Many of us are on the hunt for the key to staying young. In the race to live a happy and healthy life, it’s essential. As we grow older, things breakdown. Additionally, our:

• Skin wrinkles
• Bones & muscles weaken
• Immune system falters
• Blood glucose gets out of whack
• And we lose our marbles

Humans have been enamored with remaining youthful since before Ponce De Leon and his search for the fountain of youth. Currently, in model organisms such as mice, we can extend “youth” via things like calorie restriction and exercise.

So why not in us? There’s currently a pretty large movement in science to untangle the causes of aging to find ways in which we can manipulate it. This is a crucial first step, and normally first steps like this are the biggest hurdles because they require us to refute long-held beliefs.

But we don’t have to refute that aging is an inevitable process. What we truly want to do is slow it down, not eliminate it. And since we can slow aging in mice, why not us?

Defining aging and youthfulness

When we look at what aging is, most people associate it with time. But while aging obviously shares a relationship with time, it’s not how we define it biologically.

In biological terms, aging is a process where organisms lose their ability to survive and reproduce over time. Many look at aging as something that happens to us from the minute we’re born. However, the first 20 or so years in humans isn’t really aging, it’s growth.

Think about it. Who’s better at survival and reproduction: a baby or a teenager? Eventually, once we reach the tipping point, move into our 20s and exit into our 30s, we are aging. And with it the breakdown begins.

This is going to happen to us, it is inevitable. On the other hand, just because it’s going to happen doesn’t mean we can’t manipulate the speed at which it happens.

In order to do this, we need to identify the key to staying young, or more likely, keys. A recent series of papers identifies a nice little network between our hypothalamus and fat cells that may be a significant key to staying young.

The key to staying young #1: The hypothalamus

At the base of our brain resides a tiny little area known as the hypothalamus. Though undersized in relation to other area of the brain, the hypothalamus has oversized ambitions.

Known as the control center of the body, the hypothalamus regulates many important functions that help the body maintain homeostasis including:

• Body temperature
• Thirst
• Appetite
• Mood
• Sleep cycle
• Childbirth
• Digestion
• Fluid balance
• Hormone balance

These functions are regulated via communication between the hypothalamus and pituitary gland. Essentially, the hypothalamus senses what we need, and it tells the pituitary gland which hormones to secrete.

There is also evidence that the hypothalamus regulates the aging process through multiple avenues including:

• Circadian rhythms
• Energy homeostasis
• Hormonal balance

Inflammation and dysregulation of nutrient sensing pathways are key drivers of hypothalamus-induced aging. So if we can affect these pathways positively, we may be able to slow down the aging process.

One in particular we may want to keep an eye on is the Sirtuin/NAD+ pathway.

The key to staying young #2: Maintaining NAD+ levels

Nicotinamide adenine dinucleotide, or NAD+, is a prolific molecule in health and aging. In energy metabolism, it acts as a redox molecule, which is its main function. Without it, we wouldn’t be able to synthesize ATP.

But NAD+ also plays a role in other biological functions, particularly in DNA repair and epigenetic regulation via sirtuin activity. The sirtuin pathway functions as a nutrient sensing pathway, acting as a molecular switch between energy metabolism and repair.

During fasting, NAD+ levels build up since ATP needs are low. At the same time, sirtuins are activated to trigger DNA repair and deacetylation, an epigenetic process. Sirtuins are NAD+ dependent enzymes, so without adequate NAD+, activation of sirtuins does nothing.

We make NAD+ from nicotinamide(NAM), a form of vitamin B3. In humans, the enzyme NAMPT controls the rate of this process. When sirtuins utilize NAD+, they convert it to NAM, which inhibits sirtuin activity.

Interestingly, sirtuins and NAD+ function as the metabolic arm of the circadian clock, and NAMPT is under circadian control. Unfortunately, they’re not only contending with energy metabolism for NAD+. Another NAD+ dependent enzyme known as CD38 also uses up NAD+, converts it to NAM, and blocks sirtuin activation.

In mice, CD38 is the primary driver of declining NAD+ levels with age. Inflammation and lipopolysaccharide both increase NAD+ consumption through CD38. Since we’ve covered this in a more in depth blog, we won’t bore you with the details. But if you’d like to geek out on it, click here.

The problem we run in to here is that NAMPT has very low expression in the hypothalamus to begin with, and declines as we age. Just in time for chronic inflammation to increase NAD+ consumption further.

Looks like the hypothalamus needs a little help from a friend.

The key to staying young #3: Fasting and fat for the win

Though NAMPT levels are low in the hypothalamus, other cells secrete a different form of NAMPT called eNAMPT. Cells wrap up this NAMPT in to packages called extracellular vessicles and ship it off to other cells in need. So the hypothalamus isn’t totally SOL.

In a series of studies, the concept of the NAD+ world was created. The activation of sirtuins in fat tissue during fasting at night increases the secretion of eNAMPT from fat cells. Packaged in to extracellular vessicles, this NAMPT goes to the hypothalamus and increases NAD there.

With age, NAD+ levels in the hypothalamus decline. Treating mice with either NAD+ precursors or eNAMPT delays aging and increases lifespan, at least in females. It also increased physical activity and improved sleep, 2 factors likely boosting the results.

Males weren’t so lucky. Though it’s important to point out they lived longer than females at the beginning. As a result, the treated females only caught up to them in the end.

In humans, fat cells secrete eNAMPT, and those levels decline with age. But other than that, we await an experiment in humans to determine if what happens in mice happens in us.

Conclusion

We’d all love to slow down the aging process to get more years out of our life and life out of our years. Research in mice indicates that the rate of aging is a process we can manipulate, at least to a minor extent.

Currently, calorie restriction and exercise are the 2 best ways to increase our disease-free years, also known as healthspan. There is a good amount of evidence in humans that both are valid ways to slow down the aging process.

Looking at the mechanisms through which this works in mice gives us a glimpse in to how we may eventually be able to slow down aging in a more effective way. Essentially all of the pathways currently being researched are nutrient sensing pathways, the sirtuin/NAD+ pathway being a very important one.

The use of NAD+ boosters like nicotinamide riboside is currently very popular among biohackers looking for the key to staying young. Certainly it’s an option, but could be problematic.

We can’t control which processes use NAD+ other than through behavior. And increasing NAD+ may increase inflammation through increased CD38, and inhibit sirtuins via increased NAM.

Ultimately, the best approach likely involves:

• Optimizing circadian rhythms so fat makes eNAMPT when sirtuin activity is high
• Decreasing inflammation by building a healthy gut(Most LPS comes from the gut and increases CD38)
• Inhibiting CD38 using apigenin(Quercetin does this too but has bad effects elsewhere)
• Taking NAD+ boosters when the coast is clear.