John Robert Cardillo

There’s an old expression in sports: “Father Time is undefeated.” That means aging athletes can rarely turn back the clock to their glory days as their careers wind down. Up to now, the same expression has held true; you can’t turn back the clock on aging. But a Harvard University professor is working to disabuse that idea with research and experiments that could lead to humans living longer while enjoying a better quality of life.

PhD geneticist David Sinclair, a professor at Harvard Medical School, may have solved the mystery that revolves around aging and has slowed the process to a standstill. Through many studies, Sinclair has demonstrated that the aging cycle can be slowed through manipulation and potentially reversed when certain factors are introduced into the human life cycle.

Sinclair has received numerous awards for his research and in 2018 was featured in Time magazine as one of the 50 most influential people in health care. Sinclair is credited with several discoveries around aging and slowing the process. As a successful author and renowned scientist in the field of anti-aging, Sinclair says, “You can’t defy the aging cycle, but you can extend life beyond the current expectancy if you adopt a lifestyle change.”

He defines this change in his New York Times bestseller Life span: Why We Age and Why We Don’t Have To. According to Sinclair, the simple explanation of his studies is that you won’t die early if you don’t have chronic conditions or disease; you will live longer.

Sinclair started down the anti-aging road with experiments using yeast, and for the past 20 years, his work has been at the forefront of the anti-aging frontier. The yeast experiments yielded critical factors that were previously unknown. In his experiments, Sinclair found that the cause for aging in yeast is based on the role of sirtuins in epigenetic changes that are driven by genome instability. His research focused on sirtuins, which are enzymes in our cells that act as defensive mechanisms against aging. They are enzymes modified with protein that respond to changes in the NAD+ levels. Sinclair has studied sirtuins in his Harvard lab and has proven that there are some things you can do right now to slow down the aging process. One of those things is to boost the sirtuin pathway.

Sirtuins are the longevity genes within our cells. These unique genes have a significant impact on our health, our muscle endurance, our cardiovascular and cognitive functions and, more importantly, how rapidly we age. Geneticists working on aging research have discovered that we can do things to energize these little genes and make them more effective.

There’s been a lot of talk in the media lately about sirtuins and NAD and the impact they have on the aging process. It’s important to understand what sirtuins are and how they affect aging, the impact NAD+ has on sirtuins and how supplementing with NAD+ precursors can influence sirtuins.

Sirtuins are in a class of seven different proteins that play a critical role in regulating cellular health. They are genes referred to as “the longevity genes,” because they regulate many functions that influence the aging process. Specifically, they regulate the creation of new mitochondria, which is called mitochondrial biogenesis. They also stimulate apoptosis (the programmed death of cells) and autophagy (the recycling of cellular materials). They inhibit inflammation and are responsible for stimulating signaling between the nucleus and the mitochondria on the cellular level, as well as between the hypothalamus and fat tissue on the systemic level. Three of the sirtuins are indispensable for the repair of damaged DNA.

NAD+ Effect on Sirtuins

Sirtuins can function only in the presence of nicotinamide adenine dinucleotide (NAD+), which is a derivative of nicotinic acid, also known as niacin or vitamin B6.

NAD+ comes in two forms: NAD+ and NADH. It’s a coenzyme that helps convert nutrients into energy, which plays an essential role in energy production in the mitochondria. It’s also a molecule that helps proteins that require other biological activity. Sirtuins can only function in the presence of NAD+, and that’s why NAD+ is vital.

NAD+ is a molecule in our cells that we need to sustain life. It’s used for all chemical reactions in our cells. One of Sinclair’s biggest discoveries from his experiments comes from the slowing of the aging cycle. His work with NAD+ and biosynthesis that produces regulation of the life span has had an immediate impact on the field of study. It demonstrates that sirtuins are involved in mammals through experimentation with different animal subjects. NAD+ is our cells’ mechanism for fighting disease and aging. As we get older, we have less NAD+ in our cells, and as NAD+ declines, we age faster and become more susceptible to diseases.

NAD+ is also used by DNA-repairing proteins called PARPs. Aging individuals have more PARPs than younger people. Even though it’s necessary to activate many NAD-dependent molecules such as sirtuins and PARPs, too much activation can exhaust NAD+ supplies and can cause cell death if the damage to the cell is too severe. It can also cause excessive expression of the protein P53. This protein is responsible for eliminating cancer cells, and the more it gets activated or expressed, the more it accelerates the aging process.

Aging is accelerated when NAD+ levels go into decline and sirtuins become less functional. When NAD+ levels decline, energy transfer decreases, which slows down mitochondrial function and increases oxidative stress. This results in cognitive dysfunction, chronic inflammation and DNA damage caused by an increase in free radicals.

Reversing NAD+ Decline

A way to reverse the decline in NAD+ levels is by supplementing with NAD+ precursors. Sinclair’s studies have shown that taking an NAD+ precursor can elevate NAD+ levels by as much as 60 percent.

There are several precursors to NAD+, with varying levels of absorption and effectiveness. Two of the most effective are nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR). There’s a lot of debate as to which passes through the cell membrane more easily and, therefore, more effectively. According to Sinclair, across numerous studies on both substances, NMN seems to be edging out NR in terms of effectiveness. Evidence is strong that NMN is beneficial for energy, endurance, heart disease, Alzheimer’s, aging DNA repair, weight, neurological function and vision.

When supplementing with an NAD+ precursor, there are a couple of caveats. The first has to do with the cost and the dose you take daily. Typically, both NR and NMN come in doses of 300 milligrams and 250 milligrams per day. Sinclair takes NMN himself and recommends taking a gram per day. That’s 1000 milligrams. Published articles on NR suggest a daily dose of 500 milligrams to 1000 milligrams, which can cost you $100 per month. Taking one gram of NMN per day can cost you between $150 and $200 per month.

NR and NMN are derivatives of niacin. The recommended daily allowance for any form of vitamin B6 is 16 milligrams per day, with an upper limit of about 35 milligrams per day. The lack of methylated niacin metabolites in the urine is a sign of niacin deficiency. Methyl groups are important for a lot of biological functions such as synthesis of choline, creatine, and neurotransmitters. Therefore, if you are taking one gram per day of NR or NMN (that’s more than 60 times the recommended daily allowance), you need to be including at least a one-to-one ratio of trimethyl glycine (TMG). TMG usually comes in 500-milligram doses, so if you’re taking one gram of NMN or NR per day, you should also be taking two capsules or one gram of TMG.

By taking NMN, we can raise levels of NAD to help us defend against disease and aging. Experiments with elderly mice has shown that when given NMN, they were able to run 50 percent faster after just four weeks of supplementation.

Sinclair’s Resveratrol Discovery

The discovery of resveratrol is considered Sinclair’s greatest triumph in the science of anti- aging. It’s a polyphenol (like quercetin) compound found in many foods such as red grapes, grape skins, dark chocolate, peanuts, red wine and berries. Sinclair’s studies have focused much of their attention on resveratrol and how this compound in small molecules activates SIRT1.

Resveratrol boosts the activity of sirtuins by elevating the mitochondrial function in a way that’s like fasting or calorie restriction. Sinclair has demonstrated in experiments that supplementing with resveratrol extends life span.

Lab Studies

Sinclair has written extensively on how calorie restriction, (a reduction of daily intake of food) will slow aging in many species. By calorie reduction, Sinclair is talking about a reduction in food intake beyond what is normal or comfortable.

Sinclair pointed to his study with lab mice as the perfect example of the slowing of the molecular clock. He applied the lessons learned in other experiments and was able to extend the life cycle of mice by 50 percent when they were subjected to fasting and exercise as part of the experiment’s regimen.

The study Sinclair performed on mice was conducted to determine if the effects of vascular aging could be stunted or eliminated using fasting and exercise. When the mice were subjected to stress (exercise) and fasting, the test subjects demonstrated an increase in endurance and stamina. The aging cycle was slowed and reversed in many cases. This was achieved through NAD+ and sirtuins that were boosted during the stressful activities that caused blood vessels to expand and proliferate in the vascular system. The group of mice that weren’t subjected to exercise and fasting saw a decrease in protein and blood cell regeneration, because the process wasn’t stimulated.

The next step in the anti-aging experimentation is to test the results garnered from mice against human subjects through the replication of the process used on mice. The problem that will have to be overcome is the biological differences between humans and mice.

For more on John Cardillo, check out his website at johnrobertcardillo.com, his instagram at @johnrobertcardillo or right here at Muscle Insider at John Cardillo.

To keep up with the latest fitness industry news and product releases, subscribe to our free newsletter HERE!