Reverse Aging: How To Live Longer and Healthier

The following article is a summary of the first season of the Lifespan Podcast, from world-renowned research doctor David Sinclair, Ph.D.

Dr. Sinclair is a professor of genetics and co-director of Harvard Medical School’s Center for Biology of Aging Research.

I found this podcast to be truly amazing. The information is very digestible. Dr. Sinclair has a co-host, Matthew LaPlante. Although Mathew knows a lot as well, he is very much less serious and a funny guy, and he makes the podcast much more enjoyable. They found a great way to teach science in an entertained way.

In these 8 episodes they talk about: The science of aging, Nutrition, Exercise, Drugs and Supplements, Hormones, Cosmetic Aging, Brain Health and Technologies.

My goal is just to share my notes and summaries from each episode + a little bit of my own research. If you find this interesting, I encourage you to listen to the podcast as well.

This is a lot of information, so feel free to jump right into what interests you. However, if you go in order you will have a much deeper understanding.

KEY TAKEAWAYS

The most important takeaway of Dr. Sinclair’s work is the following:

AGING IS A DISEASE. A TREATABLE DISEASE.

For now, treating aging requires to do the right thing, there’s not just a magic pill. The most critical things are:

• Eat the right way.
• Eat less often.
• Get exercise.
• Get quality sleep.
• Stress your body: adversity mimetics.
• Supplements.
• Track your data.

It’s on our hands to slow down aging. And even reverse it. Let’s dive into the science and tools to do it the right way!

The Science of Aging

Three Longevity Genes

We want to trick the body into thinking it’s under threat of survival thru different methods and mechanisms. This activates these 3 longevity genes.

1. mTOR

Mammalian target of rapamycin (mTOR) is a protein kinase that regulates protein synthesis and cell growth in response to growth factors, nutrients, energy levels, and stress.

Basically, mTOR makes a protein that senses amino acids. When you eat a big steak, mTOR is activated. We want to inhibit mTOR to have longest lifespan. Low activities of mTOR is a signal that times are tough.

Low levels of mTOR activates Autophagy, which is the body’s way of cleaning out damaged cells, in order to regenerate newer, healthier cells.

2. AMPK

AMP-activated protein kinase (AMPK) is an enzyme that is present in all mammalian cells.

It makes the body more sensitive to insulin (good thing, it sucks the sugar out of your bloodstream).

It ramps up the energy producing centers of the body: mitochondria.

AMPK is a sensor of energy, and low energy is a good thing for longevity. In response, it protects the body because it thinks it’s going to run out of food.

We want more AMPK.

How to activate AMPK? Exercise and Fasting.

The drug that increases AMPK is metformin (usually used for type 2 diabetes).

3. Sirtuins

Sirtuins are a family of signaling proteins involved in metabolic regulation. They are important central regulator of longevity. Fasting and exercise activate the sirtuins.

Ex-Differentiation

First, a little recap of Middle School Biology:

The nucleus of the cell is the genetic information of the cell, encoded in DNA. The cells wraps the DNA around proteins called histones, which attract each other and form the chromosomes.

When the cells replicate, the best thing is that they replicate into the same type of cell (we have liver cells, skin cells, nerve cells, etc.).

But as we age, the packaging of the DNA that allows a cell to remain a certain type of cell forever starts getting lost.

This is what we call Ex-Differentiation, which means that the cells become confused. The cells become more of a generalized type of cell rather than a specific one because that genes shouldn’t be on start come over time.

This is the process that give birth to most diseases (Dementia, Alzheimer, Diabetes, Heart Disease). If you slow down Ex-differentiation, it means you are getting the cells to remember how to behave. And consequently, you reverse aging.

The 3 regulators (mTOR, AMPK and Sirtuins) slow down the Ex-differentiation process.

What To Eat and When To Eat

Main takeaways:

1. Eat less often.
2. Avoid sugary drinks and foods.
3. Reduce meat intake for longevity.
4. Its never too late for dietary changes.
5. Find veggies that have been stressed out (organic, colorful veggies).
6. Never start a meal with sugars, if you do eat them at last (desert).

Going deeper

There is a genetic pathway that gets triggered by low energy.

These genes (sirtuins) respond to low energy (low glucose levels -caloric restriction-), high heat, low amino acids, high salt (stressors). The sirtuins take care of the DNA repair and the stabilization of the epigenome.

When the body is hungry, it makes NAD (fuel for the sirtuins).

Fasting

It inhibits mTOR and activates AMPK and the Sirtuins.

There are different protocols for Fasting. The most common one is the 16–8 (8hr feeding window plus 16hr fasting). Dr. Sinclair does OMAD (one meal a day), which can be more challenging for most people.

The Big Killer: Sugar

Sugar spikes glucose. Glucose shut down sirtuins and AMPK.

Defenses against disease and aging shut down.

What about Protein?

We should avoid high protein diets (specially red meat) for longevity. It activates mTOR, and we want to inhibit mTOR.

Amino acids: three important ones → Leucine, isoleucine, and valine: BCAAs. Are used to sense protein intake. The sensor is mTOR. The mTOR activates when you get them. mTOR repairs and build muscle. In the short run, this is good for building muscle, etc. But in the long run it is not good for longevity , as mTOR is responsible for autophagy.

Plant based diets: the more vegetarian you are, the longer you live. The best, Okinawa diet, is plant base diet with fish — (probably because of Essential fatty acids).

Adversity Mimetics

Exercise, Heat, Cold & Other Stressors are “Adversity Mimetics”.

As talked before, we want to trick the body into thinking it’s under threat of survival.

Exercise

Exercise prevents diseases and reduces mortality.

Walking after a meal stimulates the production of new blood vessels and turns on AMPK (registers energy -ATP-).

Vigorous exercise makes us have Low levels of oxygen (Hypoxia), which is good (though doesn’t feel good).

As we get older, our muscles become less sensitive to the insulin that the pancreas is putting out. This is due to aging. Glucose in the bloodstream damages blood vessels.

Exercise impacts the epigenome (regulator of DNA) in a positive way.

Weight training maintains hormone levels, the ability to walk well and to have good posture, and also makes you look better, which can boost your confidence and reduce anxiety and stress.

It is hard to build muscle as you get older. Breaking your hips is equivalent to have stage 4 cancer. Mortality rates are that bad after hip injury. How to avoid breaking hips? Build muscle and work on flexibility while you can.

Senescent cells: when the epigenome becomes deregulated, cells can either die or they can be shut down, so they are zombie cells. Slowing the formation of zombie cells or killing them is important. Exercise kills these cells.

Hyperbaric Oxygen Therapy (HBOT)

• Hyperbaric chamber where pressured is increased.
• Can reverse aging.
• It’s similar to hypoxia. So it’s similar to exercise.

Cold Therapy

• Production of brown fat (burns white fat and enhances metabolism).
• Some forms of cold therapy: Cryotherapy, cold showers, ice baths, sleep with few blankets.

Heat: Saunas

• Positive effects of Saunas: the immune system is strengthened, the metabolism is activated and the cardiovascular system is trained.
• Saunas can reduce by 20% cardiovascular disease.

SUPPLEMENTS

Some Biology

NAD (nicotinamide adenine dinucleotide) is a critical coenzyme found in every cell in your body, and it’s involved in hundreds of metabolic processes.

Our cells use NAD to transfer hydrogen atoms between proteins. Without it we can’t make ATP (energy). It activates the sirtuins (defensive enzymes). It’s a sensor for adversity.

Problem: As we get older, we make less NAD…

Supplements: NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide)

They are both supplements to raise NAD levels. They are also known as NAD boosters.

They mimic caloric restriction and enhances sirtuin activation.

NR is converted by the body into NMN, which is used to make NAD.

Benefits: More mitochondria, less inflammation. Burns more fat, improved metabolism. Increases in lifespan. Enhances insulin sensitivity.

Vitamin B3 is a precursor of NAD, but is not as effective. So you can’t just take B3 to receive these benefits.

Doses? Low dose: 250mg — High dose: 1g.

NMN works better than NR. NR is cheaper to make because it doesn’t have phosphate.

Consuming NAD directly is not effective because it is too big and the body doesn’t use it properly. So we use NMN or NR.

Caveat: if you are predisposed to cancer, NAD boosters can accelerate the disease. So be careful there.

RESEVERATROL

Activates Sirt-1 (One of the 7 sirtuins).

It’s found in red wine. (However, to get the right levels of resveratrol you’d need dozens of glasses of wine per day, so not recommendable LOL).

Doses? 250mg to even 2g a day.

How to ingest it? You can’t just swallow it. It’s insoluble. So you need to mix it with some food. It’s hydrophobic. Better to consume it with a fatty meal.

Animal studies: Fat Mice on resveratrol lived as healthy as lean mice.

In humans studies: increase insulin sensitive. Lower cholesterol levels, raise HDL (Good cholesterol).

METFORMIN

It activates mitohormesis (a biological response where the induction of a reduced amount of mitochondrial stress leads to an increment in health and viability within a cell, tissue, or organism).

Metformin makes the body more sensitive to insulin and lowers the blood glucose. It’s used for diabetes.

Metformin Inhibits mTOR, activates AMPK, raises NAD levels. It comes from plants.

Studies in humans show: glucose lowering, more energy, muscle switching (become more like an athlete). Lowers risk of all other diseases.

Caveat: Muscle loss. Metformin reduces the body’s ability to make energy so you don’t train as hard so you don’t grow as much. However, it is a minor effect: 5% difference in muscle mass, according to studies.

Other Supplements

Quercetin: Reduces fatty liver and inflammation in the body. It can only be used on clinical trials.

Fisetin: plant molecule, found in grapes, apples and strawberries. Reduces inflammation. (Dose: 20mg per kg of bodyweight).

Quercetin & Fisetin both kill senescent cells (zombie cells), which cause cancer.

Rapamycin and Rapalogs: Inhibit mTOR (by mimicking fasting). Mimics low protein intake. The body starts recycling old proteins thru autophagy.

Spermidine: It stimulates autophagy. Stabilizes changes in the epigenome (major cause of aging). Studies showed improved cognition and memory.

Berberine: Activates AMPK. Take it with food. Mimics the effect of metformin. Dose: 1–2g per day. It is also a glucose disposal agent, so it helps enter into a fasted state quicker.

Dr. Sinclair’s Protocol

In the Morning:

• 1g of resveratrol with yogurt or olive oil
• 1g NMN
• Spermidine: 1g
• Fisetin and quercetin: 500mg

At night: 800mg Metformin, after dinner. Not the night before doing weightlifting.

Medical Interventions

Testosterone

• Testosterone decreases as we age.
• Signals our body that times are good (build muscle, reproduce, etc.).

Testosterone replacement therapy

• Benefits: Increase in muscle mass, more power, aerobic capacity.
• Side effects: worsen sleep apnea, shrinking testicles, increasing red blood cell protection (leads to blood clots). Not conducive to longer life.

Hormone replacement therapy for women

The female reproductive system ages earlier than the rest of the body.

Women evolved to become infertile at the age of 40/50 because they need to be young to have a child and bear the physical consequences of it. And then, they need at least a decade to raise the child, which takes a lot of energy and effort.

Transition thru menopause can be eased with menopausal hormone therapy (estrogen replacement).

The dual use of estrogen and progesterone in the right combination is really important.

Women should test their baseline levels of estrogen and progesterone in their 30s and 40s, so when they go thru menopause they know what is the baseline to supplement.

Human growth hormone

People with low HGH have less risk of cancer and live longer.

Side effects of HGH: soreness in joints, increased insulin resistance (type 2 diabetes).

HGH is not bad, bringing it to normal and natural healthy levels is good. But increasing it too much is not good for long-term.

Peptides

Peptides are short chains of amino acids linked by peptide bonds. They are signals to the body. They help increase cellular communication.

Insulin is a peptide.

Some other peptides (all anecdotal evidence, not robust science):

• BP-157: increase blood flow, lower inflammation, regenerate neurons.
• SS-31: Improves mitochondrial function.
• GHK-Copper: wound healing, attract immune cells, anti-oxidant, stimulates collagen, protects tissues and grows hair.
• MOTS-C: Comes from mitochondrial DNA. Lowers blood sugar levels and improves fatty liver → Good for longevity. Side effects possible: arthritis (because the body identifies peptides as foreigners).

Yamanaka factors

The Yamanaka factors are a group of protein transcription factors that play a vital role in the creation of induced pluripotent stem cells. They control how DNA is copied for translation into other proteins.

Stem cells are cells that have the ability to become any cell in the body. They can divide asymmetrically to produce cells that go on to make tissues and they retain youth.

CELLULAR REPROGRAMMING: Instead of using the 5 Yamanaka factors, you use 3 of them. Using the 5 makes the cell go back to zero-age and it causes cancer. Using just 3 you makes the cell rejuvenate by 80%!

Study in mice: injecting these genes in blind mice made them recuperate their vision.

These studies have been done for all kinds of cells. This can be a universal mechanism to rejuvenate the body and reset diseases.

The Science of Looking Younger

You are as old as you look

The skin is the largest organ in the body. It makes up 1/6 of the entire body weight.

Epidermal thinning: as we age, skin gets skinnier.

Having thin skin is bad. The skin is the main barrier against intruders.

Skin ages faster than the rest of the body because it’s exposed to sunlight.

Skin is full of senescent cells. If you delete these cells, you rejuvenate the skin.

Collagen is a protein responsible for healthy joints and skin elasticity, or stretchiness. It starts to attenuate at mid-20s.

Retinae: boosts the production of collagen, increase the growth of the epidermis, lower skin pigmentation, lower the lipid. Inhibit MMPs. If you use it you get dry skin, so use moisturizer and sunscreen. It is unclear for the long-term longevity.

Nails: the rate of nail growth is an indicator of state of aging.

Hyaluronic acids: important for plumpness of the skin. HA is involved in protecting animals from cancer. HA is a big chain of chemicals.

Botox. Is a toxin. It inhibits neurotransmissions. It numbs the nerves and thus reduces wrinkles.

Things bad for skin:

• Sun.
• Smoking.
• Alcohol.
• Bad foods.

Hair Loss & Grey Hair

It has a strong genetic component and it is NOT an indicator of aging.

Boldness and grey hair indicates you are older. Evolutionary speaking, this was a great thing because you were seen as more wise and dominant. This was a sign that you should be given respect.

Why hair loss occurs? Stem cells important for hair regrowth get kicked out of the hair follicle.

Treatments for Hair Loss:

• Topical treatments: minoxidil works. Stimulates nitric oxide production.
• Pill: finasteride. It inhibits DHT. However, DHT too low can be bad for health as well.
• Fricking laser beams: Low laser light therapy. Slow down hair loss.
• Platelet rich plasma injections.

Grey Hair:

Associated with stress.

It doesn’t have to be permanent. Grey hair is reversible in the early phases.

Fun fact: Eunuchs live 15 years longer than average men. Cutting your balls off is the best strategy for longevity LOL.

Keeping the Brain Healthy

The brain ages slower than the rest of the body. It has protective systems that prevent itself from aging.

The volume of the brain after the age of 40 reduces 5% per decade.

In the old days, people didn’t need their executive functions to be extremely acute. There were not new things to learn every day and keep up to. Life was pretty much always the same.

We now live in an ever changing environment and that requires tons of plasticity.

The three longevity factors all work together to keep the brain young and healthy.

Diet for Brain Health

Mediterranean type-diet prevents brain aging (Olive oil, red wine and no red meat).

Olive oil: oleic acid activates the sirt1 enzyme.

This diet mimics adversity and activates the longevity pathways.

Western diets are more like abundance mimetics. They are full of calories and constantly tell you that the times are good.

B vitamins are responsible to make the methyls that are added and subtracted from the DNA that controls the DNA methylation clock. Low levels of B12 messes up the epigenome and accelerates brain diseases.

Fatty acids

Omega 3 fatty acids: we don’t make them ourselves. They are the building block of the brain. (Salmon, mackerel, krill, sardines). Sources of omega 3.

The three main omega-3 fatty acids are: EPA, DHA and ALA

We should try to consume at least 1g per day of EPA .

For plant based diet: ALA(flaxseed, walnuts, seaweed): 10% gets converted into DHA and EPA.

Exercise for brain health

Improves memory and cognition as you get older. Two reasons: Better blood flow & Better neuronal activity.

It activates sirtuin pathway.

Improves executive function of the brain.

Both aerobic and strength training works.

Supplements for the brain

• Metformin. Raises NAD levels and activates sirtuins. Releases free radicals. So the body makes more mitochondria.

One way to stay focused is to have steady levels of glucose.

• NAD boosters:

Increase blood flow. Vascular flow is really important for the brain.

Sleep

Good quality sleep is the most important thing you could ever gift yourself. It is the foundation of every healthy life.

SIRT1 and NAD go up in the morning, and come down later in the day to get your body ready to sleep. In doing so, they turn a gene called BMAL, which tells the body to calm down. If you lose SIRT1 function and have low NAD levels you are not going to sleep well.

As you get older you lose the ability to sleep, so you have to intervene.

Key things: NMN in the morning (because it raises NAD levels).

Magnesium and L-theanine are good things.

Get light in the morning and dim lights at night. This helps regulate the circadian clock.

Health Technologies

Healthcare model: wait till you get sick and then go see your doctor. It made sense in the past, but not anymore.

Five key biomarkers to monitor:

• Glucose.
• Heart function.
• Inflammation (keep CRP low).
• Cortisol.
• Lactate (tells if the body is able to do exercise adequately).

Why Measure yourself?

Data allows our doctors to see the state of your health before you get sick.

How to measure? Wearables: Fitness watch, Continuous glucose monitor, Biobutton. All these technologies are getting finer and cheaper by the day.

Based on data, we can have Personalized diets, exercise routines, Meal& restaurants recommendations, gym routines, supplementation, etc.

Data is going to have to be managed by Artificial Intelligence. So… One concern: Where does the data go? Who handles it?

We need to put the rules in place before the technology has massive adoption and big companies have access to incredible amounts of personal data.

Concerns about environment and economics

As we live longer, there’s a lot of people worried about how this is going to impact the job market, the environment and our quality of life.

The money that is saved from the improvements in health can be allocated to more productive uses.

With a longer life you have more freedom and opportunities. You’ll be able to take the time you need before making a decision because time is not constantly pushing you. You may be able to build an entire new career at age 60. Or start a new sport at age 70.

I hope you found this useful, but I still highly recommend watching the episodes.

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