"A Privileged Way of Knowing:" Science and Aging Gracefully

Part 2: Attempts to increase our health span and ward off the effects of age.

Posted Feb 05, 2020

 Wikimedia Commons/Public Domain
"The Assassination of Cicero," 15th century, by an unknown artist. Cicero, the Roman statesman and orator, was only about 63 years old when he was killed on the order of his political rivals. He never was able to experience the joys of advanced old age he chronicles in his essay, written within the year before his death.
Source: Wikimedia Commons/Public Domain

Marcus Tullius Cicero, the Roman statesman and perhaps the greatest orator of his era, wrote his classic work de Senectute, On Old Age, when he was about 63 years old. Alas, Cicero never got to experience the glorious benefits of advanced old age that he chronicles: within the year, he was assassinated—beheaded—on the order of his political rivals.

Cicero had even successfully defended in court the man, merely attempting to curry favor with those in power, who murders him. (Peck, editor, Harper’s Dictionary of Classical Literature and Antiquities, pp. 339-345, 1963) And we think our American politicians behave egregiously!

 In de Senectute, though, Cicero makes an heroic effort to persuade his audience that elegance and authority come with old age. Most people, though, will find Cicero’s essay unconvincing and prefer to avoid the almost inevitable frailties and deterioration that old age brings. Both the mythological figures of the Cumaean Sibyl, the prophetess of Apollo, and Tithonus, son of a king of Troy, were granted long life by the gods but without remaining young, they bemoaned their fate of a withering and infirm old age and even preferred a death that was no longer available to them. 

Wikimedia Commons/Public Domain
"The Young Cicero Reading," painting, circa 1464, by Vincenzo Foppa. The Wallace Collection, London.
Source: Wikimedia Commons/Public Domain

In Part I, I wrote about the declining levels of NAD+—nicotinamide adenine dinucleotide—that occur naturally with age and the possibility of replacing these levels by administering precursors such as nicotinamide riboside (NR). The pharmacokinetics within the human body, though, remain poorly understood, including how these precursors are metabolized in the liver and blood after oral administration. (Yoshino et al, Cell Metabolism, 2018) Further, there is even a report that increasing NAD+ levels could foster the growth of tumors since drugs that deplete NAD+ levels are in development as a cancer treatment. (Yoshino et al, 2018)

 Metropolitan Museum of Art, NYC/Public Domain. Credit: Bequest of Benjamin Altman, 1913.
Self-Portrait, Rembrandt, 1660. Rembrandt was only age 54 when he painted this portrait, one of 40 self-portraits that survive. He was "unsparing in depicting the signs of aging in his own face." (Met Museum description.)
Source: Metropolitan Museum of Art, NYC/Public Domain. Credit: Bequest of Benjamin Altman, 1913.

Investigators emphasize that many people take these supplements outside of clinical trials and hence side effects may typically go unreported. “Although the therapeutic potential of boosting NAD+ levels is undeniable, it is time to pause and ponder the potential repercussions" related to the NAD+ replacement. (Katsyuba et al, Nature Metabolism, 2020.)

The first clinical trial of NAD+ supplementation in 12 healthy volunteers, administering different dosages on three separate days, occurred only in 2016 and demonstrated that NR did increase blood levels of NAD+. (Trammell et al, Nature Communications, 2016) There have been a few other short-term studies. Depending on the population studied, nicotinamide riboside (NR) did not lead to any serious adverse effects, “but did not result in any striking improvements in any disease to date.” (Katsyuba et al, 2020) There is some suggestion that after 21 days of supplementation, there were diminished levels of inflammatory cytokines as well as a trend to decrease blood pressure.  Further, researchers caution that we need better methods for accurate measurements of NAD+ levels. (Katsyuba et al, 2020)

Substances that have also gained the interest of both scientists and the media are the stilbenes—natural phytochemicals (400 different ones have been identified) that are found in many plants, fruits, and vegetables. (Pan et al, Biofactors, 2018) These are anti-oxidants, i.e., reduce oxidative stress; they are protective against free radicals (Li et al, Biofactors, 2018) and are similar to resveratrol, the substance found in red wine and grapes. Because of their slightly different chemical structure, these stilbenes have better cellular uptake, membrane permeability, bioavailability, and a longer half-life than resveratrol. (Riche et al, Journal of Toxicology, 2013; Pan et al, 2018) One of them, pterostilbene, is a potent anti-inflammatory and is the natural compound found in blueberries.

In recent years, blueberries have been labeled a “superfruit,” but this is a “virtually meaningless term in scientific research,” clarifies James Hamblin, MD (The Atlantic, November 15, 2017). Their popularity has more to do with savvy marketing than any super property. There have even been conferences worthy of the American Civil War, with titles like “The Blue Versus the Gray” in which researchers tout the potential benefits of blueberries for healthy aging. (Ingram, Journals of Gerontology, Series A: Biological Sciences and Medical Sciences, 2019)

 Wikimedia Commons/Public Domain
Gustave Caillebotte's "Fruit Displayed on a Stand," circa 1881. Museum of Fine Arts, Boston. Many studies of blueberries have been criticized. Labeling the blueberry as a "super fruit" reflects savvy marketing and is a "virtually meaningless term in scientific research."
Source: Wikimedia Commons/Public Domain

Studies, though, are difficult to conduct and have been subject to criticism.  For example, Allison and colleagues (Vorland et al, Letter to the Editor, PsyArXiv Preprints, 2020), after conducting a thorough statistical analysis, were not able to replicate findings presented in the systematic review by Hein et al (The Journals of Gerontology. Series A, Biological Sciences and Medical Sciences, 2019) on the effects of blueberries on cognition. Likewise, Brydges and Gaeta, in a Letter to the Editor, found errors in another systematic review on blueberries and concluded, “Based on the current research, researchers should avoid drawing definite conclusions regarding the effects of blueberries on cognitive performance or mood.” (Brain, Behavior, and Immunity, 2019.)

Nevertheless, pterostilbene (PT) itself has been subject to study, particularly to assess its safety. (Riche et al, 2013; Riche et al, Evidence-Based Complementary and Alternative Medicine, 2014) These researchers emphasize that since it is classified as Generally Recognized as Safe (GRAS), it remains exempt from any premarket FDA regulations. They found, in their randomized controlled study of 80 subjects, that PT reduces blood pressure (dose-dependent) but increases levels (unknown significance and cause), of LDL and total cholesterol. (Riche et al, 2014)

 Wikimedia Commons/Public Domain
William Blake's, Songs of Innocence and of Experience, London," 1794, Fitzwilliam Museum, The William Blake Archive.
Source: Wikimedia Commons/Public Domain

In another study, nicotinamide riboside (NR) was given with PT. The combination of the two was predicted to work synergistically. This was the first trial of a repeat dose in 120 healthy adults between 60 and 80 with this combination. There was a rise in total cholesterol and LDL but when subjects were stratified by BMI, increased levels were not considered significant and may have also been the result of the “vagaries of randomization” and the fact that LDL levels can vary by as much as 9%. (Dellinger et al Nature Partner Journals:  Aging and Mechanisms of Disease, 2017)  There are currently four trials sponsored by industry and registered with ClinicalTrials.gov in which researchers are using a combined pill of pterostilbene and nicotinamide riboside to study inflammatory markers; muscle metabolism and exercise; subjective well-being after falls in elderly patients; and changes in liver fat.

 Gift of Thomas F. Ryan, 1910.
"The Old Courtesan," by Auguste Rodin, ca. 1885, cast 1910. Rodin captures the withered and deteriorated body of old age.
Source: Metropolitan Museum of Art, NYC. Public Domain, Credit: Gift of Thomas F. Ryan, 1910.

Lee McIntyre writes that what is distinctive about science is not its subject or its method but its attitude toward empirical evidence and a willingness to change its theories on the basis of evidence (The Scientific Attitude:  Defending Science from Denial, Fraud, and Pseudoscience, p. 7, 2019). For McIntyre, science is a “privileged way of knowing” (p. 205), and the scientific attitude “is more than an individual mindset; it is a shared ethos that is embraced by a community of scholars who are tasked with judging one another’s theories...” (p. 112)

Wikimedia Commons/Public Domain
"Old Woman Dozing," by Nicolaes Maes, circa 1656, Royal Museums of Fine Arts of Belgium.
Source: Wikimedia Commons/Public Domain

The bottom line:  Replenishing naturally declining coenzyme levels or phytochemicals to stave off the mental and physical withering effects of old age makes clinical sense.  Preclinical animal studies, particularly mouse models, provide strong evidence that metabolic and cardiovascular diseases can be ameliorated or even reversed, and analogously may increase our own human healthspan, i.e., not necessarily living longer, but living healthier and relatively disease-free as we age.

Wikimedia Commons/Public Domain
Lucas Cranach, the Elder, "The Fountain of Youth," 1546. Gemaldegalerie, Berlin.
Source: Wikimedia Commons/Public Domain

The transition from "bench to bedside," though, may not be so straightforward and requires gathering considerably more empirical evidence. There are currently many human studies registered with ClinicalTrials.gov that are evaluating the effects of administering compounds to replace either nicotinamide adenine dinucleotide (NAD+) and/or the anti-oxidant pterostilbene. Because these substances are registered as Generally Regarded As Safe (GRAS), they are not subject to the rigorous testing and regulations of the FDA.

To date, most of the studies are in the recruitment phase or are still ongoing, and hence there are very few results that are published in peer-reviewed journals or even available for evaluation. Further, research is short-term (e.g., several weeks or months).  We do not know the effects of these substances when taken chronically or even the most efficacious dose to recommend.

Fortunately, science, the “privileged way of knowing,” that involves gathering evidence and being willing to change our theories in light of new evidence, will enable us to evaluate this research.

This is the second part of a two-part blog on aging and NAD+. Click here for the first post.