Meet the characters of longevity

Lets look deeper into some of the variables at play here, and some of the tools we may be able to use manipulate them and combat aging. For each mechanism, we will share some of the latest research as well as potential interventions that are currently on the market. Some of the ideas are based on studies on other organisms like yeast or mice, while others are further along with studies or examples on humans.

Genetics

Epigenetics

While your DNA’s original code doesn’t really change, your genetics and their expression are not constant. Many variables are turned on and off in different situations, across every cell in your body. This complex status of gene expression is sometimes referred to as epigenetics. Unlike your original genes, this can be constantly updated and maintained. Your epigenetics are affected by everything from your childhood, to what you did this week.

You can think of your genetic code like the menu at a restaurant and your body’s epigenetic state like ordering items from that menu. After a while, depending on what was ordered, from the same exact menu you could end up with an infinite variety of experiences, from a really great dining experience to something very unappetizing.

Imagine every time you were stressed, you ordered 10 pickles. All of a sudden your table is overflowing with pickles and the meal is quite strange, but it may not be the menu’s fault. Rather than ordering things from a literal menu, your cells achieve this by the presence of hormones, nutrients, or even time of day. This then “orders” various proteins or causes different pathways to be executed.

Many of the focuses of longevity involve the maintenance and control of these epigenetics, which start off pristine but can deteriorate over time, as damage accumulates and errors compound.

Hormesis

As you’ve probably heard many times, chronic stress is problematic for longevity, reducing both healthspan and total lifespan. However, that doesn’t mean all stress should be avoided. An extremely relaxed and pampered life goes too far in the other direction.

The expression “what doesn’t kill you makes you stronger” is not scientific advice, but may not be far from the truth when it comes to how the human body works.

Most people would benefit from less mental and emotional stress (which is often constant and unnecessary), and more physical stress on their body (which is now rare in our sedentary and technological environments).

Many types of acute (short term) stressors can help trigger growth and make your body stronger. This is how exercise works, for example. Many other types of stress can also have beneficial outcomes, such as changing temperature (with sauna or cold exposure), intermittent fasting or caloric restriction, oxygen levels (hypobaric chambers or breathwork).

The challenge here is to not over-stress your body if it is already near its limits, but still generate enough stimulus to get a response. Lets look at some of the more specific ways this could be accomplished. Much of this research is extrapolated from behavior in other organisms like yeast and mice, but there are many lessons we can learn and start to apply in our human lives.


This is where it is useful to understand how things work, rather than developing superstitions about them simply increasing longevity. Being able to actually measure these variables (like how stressed your body currently is) will help to better find this balance. Lets look at some of the actual mechanisms involved here, and what tools we can use to adjust them.

Genetics

Telomeres

Telomeres are protein caps at the end of your chromosomes that protect the integrity of your DNA. Telomeres keep your chromosomes from unraveling and fusing together to maintain healthy cell division and aging. Scientists have found that shorter telomeres are associated with aging, earlier death, disease development, and neurodegenerative disorders. They generally start out longer when you are young and healthy, and get shorter over time as you age, eventually becoming less effective.

The good news? A healthy lifestyle — all the habits discussed previously — have been shown to reverse aging by lengthening your telomeres! *, *, *

Keeping your telomeres long sound appealing and a very simple measure of longevity. How can we actually make that happen?

Sirtuins & NAD

Sirtuins are a family of seven signaling proteins (abbreviated as SIRT1, SIRT2, … SIRT7) that are involved in DNA repair, controlling inflammation, and protecting against oxidative damage. Additionally, they are involved in producing new, healthy mitochondria. These make sirtuins a great target for anti-aging research. There are many genes and chemicals involved in this entire process.

Sirtuin activity increases with NAD+ levels (Nicotinamide adenine dinucleotide), which is a molecule used in all our cells for electron transport and to facilitate many important chemical reactions. Sirtuins need NAD to function, but unfortunately, these levels decline as we age. **

“Rising NAD+ content, followed by sirtuin activation, has been reported to increase lifespan in yeast *, *, *, worms * and mice *

Humans are different from yeast, worms or mice. However, this pattern suggests similar benefits could appear in humans from increased NAD+ levels. Human research is still being conducted, but keeping our NAD+ levels high seems like a promising mechanism to control our longevity. It is not easy to directly measure our current levels, but certain behaviors have been known to increase it.

NAD+ (or rather precursors to NAD+, like NMN and NR) is a popular longevity supplement. However, there are many other cheaper and more effective ways to boost your levels, which are important to do even if supplementing. Exercise is one of them!

So you may have known that exercise is considered “healthy” but now we have a better idea of what it actually does behind the scenes. The next time you have an intense workout, you may be increasing your NAD+ levels and helping your sirtuins function all across your body.

*, *, *, *, *

Energy

Mitochondria

Mitochondria are organelles found within your cells, often referred to as “powerhouses” because of their role in generating usable energy (ATP) for the cell. However, mitochondria do much more than create energy. They participate in intracellular signaling, mediate cell death, regulate innate immunity, and even modulate stem cell activity.

But what is their role in aging? Mitochondria are linked to a wide range of processes associated with aging including cell senescence, inflammation, and age-dependent decline in tissue and organ function. As you age, your mitochondria age.

They become susceptible to errors in their own mitochondrial DNA the older they get. Studies in mice have shown that an increase in errors within mitochondrial DNA is associated with signs of premature aging and a reduced lifespan. Additionally, changes in human mitochondrial DNA are responsible for a variety of diseases such as Alzheimer's, Parkinson’s disease, and cataracts.

Reduced efficiency of mitochondria can create an accumulation of reactive oxygen species (ROS) within your cells. ROS can damage DNA, proteins, lipids, and other molecules to accelerate disease. This may be responsible for additional “aging” effects, but is less understood.

In short, because of the many ways mitochondria are involved in aging, targeting the health of your mitochondria might be a way to go “upstream” and slow down the aging process before molecular or cellular damage can cascade into other problems that accelerate aging. *, *, *, *, *,

Senescent Cells

Sometimes referred to as “zombie cells,” senescent cells are cells that have stopped proliferating (copying themselves to create new cells) but they also don’t die, hence the nickname. They are thought to contribute to aging because they release pro-inflammatory cytokines into surrounding cells, accelerating their aging as well.

In rat studies, when senescent cells were injected into rats, healthy cells became more likely to become cancerous or experience other tissue disfunction. *

Aged mitochondria are more likely to cause cells to become “senescent.” Improving mitochondrial health is a great start to preventing senescent cells.

In addition, there is emerging evidence that these senescent cells may soon be able to be targeted using pharmaceuticals, and encouraged to “die” before they wreak havoc on healthy cells. Something to keep an eye out for in the coming years! *, *

Now let’s learn about some of the molecules that affect these important variables...

mTOR

Short for “mammalian target of rapamycin”, mTOR is a protein that regulates important cell functions like growth, proliferation, motility, autophagy (programmed cell death), and transcription. *, *

While growth and mTOR are important for our daily function, elevated mTOR levels are associated with mitochondrial dysfunction, cell senescence, flawed proteostasis, and many other hallmarks of aging.

Inhibiting mTOR has been shown to increase lifespan in mice and is an emerging science for human studies as well. One of the most well-recognized ways to inhibit mTOR in humans is through periodic fasting.

AMPK

Autophagy of cells (“auto” means self and “phagy” means eat, so basically cells eating themselves to clean up) happens automatically when cells are ready to die and reuse their materials. This is an important step in cleaning up damaged or older cells and constantly rejuvenating ourselves. If this process is delayed or not happening consistently, some of these cells can even become cancers, so promoting autophagy is thought of as one of the techniques for longevity. *

“Activating protein kinase” (AMPK) is one of the major autophagy regulators in your body. It activates a bulk protein degradation to get rid of old, possibly damaged proteins so your body can make new, healthier proteins that will be better at their jobs, thus promoting healthier aging.

AMPK activation and responsiveness naturally decline with age, but studies have shown that you can increase AMPK to improve the effects of aging and extend your lifespan. *

Calorie restriction

In mice studies, eating less (80% of normal calorie intake) showed a 20% increase in life span. Of course, humans are not mice, so restricting your calories may not cause the same 20% increase in your lifespan. Still, this can be an indicator that there are promising mechanisms here. *

Anecdotally, people in the aforementioned “blue zones” seem to have relatively moderate calorie intake as well. More research is needed here to better understand the mechanisms.

Calorie restriction or intermittent fasting is often thought of as simply a bodyfat reduction tool, but may have more implications for longevity through other mechanisms like mTOR or AMPK. With this in mind, having a consistently high calorie intake, especially from processed foods or when not intentionally building muscle, should probably be avoided. *

Nutrition

Advanced glycation end-product (AGE’s)

“Compounds that have been found to inhibit AGE formation in the laboratory include Vitamin C, Agmatine, benfotiamine, pyridoxamine, alpha-lipoic acid, *, taurine, *pimagedine, aspirin, carnosine, metformin, pioglitazone and (https://en.wikipedia.org/wiki/Advanced_glycation_end-product#cite_note-Rahbar&Figarola2003-42) and pentoxifylline Activation of the TRPA-1 receptor by lipoic acid or podocarpic acid has been shown to reduce the levels of AGES by enhancing the detoxification of methylglyoxal, a major precursor of several AGEs.” *

Studies in rats and mice have found that natural phenols such as resveratrol and curcumin can prevent the negative effects of the AGEs.

Theoretically, eating a diet high in all these compounds could help to reduce the pace of aging.

Ultra-processed foods, or even just imbalanced meals that are too high in sugar and cause a spike in glucose, can increase the rate of AGE formation. A relatively simple and effective way to reduce these will be to stay metabolically healthy and avoid extreme spikes in glucose. This may be one of the mechanisms through which eating a diet without processed foods becomes protective for longevity.

Omega 3/6 ratios

To promote healthy levels of inflammation in your body, you must eat a good balance of omega-3 and omega-6 fats. The optimal ratio is about 1:4, respectively. Currently, it's estimated that most people who eat a westernized diet are eating between to 1:10-1:20 omega 3 to omega 6 fats. *

This drives inflammation and many chronic diseases. Omega 6 fat sources are extremely common in our current food system. Many cheap, common foods provide omega-6 fats to our diet including soybean oil, corn oil, safflower oil, and of course fried and ultra-processed foods like chips or mayonnaise.

Replacing these foods with more Omega-3 rich foods like salmon, anchovies, trout, wild game, leafy greens, and flax seeds can mitigate chronic inflammation. *

Gut Bacteria

It is common to think of yourself as human, with human DNA, but that is far from the truth. In reality, you are a moving city of many species working together. Many of those are bacteria, especially in your digestive system.

Not only is your gut bacteria part of your digestive system to provide nutrients and energy, but also part of your nervous system producing neurotransmitters. That means your gut bacteria is essentially part of your brain, and plays a large role in how you feel and think! Imbalances with the gut bacteria can cause more inflammation and aging. *

The more diverse your gut microbiome, the better for longevity. Taking care of this colony of bacteria will help make sure you also feel good. *

A diet with the correct amounts and types of fiber (see fiber.guide for more specific insights) is a simple but powerful way to support your gut bacteria.

Conversely, an unhealthy diet high in unprocessed foods (almost always deficient in fiber) or high in added sugars can cause a proliferation of the undesirable bacteria. Eating whole foods and fermented foods can help promote the right type.