Longevity: What the Research Says About Metformin, Rapamycin & NAD+

What if some of the most interesting tools being studied for longevity aren’t new at all? Metformin has been prescribed for diabetes for decades. Rapamycin was first discovered in bacteria from Easter Island. And NAD+ is already hard at work inside nearly every cell in your body. Today, all three are at the center of a much bigger question: can we influence the biological processes that change as we age? Researchers are looking at everything from cellular energy and DNA repair to the pathways that tell our cells when to grow, slow down, or conserve resources. Here’s what we know so far, and where the science gets especially interesting.

Key takeaways:

• Rapamycin may slow aging by targeting mTOR and increasing histone levels in gut cells
• Metformin appears to trigger a cellular pro-survival mode by reducing mitochondrial activity and activating AMPK
• NAD+ declines with age, weakening DNA repair, energy production, and sirtuin activity
• Direct delivery of NAD+ into the bloodstream may be the most effective way to restore levels
• AgelessRx ran the PEARL study, the first large-scale human trial that looked at Rapamycin’s influence on aging

Can Rapamycin Help Slow the Aging Process?

Rapamycin is a natural antifungal produced by a type of bacteria originating from Easter Island or Rapa Nui to use its Polynesian name. At high doses, it is used to combat organ rejection but there is some evidence it may also influence the aging process too.

How Rapamycin Targets the mTOR Pathway

In low doses it appears to slow down aging in various species by targeting the mechanistic target of Rapamycin (mTOR). mTOR is one of the four pathways that control metabolism and is involved in the aging process known as deregulated nutrient sensing. Various studies have shown that reducing the activity of mTOR reliably increases lifespan in yeast, worms, flies, and mice.

Rapamycin, Histones, and Gut Health

Recently, research has also shown that Rapamycin improves DNA storage in the nucleus. It is hard to believe that our DNA is two meters long and yet manages to fit into our cell nucleus. It achieves this thanks to it being wound around the histones, a protein family that compacts DNA into chromatin. Once our DNA is compacted and wound around the histones, it can form chromosomes.

Most importantly, how tight our DNA is wrapped around the histones determines what genes can be expressed. Unfortunately, the number of histones we have falls as we age which then makes our DNA less tightly packed and allows for more genes to be expressed. This is not good as many of these additional genes that are expressed are associated with the aging processes.

The researchers also found that Rapamycin treatment was able to increase histone levels in fruit flies and mice. What was most unusual about this was that histones only increased in gut cells known as enterocytes and not in other tissues. The increased level of histones in the enterocytes was shown to reduce tumor incidence and growth. Gut health was also improved and led to increased lifespan in the animals.

We believe that Rapamycin has untapped potential in the fight against aging so we launched the Participatory Evaluation of Aging with Rapamycin for Longevity (PEARL) study to find out. PEARL is a double-blind, randomized, placebo-controlled human trial and the first large-scale trial studying Rapamycin’s influence on aging.

How May Metformin Support Healthy Longevity?

Metformin is a prescription drug commonly used to treat type 2 diabetes. It is part of a class of medications called biguanides. It comes from a compound originally isolated from the French lilac (Galega officinalis).

Over the last decade or so, a number of studies have suggested that Metformin may influence age-related diseases. Some researchers believe that this could make it useful in the pursuit of healthy longevity. It appears that the drug works by slowing down metabolism which in turn influences the aging process.

Our cells are constantly balancing anabolic processes which create energy from nutrients, with catabolic processes which consume this energy. This balance becomes most important when the availability of nutrients is too low to keep our cells fuelled and functional, such as during a famine.

When this happens our cells engage a pro-survival mode and place self-preservation above growth. By entering this state our cells become more resistant and help us to remain alive. No doubt our ancient hunter gatherer ancestors who were more vulnerable to famines and the environment relied on this to survive and thrive.

So How Does It Actually Work?

Metformin appears to encourage this pro-survival effect by reducing the activity of our mitochondria, the powerhouses of our cells. The result of which is that the mitochondria slow down how fast they convert nutrients into a form of energy called adenosine triphosphate (ATP). Less ATP triggers AMPK, an enzyme that detects low energy levels. AMPK then activates a number of survival systems that cause the cell to enter that pro-survival mode and conserve energy and resources.

Metformin may also support longevity by lowering both insulin resistance and blood sugar levels. Essentially it lowers blood sugar levels by improving the way your body manages insulin.

What Is NAD+ and Why Does It Matter for Aging?

Another exciting area of research and one which also focuses on the metabolic aspect of aging is NAD+ Injections and its precursors. It is found in all living cells and is one of the most versatile molecules in the body. NAD+ is needed for cellular function and life itself and it performs many functions in our bodies.

First, it acts as a coenzyme and allows the mitochondria to create ATP, a form of universal energy used by cells. Without NAD+ to help drive the creation of this energy there would be no fuel for our cells to use.

Second, important metabolic processes including the citric acid cycle (TCA/Krebs cycle), glycolysis, and the electron transport chain in our mitochondria all rely on NAD+ to work.

Third, it functions as a ligand. NAD+ binds to enzymes and allows the transfer of electrons between molecules. Given that electrons are the atomic basis of cellular energy, NAD+ works like a battery charger. A battery goes flat once its electrons have been exhausted by producing energy and cannot return to its charged state without a jolt. The same applies to our cells. NAD+ gives them the jolt they need to become charged again. In this way, NAD+ controls enzyme activity, gene expression, and cellular signaling.

Fourth, NAD+ supports DNA repair. A key protein involved in DNA repair is Poly (ADP-ribose) polymerase (PARP) and it is dependent on the availability of NAD+ to function.

Fifth, NAD+ allows the sirtuins to work. The sirtuins are often called the “longevity genes” and play an important role in cellular function and health. They are a group of enzymes involved in cellular stress responses, cellular repair, and insulin production. The sirtuins rely on the presence of NAD+ to work and are important in aging.

This is far from being an exhaustive list of the things NAD+ does but it serves to show how important it is for life.

How NAD+ Is Created

NAD+ can be created in a number of ways.

• De novo pathway. It can be built from scratch using the needed amino acid L-tryptophan. This is the only non-vitamin B3 method of creating NAD+
• The Preiss-Handler pathway which starts with either nicotinic acid (NA) or niacinamide (NAR) present in food or supplements, ending with a series of enzymatic reactions into NAD+
• The salvage pathway converts nicotinamide (NAM), also known as niacinamide, into NAD+; this is also how NAD+ precursors are converted into bioavailable NAD+

Unfortunately, as we age NAD+ levels begin to fall and that starts to cause all the above processes to break down or become less efficient. Because of this some researchers have been trying to find ways to reverse this loss of NAD+ with a view to slowing down aging. There are a few ways in which NAD+ levels might be restored.

NAD+ precursor pills have been the most recent focus of efforts to restore NAD+ and reverse its age-related decline. While animal data is promising, there is limited human data for them as yet and it remains to be seen how effective at boosting NAD+ they are in humans.

Niacin, another NAD+ precursor, has also recently been shown to increase NAD+ in skeletal muscle tissue in people.

Last but not least, is the delivery of NAD+ directly into the bloodstream. While NAD+ is a large molecule and does not appear to enter cells directly, it is rapidly converted into NR which can. It may be the case that directly injecting (or other direct means, such as a patch) NAD+ into the bloodstream and bypassing the liver is the most direct way to boost NAD+ levels.

Are These Longevity Interventions Available Now?

Interventions that target our metabolism are probably the most near-term approaches to slowing down aging. All of the above are already here and are currently being tested in the context of aging and it isn’t a stretch to see them entering wide usage for aging in the near-future. That is assuming the human trials return favorable data of course.

For much more on Metformin, or to complete a free online visit, read about Metformin.

For much more on NAD+, or to complete a free online visit, see NAD+ options.

To learn more about Rapamycin and read our PEARL findings, visit the PEARL study page.

Benefits outlined on agelessrx.com are based on 3rd party studies. Talk to your healthcare provider to see if Rapamycin, Metformin, or NAD+ is right for you. Prescription products require an online consultation with a clinician who will determine if a prescription is appropriate.

Note: The above statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure, or prevent any disease.