There are several NAD+ supplements available, yet many fail to address the root causes of NAD+ decline. This article will examine why Nuchido TIME+ uses a whole-system approach to increase NAD+, our pilot study data and the mechanism of action of our ingredients.
NAD+ Decline is complex
At a basic level, NAD+ decline can be explained by a decrease in NAD+ supply, coupled with an increase in NAD+ demand.
Older cells are unable to synthesize sufficient levels of NAD+, whilst simultaneously an accumulation of DNA damage and increasing levels of inflammation consume vast quantities of NAD+. Overall, this leaves the cell with an NAD+ deficit that contributes to the cellular aging process.
Nuchido TIME+ Data
Nuchido TIME+ is formulated using a whole-system approach targeting parts of the NAD+ network which have become dysfunctional with age causing NAD+ decline, these include:
- Enhancing the NAD+ recycling capacity of the cell by increasing NAMPT levels
- Preventing NAD+ wastage by inhibiting CD38
- Preventing excretion of the raw materials used for NAD+ synthesis by inhibiting NNMT
- Increasing conversion of NADH to NAD+
- Providing additional raw materials which can be used and recycled via the salvage pathway
Nuchido TIME+ is supported by clinical research. A randomised, double-blinded, placebo-controlled crossover clinical trial was performed on the Nuchido TIME+ dietary supplement. Participants were male and female, aged 20-80 years old.
The study demonstrated that:
- Nuchido TIME+ significantly increases cellular NAD+ after only 7 days
- Unlike NR or NMN it works by switching back on youthful cellular NAD+ production by reactivating a key enzyme in the Salvage Pathway
- An increase in the longevity protein SIRT1, a downstream target of NAD+
- A reduction of inflammatory cytokines indicating that NAD+ is being directed towards beneficial processes rather than inflammatory CD38
- A reduction in biomarkers of glycation
- A reversal of biological age
Nuchido TIME+ Mechanism of Action
Restoring the cell’s youthful ability to make NAD+
To achieve the largest increase in NAD+ levels, the cell’s youthful ability to make NAD+ must be restored. NAD+ is a large molecule so it struggles to cross the membrane of many cells. This means young cells naturally synthesize the NAD+ they require within the cell via the Salvage Pathway. This recycling system converts nicotinamide (NAM) – the waste material left behind once NAD+ has been used by cellular processes – back into fresh NAD+ which can then be used again. It is the loss of this recycling capacity which causes the reduction of NAD+ production with age. Specifically, it is the decline of the rate limiting enzyme NAMPT which causes this loss of recycling ability.
Nuchido TIME+ contains the flavonoids quercetin, rutin and troxrutin extracted from Sophora japonica for their ability to activate NAMPT and restore the cell’s youthful ability to recycle NAD+ via the Salvage Pathway. As well as the ability to boost NAD+, robust scientific evidence has shown that these compounds provide a wide range of health promoting benefits including anti-oxidant, anti-inflammatory, anti-aging and anti-viral properties. Quercetin also falls into a unique category of substances called senolytics (compounds that clear senescent cells from the body).
Activating the AMPK Pathway
AMPK is the cells energy sensor, that is activated by exercise and fasting, leading to increased NAD+ levels in the cell. AMPK detects fluctuations in the cellular environment and activates downstream pathways which regulate many cellular functions including sirtuins, metabolic pathways, antioxidant pathways and mitochondrial pathways. Another key function of AMPK is regulating autophagy (the cells recycling system), which has also been shown to decline with age, contributing to the accumulation of damaged cellular structures and cellular aging. Therefore, activating AMPK has many benefits beyond increasing NAD+ levels.
Nuchido TIME+ contains Alpha Lipoic Acid (ALA) for its ability to activate the AMPK pathway, which boosts NAD+ production by both increasing levels of the NAMPT recycling enzyme and promoting the conversion of NADH to NAD+ within the cell. The ratio of NADH to NAD+ has been shown to change in favour of NADH with age further contributing to NAD+ decline. ALA activates NQO1 which promotes the conversion of NADH to NAD+.
ALA is also known to be a powerful antioxidant, known to active Nrf2 and glutathione which mop up free radicals that can accumulate with age and contribute to cellular damage.
One of the hallmarks of aging is increased number of senescent cells. These ‘zombie cells’ no longer replicate but remain metabolically active. A proportion of senescent cells develop a senescence associated secretory phenotype (SASP) meaning that they excrete pro-inflammatory molecules into the cellular environment. This encourages neighbouring cells to become senescent and contributes to the increase in baseline inflammation which occurs during aging (termed inflammaging).
Inflammaging and increased numbers of senescent cells impacts cellular levels of NAD+. One of the inflammatory molecules known to increase with age is CD38. It is the largest mammalian consumer of NAD+, wasting over 100 molecules of NAD+ for every enzymatic reaction performed. Studies have shown that inhibiting CD38 alone can increase NAD+ levels.
It is now also known that there is a hierarchy of NAD+ consumers. With CD38 exerting dominance over other beneficial consumers such as the sirtuins. Meaning without also implementing strategies to inhibit these wasteful NAD+ consumers the benefits of increasing NAD+ are limited.
Nuchido TIME+ contains Parsley for its source of apigenin which has been shown to inhibit CD38. Parsley is also rich in antioxidants that protect cells from damaging free radicals.
Reducing NAD+ Wastage
Nicotinamide (NAM) is the bodies preferred NAD+ precursor as it is naturally produced by the breakdown of NAD+. Unlike other NAD+ precursors it can diffuse directly into the cell without the requirement for transporters and has the ability to cross the blood-brain-barrier.
In youthful cells, NAM is maintained at the desired level because the salvage pathway works to efficiently recycle NAM back into fresh NAD+. However, in older cells, NAM accumulates as the activity of the salvage pathway declines. Cellular processes work optimally when there is homeostasis (everything is in balance) so the excess NAM must be methylated (addition of a methyl group) by the enzyme NNMT and excreted. Levels of NNMT within the cell are known to increase with age to counteract the loss of NAD+ recycling.
Nuchido TIME+ contains epigallocatechin-3-gallate (EGCG) extracted from Green Tea Leaf for its ability to inhibit NNMT and therefore the excretion of NAM. Together with restoration of the cell’s recycling capacity by other ingredients in the formulation, NAM can now be recycled into NAD+. Studies have also shown that regular consumption of green tea extract has a multitude of health promoting benefits.
Increasing NAD+ precursor ingredients
Nuchido TIME+ contains the NAD+ precursor NAM (the body’s preferred precursor). As cells can now recycle NAM into NAD+ its addition further enhances NAD+ levels. Nicotinamide has also been demonstrated to have a neuroprotective effect and to support neuronal health.
Many other NAD+ boosting supplements only contain precursors in isolation such as NR or NMN. Whilst these ingredients may cause small increases in NAD+, it is now clear that this approach doesn’t inhibit hyperactive NAD+ consumers such as CD38, meaning that the majority of NAD+ will be wasted and not used by beneficial longevity pathways. Furthermore, because the Salvage Pathway hasn’t been restored, waste NAM fails to be recycled and must be methylated and excreted. This can further disrupt the NAD+ network and lead to methyl donor depletion if large amounts of waste NAM are methylated. In this situation methyl donors such as trimethylglycine (TMG) are often taken alongside precursor supplements. This issue is entirely avoided with Nuchido TIME+.
Maximising the health benefits
The final aspect of the Nuchido TIME+ formulation is designed to maximize the overall health benefits. That is why Nuchido TIME+ contains black pepper extract, vitamin C and zinc.
The black pepper extract contains the active molecule piperine which helps to increase the uptake of nutrients from the small intestine, allowing them to enter the blood and access the rest of the body. Piperine is also known to increase metabolism by activating thermogenesis which is a process that breaks down fat cells.
Nuchido TIME+ also contains zinc and vitamin C for their proven ability to promote immune function and support healthy aging. As we age, there is a progressive decline in the immune response. Zinc is an essential micronutrient and plays a vital role in normal immune function and vitamin C has a reputation for being able to fight infections. Beyond immunity, studies have also shown that people who take regular doses of vitamin C are found to live longer than people who don’t. This is likely because it reduces inflammation, protects the integrity of DNA and reduces biomarkers of cellular stress – all of which contribute to aging if left unchecked.
Overall, the age-related decline in NAD+ is due to disruption of the finely controlled NAD+ network. NAD+ consumption begins to overtake NAD+ production and recycling, creating the NAD+ deficit that drives the cellular aging process. Research has shown that to restore a youthful NAD+ network and ensure optimal NAD+ supply, the causes of both decreased NAD+ production and increased NAD+ consumption need to be addressed. It has become obvious, that neither of these issues are addressed by taking precursor supplements or pure NAD+ alone, only with a whole system approach such as Nuchido TIME+ is this achieved.