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Longevity 101: Metformin, Rapamycin & NAD+


Longevity 101: Metformin, Rapamycin, and NAD+

An overview of what you’ll learn from this blog post:

  • How Rapamycin may help combat aging

  • How Metformin seems to slow down aging

  • What NAD+ is and how increasing it may help us age slower

Perhaps the most near-term approaches that may reverse aging are those that are already with us. There are a number of drugs such as Rapamycin and Metformin that according to research may slow down the aging process as well as their already known actions.


Rapamycin


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.


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.


Recently, research has also shown that Rapamycin improves how our DNA is stored 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 dictates 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 examining Rapamycin’s influence on aging.


Metformin


Metformin is a prescription drug commonly used to treat type 2 diabetes. It is part of a class of medications called biguanides. It is derived 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 has an impact on a number of 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 prioritize self-preservation over 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.


In this way, Metformin may prove to be useful in promoting healthy human lifespans. It could also turn out that other existing drugs may impact the aging processes and some researchers are busy mining drug databases using AI to find them.


NAD+


Another exciting area of research and one which also focuses on the metabolic aspect of aging is Nicotinamide adenine dinucleotide (NAD+) and its precursors. It is found in all living cells and is one of the most versatile molecules in the body. NAD+ is essential 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 facilitate 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+ regulates 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 highlight how crucial 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 essential 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. The NA or NAR is then converted via a series of enzymatic reactions into NAD+

  • The salvage pathway converts nicotinamide (NAM), also known as niacinamide, into NAD+. This includes nicotinamide mononucleotide (NMN) as an intermediate and nicotinamide riboside (NR) also feeds into this pathway

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.


NMN and NR 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.


These interventions are already here


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.


In an upcoming blog post, we will be taking a look at a technology that is probably a few more years distant but one that holds greater potential.


For much more on Metformin, or to complete a free online visit, click here.


For much more on NAD+, or to complete a free online visit, click here.


To learn more about Rapamycin and participate in our PEARL trial, click here.


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