Alzheimer's and many other ailments are not diseases themselves, but just symptoms of an underlying disease: aging.

Smoking dramatically increases aging clock, with smokers dying on average 15 years earlier.

Our hospitals currently treat a single disease at a time, then push the patient out the door until the next disease hits (or they die).

[bq] "The current solutions, which are focused on curing individual diseases, are both very expensive and very ineffective when it comes to making big advances in our healthspans. What we need are medicines that knock down all the hurdles."

Calls current medicine a "whak-a-mole system."

The problem is that aging is not recognized as a disease, so it doesn't fit into our system for policy, drug development, research funding, etc.

[bq] "We can eliminate the symptoms of aging altogether. The disease is treatable."

II. What We're Learning (The Present)

4. Longevity Now

[bq] "If there is one piece of advice I can offer, one surefire way to stay healthy longer, one thing you can do to maximize your lifespan right now, it's this: eat less."

Many studies have shown that caloric restriction without malnutrition extends lifespan.

Keeping the body in a state of alert (without actually inducing malnutrition) triggers the sirtuins/epigenome to be in defense/repair mode.

Even small but sustained caloric restriction can have positive effects on blood markers, health, and signs of aging.

The earlier you start the caloric restriction the better, but doing it from your 60s still has positive effect on longevity.

But general calorie restriction is hard to practice over long run. Luckily, cutting food out completely for a while, from time to time, is much easier and has similar benefits.

[bq] "The important thing is not just what we eat but the way we eat."

Fasting, whether regular intermittent fasting or slightly less regular longer fasts, don't "rest" our body. Rather the opposite. But this good stress puts us into hormesis, and our body starts repairing itself.

Meat, especially red and processed meats, can have carcinogenic effects if consumed too much.

The amino acid leucine, found in chicken, fish and eggs, but also many protein shakes, activates mTOR, "which essentially calls out to your body, 'Times are good right now, leet's disengage the survival circuit.'" Great for quickly building muscle, not great for longevity.

Reducing meat and amino acid intake inhibits mTOR, leading to more damage repair.

Exercise, especially high intensity interval training, lengthens telomeres and again engages repair mechanisms.

[bq] "Exposing your body to less-than-comfortable temperatures is another effective way to turn on your longevity genes."

Actually calorie restriction has the effect of slightly lowering core body temperature.

Cold exposure also activated brown fat, and that, too, is linked to longevity.

[bq] Should start as young as possible "because making brown fat becomes harder as you get older."

Moderation is key. As with all hormesis, want to push the body to the edge, but not beyond.

While the science and exact mechanisms are still less clear, heat exposure like sauna also seems to have a positive effect.

[bq] "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."

Avoiding radiation and excessive chemical exposure also a good bed to stabilise epigenome.

5. A Bitter Pill to Swallow

[bq] "Science moves forward with small steps and big steps, but always one step at a time."

Rapamycin was found as a byproduct of a bacterium found on Rapa Nui. Initially it was used for its immune suppressant properties to help with organ transplants. But later people realized it also acts as an mTOR inhibitor and extends lifespan. Its side effects are problematic, but scientists are now looking for "rapalogs," drugs which act in a similar way on TOR but without the side effects.

Metformin, a drug used to treat diabetes, has recently also been found to extend lifespan, mimicking the effects of caloric restriction, inhibiting cancer cell metabolism, increasing mitochondrial activity, and removing misfolded proteins. By activating AMPK, producing more NAD and turning on sirtuins, it protects against all aspects of aging.

Right now it is still a prescription drug and only for diabetes, since aging is not yet recognised as a disease, but studies in the US are working on changing that.

[bq] "The three main longevity pathways mTOR, AMPK, and sirtuins, evolved to protect the body in times of adversity bu activating survival mechanisms."

Plants that are stressed produce xenohormetic molecules telling their cells to prepare for adversity, but when we eat them they can also trigger our survival mechanism.

Interestingly the most stressed plants are often the tastiest, like grapes or strawberries that grow in dry areas with high sun exposure.

Organic foods are grown under more stressful conditions which might add to their health benefits.

Resveratrol, a compound found in grapes and red wine, was shown to be another potential longevity drug. Lab studies on yeast, mice, and even human cells showed the equivalent of 15 additional healthy years. The problem is it's not very potent or solvable, and the concentration in those natural sources is way too small for any effect. But after resveratrol, other sirtuin activators were discovered, like NAD.

Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have both been found as effective NAD precursors that could extend mice lifespan tremendously, and human trials are under way.

There is anecdotal evidence that women in their menopause became fertile again after taking NMN, which would completely change our understanding of reproductive biology.

All these compounds were discovered by chance, without researchers actually looking for aging drugs. but now that they are, there is a good chance we will find even more potent molecules.

6. Big Steps Ahead

Senescent "zombie" cells are one of the biggest hallmarks of aging. They can sit in our tissue for decades, secreting factors that accelerate cancer, inflammation, and turn other cells into zombies. They increase inflammation by releasing cytokine proteins. Inflammation is central to many age-related diseases, doctors even call it "inflammaging".

Killing senescent cells should be a key goal of extending health span.

Evolutionarily, senescent cells are actually a way to prevent cancer in our 30s and 40s. The fact that this trick leads to more problems later on was an acceptable trade off for evolution.

[bq] "A class of pharmaceuticals called senolytics may be the zombie killers we need." They "kill senescent cells by induing the death program that should have happened in the first place."

[bq] "If senolytics work, you could take a course of medicine for a week, be rejuvenated, and come back ten years later for another course."

Yamanaka factors are four genes that can turn adult cells back into pluripotent stem cells. This shows that the information loss in aging can be reversed. There is a data backup stored in our own body.

Can imagine in a not too distant future getting a shot at age 30 of an engineered virus with Yamanaka factors that can be turned on by a certain molecule. The virus would embed them into our cells, and then at regular intervals, say every decade, we would take the activating substance for a week or so, and rejuvenate  ourselves by a decade. This would not just slow or prevent aging, it could actually reverse it.

Of course, this raises lots of ethical questions.

7. The Age of Innovation

Cancer can now be fought with CAR T-cell therapy that is tailored specifically to a patient's genes. Checkpoint inhibition therapy is another method with great potential. Overall, there are currently many gene-based cancer treatments in trial that show huge potential and great remission rates of over 80%.

[bq] "Yet in many hospitals around the world the if-it-is-here-it-must-be-this and if-the-symptoms-are-this-it-must-be-that modes of diagnosis are still practiced."

DNA sequencing is getting cheaper and cheaper and has the potential to make medicine ever more personal and specific.

Even the extremely obvious difference between male and female has been largely ignored in the development of drugs and treatments until very recently, with most clinical trials focusing on males.

[bq] "It won't be long before prescribing a drug without first knowing a patient's genome will seem medieval."

When we buy a car we demand sensors and immediate feedback.

[bq] "We know more about the health of our cars than we know about our own health. That's farcial. And it's about to change."

We're already seeing the beginning of this, but soon biosensors will be ubiquitous and tell us personalized recommendations, as well as spot problems long before symptoms emerge.

Collective bio-tracking could also help us prevent pandemics.

There will definitely be privacy concerns around this, but for many, the tradeoff will be worth it.

The way most microbiology labs and clinics test for pathogens hasn't changed much since the late 19th century! But soon we'll be able to use sequencing to spot pathogens precisely. Those we expected and set out to find as well as those a doctor wasn't even thinking to look for.

Vaccinations, too, have tremendous potential (but get a lot of societal pushback, making progress on them much slower than it could be...)

Organs fail with old age, or through disease or accidents at any age. Currently most donor organs come from car accidents. There is already an organ shortage, but with traffic becoming saver, especially once self-driving cars take over, this issue will become much worse. But new advances such as growing human organs in animals or 3D printing them might soon solve this issue completely.

III. Where We're Going (The Future)

8. The Shape of Things to Come

[bq] "As we move faster and faster towards a Star Trek world, for every month you stay alive, you gain another week of life."

Despite its ethical challenges, significantly increasing lifespan is very likely to happen, and most experts discuss how to deal with it when it happens, not if it happens.

[q] "Embrace things rather than try and fight them. Work with things rather than try and run from them or prohibit them."

[bq] "Greater longevity is inevitable; I'm sure of it. What if it inevitably leads to our self-destruction."

Sinclair acknowledges the issue but is optimisitc.

Overpopulation would be one of the first issues, one we are already facing today to some extent. By some estimates the earth can support only 8 billion people, more or less where we are right now.

Social insurance, at least in its current form, will also become less and less viable.

[bq] "If past is prologue - and it so often is with human behavior - politicians will watch this slow moving disaster until it becomes a fast moving disaster; then they will sit and watch some more."

In 2018 the richest 10% of Americans lived on average 13 years longer than the poorest 10%. And this gap might grow dramatically. Especially while longevity drugs and treatments are not seen as essential and covered by health care, the rich will be the main group using and benefitting from them.

Yet, Sinclair is optimistic.

We've actually been through similar changes. Over the last 150 years, life expectancy in the UK doubled due to advances in health care and hygiene (triggered by the issue of overcrowding).

Despite a different perception, data shows that older workers have better job performance in almost any job (assuming they don't go through cognitive decline yet). Especially in leadership positions.

Some countries (especially in Europe) even force their workers into retirement.

[bq] "It's Europe's loss, and it's completely backwards."

Healthy old age is important for many reasons.

[bq] "Adults who get sick stop making money and contributing to society at the same time they start costing a whole lot to keep alive."

With all the healthy, smart older people contributing, we will have lots of people working on the big issues that face humanity.

9. A Path Forward

A future where the average lifespan is drastically longer seems inevitable. So we should prepare for it, otherwise we will run into many of the problems people are worried about.

First, we need to increase, or at least maintain research funding. And some of this funding should go towards aging research. The problem here is that as long as aging isn't classified as a disease, it's very hard for scientists to get funding for it.

[bq] "Aging is a disease. This is so clear that it seems almost insane that those words need to be repeated again and again [...] And not only is it a disease, it is the mother of all diseases, the one we all suffer from."

Most longevity drugs luckily also increase healthspan and prevent the onset of many chronics diseases. So despite the longer lifespans, we would actually reduce the burden on the healthcare/insurance system.

We need a system that is at least as focused on disease prevention as late-stage treatment.

Currently a lot of our late stage medicine just prolongs pain, grief, and suffering. But longevity studies in mice show that the longer they are made to live, the faster their final decline and death. Not only does their life get longer, but the painful part of it gets shorter.

And once the time comes, we should give people a right to die on their own terms.

[bq] "In my mind, there are few sins so egregious as extending life without health."

Conclusion

Sinclair himself takes 1g NMN, 1g resveratrol, and 1g metformin every morning.

[bq] "Living longer make no sense if you don't have your friends and family around you. Even our three dogs [...] have been on NMN for a couple of years.”