New approach to staving off the detrimental effects of aging

The original concept of the NAD World.20 The NAD World is a systemic regulatory network that fundamentally connects NAD+ metabolism, biological rhythm, and aging and longevity control in mammals. Two critical components comprise the NAD World: the mammalian NAD+-dependent protein deacetylase SIRT1, and systemic NAD+ biosynthesis mediated by nicotinamide phosphoribosyltransferase (NAMPT). While SIRT1 functions as a key mediator that orchestrates metabolic responses to changes in nutritional availability in multiple tissues, NAMPT-mediated NAD+ biosynthesis functions as a pace maker that produces circadian-oscillatory NAD+ production and fine-tunes SIRT1 activity at a systemic level. NAMPT has intra- and extracellular forms in mammals, iNAMPT and eNAMPT, respectively. iNAMPT is ubiquitously expressed, but its levels are varied (The font size reflects a relative level of iNAMPT). eNAMPT, which is actively secreted from adipose tissue and has a higher enzymatic activity than iNAMPT, likely synthesizes nicotinamide mononucleotide (NMN) from nicotinamide (Nic) extracellularly. The availability of NMN is particularly important for tissues and organs that possess very low levels of iNAMPT, such as pancreatic β cells and central neurons. The concept of the NAD World provides several important predictions for the biological robustness and trade-offs in mammalian aging and longevity control. See text for details.

New research has identified a novel approach to staving off the detrimental effects of aging, according to a study from Washington University School of Medicine in St. Louis.

The study suggests that a protein that is abundant in the blood of young mice plays a vital role in keeping mice healthy.

With age, levels of this protein decline in mice and people, while health problems such as insulin resistance, weight gain, cognitive decline and vision loss increase.

Supplementing older mice with the protein obtained from younger mice appears to slow this decline in health and extend the life spans of older mice by about 16 percent.

The study is published June 13 in the journal Cell Metabolism.

The circulating protein is an enzyme called eNAMPT, which is known to orchestrate a key step in the process cells use to make energy.

With age, the body’s cells become less and less efficient at producing this fuel – called NAD – which is required to keep the body healthy.

Washington University researchers have shown that supplementing eNAMPT in older mice with that of younger mice appears to be one route to boosting NAD fuel production and keeping aging at bay.

“We have found a totally new pathway toward healthy aging,” said senior author Shin-ichiro Imai, MD, Ph.D., a professor of developmental biology.

“That we can take eNAMPT from the blood of young mice and give it to older mice and see that the older mice show marked improvements in health – including increased physical activity and better sleep—is remarkable.”

Imai has long studied aging, using mice as stand-ins for people.

Unlike other studies focused on transfusing whole blood from young mice to old mice, Imai’s group increased levels of a single blood component, eNAMPT, and showed its far-reaching effects, including improved insulin production, sleep quality, function of photoreceptors in the eye, and cognitive function in performance on memory tests, as well as increased running on a wheel.

Imai’s group also has shown other ways to boost NAD levels in tissues throughout the body.

Most notably, the researchers have studied the effects of giving oral doses of a molecule called NMN, the chemical eNAMPT produces. NMN is being tested in human clinical trials.

“We think the body has so many redundant systems to maintain proper NAD levels because it is so important,” Imai said.

“Our work and others’ suggest it governs how long we live and how healthy we remain as we age.

Since we know that NAD inevitably declines with age, whether in worms, fruit flies, mice or people, many researchers are interested in finding anti-aging interventions that might maintain NAD levels as we get older.”

Imai’s research has shown that the hypothalamus is a major control center for aging throughout the body, and it is directed in large part by eNAMPT, which is released into the blood from fat tissue.

The hypothalamus governs vital processes such as body temperature, thirst, sleep, circadian rhythms and hormone levels.

The researchers have shown that the hypothalamus manufactures NAD using eNAMPT that makes its way to the brain through the bloodstream after being released from fat tissue.

They also showed that this eNAMPT is carried in small particles called extracellular vesicles.

As levels of eNAMPT in the blood decline, the hypothalamus loses its ability to function properly, decreasing life span.

In an intriguing finding, Imai and first author Mitsukuni Yoshida, a doctoral student in Imai’s lab, showed that levels of eNAMPT in the blood were highly correlated with the number of days the mice lived.

More eNAMPT meant a longer life span, and less meant a shorter one.

The researchers also showed increased life span with delivering eNAMPT to normal old mice.

NAD is a vital molecule in all organisms and a major component of both energy and signal transduction processes [12].

NAD can be synthesized from different routes, including a de novopathway starting from tryptophan and various pathways that salvage the three forms of vitamin B3, namely nicotinamide, nicotinic acid and nicotinamide riboside (NR).

Nicotinamide, which is released by NAD-metabolizing enzymes, is the major source to maintain NAD levels, linking substrate and product in a functional loop [36].

Nicotinamide is recycled back to NAD via a two-step pathway involving nicotinamide conversion to NMN, and NMN adenylation to NAD.

The enzyme nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the first and rate-limiting reaction of the pathway [78].

Beside this canonical intracellular activity, NAMPT was discovered to be present in the extracellular milieu where it exerts cytokine/adipokine-like actions [eNAMPT, aka pre-B cell colony enhancing factor (PBEF) or Visfatin] [9].

Elevated eNAMPT levels are typical of acute and chronic inflammatory conditions [810], metabolic disorders [1114], and cancer [1516].

Even if the mechanisms underlying eNAMPT secretion remain unknown, there seems to be a direct correlation with intracellular (i)NAMPT concentration [81718].

We recently studied eNAMPT functions in the plasma of patients with chronic lymphocytic leukemia (CLL), a disease where tumor-host interactions and local inflammation are critical in regulating disease progression.

Our results indicate that eNAMPT levels correlate with disease burden and that eNAMPT creates favorable conditions for tumor growth, by contributing to the development of a population of type 2 macrophages [19].

The mechanisms of action of eNAMPT remain unclear, even if the enzymatic activity appears dispensable.

The group of Garcia recently proposed that eNAMPT may bind toll-like receptor 4 (TLR4), activating its signaling pathway, at least in a model of lung endothelial cell injury [20].

Elevated eNAMPT levels were also described in supernatants from melanoma cell cultures, where both autocrine and paracrine functions were hypothesized [21].

Our recent data indicate that NAMPT becomes the master regulator of NAD synthesis in BRAF-mutated melanoma cells that acquire resistance to BRAF inhibitors (BRAFi) [22]. Consistently, these cells are uniquely sensitive to NAMPT inhibitors, both in vitro and in vivo.

Starting from these observations, we measured eNAMPT levels in melanoma cell lines and in a large cohort of patients with BRAF-mutated metastatic melanomas, before and after therapy, suggesting that eNAMPT is a novel disease marker in BRAF-mutated melanoma patients.

All mice that received saline solution as a control had died before day 881, about 2.4 years. Of the mice that received eNAMPT, one is still alive as of this writing, surpassing 1,029 days, or about 2.8 years.

“We could predict, with surprising accuracy, how long mice would live based on their levels of circulating eNAMPT,” Imai said.

“We don’t know yet if this association is present in people, but it does suggest that eNAMPT levels should be studied further to see if it could be used as a potential biomarker of aging.”

The study also found sex differences in levels of eNAMPT, with female mice consistently showing higher levels of the enzyme.

“We were surprised by the dramatic differences between the old mice that received the eNAMPT of young mice and old mice that received saline as a control,” Imai said. “These are old mice with no special genetic modifications, and when supplemented with eNAMPT, their wheel-running behaviors, sleep patterns and physical appearance—thicker, shinier fur, for example—resemble that of young mice.”

Imai and his colleagues, including co-author Rajendra Apte, MD, Ph.D., the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences, noted that eNAMPT also is carried in extracellular vesicles in humans. As such, future studies should be done to investigate whether low levels are associated with disease in aging people and whether supplementing eNAMPT in extracellular vesicles could serve as an anti-aging intervention in older people, they said.

Journal information: Cell Metabolism
Provided by Washington University School of Medicine


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