Regulating PARP-1 and CD38 and Conserving NAD+

The third way to maintain NAD+ levels is to conserve it. Besides the sirtuins, the most important NAD+ consumers are PARP-1 and CD38. PARP-1 is an enzyme that uses NAD+ to repair DNA. The more oxidative DNA damage and the more single- and double-strand DNA breaks occur, the more enzymes like PARP-1 have to be activated to come to the rescue. That consumes a lot of NAD+. Because more and more DNA damage occurs with age, the rising demand for repair enzymes like PARP-1 puts a heavy strain on NAD+ levels. That is why people set out to search for PARP-1 blockers so that NAD+ levels would be preserved, but instead of preventing DNA repair, wouldn’t it be better to work on preventing the damage? The chapter “Oxidation” describes how to do that.

CD38 is the other big NAD+ hog. It is an enzyme that uses NAD+ to generate cellular messenger molecules. It is concentrated on the surface of immune cells and is strongly stimulated during inflammation. Its activity is thought to increase with age due to persistent activation from inflammaging, that is, age-related inflammation, which could be one of the main causes of declining NAD+ levels. For example, it was found that blocking CD38 in older mice can raise NAD+ levels to those of younger mice. In the chapter on reducing inflammation and in my video see.nf/conservingnad, I discuss a number of natural CD38 inhibitors found in foods.

In Closing

In the anti-aging journal Rejuvenation Research there was a comment titled “Finally a Lifestyle That Extends the Human Life Span.” I was all ears (or rather, eyes.) Was it about a new exotic gene therapy or stem cell treatment? No, it was a reference to an analysis out of Harvard titled “Impact of Healthy Lifestyle Factors on Life Expectancies in the US Population.” More than 100,000 men and women had been followed for 34 years, and it turned out that a few simple lifestyle habits can extend the life of an average 50-year-old by about 13 years. Even starting at 70, about ten more years are still possible. A study in Canada started earlier, before age 50, and found that with simple, reasonable, health-conscious behavior, nearly 18 more years can be gained.

A life extension on that order would be expected if we extrapolated some of the longevity advances in laboratory animals, but despite decades of research and hundreds of millions of dollars, all efforts to translate these successes to humans have largely been in vain. But now we have human data showing that we can all extend our lives sensationally, right here and now. We already have the trillion-dollar pill that anti-aging biotechnology promised us. We just have to pick it up and take it from the produce section and the gym. With wise foresight, a geriatrics textbook more than 65 years ago already said: “A more promising approach to extending life in later years appears to be the prevention of degenerative diseases through a healthy diet.”

Could the large differences in life span be attributable to lifelong behavior patterns? To make sure it isn’t too late to turn back the clock, researchers observed what happened to men and women who tried to kick their bad habits starting in midlife. A shift between ages 45 and 64 to a bare minimum—eating at least 5 servings of fruits and vegetables a day, walking about 20 minutes daily, maintaining a healthy weight, and not smoking—led to a significant reduction in mortality, even in the near future. We’re talking about a 40 percent lower risk of dying in the following four years. The researchers concluded that their results would emphasize that “it is extraordinarily worthwhile to make the necessary changes to live healthily, and it is certainly not too late to do so even in middle age.”

And that’s just the beginning. Because that still doesn’t include the dozens of other recommendations I make in Part I of this book, the healthiest of all healthy foods and dietary patterns from Part II, “Optimal Anti-Aging: Here’s How,” the cardiovascular and immunity tips from Part III for facing down death, and not necessarily every one of my “Eight Anti-Aging Tips” from Part IV. There is so much we can do to extend our life span and our health span. For example, a remarkable study recently with more than half a million participants found that those who added salt at the table to their food (in addition to the salt used in cooking, in whatever amount) had a life expectancy at 50 that was two years shorter than those who didn’t add salt at the table. So if you simply swap the saltshaker for another tasty, salt-free seasoning, you might extend your life by a few years.

And all of that with tiny changes to basic things, without really taking diet seriously. What we eat is considered the “probably most powerful and flexible tool we have to achieve a lasting and systemic modulation of the aging process …”. The obvious benefit is so extraordinary that it has been used to discredit nutritional epidemiology as a whole. Meta-analyses showing that you can extend your life by years just by skipping eggs and bacon, or eating nuts every day, or eating certain fruits? That sounds too good to be true. Regardless of the absolute extent of its effect, diet is viewed as the most important determinant of length of life. You are what you eat.

Declining Life Span

Martin Luther King Jr. once warned that “human progress is neither automatic nor inevitable,” and that could also apply to the human life span. In 1850, life expectancy in the United States was under 40 years, but over the past 200 years it rose steadily, by about two years per decade—at least until recently. Then the increase stalled and began to reverse in 2015. Mainly due to the obesity epidemic, the first US generation may now be growing up that will live shorter lives than their parents. And that was before Covid-19 shortened life expectancy in the United States by two years—a decline not seen since 1943, the deadliest year of World War II.

As we age, our organs’ reserves decline, making it even more important to eat and live healthily. We can’t keep going with the fast-food lifestyle we may have followed as teenagers with youthful recklessness. Unfortunately, the message has not gotten through to most people. The American Heart Association has been tracking diet and lifestyle trends in the United States for decades. In its 2012 annual report, it found that by now most Americans no longer smoke and almost half meet their “ideal” physical activity goal (at least about 20 minutes of moderate-intensity activity every day). But when it came to the measure of a healthy diet, only about one percent achieved a 4 or 5 on the diet-quality scale from 0 to 5. And the “ideal” criteria consisted of things like, for example, drinking less than four and a half cups of sugary soda per week.