This article was originally published on medium.com on January 18, 2020.

Reading time: 11 min

Disclaimer

This article is based on my research of information from publicly available sources and my personal experience. The information, opinions, and references provided in this article are for informational purposes only. This article is not a medical advise and is not intended to treat, diagnose or prescribe for any illness or condition. Please consult your doctor or healthcare provider for your specific diagnosis and treatment.

Longevity principles series

This is the 2nd article in the Longevity Principle series. In part 1, we discussed how long we are likely to live and how to increase a chance of living to 100+ and possibly to 200. We concluded that we want to be in the dark green “strong health” quadrant — it would increase a chance of living to 100+ years from 2% to 5%.

Here in part 2, we will cover:
— Why humans age?
— How to reverse or at least minimize aging?
— The 8 longevity principles to stop aging

Why humans age?

• There is no single cause of aging; multiple aging pathways exist. We will look at them shortly
• Some scientists describe aging using hallmarks; other scientists — using damage types
• But many researchers agree that aging is a disease, i.e., it can be prevented. ”Lifespan” by David Sinclair is a must read for everyone interested in longevity

Importantly, it is relatively easy to prove correlation but difficult to prove causation between the causes and the results of aging. It means that not all longevity recommendations will extend life but they may. Our objective, as health-conscious individuals, is to maximize chances of moving from the dark grey quadrant “standard American diet” to the dark green “strong health” quadrant.

Below is a visual summary of a comprehensive framework on causes, responses, and results of aging proposed by Carlos López-Otín et al. in a paper titled “The Hallmarks of Aging”.

The authors define the aging hallmark as follows:

“Each hallmark should ideally fulfill the following criteria: (1) it should manifest during normal aging; (2) its experimental aggravation should accelerate aging; and (3) its experimental amelioration should retard the normal aging process and hence increase healthy lifespan.” — Carlos López-Otín et al.

Unfortunately, these hallmarks of aging are not actionable for normal people. My intention is to translate them into actionable recommendations.

A more actionable way to look at this is from the aging-related disease standpoint. Let’s look at the global deaths statistics — two thirds of people die from the aging-related diseases such as cancer, cardiovascular diseases, and diabetes. Interestingly, animals rarely have these diseases because they normally have healthier lifestyles.

Let’s simplify — to be healthy to 100+, you want to avoid the aging-related diseases which kill two thirds of people.

How to reverse or at least minimize aging?

• Reversing or minimizing aging is not guaranteed; it’s all about maximizing chances by doing as many health and longevity promoting activities as possible
• It is relatively clear how to maximize chances of living longer: we need to upregulate or downregulate several key molecular pathwayswhich influence the hallmarks of aging
• We have plenty of highly effective and accessible tools at our disposal: nutrition, supplements, environment, physical activity, stress management, and accessories

You can minimize aging and potentially reverse it by focusing on several key molecular pathways using simple tools such as nutrition, supplements, environment, physical activity, and accessories.

Longevity science vs. Applied longevity

Would all recommendations we discuss here extend human lifespan? Probably not all but some of them would. They may also work more effectively in combination. They will certainly increase your chances of being in the top quartile of the “strong health” dark green quadrant above.

The reality of the biological studies and experiments is that it’s hard to set them up perfectly — they will always be different from real life and always have imperfections. So it’s challenging to fully rely on them and know what is guaranteed to work for humans. For example, studies on mice may not translate perfectly on people. Recall from part 1 that humans already live 3–4 times longer than mice (when you adjust their lifespan the right way using the mass-metabolic rate ratio). So may be the drugs such as rapamycin that almost double the mice lifespan only move them closer to humans and will not have the same effect on us (if and when they become approved for humans)? Peter Attia has an excellent series of essays on “Studying Studies” — highly recommended for people interested in better understanding scientific studies.

It’s important to realize both the importance and the limitations of science. That said, doing more of the healthy things in life will likely make you more healthy and help you live longer. There are, however, misconceptions about what is healthy. For example, is growing big muscles healthy? The answer — it’s not because it ages you. In my research and writing, I aim to provide a link between recommendations and how they impact health and longevity.

The key longevity pathways to influence the hallmarks of aging

If you study scientific literature on longevity, you will find that there are10–15 key pathways associated with health and longevity. To live longer, you need to upregulate, downregulate or maintain them in balance.

Since we started to use some technical terms, I’ll take a second to introduce them:

• Biological pathway is a series of interactions among molecules in a cell or communication between cells that leads to a certain product or a change in a cell.
• Upregulation or downregulation are the processes by which a cell increases or decreases, respectively, the amount of a cellular component such as RNA or protein.
• Technically, pathways cannot be “maintained in balance”. They need to be upregulated or downregulated. However, I added a few pathways to be “maintained in balance” because it is clear from research how their misregulation leads to aging.

Also, I use a broad definition of longevity pathways which includes molecular level (e.g., mTOR activity), cellular/tissue level (e.g., autophagy), and systemic/organism level pathways (e.g., inflammation). The reason is simple — longevity, i.e., extending your lifespan, is not possible without keeping good health. Here are 2 examples of why it is important:

• Many people think that you can take a “magic pill” and reverse aging. Metformin, resveratrol, and NMN recently gained popularity as anti-aging supplements. The truth is that taking the “magic pills” may give you an extra edge (0–10+ years in lifespan) if you’re in strong health but wouldn’t cover the basics of not doing simple health hygiene (for example, not overeating)
• This week, I attended a panel on extending human lifespans as part of J.P.Morgan Health Conference. There was a question from the audience if it was proven that not eating sugar extends lifespan? The panelists responded that it wasn’t. Well, I would argue that not eating sugar may not extend a maximum achievable human lifespan but eating sugar will negatively impact your health and decrease your actual lifespan— it deteriorates the insulin signalling pathway (“deregulated nutrient sensing” aging hallmark).

In the chart below, I summarized key pathways should be upregulated, downregulated or maintained in balance to prevent aging and extend lifespan. Here is a deep-dive by GenomeNet for folks interested in more details.

It’s important to note that:

• These pathways act at different levels: molecular (e.g., mTOR activity), cellular/tissue (e.g., autophagy), and systemic/organism level (e.g., inflammation)
• These pathways are often interrelated but it is helpful to think of them separately as they can have different ways to influence them
• Many more longevity pathways exists — this is a deliberately simplified list. For example, FoxO3 — one of the major longevity genes/pathways — which is activated by multiple pathways

Now that we know the longevity pathways, what can we do with them? This is where the majority of my research focused to tie the longevity pathways with specific recommendations on nutrition, physical activity, supplements, changes in your environment, and use of accessories.

The 8 longevity principles to stop aging

There are many practitioners and scientists who have great research on longevity and health: Dave Asprey (the BulletProof inventor and an inventor of the term “biohacking”), Steven R Gundry MD(a former cardiac surgeon who now specializes on nutritional medicine), Satchin Panda (the leading expert in the field of circadian rhythm research), Peter Attia MD (a former cancer surgeon who now specializes on the applied longevity), Rhonda Patrick (the founder of FoundMyFitness), and many others. They inspired me to start my longevity quest.

While seeing many health and longevity recommendations with solid scientific evidence, I still couldn’t make sense of a bigger picture. How do they all fit together? If there is a new health recommendation, by which specific mechanism would it make a human healthy or unhealthy? Is there a MECE (mutually exclusive and collectively exhaustive) longevity framework that would tie the longevity pathways with practical recommendations?

My research led me to believe that everything you can do to live longer aims to reach one or more of the 4 objectives:

• Follow biological clocks, specifically, circadian and circannual cycles
• Improve cellular energy by protecting existing mitochondria and growing new mitochondria
• Keep strong gut by protecting your gut-blood barrier and enriching your gut microbiome
• Protect & repair cells by protecting your genomic library and detoxifying

Each longevity objective can be achieved by following the 8 longevity principles. Let’s take a closer look at them.

Objective 1: Follow biological clocks

If you remember only one thing from this article, it’s that you need to follow your daily and annual (seasonal) clocks because that’s how your genes have evolved over thousands of years.

Longevity principle 1. Sync with your daily clock

Your daily clock is called Circadian Rhythm — a natural cycle repeating approximately every 24 hours which controls gene expression, molecular pathways, cells, and tissues.

The Circadian Rhythm exists because we can’t have all biological functions running at the same time. Up to 20% of different genes can be turned on or off at different times of day. That’s the main reason why you should be in sync with it. Circadian Rhythm disruption puts you at an increased risk of cancer, diabetes, Alzheimer’s, and other major diseases.

Longevity principle 2. Pause growth mode

Pausing growth mode means being in sync with your bigger growth cycle called Circannual Cycle — a self-sustained rhythm of approximately 1 year which controls major biological processes. In mammals it consists of two distinct states: ‘Summer’ — genes are active, i.e., growth & ‘Winter’ — genes are silenced, i.e., regression.

Circannual Cycle exists so that organisms can adapt to periods of low and high energy availability. Unfortunately (for the circannual cycle and our health), food has become widely available 365 days a year very recently. So the growth genes (such as the mTOR) are always active which accelerates aging and increases risks of diseases such as cancer and diabetes.

Objective 2: Improve cellular energy

~90% of our energy (in the form of ATP or Adenosine Triphosphate) is produced by mitochondria — tiny organelles inside cells.

There are hundreds to thousands of mitochondria in each cell.

Mitochondria decide if a cell should live, grow or die based on the levels of cellular energy.

Longevity principle 3. Protect mitochondria

Mitochondria regulate a variety of important functions in the bodysuch as apoptosis (programmed cell death), inflammatory responsethrough mitochondrial reactive oxygen species (aka free radicals), and other metabolic tasks (membrane potential, calcium signalling, steroid synthesis, hormonal signalling).

Mitochondria generate free radicals which attack our genes 10.000 to 100.000 times a day. To live to 100+, we need to prevent excess free radical leakage and maintain a healthy proportion of mitochondria in a cell.

Longevity principle 4. Grow new mitochondria

Mitochondria commit mitochondrial suicide (mitophagy) when it’s energy production capacity is below a certain minimum to eliminate potentially mutant mitochondria. Mitochondrial biogenesis exists to compensate for unhealthy mitochondria and improve cell metabolic(energy production) capacity; if the latter is low, mitochondria may trigger cell death (apoptosis).

If we want to be like birds and live to 200 years old, we need to grow new mitochondria all day every day to compensate for unhealthy/inefficient mitochondria and put less stress on each individual mitochondrion.

Objective 3: Keep strong gut

Over thousands of years of evolution we outsourced a lot of our functions to bacteria. In fact, we might be only 10% human — our gut microbes carry 3+ million genes which is ~150 times more than humans (who carry ~21.000 genes).

Longevity principle 5. Protect gut-blood barrier

Gut-blood barrier is a complex multilayer system which controls the absorption of nutrients, water, and other substances.

Gut-blood barrier exists to let the good stuff into the bloodstream while keeping the bad stuff (germs, toxins, and other harmful substances) away from it. Having bad stuff in your bloodstream ages you.

Longevity principle 6. Enrich gut microbiome

Gut microbiome is a genetic material of all microbes living in the human gut. Gut microbiome exists so that humans can adapt to consuming different types of foods (i.e., we outsource many tasks to microbesinstead of having to rely on our own genes).

There is a proven link between healthy gut microbiota and longevity — centenarians have bacteria strains similar to 30-year olds. Improving your gut may make you a centenarian.

Objective 4: Protect & repair cells

Damage to our cellular DNA occurs at a rate of 10,000 to 1,000,000 molecular lesions (damages) per cell per day; most of this damage gets repaired but we age when the repair mechanism is inefficient or there is too much damage.

Longevity principle 7. Detoxify

Our bodies constantly accumulate toxins acquired from exogenous(food, water, and environment) and endogenous sources (cellular and metabolic waste from our blood and organs) which damage our genes and cells and disrupt biological processes. Toxin removal leverages multiple organs: liver, kidneys, lymph, colon, lungs, and skin.

Excess toxin intake and/or disfunction of any phase of detoxification leads to aging and disease. To live to 100+, you need to be master the detox.

Longevity principle 8. Protect your genomic library

The human genome is ”the collective library” of genes. The human epigenome is ”the recipe book” from “the collective library” used to build different types of cells.

To live long, we need to: (1) have the right books in the library (genome); (2) make sure the right ones are used to build specific types of cells (epigenome); (3) get rid of the bad cells early, the ones which were built using the wrong books or damaged afterwards (proteostasis).