How you might not have to get old

The Science behind aging, and how we’re tackling it — for nonscientists.

I know, I know, you’ve heard this before.

Time > money.

But *what if* you could exchange lives with Warren Buffet? Would you do it?

You’d have all the money you could ever dream of. But, you’d also become an 86 year old man — 8 years above the average lifespan in the US.

Lots of money. Not lots of time. I don’t think I’d do it.

I also think Warren would give up his wealth to become a broke teenager again.

Time is a finite, but what if we could make more of it? What if Warren could live another 50 years? 100? I’m not gonna say no to living longer.

Not only is time finite, but getting old sucks.

As we get older, we get more chronic illnesses.

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We lose our teeth.

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Our cognitive abilities decline.

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Our bones get weaker.

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You get the point — aging produces dramatic graphs.

Luckily, scientists are working on extending our lives by smacking aging in the face. As a result, we’ll have more time on our hands.

Are we in a fridge? Because things are about to get super cool — let’s dig in.

The process of aging

Your body is full of biological mechanisms (e.g., DNA, cell membranes and mitochondria). Each of our mechanisms performs a specific task. For example:

  • DNA encodes for proteins
  • Cell membranes protect what enters/exits the cell
  • Mitochondria produce ATP (energy) which powers bodily processes

Over time, your body gets worse and worse at these tasks because the mechanisms deteriorate.

It’s like a doomed marriage.

When you first get married, you’re in love. You have a fancy destination wedding with your awesome friends. Everything is great.

Over the years, your marriage loses its youthful spark. And soon, it’s been 50+ years and you’re sick of each other, constantly arguing and the only thing keeping you together are bingo Thursdays. Because otherwise, you wouldn’t have a bingo buddy.

You were once in love and now your relationship only exists for seniors games night.

That’s what happens in your body, only at a much more complicated scale.

When you’re young, your cells, and biological mechanisms cooperate. They’re in “love.” But, as you get older the frequency of “arguments” increases. Your body becomes a feisty old couple.

Why do our cellular mechanisms become argumentative and uncooperative?

In a nutshell, aging is the accumulation of damage at a cellular level.

This causes cells to malfunction (or “fall out of love”). They stop communicating and doing their job.

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here’s how our cells behave when they’re not old — they listen to eachother.
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here’s how they interact when they’re old — mechanisms don’t always listen to one another.

The process of aging is when our bodies start to break down.

This results in slower functioning (i.e., takes longer to do a certain task) or malfunctioning (i.e., some tasks aren’t done at all).

We tend to use the analogy of a car getting old. Cars, like other mechanisms, rely on many parts to function. When a part breaks, the car needs to go to a mechanic to fix it.

Our body is much more complex than your average Honda Civic.

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The labelled diagram of a car is as complex as one metabolomic pathway (set of chemical reactions) in your body.

And there are 37 thousand billion billion chemical reactions happening per second in your body.

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One metabolomic pathway in your body

Our body’s “cars” breakdown because too much damage builds up.

In a marriage, you’ll have disputes, affairs, and all sorts of things that lead to a big “disaster” (e.g., divorce).

Aging, like a deteriorating relationship, is also multifactorial.

Here are some of the scientifically identified types of damage buildup:

  • Loss of stem cells. Stem cells are crucial to repairing tissues and organs. We could only survive for 1 hour without any stem cells.
  • Accumulation of naughty cells. We also call these “senescent cells.” More on them soon.
  • Nuclear mutation. Nucleotides are the building blocks of DNA and RNA. Different mutations in the nucleotides yield different biological structures/processes (e.g., proteins). Variations can be dangerous or helpful. It all depends…
  • Mitochondrial mutation. Mitochondria are… (me: *don’t say it, don’t say it…*), you: THE POWERHOUSE OF THE CELL. Ok, look who passed biology 😍. Without mitochondria, we’d survive for 30 seconds. Yup, they make stem cells seem 120X less important.
  • Intercellular junk. When our lysosomes (vacuums that remove waste) get lazy, garbage stays within the cell. Just like, if no one does the dishes, the dishes will remain in the sink. Our bodies have a lot of undone dishes (and lots of sinks!).
  • Extracellular Junk. Junk, outside your cell.
  • Nonfunctioning proteins. Over time, our proteins misfold and lose their structure. Their structure is a huge component of their function. Imagine you replaced your lungs with a sharp, metal box. It would take your breath away! The shape + material (i.e., alveoli) of your lungs is critical to its function. Proteins are the same. More on proteins soon.

When it comes to aging, there’s lots to consider and cover. In this next part, I’ll take a bite into the main systems involved with aging.

Hypothalamus and Aging

I can summarize countless hours of longevity research paper reading in 3 words:

We need homeostasis.

Over time, we lose information about how our bodies should behave.

Homeostasis is when our bodies are in a steady, internal state. That is, everything is functioning as it should be.

Keeping this stable environment (homeostasis) within our bodies requires adaptation. We call this homeostatic regulation.

Anytime something happens to you; your body uses mechanisms to bring you back to normal.

It’s like the equal sign (=) in a math equation. It keeps both sides in balance. Therefore, every time you make a change to one side of the equation, you need to make the change on the other.

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As we get older, our ability to deal with equations gets worse. (Literally, check the graphs above). We start to miscalculate.

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Our body starts to think 5=6

Homeostasis is like the ability of married couples to recover from arguments. You quarrel, and most of the time, you get over it.

The 10th fight is going to be easier to get over than your 2000th fight. You’ll be more optimistic (because there’s less of a history of fighting). Whereas, with the 2000th, it’s going to start to get annoying.

You’re more resilient and forgiving earlier on in the relationship. You get over things faster.

Same with your body. The 10th time going back to homeostasis is going to be more comfortable than the 2000th.

First, let us consider how we do homeostatic regulation.

Hormones.

Hormones regulate the activity of cells. They’re signalling molecules.

The endocrine system (the system that makes hormones) is responsible for your body’s feedback loops.

When something happens to you, a stimulus will go off. That stimulus will trigger hormonal reactions to inform your body that homeostasis is endangered.

We have two types of feedback loops:

  • Postive: increasing the original stimulus
  • Negative: decreasing the original stimulus (this is more common)

There are several feedback cycles happening at any given time. Examples:

  • Rise in blood glucose (stimulus) → more insulin
  • Rise in body temperature (stimulus) → sweating
  • Rise in the concentration of carbon dioxide → lungs exhale

The hypothalamus is the part of the brain responsible for the effect (change). It’s the “control center.” Whenever a stimulus happens, something has the regulate the change (i.e., something has to be the “→ “).

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The hypothalamus is the “sensor” which takes in inputs and determines the correct response.

The same way you get tired at the end of a workout, the hypothalamus gets tired nearing the end of its life, which off-balances our homeostasis.

When your body can’t regulate itself, you get diseases.

  • [Type 2] Diabetes = inability to control blood glucose levels (with insulin). You’re more likely to get it if you’re 45+
  • Heatstroke = inability to regulate body temp.
  • Heart disease = inability to remove plaque buildup

If you think about it, most diseases have some correlation with bad homeostasis. A disease means something is wrong with your body. To get rid of one, you bring your body to where it was before (i.e., homeostasis).

Like any human body part, your hypothalamus gets less sharp. It makes more errors. Its cells are not as young as they used to be.

Studies have found that brain function is highly correlated with aging. It controls hormones, which correlates to many pathways of ageing.

A biological pathway is a series of interactions in your body. A feedback loop is a biological pathway.

As an example, your insulin signalling pathway (IGF-1) is well connected to longevity. We control the pathway through hGH (human growth hormone). We control hGH in the hypothalamus. More on IGF-1 soon 😉.

The hypothalamus controls the hormones, which control our “longevity pathways.” How do we improve it? We have two options:

  1. Reduce the number of stimuli experienced throughout life. This is so the hypothalamus can stay younger, longer. (E.g., if you had a jar of 100 jelly beans, instead of eating 100 in 1 day, eat 1 daily for 100 days. It will last 100x longer)
  2. Increase the capacity for stimuli (e.g., add 100 more jelly beans, so that you have 200 total).

The environment influences your stimuli.

For example, If you’re not a smoker, but are surrounded by smokers (i.e., you’re a second hand smoker), this impacts homeostasis.

If you’re in a stressful environment, you’ll raise your “stress levels.” And, yup, that also impacts homeostasis.

The less we make our hypothalamus work, the slower it’s going to wear down. But this method is like buying a new pair of shoes and never wearing them. It doesn’t actually solve the quality of the shoes. Let’s focus on the more interesting part: making the shoes better.

Stem Cells

We used to think that the brain had no stem cells, and neurons lack the ability to renew. Now we know that some parts of the brain, like our beloved hypothalamus have Neural Stem Cells (NSCs).

Scientists injected stem cells into mice’ hypothalamus, and they lived 10% longer. 🤯 They also had boosts in their cognitive and physical function.

As this part of the brain ages, stem cells die off. That’s why hypothalamic stem cells are critical to better functioning homeostasis control centers!

eNAMPT

The protein extracellular nicotinamide phosphoribosyltransferase (eNAMPT) helps our cells create Nicotinamide adenine dinucleotide (NAD). And that’s why we use abbreviations in biology.

NAD is crucial to our survival and cellular function. (We’ll dive deeper into NAD soon). A specific type of NAD, is NAD+.

Less eNAMPT = less NAD+. Less NAD = sad, dysfunctional biological system 😢. This also impacts the hypothalamus.

But if we add more, then, the anti-aging party begins. And scientists thought so too.

Recap:

  • Homeostasis is the maintenance of internal balance. It’s controlled by a region in the brain called the hypothalamus.
  • The hypothalamus can be enhanced with more NSC, and eNAMPT.

Menopause and aging

We now know that homeostasis is important. But didn’t we just solve the problem by enhancing the hypothalamus?

That’s only a portion of the system. In order for the hypothalamus to monitor the body, it needs to sense any changes by receiving feedback from the body (through hormones).

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homeostasis relies on hormones (“signals”) and hypothalamus (“change makers”).

When women go through menopause, their hormones plummet — estrogen in particular, which goes from 100% of its levels to <1%. This dramatic change in hormone levels affects the body in many ways, one of which is homeostasis.

You might be thinking: men experience a decline in hormones too

Men, after 30, decrease the amount of testosterone in their bodies. This is slow and steady.

For women, their drop in estrogen hits them like a truck. One day they have sex hormones; the next day, they’re entirely gone.

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Graphs for contrasting purposes only.

What’s our best treatment for menopause? “Just deal with it” or hormone replacement therapy (HRT).

Because this isn’t a post about the problems with how we treat women, I’m going to focus on HRT and menopause.

Hormone replacement treatment is when women take hormones to replenish their system.

Women, who have exited menopause lack estrogen, so they replenish their stock.

Too much estrogen can lead to endometrial cancer (not breast cancer; that’s a myth), so they take estrogen with progesterone. This offsets the cancerous effects.

If we gave every post-menopausal woman in America HRT, we’d add 3.3 years to their lifespan. [source]

Why? Replenishing hormones reduces the risk of dying from other diseases:

  • Estrogen / hormonal balance can reduce Alzheimer’s risk by 20–50%
  • Reduces the risk of cardiovascular disease. Which kills more women than the next 16 causes of death combined
  • Increase bone elasticity, reducing the risk of hip fractures. Targeting osteoporosis and other bone disorders. The same number of women die from hip fractures as breast cancer.
  • Decreases risk of breast cancer after the first year of dosing.

Why do hormones reduce the risk of dying from diseases? They help the female body deal with homeostasis.

And if they’re better at homeostatic adjustment, they’re more fit to battle disease.

For example, estrogen is cardioprotective. It protects the buildup of plaque in our arteries called atherosclerosis.

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When women go through menopause, they have low levels of estrogen. This produces painful side effects:

  • There’s a correlation between estrogen and serotonin (happiness hormone). Women going through menopause have increased depression.
  • Causes night sweats and heat flashes. The body is changing abruptly and is having trouble adapting.

Menopause is hard for the same reason that any drastic change is hard. It’s different, and one has to get used to it.

HRT seems like a miracle drug. Take Alzheimer’s; what other supplement has the potential to reduce risk by 20–50%? Women are 2x more likely to get Alzheimer’s than men: the theory right now is hormonal changes. By slowing (or stopping) hormonal changes, we reduce the risk.

The only reason this happens is that there’s an in-balance in the first place.

Recap:

  • After menopause, women dramatically decrease their amount of female hormones.
  • Hormones are vital to homeostasis, so, postmenopausal women are far more susceptive to dangerous diseases.

Note: I’ll be writing more detailed blogs about women’s health, be sure to follow me on medium or subscribe to my newsletter to stay updated!

The Common Biological Pathways of Aging

A marriage doesn’t often end for ‘one reason.’

Aging also doesn’t begin for ‘one reason.’

In biology, we’ve identified some key ‘pathways’ for aging. These pathways work together to wrinkle your skin and turn your memory into a goldfish’s memory. I’ll dig into each of them here.

Overview

(Don’t let the acronyms scare you)

  1. NAD+/sirtuin pathways
  2. mTOR/AMPK signalling
  3. IGF-1/Insulin

Nicotinamide adenine dinucleotide (NAD) plays an essential role in metabolism. (On top of also rolling right off the tongue).

It has two essential functions:

  • Turning nutrients into energy
  • Being a helper molecule that regulates cell function (e.g., helping cell-communication)

It’s a coenzyme. Meaning, it works together (“co”) with other molecules (“enzymes”) to catalyze reactions.

Let’s use the analogy of Santa and his elves. Santa might have an awesome idea (giving presents on Christmas). But, without his helpers, there will be no gifts to give.

NAD+molecules are the elves, to hundreds of chemical reactions.

Overtime, we use up our NAD+ molecules. (Hence, why we lose energy as we age).

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Our NAD+ experiences exponential decay

If we can replenish this “stock”, we have a good shot at keeping our bodies functioning optimally for longer.

Several biological components operate because of NAD+. In other words, NAD+ needs to be present for certain reactions to occur.

Two important Examples:

  • PARP or poly (ADP-ribose) polymerases, which help repair DNA damage

NAD (activates) → PARP

  • Sirtuins often called the “longevity genes,” help regulate cellular homeostasis.

NAD (activates) → Sirtuin genes (there are 7).

If our NAD+ levels dropped to 0, we would die.

Why are PARPs and Sirtuins important?

When DNA gets damaged, PARPs come to the rescue.

Our bodies use PARP in DNA repair pathways. If we damage our genome, it’s important to fix it as soon as possible. The downside of having PARP is it utilizes our NAD+ deposits.

That is, the more damage you have, the more we signal PARP, the more NAD+ we use up.

Sirtuins are the CEOs of your cells. They manage all the shenanigans that go on in there.

There are 7 types of sirtuins (SIRT1, SIRT2, and so on). 3 of them work in the mitochondria, 3 in the nucleus, and 1 in the cytoplasm.

They control a plethora of functions.

Mitochondrial sirtuins deal with energy.

Nucleus sirtuins help with DNA damage and apoptosis.

The lonely cytoplasmic sirtuin aids with signalling.

In short, they regulate the genes/proteins you express in result to stimuli. They control the cellular thermometer.

In a way, sirtuins are like a local hypothalamus for the cell — the control center for homeostasis. They help with repairing DNA, and maintaining the structure of cellular components (e.g. chromatin).

Research concludes that not all sirtuins are made equal when it comes to aging. Certain ones have greater impact (i.e., SIRT1, SIRT3, SIRT6).

NAD+ activates sirtuins, but so does resveratrol and caloric restriction.

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Mickey’s lacking his sirtuins

NAD+ is too big to enter our cells as a pill, so we have ‘precursors’ available, which boost the body’s NAD+ stock.

There are two main ones right now:

  • Nicotinamide mononucleotide (NMN)
  • Nicotinamide Riboside (NR)

Precursors aren’t the only way to level up the body’s NAD+ levels. Companies like Nuchido have a way to boost NAD+ by 242%, without any precursors.

Some recent studies:

(I’ll link this at the bottom as well)

  • NAD+ is an essential coenzyme that helps make energy, and facilitate cell function.
  • NAD+ activates PARP, which repairs DNA
  • NAD+ activates sirtuins which are important for cellular homeostasis and cell function.
  • NAD+ is too large of a molecule to enter the cell, so we need to inject precursors which help make NAD+ in the body.

Anti-diabetes drugs correlate to longevity. A 9-person trial is our first sign of age-reversal in humans.

One of the most studied areas in longevity is the link with insulin/IGF-1 signalling (IIS).

The conclusion?

The more insulin sensitive you are, the longer you’ll live.

One of the first great “finds” in longevity was the Daf-2 gene. By doing a few small tweaks to an organism’s genome, we can double its lifespan.

We studied the DAF-2 gene in C.elegans (worms).

DAF-2 (gene) codes for a receptor protein.

Receptor proteins sit on top of, or inside cells. They try to receive chemical signals (hormones).

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Activating (turning on) DAF-2 in worms sped up the aging process. By muting it (turning off), the lifespan of worms doubled.

This is in worms. What about humans?

DAF-2 codes for a receptor that’s similar to human insulin and IGF-1 receptor.

  • Insulin receptors promotes food uptake (i.e., makes you hungry)
  • IGF-1 receptors promotes growth

These two processes (eating and growth) increase the speed of aging.

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That seems counter-intuitive, but it’s a theme in nature. Animals that live longer tend to grow slower.

And, smaller animals tend to outlive larger ones. For example, small dogs live longer than big dogs. (It is also found that small dogs have less IGF-1).

What this means:

  • Less insulin = less food entering cells = more longevity. (Why? Cells are forced to use their existing materials, which clean up the cell. As an example, cells will burn fat when there’s no more sugar)
  • Less IGF-1 = less growth = more longevity).

Currently, the only ‘concrete’ method for longevity is Caloric or Dietary restriction. Eating less down-regulates IIS.

When the body has high levels of glucose, the pancreas creates insulin. The insulin stimulates the consumption of glucose. When the body has low glucose, it will turn to its fat reserves.

With low food levels, we have a transcription factor called FoxO. It adapts cells to food shortages.

So,

Less insulin/IGF-1 = more FoxO

FoxO is the cool kid on the metabolic block. It reduces inflammation, improves cellular stress resistance and helps cells burn fat.

IGF1/insulin receptor deactivates FOXO. By turning it off, we can activate FOXO and all its longevity benefits.

A line with a “ — “ at the end means inhibit, while a line with a “ →” means activate.

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note: CR = caloric restriction

TLDR: the less you eat, the longer you live.

Less food = less glucose in blood = less insulin/IGF-1 = more FoxO

Some recent studies:

(will be linked at the bottom as well)

When mTOR is on, AMPK is off, and vice versa.

At a glance:

  • mTOR: critical for growth. It is activated by high amino acid levels (i.e., when you consume a lot of proteins)
  • AMPK: it’s an enzyme critical for autophagy (cell cleaning) and is activated by low amino acid levels (i.e., fasting).

Scientists altered AMPK/mTOR and IGF-1/insulin signalling (together), which resulted in a 500X increase in lifespan (in worms).

They decreased the activity of IIS. Inhibiting this pathway increases lifespan by 100%.

Scientists also inhibited the mTOR pathway (thus, activating AMPK). This increases lifespan by 30%.

100 + 30 = 500%???

When we put the pathways in ‘longevity mode,’ they work exponentially better. Why 500X? We don’t know.

Playing with biology is exciting, but let’s focus on the mTOR and AMPK pathway.

Less mTOR = more autophagy.

More AMPK = less mTOR

When mTOR is off, the body is no longer in growth mode. We activate this pathway when the body has ‘high nutrition.’ In evolutionary terms, times are good.

But when ‘times are not good,’ your body no longer wants to be in growth mode. It’s in survival mode. It’ll be relentlessly resourceful with all its molecules and cells.

It’s like a startup. When a startup has funding, it can hire. We activate mTOR. Because you have money, you don’t need to be as careful with how you spend it.

When it doesn’t have funding, startups have to be intentional with their capital. They can’t grow like crazy. They need to use their resources and talent as best as possible. It’s like activating AMPK.

In some sense, startups need a bit of both: some funding to keep you going and a strong, efficient team.

Your body also needs both. But we’re more often in ‘growth mode’ (mTOR activated) than ‘plan/organize mode’ (AMPK).

Why is plan/organize mode important?

  • It activates Autophagy: ‘cellular clean up crew.’
  • It encourages fat burning + more efficient energy use (cells are in survivor mode)
  • It inhibits NF-kB, which is in charge of activating inflammation. More inflammation = more aging.
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Autophagy is one of the godfathers of longevity.

Right now, our bodies are behaving like capital-rich corporations. Innovation is slow, and the management is highly layered. We need our bodies to be high leverage startups.

If we can empower our bodies to be ‘resourceful,’ longevity will flourish.

Because mTOR is active when “time are good” (i.e., you have food), we can shut it off by fasting.

Caloric restriction; increasing our lifespan once again.

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Recap:

  • Sirtuins help with DNA repair, and cellular homeostasis. They’re activated by NAD+
  • NAD+ is vital to cell energy production, and most processes (e.g., DNA repair with PARP).
  • ISS, when downregulated, promotes FOXO’s function. Insulin sensitivity is correlated with longevity.
  • mTOR/AMPK are two well studied longevity pathways. To promote living longer, we want AMPK mostly turned on, and mTOR mostly turned off.
  • Turning on AMPK promotes autophagy, the cleaning of a cell.

Some recent studies:

(I’ll link these at the bottom as well)

Mitochondria and Aging

We all know that mitochondria are the powerhouses of the cell.

They carry out important metabolic processes (like producing energy).

All cells in your body rely on the energy that the mitochondria produce.

Mitochondria are like a married couple’s kids. At first, they’re exciting and novel. Then, they get all-teenagery. Soon, they move out.

During childhood, kids become the central focus of the married couple’s relationship. They don’t get in fights “for the kids.” They stay together, so “the kids have a normal childhood.”

But once these kids are out, the relationship gets rocky. There are more fights — less alignment. Sometimes, the long-awaited divorce.

In your body, the mitochondria provide the energy that keeps you going (i.e., fuel).

The married couple’s kids “provide the energy” that keeps their relationship going.

But, like kids, mitochondria grow up and stop functioning. And then, “aging” or “marital fighting” begins.

Our mitochondria lose their ability to make energy as we age.

They start to look like this:

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Young → Old Mitochondria

The decline in mitochondria is why elderly people have less energy. They need more naps. They have a slower cognitive function because they have less energy.

There is a correlation between aging and mitochondrial function. We need them on their A-game!

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Flow chart diagram explaining how irregular mitochondria result in aging.

There are three main important functions of our mitochondria:

  1. Bioenergetics (i.e., how a biological organism gets its energy)
  2. Biosynthesis (i.e., how we “synthesize” compounds)
  3. Signalling (i.e., messaging)

Mitochondria get damaged over time because of oxidative stress.

Anyone over the age of 7 knows we need oxygen to survive. It helps make helpful substances bla bla bla.

What it also does is damage our cells over time. You know what they say, what makes you stronger also kills you.

This happens because of free radicals.

Free radicals are (naughty) atoms that are incredibly desperate for electrons. They have one unpaired valence electron. They get feisty.

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I have a dog. If I ever have a treat or food in my hand, my dog will run and aggressively jump on me. She is always on a mission to eat. Free radicals look for electrons with the same determination as my dog for snacks.

Some level for free radicals are ok, and even somewhat beneficial for the body.

Oxidative stress is when we have too many free radicals, and not enough ways to get rid of them. This stress can impact DNA (mutating it), cell membranes and more…

And, as I’m sure you could guess by now, the more you age, the worse you are at cleaning up free radicals.

Oxygen is a byproduct of making energy. Mitochondria release Reactive Oxygen Species (ROS), in the form of superoxide (O2−).

They’re make ATP (adenosine triphosphate) through a process called oxidative phosphorylation. “Oxidative,” meaning they use oxygen. ATP is how our body stores energy.

In short:

  • They take in oxygen (O2) and food molecules
  • Go through the “Krebs cycle” and ETC (electron transfer chain)
  • This produces ATP (energy) and ROS.

We need ATP, and we also need a little ROS (used in signalling + cell communication).

Ironically, ROS damages the DNA inside a mitochondrion, which damages its ability to function.

Mitochondria are so cool that they have their own type of DNA: mtDNA.

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The structure of mtDNA is very different from nuclear DNA

Nuclear DNA has histones + chromatin structures, which protect it from oxidative stress.

But, mtDNA lacks the same protective measures. It’s 10-fold more prone to mutagenesis (a fancy way for saying “mutations”).

So, it produces ROS, which damages the unprotected DNA, which screws up the production of ATP. When there’s not enough energy to power the body, we cause mitochondrial dysfunction.

To deal with our mitochondrial decline in function, we need to consider three things:

  • Reducing the # of mutations ( — or being able to ‘reset’ the mtDNA, so it’s not mutated)
  • Mitophagy: the removal of bad mitochondria.
  • Ways to keep the mitochondria young for longer (augmenting it)

Mutations

Reducing mutations means we need to:

  • Stop them from happening in the first place (protect)
  • Or — replenish existing mtDNA to its un-mutated form.

There’s no “decided” way to attack repairing mutations right now. But, there has been some exciting research.

Mitophagy

Autophagy is the process the body uses to clean itself up. Mitophagy is the mitochondrial-specific version of autophagy.

Mitochondria need to regulate their homeostasis. I.e., when there is a stable amount of healthy mitochondria. We do this through mitophagy and biogenesis (destruction and creation of mitochondria).

Lysosomes are the parts of the cell that perform mitophagy. Over time, they start to get lazy. Hence, a buildup of low-performing mitochondria!

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Mitophagy

Keeping Mitochondria young

Sirtuins are the secret. They’re unique “longevity genes” with superpowers. Studies have found that SIRT3 helps mitochondria stay more youthful.

A lot of the damage accumulated impacts the mtDNA. Although mtDNA has 16,569 DNA base pairs, vs the standard 3.3M, we still haven’t been able to sequence it cheaply. 🤦‍

Let’s connect this back to our favourite topic: homeostasis.

Mitochondria deal with energy and energy homeostasis. They are the fuel for everything going on in your body. So, by augmenting mitochondria, we’re impacting our energy homeostasis.

Recap:

  • Mitochondria get harmed because of oxidative stress — the start to malfunction
  • Malfunctioning mitochondria impacts our energy homeostasis and bodily function.
  • We can fix our mitochondrial problems through mitophagy, Sirtuins and repairing the mtDNA (if we can sequence it first!).

Epigenetics and aging

As mentioned, our DNA has protective mechanisms surrounding itself.

Protective chemical or protein mechanisms cover the surface of nuclear DNA. One example is a histone.

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Epigenome wraps the DNA

We call these your epigenome. Your epigenome determines the expression of your DNA.

DNA = a cookbook of all your genes. Genes = the recipes.

The epigenome determines what recipes you cook for dinner (i.e., what you express).

How? It can “hide” some DNA. One example is DNA methylation. By adding one methyl group (CH3) to the nucleotides, we inhibit transcription.

(Transcription is an important part of making proteins. That’s all you need to know for now).

The epigenome determines what proteins are expressed by each cell. It’s what differentiates a heart cell from a liver cell.

As cells proliferate, they “forget” what their epigenome structure is.

This can cause a skin cell to behave like a hair cell. That’s why we grow hair in weird places when we’re older!!

This also makes us more sensitive to diseases, like cancer, as we age. Our body is not in shape it used to be.

I mean, when your liver thinks it’s a pancreas, times are tough.

Our genes have protective mechanisms that, when we’re young, protect us from diseases. The reason they don’t work when we’re older is our body forgets to express them.

As our epigenome gets older, the outside proteins/chemicals get altered. This changes the epigenome, and the DNA expression as a result.

What if we could ‘turn back time’ and reset to our old epigenome structure? We’d express the same proteins we did when we were young. Cue Adele.

This is the reprogramming part.

Cells have an ‘embryonic state.’ As time goes on, they mature and differentiate. They are no longer like their embryonic [younger] cellf. (😉)

But, using Yamanaka factors, we can reverse the ‘aging’ of the cell. It can become young again.

I’ll use an analogy. Whenever I wash my hair, it’s wavy. Sometimes I’m in a straight mood, so I use a flat iron. But, once I wash it again, my waviness is back.

The waviness is like an embryonic state. The flat iron differentiates hair, so it becomes straight. Washing my hair is like Yamanaka factors. It reverses my state from straight to wavy.

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This is the same process scientists use to reverse the age of differentiated cells.

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Yamanaka factors rewind the epigenetic clock. They remove any obscure methylation patterns and reset.

In the context of resetting the epigenome, we don’t want to use all the Yamanaka factors (there are 4). Doing so will turn our body into a bunch of embryonic stem cells!

Instead, scientists are using 3/4 of the factors to reset the DNA partially. It’s far enough of a rewind to remove any out-of-place epigenome-ness. But, the cell won’t turn into a stem cell; it will still be differentiated/specialized.

E.g., if it’s a heart cell, we can turn it back in time enough to *stay* a heart cell. With all four factors, it would lose its identity as a heart cell.

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Cellular reprogramming will have us reset the epigenetic clock in our bodies. 🤯.

Recap:

  • Our epigenome shapes our genome, and determines what is expressed. It creates the “identity” of cells. However, the proteins making up the epigenome lose their structural abilities as they get old.
  • We can reprogram our cells to renew their younger self’s epigenome.

Maybe one day we’ll have anti-aging machines like this one:

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Loss of Proteostasis and aging

There are 20,000 proteins in your body. And, 2,000 molecular components manage the production of proteins.

Each protein is like a little machine. Together, they make up a factory (you).

We don’t appreciate just how complicated our biological system is.

If you were to scale up your all the proteins working in your body to the size of pennies (small coins), you’d have enough coins to fill the pacific ocean.

These billions of trillions of little proteins run your body, and they make up your proteome.

The constant maintenance of your protein network is proteostasis. It’s a type of homeostasis. As we get older, our cells get worse at maintaining these proteins.

As a result, proteins get misfolded, aggregated and not created. Which is all just fancy ways of saying ‘they stop working properly.’

And, when the machines in the factory wear down, so does the factory.

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Why Proteins are the most marvellous molecules on the block:

There are seven types of proteins.

  • Hormones: help with communication and messaging.
  • Enzymes: carry out chemical reactions. (They’re a pretty big deal considering you have 37 thousand billion billion chemical reactions happening in you per second).
  • Antibodies: help kill dangerous cells (e.g. viruses).
  • Contractile proteins: actin and myosin are the major proteins involved with muscle contraction. You can walk because of them!
  • Structural proteins: provide structure to the organism (e.g. your extracellular matrix)
  • Transport proteins: move things around the body. (E.g., hemoglobin brings oxygen to your cells)
  • Storage proteins: act as a storage place for metal ions and amino acids.

Almost every function requires proteins. Everything you do is the work of proteins.

Normally, this is how we make proteins:

DNA → RNA → Ribosomes → Protein

Where going from DNA to RNA is transcription. Transcription turns genetic code into code that can make proteins.

Then, we translate the RNA into (functioning) proteins.

There’s a ton of shenanigans going on inside you. For that reason, protein synthesis processes have a chaperone network. It looks out for non-functioning proteins and removes them.

The chaperone network protects the body from malfunctioning proteins.

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Depending on the error, our body has evacuation plans to deal with it. Trust me, this is the simplest flow chart I could find.

Proteins can become malfunctioned by:

  • Becoming misfolded (thus, not function)
  • Being unfolded (thus, ceasing to function)
  • Becoming aggregated (grouping with other proteins, thus, causing diseases like Alzheimer’s)

The challenge is, as we age, our protective control mechanisms decrease. That is, the chaperone network becomes less reliable.

  • Lysosomes get clogged up. They’re the vacuum cleaners of the cell, i.e., they remove the crappy proteins. We need them to be on their A-game.
  • Cells run out of ubiquitin, the molecule that kills proteins.
  • Cells are missing the proteins they need to function and go through apoptosis.
  • Cells don’t know what to do with the misfolded proteins and go through apoptosis.
  • There’s an accidental accumulation of damage. (Accidental because ‘regulation’ doesn’t catch, and stop it).

Loss of proteostasis is like being a broke college student living in a dorm without a vacuum cleaner or any garbage disposal.

Somehow, you have all IKEA’s inventory, along with piles of useless items in the dorm. It’s a mess. But, you can’t clean it up because (somehow) garbage cans and dumpsters don’t exist in the universe of this analogy.

Recent Research:

Recap:

  • Proteins are the soldiers of the body, they make everything happen.
  • Mistakes are made during protein synthesis, and prevalence of mistakes increase with age.
  • There’s a “chaperone network” looking out for mistakes, but the attentivity of the network declines, resulting in a loss of proteostasis.

Telomeres and Senescence

Earlier I described DNA as the “cook” book for our “recipes” (aka genes).

Each of our cells have DNA. Many of our cells also proliferate (make copies of itself). This process isn’t perfect, so we lose a little DNA at the end during each replication.

To protect this, our genes have telomeres at the end of our chromosomes (part that holds DNA). They don’t code for anything important, so we’re ok with losing them during replication.

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Overtime your telomeres get shorter. Sometimes they even disappear, meaning, your actual DNA gets shorter (and mutated).

Cells lose the cookbook. They forget how to function.

When there is damage in the DNA, cells enter a state called senescence. Senescent cells accumulate in the body. They fiddle with chemical signals and cause your system to malfunction. They’re no good!!

How do we avoid this state of senescence? Avoid DNA damage due to shortening telomeres.

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Telomerase is a ribonucleoprotein (RNP). Nucleoproteins are proteins linked to nucleic acid. It’s either linked to DNA (deoxyribonucleic acid) or RNA (ribonucleic acid).

Telomerase grows the telomeres. With longer telomeres, our cells can replicate without cutting DNA for longer.

Sounds like a win-win? Why don’t we inject ourselves with more telomerase?

For one, there are high telomerase levels in cancer cells. Unless you want your body to be a massive tumour, that might not be the best way to go.

A telomere length maintenance mechanism (TMM) helps cells re-lengthen their telomeres. That’s what tumour cells do to keep themselves alive.

But, then again, we have other non-tumorous cells that have telomerase. Stem cells and germline cells (eggs, sperm) maintain their telomere length through telomerase, and don’t experience the same aging effects like our other cells.

Somatic cells (the rest of our cells) have low levels of telomerase; thus, they experience aging.

  • Telomerase is vital to cancer. Without it, tumours would die.
  • Telomerase keeps telomeres lengthy, which stops somatic cell aging.

🤔

We haven’t figured out the telomerase situation yet. But there’s been some interesting research which supports our telomere-theories:

Telomere shortening is one of the primary causes of senescent cells. They are also created by DNA damage and by unbalanced mitogenic signals.

Senescent cells are cells that no longer function, but stay in your body. They use up your resources, like fuel, but don’t provide any value to the biological system.

How they happen:

Cells replicate many times → their telomeres shorten → DNA gets damaged → trigger apoptosis → which sometimes backfires so we get a senescent cell.

These cells have senescence-associated secretory phenotype (SASP). Which means they produce dangerous proinflammatory signals and send out cytokines. (Cytokines are signalling proteins)

One of their main burdens is causing chronic inflammation. But they suck in a lot of ways.

  • They steal resources from other cells
  • They damage the structure of chromatin and gene expression. Remember the epigenome? Senescent cells damage it.
  • Remodel proteins in the body (e.g. extracellular matrix)
  • Inhibit stem cell function
  • Trigger unwanted cell death
  • Eat their healthy, cellular neighbours
  • The list of why senescent cells suck is longer than a 6-year-old’s Christmas wishlist.

What it all boils down to is this:

More senescent cells = more dysfunction in the body = more diseases

Again, the disruption of homeostasis.

Senolytics is a drug class aimed to target the removal of senescent cells.

We don’t have anything on the market (yet!) to flush your senescent suckers out of your body. But, 2019 was a big year for senolytics. We finished the first human trials.

We’re investigating the DQ duo (dasatinib and quercetin, duh) for senolytics. So far, we’ve seen promising results for Alzheimer’s.

Recap:

  • Cells with telomere lengthening abilities (telomerase) don’t experience the classical effects of aging.
  • Senescent cells accumulate in the body causing damage. We want to use senolytics to remove these cells.

Soon, the only thing that will age will be cheese.

To sum it up:

  • Homeostasis worsens over time: menopause is an example of homeostasis going crazy. This is because of imbalanced hormones.
  • We have biological pathways that activate longevity: we only need to activate them.
  • An un-excited mitochondrion: no powerhouse = no functioning cell
  • Mis-shaped epigenome: means the body will start expressing the wrong genes. This grows hair in weird places.
  • Loss of proteostasis: Aging machinery (proteins) means malfunctioning systems. As a result, junk builds up over the body.
  • Telomere shortening: causes the rise of zombie (senescent) cells

Homeostasis

Hypothalamus + mice microRNA

NADH vs NAD+

Overview of mTOR

DAF-2 in worms

Free Radicals

Mitochondria and mutagenesis

Telomere Lengthening

Intro to senescence

Senolytics for human longevity

Yamanaka Factors rewind the epigenetic clock

Sirtuins and PARP in aging

NAD precursors

AMPK

We need AMPK for longevity

Autophagy and reversing aging

How to activate AMPK

3 drugs that increased lifespan by 48%

Intro to IGF-1

Olfactory neurons correlate with proteostasis

Proteostasis and aging

Protein damage

Follow my work :)

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17 yo building better maternal healthcare in developing countries.

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