Mouse on an exercise bike
Source: JamesBrey/Getty Images

Studies by a Washington University School of Medicine-led research team has found that an enzyme that circulates in the blood of animals including mice and humans can act as a kind of elixir of youth when given to older mice, holding back the detrimental effects of aging and even extending lifespan.

Headed by Shin-ichiro Imai, MD, PhD, a professor of developmental biology, the researchers showed that levels of the enzyme extracellular nicotinamide phosphoribosyltransferase (eNAMPT), normally decline with age in both mice and humans. But, remarkably, old mice given supplements of NAMPT obtained from young animals stayed more youthful, healthy, and active for longer than their peers. The NAMPT boost in older animals was linked with significantly improved physical activity, metabolic and brain functioning, and a longer healthy lifespan.

“We have found a totally new pathway toward healthy aging,” said Imai, who is senior author of the team’s published paper in Cell Metabolism. “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.” The researchers report on their studies in a paper titled, “Extracellular Vesicle-Contained eNAMPT Delays Aging and Extends Lifespan in Mice.”

Source: Mitsukuni Yoshida/Washington University School of Medicine in St. Louis.

As we get older, declining levels of the coenzyme NAD+ in our body tissues are directly linked with the aging process. In mammals, the enzyme NAMPT represents a rate-limiting step in the production of NAD+, and activity of the enzyme produces the NAD+ intermediate nicotinamide mononucleotide (NMN). The Imai lab and others are working to develop NMN and another NAD+ intermediate, nicotinamide riboside (NR), as anti-aging strategies. “Indeed, many studies have already proven the efficacy of NMN and NR to mitigate age-associated functional decline and treat age-associated disease conditions in various mouse models,” the authors wrote.

“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.”

The investigators’ prior research had shown that genetically deleting NAMPT from fat tissues in mice affected levels of the extracellular, circulating form of the enzyme (eNAMPT), and was linked with reduced levels of NAD+ in distant tissues, including the hypothalamus in the brain, which controls key processes including body temperature, thirst, circadian rhythms, and hormone levels. The hypothalamus manufactures NAD+ using the eNAMPT that is released from adipose tissue and transported to the brain via the bloodstream.

“Because the hypothalamus has been suggested to function as a high-order control center of aging in mammals, we hypothesized that eNAMPT secreted from adipose tissue plays a critical role in affecting the process of aging and eventually lifespan,” the researchers noted. Their initial studies in both mice and humans confirmed that blood eNAMPT levels declined with age, “suggesting that the process underlying eNAMPT secretion and its potential significance during aging might be conserved in both species.” Intriguingly, the team also found that in mice, blood levels of eNAMPT correlated closely with the number of days that the animals lived after the measurement was taken. The higher the eNAMPT level, the longer the remaining lifespan. “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 results led the team to put forward what they describe as “the interesting hypothesis that circulating eNAMPT might play a critical role in regulating not only the process of aging, but also lifespan in mammals.” To investigate this in an animal model the team genetically engineered mice that continued to produce the high, youthful levels of NAMPT in their adipose tissues even as they aged. Initial tests confirmed that these adipose-tissue-specific NAMPT knockin (ANKI) animals maintained youthful circulating levels of eNAMPT and increased NAD+ levels in different tissues, including the hypothalamus, hippocampus, pancreas, and retina. The animals also demonstrated enhanced wheel-running activities when compared with normal aged mice, as well as better sleep quality. Improvements in metabolic, photoreceptor, and cognitive function correlated with the increased pancreatic, retinal, and hippocampal NAD+ levels evident in the ANKI animals.

Interestingly, female ANKI mice, but not male mice, demonstrated longer median lifespan and delayed aging. “… ANKI female mice exhibited significant delays in age-associated mortality up to ~ 2 years of age,” the investigators commented. “These results demonstrate that maintaining youthful levels of circulating eNAMPT is critical to delay aging and extend healthspan in mice, although there is a significant sex difference … Further investigation will be necessary to elucidate the molecular mechanisms of these sex-specific preferences.”

Further tests showed that the eNAMPT produced by the adipose tissue was carried in the blood encapsulated in extracellular vesicles (EVs), which were taken up by cells to enhance NMN/NAD+ production. This encapsulation appeared to be critical, as unencapsulated NAMPT protein wasn’t internalized by cells.

“Remarkably,” the authors reported, aging could be held back in normal mice by giving them injections of encapsulated eNAMPT isolated from young mice. The treated, old animals stayed more youthful and active than their control counterparts. “The EV-injected aged mice generally maintained much healthier looking and higher activity compared to vehicle-injected age-matched control mice,” the authors stated.

“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.”

Perhaps even more remarkably, eNAMPT supplementation significantly extended the lifespan of aged mice. All of the mice that received saline solution as a control died before day 881, about 2.4 years. Of the mice that received eNAMPT, one was still alive as the report was published, surpassing 1,029 days, or about 2.8 years.

eNAMPT is similarly carried in extracellular vesicles in humans, and the researchers note that future studies should be carried out to see whether low levels of the enzyme are associated with disease in older people, and whether supplements of encapsulated eNAMPT could also hold back aging. “Our present study has demonstrated that EV-mediated systemic delivery of eNAMPT mitigates age-associated functional decline in specific target tissues including the hypothalamus, hippocampus, pancreas, and retina, delays age-associated mortality rate, and extends healthspan and lifespan in mice,” the authors concluded. “These findings open a new possibility to use the EV-mediated systemic delivery of eNAMPT as a biologic for an effective anti-aging intervention.”

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